Cardiovascular autonomic failure correlates with cutaneous autonomic devervation in PD and MSA

Cardiovascular autonomic failure correlates with cutaneous autonomic devervation in PD and MSA | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cardiovascular autonomic failure correlates with cutaneous autonomic devervation in PD and MSA Shiwen Koay, Vincenzo Provitera, Ekawat Vichayanrat, Giuseppe Caporaso, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4405619/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Sep, 2025 Read the published version in Clinical Autonomic Research → Version 1 posted 4 You are reading this latest preprint version Abstract Background Cardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling in Parkinson’s disease (PD) and multiple system atrophy (MSA). Recent studies have shown evidence of postganglionic denervation in MSA as well as PD. Objectives To characterise the relationship between nOH, autonomic failure and markers of postganglionic denervation in PD and MSA. Methods We assessed 57 patients (37 PD, 20 MSA, 18 females, median 64[IQR 59-70] years) with autonomic cardiovascular testing, plasma noradrenaline levels, dynamic sweat testing, skin biopsies for quantification of intraepidermal, pilomotor and sudomotor innervation and COMPASS-31 autonomic symptom questionnaires. Results 78% with MSA and 36% with PD had nOH≥ 20/10mmHg. Overall, compared to patients without nOH, patients with nOH demonstrated greater 1) cardiovascular autonomic failure, with significantly reduced responses to isometric exercise, deep breathing and Valsalva ratio, 2) intraepidermal, pilomotor and sudomotor denervation, 3) autonomic symptoms and Hoehn-Yahr grade. Quantitative cardiovascular biomarkers including nOH severity correlated with autonomic denervation, patient symptoms and Hoehn-Yahr grade (ρ≥0.50). Compared to PD, MSA patients had worse nOH, pressor responses to isometric exercise, sudomotor dysfunction and cutaneous denervation, with higher supine noradrenaline, but subgroup analysis showed only supine noradrenaline differed significantly between MSA and PD with nOH subgroups ( P =.04). Conclusions NOH was associated with cutaneous denervation in both PD and MSA, with significant correlations between quantitative cardiovascular autonomic biomarkers, cutaneous denervation, and Hoehn-Yahr grade. Postganglionic denervation may contribute to autonomic failure in PD and MSA and affect responses to therapeutic agents for nOH. orthostatic hypotension autonomic failure Parkinson’s Disease Multiple System Atrophy punch skin biopsy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling features of the neurodegenerative diseases Parkinson’s disease (PD) and multiple system atrophy (MSA). 1 Severe symptomatic autonomic failure and nOH are associated with shortened survival and worse disease progression in both PD and MSA. 2, 3 Compared to PD, MSA is associated with more rapid disease progression, but overlapping clinical features at presentation may cause initial diagnostic uncertainty. Previous studies have shown biomarkers reflecting postganglionic adrenergic autonomic innervation, like supine plasma noradrenaline levels and cardiac scintigraphy studies, tend to be relatively preserved in MSA compared to PD, 4, 5 suggesting that autonomic failure in MSA occurs due to degeneration and dysfunction of central autonomic networks. However, our group and others have found evidence of postganglionic sudomotor dysfunction and cutaneous somatic and autonomic denervation in MSA, suggesting both central and peripheral degeneration may contribute to the pathophysiology of autonomic failure in MSA. 6–9 We aimed to evaluate the cardiovascular autonomic profile in patients with MSA and PD, with and without nOH, alongside markers of postganglionic denervation, including plasma catecholamines, DST, and cutaneous autonomic and somatic innervation, to characterise the relationship between nOH, other quantitative biomarkers of cardiovascular autonomic failure and markers of postganglionic denervation. A secondary aim was to assess whether these biomarkers could differentiate between MSA and PD, and MSA and PD with autonomic failure. Methods Standard Protocol Approvals, Registrations and Patient Consents Patients with at least clinically probable PD and MSA according to established consensus criteria were recruited from patients referred to 1) Autonomic Unit, the National Hospital of Neurology and Neurosurgery, London, 2) Neurology Division ‘ICS Maugeri’ IRCCS of Telese Terme, and 3) Neurology Department, University of Naples Federico II, Naples, between November 2017 and December 2019, as part of a multi-centre natural history and biomarker study in Parkinsonism. 10, 11 The study protocol complied with the Declaration of Helsinki and was approved by the local Institutional Review Boards (Fondazione G. Pascale No. “5/15 Maugeri” and London Bridge Research Ethics Committee, REC reference 16/LO/1656). All subjects gave written informed consent to participate in the study. Study data were collected and managed using REDCap research electronic data capture tools hosted at University College London. 12, 13 Patients with conditions associated with peripheral neuropathies, including diabetes, HIV, connective tissue disorders and other toxic or metabolic disorders were excluded. Patients with an alternative diagnosis other than PD or MSA after 12-month follow-up were excluded from the final analysis. Clinical assessment and patient reported outcomes All patients were assessed by neurologists with movement disorders expertise, with recording of their motor examination and functional impairment using the Hoehn-Yahr scale. 14 Sensory and autonomic symptoms were collected using the COMPASS-31 and SFN-SIQ. 15, 16 Disease duration was defined as time from onset of motor symptoms to the time of recruitment to the study. Cardiovascular autonomic testing All patients had a core protocol of cardiovascular autonomic testing performed with recording of blood pressure and heart rate: at rest in the supine position after 1-, 3- and 5-minutes standing or tilt before and after isometric exercise (sustained handgrip for 3 minutes at a third of maximum voluntary contraction pressure) with deep breathing, at a rate of 6 breaths/min with the Valsalva manoeuvre (forced expiration at 40mmHg for 10 seconds). Beat-to-beat recordings of blood pressure and heart rate with analysis of the blood pressure profile in response to the Valsalva manoeuvre. Blood pressure recovery time (PRT), a marker of adrenergic control of total peripheral resistance, was defined as the time taken for the systolic blood pressure to recover from phase III of the Valsalva manoeuvre back to the baseline. 17 The Valsalva ratio was calculated by dividing the maximal heart rate developing in response to blood pressure reduction induced by the Valsalva manoeuvre by the minimum heart rate occurring within 30 seconds of the peak heart rate. 17 All medications potentially affecting autonomic testing were stopped at least five half-lives prior to testing, and patients were instructed to consume only water for four hours prior to testing. NOH was defined as a sustained fall of at least 20mmHg systolic or 10mmHg diastolic blood pressure within 3 minutes of standing or tilt according to consensus criteria, 18 with an abnormal blood pressure profile in response to the Valsalva manoeuvre, or blunted HR increase during hypotension with ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg. 19, 20 Blood was collected via intravenous catheter in the supine and tilted position for measurement of plasma catecholamines using high performance liquid chromatography. 21 Sudomotor testing All patients underwent DST at the distal leg bilaterally. DST uses pharmacological stimulation with pilocarpine to directly stimulate the M3 receptors on cutaneous sweat glands, providing an estimation of postganglionic sudomotor function. 22 After iontophoresis with 1% pilocarpine solution, skin was coated with iodine and formation of sweat gland imprints on starch covered tape was recorded. Density of activated sweat glands/cm 2 , sweat nl/min/cm 2 , and average sweat output/gland was calculated. Morphological analysis All patients had 3-mm skin biopsies collected from the distal leg bilaterally and processed for indirect immunofluorescence according to standard procedures using a large panel of antibodies, including primary antibodies against collagen type IV (ColIV), protein gene product (PGP) 9.5, a pan-neuronal marker, dopamine-β-hydroxylase (DβH), a marker for noradrenergic fibres, vasoactive intestinal peptide (VIP), a marker for cholinergic fibres, and species-specific secondary antibodies coupled with Cy2 and Cy3 fluorophores. 23 Digital confocal images were acquired using a non-laser confocal system (Apotome2 Zeiss, Jena, Germany, EU). Intraepidermal nerve fibre (IENF) density was measured according to current guidelines. 24 Quantification of pilomotor and sudomotor nerve fibres using pan-neuronal and selective cholinergic and noradrenergic markers was performed as previously described. 6, 25 For the functional and morphological studies above, the average of both sides was calculated and taken as representative for each patient. Normative data was extracted from a database of 100 healthy volunteers. Statistical Analysis Statistical analysis was performed using R, Version 3.6.0. Normality was assessed Shapiro-Wilk tests. Summary data has been presented as median (IQR) as some data was not normally distributed. Patient groups were compared with unpaired two-tailed t-tests/ Mann-Whitney tests, and subgroup comparisons were preformed using ANOVA/Kruskal-Wallis tests with Tukey/Dunn post-hoc tests with Bonferroni corrections for multiple comparisons as appropriate. Chi-squared tests were used to compare categorical data. Correlations were performed using Spearman tests. P < .05 was considered significant. Results Demographic and clinical data The postganglionic sudomotor function, cutaneous autonomic innervation and distribution of neural phosphorylated synuclein of the patients recruited to this multicentre cohort study have been described in previous reports. 7, 26 This study focused on the cardiovascular autonomic testing and the relationship between quantitative autonomic biomarkers and markers of post-ganglionic autonomic denervation autonomic innervation in patients with MSA and PD, with and without nOH. Fifty-seven patients were included in the final analysis: 37 with PD and 20 with MSA, 16 with parkinsonian subtype and 4 with cerebellar subtype. 32% (18/57) were female and median age was 64 years (IQR 59–70 years) at recruitment. The MSA and PD groups had similar sex distribution, age and disease duration at recruitment, but patients with MSA had greater disease severity as measured by the Hoehn-Yahr scale (4 [3–4] vs 1.5 [1–2], P < .001) (Table 1 ). Table 1 Clinical details and cardiovascular testing in MSA and PD Median (IQR) MSA (n = 20) PD (n = 37) P-value Clinical details Age, y 63 (55–68) 65 (58–70) .48 Sex (F/M) 6/14 12/25 > .99 Disease duration, mo 30 ( 17 – 42 ) 21 ( 12 – 23 ) .10 Hoehn-Yahr 4 ( 3 – 4 ) 1.5 ( 1 – 2 ) < .001 COMPASS-31 32 (16–45) 18 ( 11 – 29 ) .12 SFN-SIQ 9 ( 8 – 10 ) 6 ( 4 – 10 ) .26 Cardiovascular testing Δ SBP on standing 1 min, mmHg 32 ( 14 – 41 ) 7 ( 1 – 20 ) .03 3 min, mmHg 32 (19–65) 4 (-2 to 19) .004 5 min, mmHg 35 (28–77) 10 ( 1 – 26 ) .004 Isometric exercise ΔSBP, mmHg 6 (-1 to 14) 25 ( 20 – 32 ) < .001 ΔHR, bpm 5 ( 2 – 8 ) 9 ( 5 – 14 ) .04 HR DB , bpm 8 ( 6 – 11 ) 12 ( 8 – 18 ) .06 Valsalva ratio 1.20 (1.12–1.3) 1.19 (1.08–1.39) .89 Pressure recovery time, s 14.5 (7.4–23.6) 7.6 (2.8–14.6) .30 Supine noradrenaline, pg/ml 256 (240–303) 216 (158–223) .02 Δ noradrenaline on tilt, pg/ml 11 ( 5 – 12 ) 67 (38–71) .05 SBP, systolic blood pressure; HR, heart rate Cardiovascular autonomic testing Compared to patients with PD, patients with MSA had a significantly greater fall in systolic blood pressure on standing (35 [28–77] vs 10 [1–26] mmHg by 5 minutes, P = .004), and reduced blood pressure and heart rate responses to isometric exercise (6 [-1 to 14] vs 25 [20–32] mmHg, P < .001; 5 [2–8] vs 9 [4–14] bpm, P = .04). Of the 57 patients studied, 43 patients completed at least 3 minutes of standing or tilt challenge, allowing us to assess for sustained nOH according to consensus criteria. 18 The other 14 patients had assessment of blood pressure and heart rate supine and after 1 minute standing only as part of routine clinical testing and were not included in the analyses comparing patients with and without nOH. 23/43 (54%) patients fulfilled criteria for nOH: 78% (14/18) patients with MSA and 36% (9/25) with PD. Of these 23 patients, 15 patients had assessment of BP profile with the Valsalva manoeuvre, and all 15/15 (100%) had reduced or absent phase II late blood pressure recovery, phase IV overshoot and prolonged PRT, consistent with impaired adrenergic function and nOH. The eight patients with nOH on standing who did not perform Valsalva manoeuvre had minimal HR rise with 3 minutes of standing, in keeping with nOH (median ΔHR 1 [ IQR − 2 to 4] bpm; median ΔHR/ΔSBP − 0.04 (IQR − 0.05 to 0.21, ΔHR/ΔSBP < 0.5 indicates nOH). 19, 20 Overall, regardless of the diagnosis, patients with and without nOH were similar in age, but patients with nOH had a longer disease duration (33 [20–44] vs 21 [11–23] months, P = .005). They reported more severe autonomic symptoms (COMPASS-31 score 33 [25–48] vs 17 [9–30], P = .006) and had a higher Hoehn-Yahr grade (3.5 [2.75-4] vs 1 [ 1–2], P = .001) (Table 2 ). Compared to patients without nOH, patients with nOH had a more prolonged PRT (14.5 [8.9–22.4] seconds vs 2.5 [2.5–2.8] seconds, P = .02), attenuated pressor responses to isometric exercise (5 [-2 to 15] mmHg vs 22 [14–26] mmHg, P < .001; 4 [1–6] vs 11 [7–14] bpm, P = .004), HR DB (7 [4–11] bpm vs 12 [8–18] bpm, P = .048) and lower Valsalva ratio (1.10 [1.03–1.18] vs 1.33 [1.21–1.42], P = .02), reflecting more widespread sympathetic and parasympathetic autonomic failure. Cardiovascular autonomic biomarkers did not differ significantly between the MSA with nOH and PD with nOH subgroups (Table 3 ). Table 2 Clinical and cardiovascular testing in patients with and without OH Median (IQR) P-Value OH (n = 23) No OH (n = 20) Clinical details Age, y 64 (56–71) 63 (60–69) .90 Sex (F/M) 5/18 9/11 .20 Disease duration, months 33 (20–44) 21 ( 11 – 23 ) .002 Hoehn-Yahr 3.5 (2.75-4) 1 ( 1 – 2 ) < .001 COMPASS-31 33 (25–48) 17 ( 9 – 30 ) .006 SFN-SIQ 10 ( 7 – 11 ) 7 ( 5 – 10 ) .16 Cardiovascular testing Δ SBP on standing 1 min, mmHg 37 (19–56) 1 (-4-16) < .001 3 min, mmHg 37 (21–70) 4 (-2 to 9) < .001 5 min, mmHg 35 (29–74) 4 (-1 to 11) < .001 Isometric exercise ΔSBP, mmHg 5 (-2 a to 15) 22 ( 14 – 26 ) < .001 ΔHR, bpm 4 ( 1 – 6 ) 11 ( 7 – 14 ) .004 HR DB , bpm 7 ( 4 – 11 ) 12 ( 8 – 18 ) .048 Valsalva ratio 1.10 (1.03–1.18) 1.33 (1.21–1.42) .02 Pressure recovery time, s 14.5 (8.9–22.4) 2.7 (2.5–2.8) .02 Supine noradrenaline, pg/ml 242 (228–293) 232 (224–239) .72 Δ noradrenaline on tilt, pg/ml 11 ( 6 – 18 ) 93 (80–106) .06 SBP, systolic blood pressure; HR, heart rate Table 3 Subgroup comparisons Median (IQR) P-Value Variable MSA + OH (n = 16) MSA, no OH (n = 4) PD + OH (n = 9) PD, no OH (n = 16) ANOVA MSA + OH v PD + OH Clinical details Age, y 64 (55–68) 62 (59–66) 65 (58–74) 64 (60–69) .91 .81 Sex (F/M) 3/13 1/3 2/7 8/8 .35 Disease dur., mo 39 (29–59) 16 ( 10 – 20 ) 23 ( 19 – 35 ) 21 ( 11 – 23 ) .009 > .99 Hoehn-Yahr 4 (3.5-4) 3 ( 2 – 3 ) 3 ( 2 – 3 ) 1 ( 1 – 2 ) .99 COMPASS-31 33 (22–48) 22 ( 17 – 26 ) 36 (28–48) 18 ( 9 – 31 ) .07 > .99 Cardiovascular testing Δ SBP-on standing 1 min, mmHg 38 (28–51) -4 a (-9 to 8) 21 (6–59) 3 (-3 a to 16) .001 .87 3 min, mmHg 37 (30–75) 5 (-2 to 10) 21 (19–58) 4 (-2 a to 7) < .001 .95 5 min, mmHg 40 (30–84) -2 a (-4 to 8) 29 (23–44) 5 ( 1 – 11 ) < .001 .59 Isometric exercise ΔSBP, mmHg 5 (-2.5 a to 10.2) 11 ( 5 – 16 ) 10 ( 3 – 21 ) 25 ( 22 – 27 ) .99 HR DB , bpm 7 ( 4 – 9 ) 13 ( 11 – 16 ) 12 ( 4 – 17 ) 11 ( 8 – 18 ) .09 .75 Valsalva ratio 1.20 (1.13–1.28) 1.33 (1.29–1.34) 1.14 (1.07–1.19) 1.37 (1.21–1.50) .09 > .99 Pressure recovery time, b s 14.5 (7.4–23.6) NA 17.2 (14.6–19.7) 2.7 (3.5–2.8) .08 > .99 Supine NA, c pg/ml 256 (240–303) NA 158 (154–190) 232 (224–239) .04 .04 Δ NA on tilt, pg/ml 11 ( 5 – 12 ) NA 38 (22–55) 93 (80–106) .08 .81 DST Glands/cm 3 24 ( 19 – 40 ) 39 (25–46) 53 (41–55) 46 (34–57) .04 .05 Output/gland, nL 3.1 (1.5–4.3) 4.6 (3.2–5.1) 3.0 (2.5–4.1) 2.7 (2.2–4.7) .85 .95 Sweat output, nL/cm 3 73 (26–145) 79 (22–166) 149 (119–194) 119 (38–190) .25 .31 Skin biopsies IENFD, f/mm 1.8 (0.9–4.5) 5.0 (4.9–10.3) 5.9 (2.6–9.1) 7.8 (6.1–9.4) .005 .23 Pilomotor nerve fibre density, f/mm PGP 28.8 (20.0-46.7) 52.6 (50.2–59.0) 45.6 (38.2–50.7) 53.7 (39.5–59.0) .02 .77 VIP 0.0 (0.0-5.2) 25.2 (21.6–25.8) 6.6 (4.3–13.0) 9.8 (5.7–15.2) .004 .30 DβH 4.5 (0-13.6) 42.0 (38.3–43.9) 21.6 (11.9–40.2) 33.6 (20.4–45.2) .01 .35 Sudomotor nerve fibre density, nm/µm 3 PGP 0.7 (0.5-2.0) 1.9 (1.6–2.7) 3.1 (2.1–3.7) 2.8 (2.5–3.9) .02 .13 VIP 0.6 (0.0-0.9) 1.3 (1.2–1.4) 1.3 (0.7–1.6) 1.6 (1.4–1.8) .006 .54 SBP, systolic blood pressure; HR, heart rate; NA, noradrenaline; PNFD, pilomotor nerve fibre density; SNFD, sudomotor nerve fibre density. Plasma noradrenaline Seventeen patients had plasma noradrenaline levels measured: 12 with MSA, all of whom had nOH, and five patients with PD, three with nOH and two without nOH. Patients with MSA had normal supine noradrenaline (256 [240–303] pg/ml), with minimal rise on tilt (11 [5–12] pg/ml). In comparison, patients with PD with nOH had significantly lower supine noradrenaline (158 [154–190] pg/ml, P = .04), with modest rise on tilt (38 [22–55] pg/ml). Patients with PD without nOH had normal supine noradrenaline (232 [224–239] pg/ml) and preserved rise on tilt (93 [80–106] pg/ml) (Fig. 1 ). Postganglionic sudomotor function and cutaneous somatic and autonomic innervation Our group recently reported that postganglionic sudomotor function and cutaneous sudomotor innervation was reduced in patients with MSA and PD compared to healthy controls, with greater impairments in patients with MSA. 7 In this subset of patients who had cardiovascular autonomic testing, we had similar results, with more impaired sweat production/cm 2 , sweat output/gland, sweat gland density, and cholinergic sudomotor innervation in patients with MSA and PD compared to controls, with the MSA patients showing reduced sweat gland density and cholinergic sudomotor innervation compared to patients with PD (Table 4 ). There was no difference in postganglionic sudomotor function between patients with and without nOH (Table 5 ). Table 4 Postganglionic sudomotor function and cutaneous innervation in MSA and PD Median (IQR) P-value MSA (n = 20) PD (n = 37) CTRL (n = 100) † ANOVA CTRLvs MSA CTRL vs PD MSA vs PD Clinical details Age, y 63 (55–68) 65 (58–70) 61 (54–67) .22 Sex (F/M) 6/14 12/25 49/51 .10 DST Glands/cm 3 28 (18–45) 46 (37–55) 66 (62–85) < .001 < .001 < .001 .007 Output/gland, nL 3.1 (1.4–4.3) 3.5 (2.5–4.7) 11.4 (7.7–13.2) < .001 < .001 < .001 .09 Sweat output, nL/cm 3 73 (22–139) 153 (102–261) 591 (363–871) < .001 < .001 < .001 .06 Skin biopsies IENFD, f/mm 3.3 (1.4-5.0) 7.8 (5.3–8.7) 12.1 (10.5–14.0) < .001 < .001 < .001 .22 Pilomotor nerve density, f/mm PGP 37.8 (22.0-50.6) 50.7 (38.2–65.4) 70 (66–90) < .001 < .001 < .001 .21 VIP 0.8 (0.0-17.9) 8.1 (2.6–21.5) 60.3 (52.4–69.4) < .001 < .001 < .001 .59 DβH 10.6 (0.4–30.3) 33.6 (20.4–44.1) 52 (49.5–55) < .001 < .001 < .001 .18 Sudomotor nerve density, nm/µm 3 PGP 1.2 (0.6–3.2) 2.9 (2.3–3.7) 3.6 (3.1–3.9) < .001 < .001 .13 .03 VIP 0.8 (0.3–1.2) 1.6 (1.1–1.9) 2.1 (1.9–2.7) < .001 < .001 < .001 .02 † DST data available for 15 healthy controls. Table 5 Postganglionic sudomotor function and cutaneous innervation in patients with and without OH Median (IQR) P-value Variable OH (n = 23) No OH (n = 20) CTRL (n = 100) ANOVA CTRL vs OH CTRLvs No OH No OH vs OH DST Glands/cm 3 37 (21–50) 45 (30–52) 66 (62–85) < .001 < .001 < .001 .59 Output/gland, nL 3.0 (2.3–4.3) 3.0 (2.2–4.9) 11.4 (7.7–13.2) < .001 < .001 < .001 .93 Sweat output, nL/cm 3 113 (62–166) 119 (28–190) 591 (363–871) < .001 < .001 < .001 1 Skin biopsies IENFD, f/mm 2.7 (1.3–5.4) 7.4 (5.1–10.0) 12.1 (10.5–14.0) < .001 < .001 < .001 .25 Pilomotor nerve density, f/mm PGP 36.6 (23.6–48.4) 53.1 (44.2–61.1) 70 (66–90) < .001 < .001 .01 .09 VIP 2.8 (0-7.5) 11.8 (6.5–23.4) 60.3 (52.4–69.4) < .001 < .001 .002 .13 DβH 10.6 (0.4–21.4) 36.1 (28.4–45.7) 52 (49.5–55) < .001 < .001 .06 .08 Sudomotor nerve density, nm/µm 3 PGP 1.9 (0.7–3.6) 2.8 (2.2–3.7) 3.6 (3.1–3.9) .001 .001 .20 .46 VIP 0.9 (0.1–1.3) 1.6 (1.4–1.8) 2.1 (1.9–2.7) < .001 < .001 .01 .002 † DST data available for 15 healthy controls. Intraepidermal nerve fibre density was reduced in nOH (2.7 [1.3–5.4] fibres/mm) and non-OH groups (7.4 [5.1–10.0] fibres/mm) compared to controls (12.1 [10.5–14.0] fibres/mm, P < .001), without significant difference between the nOH and non-OH groups ( P = .25). Pilomotor adrenergic innervation was significantly reduced in the nOH group (10.6 [0.4–21.4] fibres/mm) compared to controls (52.0 [49.5–55.0 fibres/mm], P ≤ .001), (Fig. 2 ). Sudomotor cholinergic innervation was lowest in the nOH group (0.9 [0.1–1.3] fibres/mm), followed by the non-OH group (1.6 [1.4–1.8] fibres/mm) then the control group (2.1 [1.9–2.7] fibres/mm), with significant differences between all groups ( P ≤ .01). Correlations between OH, cutaneous autonomic denervation, patient reported outcomes, disease severity, and disease duration There was a strong correlation between the severity of nOH as measured by the fall in systolic blood pressure at 5 minutes standing and pilomotor adrenergic innervation (ρ=-0.54, P = .003). The fall in systolic blood pressure on standing also correlated significantly with patient reported autonomic symptoms on the COMPASS-31 (ρ = 0.55, P = .002), and disease severity as measured by the Hoehn-Yahr scale (ρ = 0.50, P = .004) (Fig. 3 ). Disease duration correlated with the fall in systolic blood pressure on standing (ρ = 0.59, P < .001), intraepidermal innervation (ρ=-0.41, P = .002), pilomotor adrenergic innervation, ρ=-0.41, P = .006), sudomotor cholinergic innervation, ρ=-0.51, P < .001), and Hoehn-Yahr grade (ρ=-0.46, P = .001). Supine noradrenaline did not correlate with any quantitative cardiovascular or sudomotor testing parameters or cutaneous innervation. Box 1. Illustrative clinical cases 1. A 66-year-old man with MSA, neurogenic OH and cardiovascular autonomic failure had a normal supine plasma noradrenaline level (224pg/ml) and cardiac MIBG suggesting preserved postganglionic innervation. However, we found severe postganglionic sudomotor dysfunction and cutaneous somatic and autonomic denervation (Fig. 4 ). Our study findings and this case highlight how postganglionic autonomic denervation may not occur in a uniform fashion within the disease cohort and individual patients. 2. A 55-year-old man with a 2-year history of PD, longstanding constipation, and occasional episodes of orthostatic intolerance increasing over the previous year had a minimal fall in blood pressure on standing with good compensatory heart rate rise (9/7mmHg, 25bpm), preserved pressor responses with isometric exercise (22mmHg; 16bpm), HR DB (12bpm) and Valsalva ratio (1.92). However, beat-to-beat blood pressure recording during the Valsalva manoeuvre showed reduced phase II late recovery and phase IV overshoot indicating early adrenergic failure. We suggest that patients with evolving symptoms should undergo comprehensive testing at a specialist autonomic laboratory including analysis of Valsalva maneuver to exclude mild emerging adrenergic dysfunction in absence of overt neurogenic OH. Discussion Our study has revealed insights into neurogenic OH and cardiovascular autonomic failure in MSA and PD with clinically relevant implications. In most patients with MSA and PD, nOH does not occur in isolation, but in the context of more generalised impairment of other autonomic reflexes, in keeping with more widespread cardiovascular autonomic failure. Furthermore, our results confirm previous studies showing nOH contributes significantly to functional disability in PD and MSA. 5 In a subgroup of patients emerging autonomic cardiovascular dysfunction might be present in the absence of overt nOH as illustrated by case 2 (Box1). NOH was associated with cutaneous adrenergic denervation, with significant correlations between the severity of nOH, cutaneous adrenergic denervation, patient reported symptoms, and Hoehn-Yahr grade, in both MSA and PD. To our knowledge, this is the first study demonstrating an association between cutaneous adrenergic denervation and orthostatic hypotension in PD and MSA. While cutaneous adrenergic denervation is unlikely to contribute significantly to impairment of systemic blood pressure regulation, we hypothesize that it may reflect more widespread peripheral adrenergic denervation. In healthy individuals, a series of central and peripheral autonomic networks are activated to maintain blood pressure and organ perfusion on orthostasis. In MSA, the underlying pathophysiology of neurogenic orthostatic hypotension has previously been thought to be predominantly through dysfunction of central autonomic networks, in contrast to dysfunction of peripheral postganglionic autonomic nerves in PD. Our study suggests postganglionic adrenergic denervation may contribute to the pathophysiology of nOH in patients with MSA as well as patients with PD, with potential impact on responses to therapeutic agents. We found a reduction in cutaneous adrenergic pilomotor innervation in patients with nOH compared to healthy controls, with no significant differences between the MSA with nOH and PD with nOH subgroups on post-hoc analysis. Our results are in keeping with a previous study by Gibbons et al, who compared the cutaneous innervation of 28 patients with PD with and without autonomic failure to 23 healthy controls and found patients with autonomic failure had reduced pilomotor and sudomotor innervation compared to controls. Our results may appear to contradict Donadio et al’s study that reported predominantly somatic fibre involvement with preserved autonomic innervation in MSA-P and more prominent autonomic denervation in PD with nOH. 27 However, closer analysis of the supplementary data from their study shows intraepidermal and sudomotor innervation at the distal leg was reduced in both MSA-P and PD + nOH patients compared to controls, with pilomotor innervation reduced in PD + nOH compared to both MSA-P and controls. Our cohort of patients with PD was significantly younger than theirs (median 65 [IQR 58–74] years compared to mean 74 ± SD 6.7 years) and we studied autonomic innervation using pan-neuronal, cholinergic, and adrenergic specific markers, so the studies are not directly comparable. Post mortem studies have shown a loss of sympathetic preganglionic cells in the intermediolateral cell column of the thoracolumbar spinal cord in PD and MSA patients with autonomic failure compared to patients without autonomic failure and normal controls, 28 but a loss of postganglionic cardiac adrenergic fibres in PD patients only. 29 In vivo cardiac scintigraphy studies have also demonstrated cardiac uptake of noradrenaline analogues tends to be spared in MSA compared to PD, 4, 30, 31 although these studies do not always reliably distinguish between individuals with MSA and PD. 5, 32 The differences in noradrenergic innervation at other bodily sites as assessed by 18 F-dopamine positron emission topographic scans and postmortem neurochemical data suggests that the difference between patients with Lewy body synucleinopathies, including patients with PD, and MSA is cardioselective; and there were no differences between norepinephrine levels in the sympathetic ganglia and a number of other organs studied. 33 In our study, cardiovascular autonomic testing did not differ significantly between MSA with nOH and PD with nOH subgroups, in agreement with previous reports, 5, 34 suggesting that cardiovascular autonomic testing on its own cannot reliably distinguish between patients with MSA with nOH and PD with nOH. Interestingly, while there were no significant subgroup differences, the MSA with nOH patients had the most severe nOH with standing and diminished blood pressure response to isometric exercise, whereas the PD with nOH patients had the most diminished heart rate response to isometric exercise and lowest Valsalva ratio, perhaps reflecting greater cardiac adrenergic denervation. In our study, supine noradrenaline levels were significantly higher in MSA vs PD with nOH subgroups, in keeping with previous studies, 35, 36 and in fact, supine noradrenaline was the only biomarker to differ significantly amongst the MSA and PD with nOH subgroups. The relationship between plasma noradrenaline levels and sympathetic innervation and activity is complex, and resting plasma supine noradrenaline levels are likely to reflect both production from postganglionic pre-synaptic terminals, cellular reuptake, metabolism and storage. Peripheral adrenergic denervation is likely to contribute to abnormal responses to physiological and pharmacological stimuli, including novel therapeutic agents for nOH that aim to enhance availability of noradrenaline. 37–41 Previous studies using surrogate markers of postganglionic autonomic denervation to try predict responses to novel agents for nOH have generated conflicting results. Palma et al’s study of 20 patients with nOH found supine noradrenaline levels predicted pressor response to droxidopa, a pro-drug of noradrenaline, whereas Shibao at al’s larger study of 99 patients with nOH found neither plasma noradrenaline nor cardiac innervation on MIBG were good predictors for response to noradrenaline reuptake inhibitor atomoxetine. 38, 40 In our study, plasma noradrenaline did not correlate with cutaneous adrenergic innervation, suggesting it may be oversimplistic to use plasma noradrenaline as a single biomarker to estimate global postganglionic adrenergic denervation. In this exploratory multicentre study, we chose to study 3-mm skin distal leg biopsies, for which there is excellent safety data previously reported, with no serious side effects reported in over 35000 biopsies performed over 15 years across 10 laboratories. 24 We chose to quantify cutaneous sudomotor and pilomotor autonomic innervation as our group and others have previously established and validated methods to quantify innervation to these autonomic adnexa. 24, 25, 42 The variability and complexity of cutaneous vasculature and its innervation has limited previous attempts to quantify vascular innervation. Sohn et al recently outlined a method of quantifying cutaneous vessel innervation in 20 diabetic patients and 19 controls, and had similar findings to our study, showing individuals with nOH had lower vascular innervation than those without nOH, with significant correlations between neurovascular density and cardiovascular autonomic biomarkers, including blood pressure drop during head-up tilt and blood pressure overshoot on phase IV of the Valsalva manoeuvre, and autonomic symptom scores. 43 One of the strengths of our study is that patients were systematically assessed with combination of cardiovascular, sudomotor and morphology testing and with good correlations seen between functional study and patient’s outcome measures. One of the limitations of our study is that none of the patients underwent post-mortem to confirm the clinical diagnosis, and there is overlap between the clinical criteria of MSA and PD with nOH. Nevertheless, all patients were assessed by neurologists with movement disorders and autonomic expertise and followed up for two years from initial recruitment, with exclusion of subjects who had an alternative clinical diagnosis on follow up. In summary, in our cohort of patients with PD and MSA, nOH was associated with cutaneous adrenergic denervation, with significant corelations between severity of nOH, cutaneous adrenergic denervation, patient reported symptoms and Hoehn-Yahr grade. Postganglionic autonomic denervation may contribute to the pathophysiology of nOH and autonomic failure in both PD and MSA and might influence response to therapeutic agents for nOH. Declarations Acknowledgements The authors are grateful to Laura Watson and Scott Johnstone from the Autonomic Unit at the National Hospital for Neurology and Neurosurgery for their assistance in the analysis of plasma catecholamine levels and cardiovascular autonomic data. Author Roles SK: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data VP: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data EV: Drafting/revision of the manuscript for content, including medical writing for content; Analysis or interpretation of data GC: Major role in the acquisition of data; Analysis or interpretation of data FV: Major role in the acquisition of data AS: Major role in the acquisition of data IB: Major role in the acquisition of data FM: Drafting/revision of the manuscript for content, including medical writing for content LS: Drafting/revision of the manuscript for content, including medical writing for content MN: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data VI: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data Funding Sources This study was financed by Italian Ministry of Health “Ricerca Finalizzata 2013” – project code PE-2013-02359028. Dr S Koay was supported by the Guarantors of Brain Entry Fellowship. Dr V Iodice is supported by National Institute for Health Research University College London Hospitals Biomedical Research Centre. Full Financial Disclosures of all Authors for the Past Year: Dr F Manganelli has received honoraria from Sobi, Alnylam, Pfizer and Csl Behring. The other authors have no financial disclosures to declare. Dr V Iodice has received honoraria from Theravance Biopharma Potential conflicts of Interest The authors have no potential conflicts of interest to declare relevant to the research in the submitted manuscript. References Bannister R, Iodice V, Vichayanrat E, Mathias CJ (2013) Clinical features and evaluation of the primary autonomic failure syndromes. In: Bannister R, Mathias CJ (eds) Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford University Press Low PA, Reich SG, Jankovic J et al (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710–719 De Pablo-Fernandez E, Tur C, Revesz T, Lees AJ, Holton JL, Warner TT (2017) Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease. JAMA Neurol 74:970–976 Goldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702 Lipp A, Sandroni P, Ahlskog JE et al (2009) Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch Neurol 66:742–750 Provitera V, Nolano M, Caporaso G et al (2014) Postganglionic sudomotor denervation in patients with multiple system atrophy. Neurology 82:2223–2229 Provitera V, Iodice V, Manganelli F et al (2022) Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease: A Morpho-functional Study. Neurology Riley DE, Chelimsky TC (2003) Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:56–60 Coon EA, Fealey RD, Sletten DM et al (2017) Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction. Mov Disord 32:397–404 Postuma RB, Berg D, Stern M et al (2015) MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 30:1591–1601 Gilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf 42:377–381 Harris PA, Taylor R, Minor BL et al (2019) The REDCap consortium: Building an international community of software platform partners. J Biomed Inf 95:103208 Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17:427–442 Bakkers M, Merkies IS, Lauria G et al (2009) Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 73:1142–1148 Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W (2012) COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc 87:1196–1201 Cheshire WP, Freeman R, Gibbons CH et al (2021) Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology. Clin Neurophysiol 132:666–682 Neurology TCCotAASatAAo (1996) Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 46:1470 Norcliffe-Kaufmann L, Kaufmann H, Palma JA et al (2018) Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 83:522–531 Norcliffe-Kaufmann L, Palma JA, Kaufmann H (2018) A validated test for neurogenic orthostatic hypotension at the bedside. Ann Neurol 84:959–960 Mathias C, Low DA, Iodice V, Vichayanrat E, Bannister R (2013) Investigation of autonomic disorders. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edn. Oxford University Press, Oxford, pp 259–289 Provitera V, Nolano M, Caporaso G, Stancanelli A, Santoro L, Kennedy WR (2010) Evaluation of sudomotor function in diabetes using the dynamic sweat test. Neurology 74:50–56 Nolano M, Provitera V, Estraneo A et al (2008) Sensory deficit in Parkinson's disease: evidence of a cutaneous denervation. Brain 131:1903–1911 Lauria G, Hsieh ST, Johansson O et al (2010) European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 17:903–912 e944-909 Nolano M, Provitera V, Caporaso G, Stancanelli A, Vitale DF, Santoro L (2010) Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. Neurology 75:1089–1097 Nolano M, Caporaso G, Manganelli F et al (2022) Phosphorylated alpha-Synuclein Deposits in Cutaneous Nerves of Early Parkinsonism. J Parkinsons Dis 12:2453–2468 Donadio V, Incensi A, Rizzo G et al (2020) Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson's Disease with Orthostatic Hypotension. Mov Disord Oppenheimer DR (1980) Lateral horn cells in progressive autonomic failure. J Neurol Sci 46:393–404 Orimo S, Uchihara T, Nakamura A et al (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease. Brain 131:642–650 Lenka A, Lamotte G, Goldstein DS (2021) Cardiac (18)F-Dopamine PET Distinguishes PD with Orthostatic Hypotension from Parkinsonian MSA. Mov Disord Clin Pract 8:582–586 Braune S, Reinhardt M, Schnitzer R, Riedel A, Lucking CH (1999) Cardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy. Neurology 53:1020–1025 Skowronek C, Zange L, Lipp A (2019) Cardiac 123I-MIBG Scintigraphy in Neurodegenerative Parkinson Syndromes: Performance and Pitfalls in Clinical Practice. Front Neurol 10:152 Lamotte G, Holmes C, Sullivan P, Lenka A, Goldstein DS (2020) Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies. Ann Clin Transl Neurol 7:2450–2460 Leys F, Fanciulli A, Ndayisaba JP, Granata R, Struhal W, Wenning GK (2020) Cardiovascular autonomic function testing in multiple system atrophy and Parkinson's disease: an expert-based blinded evaluation. Clin Auton Res 30:255–263 Polinsky R, Kopin I, Ebert M, Weise V (1981) Pharmacologic distinction different orthostatic hypotension Syndr Neurol 31:1–7 Goldstein D, Polinsky R, Garty M et al (1989) Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 26:558–563 Okamoto LE, Shibao CA, Gamboa A et al (2019) Synergistic Pressor Effect of Atomoxetine and Pyridostigmine in Patients With Neurogenic Orthostatic Hypotension. Hypertension. ;73:235–241 Shibao CA, Palma JA, Celedonio JE, Martinez J, Kaufmann H, Biaggioni I (2021) Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension. Hypertension 78:525–531 Shibao C, Raj SR, Gamboa A et al (2007) Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension 50:47–53 Palma JA, Norcliffe-Kaufmann L, Martinez J, Kaufmann H (2018) Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension. Neurology 91:e1539–e1544 Kaufmann H, Vickery R, Wang W et al (2021) Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial. Clin Auton Res 31:699–711 Gibbons CH, Illigens BM, Wang N, Freeman R (2010) Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve 42:112–119 Sohn E, Suh BC, Wang N, Freeman R, Gibbons CH (2020) A novel method to quantify cutaneous vascular innervation. Muscle Nerve 62:492–501 Cite Share Download PDF Status: Published Journal Publication published 12 Sep, 2025 Read the published version in Clinical Autonomic Research → Version 1 posted Reviewers agreed at journal 31 May, 2024 Reviewers invited by journal 20 May, 2024 Editor assigned by journal 14 May, 2024 First submitted to journal 13 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4405619","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304523232,"identity":"12980916-30ff-425a-af85-932e9a217f97","order_by":0,"name":"Shiwen Koay","email":"","orcid":"","institution":"University College London - Bloomsbury Campus: University College London","correspondingAuthor":false,"prefix":"","firstName":"Shiwen","middleName":"","lastName":"Koay","suffix":""},{"id":304523233,"identity":"d4f410fa-a5b4-431f-88b3-a6ef47620a47","order_by":1,"name":"Vincenzo Provitera","email":"","orcid":"","institution":"Istituti Clinici Scientifici Maugeri SpA SB IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"","lastName":"Provitera","suffix":""},{"id":304523234,"identity":"bc5bbba0-9a89-4f93-b0a0-ee89ef99b048","order_by":2,"name":"Ekawat Vichayanrat","email":"","orcid":"","institution":"National Hospital for Neurology and Neurosurgery","correspondingAuthor":false,"prefix":"","firstName":"Ekawat","middleName":"","lastName":"Vichayanrat","suffix":""},{"id":304523235,"identity":"50a628f6-0432-4e9d-a811-fed02848bd96","order_by":3,"name":"Giuseppe Caporaso","email":"","orcid":"","institution":"Istituti Clinici Scientifici Maugeri SpA SB IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"","lastName":"Caporaso","suffix":""},{"id":304523236,"identity":"c16e4bd6-0a63-4439-b35a-b578707807ba","order_by":4,"name":"Fernanda Valerio","email":"","orcid":"","institution":"National Hospital for Neurology and Neurosurgery","correspondingAuthor":false,"prefix":"","firstName":"Fernanda","middleName":"","lastName":"Valerio","suffix":""},{"id":304523237,"identity":"c16303ce-06ac-4244-8e5b-fde42cfe810e","order_by":5,"name":"Annamaria Stancanelli","email":"","orcid":"","institution":"Istituti Clinici Scientifici Maugeri SpA SB IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Annamaria","middleName":"","lastName":"Stancanelli","suffix":""},{"id":304523238,"identity":"ee2f4c27-acf9-40a8-b219-0e6607f100a4","order_by":6,"name":"Ilaria Borreca","email":"","orcid":"","institution":"Istituti Clinici Scientifici Maugeri SpA SB IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Ilaria","middleName":"","lastName":"Borreca","suffix":""},{"id":304523239,"identity":"dbdad5cb-35c9-4cb2-9c3e-caa63afccac9","order_by":7,"name":"Fiore Manganelli","email":"","orcid":"","institution":"Federico II University Hospital: Azienda Ospedaliera Universitaria Federico II","correspondingAuthor":false,"prefix":"","firstName":"Fiore","middleName":"","lastName":"Manganelli","suffix":""},{"id":304523240,"identity":"c63dfab0-c581-4d1c-bf92-8ecbfc8bef9a","order_by":8,"name":"Lucio Santoro","email":"","orcid":"","institution":"Federico II University Hospital: Azienda Ospedaliera Universitaria Federico II","correspondingAuthor":false,"prefix":"","firstName":"Lucio","middleName":"","lastName":"Santoro","suffix":""},{"id":304523241,"identity":"c63747d3-5d27-4c00-99c0-66f4ab76587a","order_by":9,"name":"Maria Nolano","email":"","orcid":"","institution":"Istituti Clinici Scientifici Maugeri SpA SB IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Nolano","suffix":""},{"id":304523242,"identity":"e481f770-c231-49a0-8f69-e030fb9d87d8","order_by":10,"name":"Dr.Valeria Iodice","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYFACxgYGHgMGBn4g6wBYgIdYLZINDAzEaoEqMjhArBaDA8yND94U2MkZ30h+cIChxo7B4MwBQloYmw3nGCQbm91IA1p0LJnB4GwDfi2SDYxt0jwGBxK33cgBOoztAIPBeQIOg2mp3zwDpOUfEVr4GSBaEgwkgFoY2w4Qdhg/M8QvhjPOPAM6ry+ZR5KQ99nY2x8+ePPHTp6/Pfnhgw/f7OT4ziQQcBkzMieByIgcBaNgFIyCUUAAAADsiUAOmmL7XwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0002-5775-5810","institution":"University College London - Bloomsbury Campus: University College London","correspondingAuthor":true,"prefix":"Dr.","firstName":"Valeria","middleName":"","lastName":"Iodice","suffix":""}],"badges":[],"createdAt":"2024-05-11 13:49:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4405619/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4405619/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10286-025-01154-4","type":"published","date":"2025-09-12T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57729054,"identity":"dc33ea1d-70fa-4282-99df-a3de2fc2b833","added_by":"auto","created_at":"2024-06-04 21:50:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18740,"visible":true,"origin":"","legend":"\u003cp\u003eSupine noradrenaline levels in MSA and PD, with and without OH. Supine noradrenaline levels were significantly lower in the PD+OH group compared to the MSA group (P=.04), with intermediate results in the PD without OH group.\u003c/p\u003e","description":"","filename":"OnlineFig1.SupineNoradrenaline.png","url":"https://assets-eu.researchsquare.com/files/rs-4405619/v1/2156284083deebabcf39a958.png"},{"id":57729052,"identity":"10adf0b1-356b-460c-90f2-aec6e3134189","added_by":"auto","created_at":"2024-06-04 21:50:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24656,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of pilomotor adrenergic innervation between patients with and without orthostatic hypotension and controls. Pilomotor adrenergic innervation was lowest in the OH group (10.6 [0.4-21.4] fibres/mm), followed by the non-OH group (36.1 [28.4-45.7] fibres/mm) then the control group (52 [49.5-55] fibres/mm), with a significant difference between the OH and control group (P≤.001)\u003c/p\u003e","description":"","filename":"OnlineFig2.DBH.png","url":"https://assets-eu.researchsquare.com/files/rs-4405619/v1/3f233165f0bd529823bf9069.png"},{"id":57729055,"identity":"e4b10f8f-c700-46d7-886b-38dee44b074f","added_by":"auto","created_at":"2024-06-04 21:50:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50128,"visible":true,"origin":"","legend":"\u003cp\u003eSeverity of OH correlated with cutaneous adrenergic denervation, patient reported symptoms, and disease severity. Severity of OH as measured by the fall in systolic blood pressure on standing correlated with pilomotor nerve fibre density with adrenergic marker DβH (A). OH severity also correlated with patient reported autonomic symptoms on the COMPASS-31 questionnaire (B) and disease status as measured by the Hoehn-Yahr scale (C).\u003c/p\u003e","description":"","filename":"OnlineFig3.Correlations2.png","url":"https://assets-eu.researchsquare.com/files/rs-4405619/v1/4441a854bb7e3f97f8f22d32.png"},{"id":57729053,"identity":"b707fd21-2043-4308-b024-1db33a0e38af","added_by":"auto","created_at":"2024-06-04 21:50:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1982935,"visible":true,"origin":"","legend":"\u003cp\u003eCardiac MIBG and cutaneous innervation in a patient with MSA (Case 1). MIBG study performed as part of clinical work up. Images acquired 10 minutes (A) and 4 hours (A1) post injection showed good tracer uptake in the myocardium with a heart to mediastinum ratio of 1.73, indicating preserved postganglionic innervation. However, punch skin biopsies from the distal legs bilaterally revealed severe cutaneous denervation with marked loss of intraepidermal (0.1-1.1 fibres/mm), pilomotor (15.2-32.0 fibres/mm) and sudomotor fibres (0.4 nm/µm3) with pan-neuronal marker PGP (B-D, control; B1-D1, patient), and a complete loss of pilomotor and sudomotor fibres with cholinergic marker VIP (not shown here). Scale bar: 100µm.\u003c/p\u003e","description":"","filename":"Fig4.MIBGandskin.png","url":"https://assets-eu.researchsquare.com/files/rs-4405619/v1/7395534e2716307cb588af5a.png"},{"id":91358981,"identity":"ac780244-8489-4301-90d5-84980a6075c8","added_by":"auto","created_at":"2025-09-15 16:03:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3255642,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4405619/v1/34ce6047-dbc2-4fbc-b0b8-8e72c9b06771.pdf"}],"financialInterests":"","formattedTitle":"Cardiovascular autonomic failure correlates with cutaneous autonomic devervation in PD and MSA","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling features of the neurodegenerative diseases Parkinson\u0026rsquo;s disease (PD) and multiple system atrophy (MSA).\u003csup\u003e1\u003c/sup\u003e Severe symptomatic autonomic failure and nOH are associated with shortened survival and worse disease progression in both PD and MSA.\u003csup\u003e2, 3\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCompared to PD, MSA is associated with more rapid disease progression, but overlapping clinical features at presentation may cause initial diagnostic uncertainty. Previous studies have shown biomarkers reflecting postganglionic adrenergic autonomic innervation, like supine plasma noradrenaline levels and cardiac scintigraphy studies, tend to be relatively preserved in MSA compared to PD,\u003csup\u003e4, 5\u003c/sup\u003e suggesting that autonomic failure in MSA occurs due to degeneration and dysfunction of central autonomic networks. However, our group and others have found evidence of postganglionic sudomotor dysfunction and cutaneous somatic and autonomic denervation in MSA, suggesting both central and peripheral degeneration may contribute to the pathophysiology of autonomic failure in MSA.\u003csup\u003e6\u0026ndash;9\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe aimed to evaluate the cardiovascular autonomic profile in patients with MSA and PD, with and without nOH, alongside markers of postganglionic denervation, including plasma catecholamines, DST, and cutaneous autonomic and somatic innervation, to characterise the relationship between nOH, other quantitative biomarkers of cardiovascular autonomic failure and markers of postganglionic denervation. A secondary aim was to assess whether these biomarkers could differentiate between MSA and PD, and MSA and PD with autonomic failure.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStandard Protocol Approvals, Registrations and Patient Consents\u003c/h2\u003e \u003cp\u003ePatients with at least clinically probable PD and MSA according to established consensus criteria were recruited from patients referred to 1) Autonomic Unit, the National Hospital of Neurology and Neurosurgery, London, 2) Neurology Division \u0026lsquo;ICS Maugeri\u0026rsquo; IRCCS of Telese Terme, and 3) Neurology Department, University of Naples Federico II, Naples, between November 2017 and December 2019, as part of a multi-centre natural history and biomarker study in Parkinsonism.\u003csup\u003e10, 11\u003c/sup\u003e The study protocol complied with the Declaration of Helsinki and was approved by the local Institutional Review Boards (Fondazione G. Pascale No. \u0026ldquo;5/15 Maugeri\u0026rdquo; and London Bridge Research Ethics Committee, REC reference 16/LO/1656). All subjects gave written informed consent to participate in the study. Study data were collected and managed using REDCap research electronic data capture tools hosted at University College London.\u003csup\u003e12, 13\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePatients with conditions associated with peripheral neuropathies, including diabetes, HIV, connective tissue disorders and other toxic or metabolic disorders were excluded. Patients with an alternative diagnosis other than PD or MSA after 12-month follow-up were excluded from the final analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical assessment and patient reported outcomes\u003c/h2\u003e \u003cp\u003eAll patients were assessed by neurologists with movement disorders expertise, with recording of their motor examination and functional impairment using the Hoehn-Yahr scale.\u003csup\u003e14\u003c/sup\u003e Sensory and autonomic symptoms were collected using the COMPASS-31 and SFN-SIQ.\u003csup\u003e15, 16\u003c/sup\u003e Disease duration was defined as time from onset of motor symptoms to the time of recruitment to the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCardiovascular autonomic testing\u003c/h2\u003e \u003cp\u003eAll patients had a core protocol of cardiovascular autonomic testing performed with recording of blood pressure and heart rate:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eat rest in the supine position\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eafter 1-, 3- and 5-minutes standing or tilt\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ebefore and after isometric exercise (sustained handgrip for 3 minutes at a third of maximum voluntary contraction pressure)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ewith deep breathing, at a rate of 6 breaths/min\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ewith the Valsalva manoeuvre (forced expiration at 40mmHg for 10 seconds). Beat-to-beat recordings of blood pressure and heart rate with analysis of the blood pressure profile in response to the Valsalva manoeuvre. Blood pressure recovery time (PRT), a marker of adrenergic control of total peripheral resistance, was defined as the time taken for the systolic blood pressure to recover from phase III of the Valsalva manoeuvre back to the baseline.\u003csup\u003e17\u003c/sup\u003e The Valsalva ratio was calculated by dividing the maximal heart rate developing in response to blood pressure reduction induced by the Valsalva manoeuvre by the minimum heart rate occurring within 30 seconds of the peak heart rate.\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eAll medications potentially affecting autonomic testing were stopped at least five half-lives prior to testing, and patients were instructed to consume only water for four hours prior to testing. NOH was defined as a sustained fall of at least 20mmHg systolic or 10mmHg diastolic blood pressure within 3 minutes of standing or tilt according to consensus criteria,\u003csup\u003e18\u003c/sup\u003e with an abnormal blood pressure profile in response to the Valsalva manoeuvre, or blunted HR increase during hypotension with ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg.\u003csup\u003e19, 20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBlood was collected via intravenous catheter in the supine and tilted position for measurement of plasma catecholamines using high performance liquid chromatography.\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSudomotor testing\u003c/h2\u003e \u003cp\u003eAll patients underwent DST at the distal leg bilaterally. DST uses pharmacological stimulation with pilocarpine to directly stimulate the M3 receptors on cutaneous sweat glands, providing an estimation of postganglionic sudomotor function.\u003csup\u003e22\u003c/sup\u003e After iontophoresis with 1% pilocarpine solution, skin was coated with iodine and formation of sweat gland imprints on starch covered tape was recorded. Density of activated sweat glands/cm\u003csup\u003e2\u003c/sup\u003e, sweat nl/min/cm\u003csup\u003e2\u003c/sup\u003e, and average sweat output/gland was calculated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMorphological analysis\u003c/h2\u003e \u003cp\u003eAll patients had 3-mm skin biopsies collected from the distal leg bilaterally and processed for indirect immunofluorescence according to standard procedures using a large panel of antibodies, including primary antibodies against collagen type IV (ColIV), protein gene product (PGP) 9.5, a pan-neuronal marker, dopamine-β-hydroxylase (DβH), a marker for noradrenergic fibres, vasoactive intestinal peptide (VIP), a marker for cholinergic fibres, and species-specific secondary antibodies coupled with Cy2 and Cy3 fluorophores.\u003csup\u003e23\u003c/sup\u003e Digital confocal images were acquired using a non-laser confocal system (Apotome2 Zeiss, Jena, Germany, EU).\u003c/p\u003e \u003cp\u003eIntraepidermal nerve fibre (IENF) density was measured according to current guidelines.\u003csup\u003e24\u003c/sup\u003e Quantification of pilomotor and sudomotor nerve fibres using pan-neuronal and selective cholinergic and noradrenergic markers was performed as previously described.\u003csup\u003e6, 25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFor the functional and morphological studies above, the average of both sides was calculated and taken as representative for each patient. Normative data was extracted from a database of 100 healthy volunteers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using R, Version 3.6.0. Normality was assessed Shapiro-Wilk tests. Summary data has been presented as median (IQR) as some data was not normally distributed. Patient groups were compared with unpaired two-tailed t-tests/ Mann-Whitney tests, and subgroup comparisons were preformed using ANOVA/Kruskal-Wallis tests with Tukey/Dunn post-hoc tests with Bonferroni corrections for multiple comparisons as appropriate. Chi-squared tests were used to compare categorical data. Correlations were performed using Spearman tests. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05 was considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and clinical data\u003c/h2\u003e \u003cp\u003eThe postganglionic sudomotor function, cutaneous autonomic innervation and distribution of neural phosphorylated synuclein of the patients recruited to this multicentre cohort study have been described in previous reports.\u003csup\u003e7, 26\u003c/sup\u003e This study focused on the cardiovascular autonomic testing and the relationship between quantitative autonomic biomarkers and markers of post-ganglionic autonomic denervation autonomic innervation in patients with MSA and PD, with and without nOH.\u003c/p\u003e \u003cp\u003eFifty-seven patients were included in the final analysis: 37 with PD and 20 with MSA, 16 with parkinsonian subtype and 4 with cerebellar subtype. 32% (18/57) were female and median age was 64 years (IQR 59\u0026ndash;70 years) at recruitment. The MSA and PD groups had similar sex distribution, age and disease duration at recruitment, but patients with MSA had greater disease severity as measured by the Hoehn-Yahr scale (4 [3\u0026ndash;4] vs 1.5 [1\u0026ndash;2], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical details and cardiovascular testing in MSA and PD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSA (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePD (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical details\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (55\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (58\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (F/M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12/25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration, mo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoehn-Yahr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMPASS-31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (16\u0026ndash;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSFN-SIQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ SBP on standing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (19\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (-2 to 19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (28\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsometric exercise\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔSBP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (-1 to 14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔHR, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003csub\u003eDB\u003c/sub\u003e, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValsalva ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20 (1.12\u0026ndash;1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.19 (1.08\u0026ndash;1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePressure recovery time, s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.5 (7.4\u0026ndash;23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.6 (2.8\u0026ndash;14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupine noradrenaline, pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e256 (240\u0026ndash;303)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e216 (158\u0026ndash;223)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ noradrenaline on tilt, pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (38\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSBP, systolic blood pressure; HR, heart rate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCardiovascular autonomic testing\u003c/h2\u003e \u003cp\u003eCompared to patients with PD, patients with MSA had a significantly greater fall in systolic blood pressure on standing (35 [28\u0026ndash;77] vs 10 [1\u0026ndash;26] mmHg by 5 minutes, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.004), and reduced blood pressure and heart rate responses to isometric exercise (6 [-1 to 14] vs 25 [20\u0026ndash;32] mmHg, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001; 5 [2\u0026ndash;8] vs 9 [4\u0026ndash;14] bpm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.04).\u003c/p\u003e \u003cp\u003eOf the 57 patients studied, 43 patients completed at least 3 minutes of standing or tilt challenge, allowing us to assess for sustained nOH according to consensus criteria.\u003csup\u003e18\u003c/sup\u003e The other 14 patients had assessment of blood pressure and heart rate supine and after 1 minute standing only as part of routine clinical testing and were not included in the analyses comparing patients with and without nOH.\u003c/p\u003e \u003cp\u003e23/43 (54%) patients fulfilled criteria for nOH: 78% (14/18) patients with MSA and 36% (9/25) with PD. Of these 23 patients, 15 patients had assessment of BP profile with the Valsalva manoeuvre, and all 15/15 (100%) had reduced or absent phase II late blood pressure recovery, phase IV overshoot and prolonged PRT, consistent with impaired adrenergic function and nOH. The eight patients with nOH on standing who did not perform Valsalva manoeuvre had minimal HR rise with 3 minutes of standing, in keeping with nOH (median ΔHR 1 [ IQR \u0026minus;\u0026thinsp;2 to 4] bpm; median ΔHR/ΔSBP \u0026minus;\u0026thinsp;0.04 (IQR \u0026minus;\u0026thinsp;0.05 to 0.21, ΔHR/ΔSBP\u0026thinsp;\u0026lt;\u0026thinsp;0.5 indicates nOH).\u003csup\u003e19, 20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOverall, regardless of the diagnosis, patients with and without nOH were similar in age, but patients with nOH had a longer disease duration (33 [20\u0026ndash;44] vs 21 [11\u0026ndash;23] months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.005). They reported more severe autonomic symptoms (COMPASS-31 score 33 [25\u0026ndash;48] vs 17 [9\u0026ndash;30], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.006) and had a higher Hoehn-Yahr grade (3.5 [2.75-4] vs 1 [ 1\u0026ndash;2], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Compared to patients without nOH, patients with nOH had a more prolonged PRT (14.5 [8.9\u0026ndash;22.4] seconds vs 2.5 [2.5\u0026ndash;2.8] seconds, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.02), attenuated pressor responses to isometric exercise (5 [-2 to 15] mmHg vs 22 [14\u0026ndash;26] mmHg, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001; 4 [1\u0026ndash;6] vs 11 [7\u0026ndash;14] bpm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.004), HR\u003csub\u003eDB\u003c/sub\u003e (7 [4\u0026ndash;11] bpm vs 12 [8\u0026ndash;18] bpm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.048) and lower Valsalva ratio (1.10 [1.03\u0026ndash;1.18] vs 1.33 [1.21\u0026ndash;1.42], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.02), reflecting more widespread sympathetic and parasympathetic autonomic failure. Cardiovascular autonomic biomarkers did not differ significantly between the MSA with nOH and PD with nOH subgroups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical and cardiovascular testing in patients with and without OH\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOH (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo OH (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical details\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (56\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (60\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (F/M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (20\u0026ndash;44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoehn-Yahr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5 (2.75-4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMPASS-31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (25\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSFN-SIQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ SBP on standing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (19\u0026ndash;56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (-4-16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (21\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (-2 to 9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (29\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (-1 to 11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsometric exercise\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔSBP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (-2\u003csup\u003ea\u003c/sup\u003e to 15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔHR, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003csub\u003eDB\u003c/sub\u003e, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValsalva ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10 (1.03\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.33 (1.21\u0026ndash;1.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePressure recovery time, s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.5 (8.9\u0026ndash;22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7 (2.5\u0026ndash;2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupine noradrenaline, pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e242 (228\u0026ndash;293)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e232 (224\u0026ndash;239)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ noradrenaline on tilt, pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (80\u0026ndash;106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSBP, systolic blood pressure; HR, heart rate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup comparisons\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eP-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSA\u0026thinsp;+\u0026thinsp;OH\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMSA, no OH\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePD\u0026thinsp;+\u0026thinsp;OH\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePD, no OH\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eANOVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMSA\u0026thinsp;+\u0026thinsp;OH v PD\u0026thinsp;+\u0026thinsp;OH\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical details\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (55\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (59\u0026ndash;66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (58\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64 (60\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (F/M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease dur., mo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (29\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoehn-Yahr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3.5-4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSFN-SIQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMPASS-31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (22\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (28\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ SBP-on standing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (28\u0026ndash;51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4\u003csup\u003ea\u003c/sup\u003e (-9 to 8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (6\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (-3\u003csup\u003ea\u003c/sup\u003e to 16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (30\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (-2 to 10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (19\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (-2\u003csup\u003ea\u003c/sup\u003e to 7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (30\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2\u003csup\u003ea\u003c/sup\u003e (-4 to 8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (23\u0026ndash;44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsometric exercise\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔSBP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (-2.5\u003csup\u003ea\u003c/sup\u003e to 10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (\u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔHR, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003csub\u003eDB\u003c/sub\u003e, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValsalva ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20 (1.13\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.33 (1.29\u0026ndash;1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.14 (1.07\u0026ndash;1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.37 (1.21\u0026ndash;1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePressure recovery time,\u003csup\u003eb\u003c/sup\u003e s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.5 (7.4\u0026ndash;23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.2 (14.6\u0026ndash;19.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.7 (3.5\u0026ndash;2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupine NA,\u003csup\u003ec\u003c/sup\u003e pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e256 (240\u0026ndash;303)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e158 (154\u0026ndash;190)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e232 (224\u0026ndash;239)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ NA on tilt, pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (22\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e93 (80\u0026ndash;106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlands/cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (25\u0026ndash;46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (41\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46 (34\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutput/gland, nL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1 (1.5\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.6 (3.2\u0026ndash;5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.0 (2.5\u0026ndash;4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.7 (2.2\u0026ndash;4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSweat output, nL/cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (26\u0026ndash;145)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 (22\u0026ndash;166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e149 (119\u0026ndash;194)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e119 (38\u0026ndash;190)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin biopsies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIENFD, f/mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.8 (0.9\u0026ndash;4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0 (4.9\u0026ndash;10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.9 (2.6\u0026ndash;9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.8 (6.1\u0026ndash;9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePilomotor nerve fibre density, f/mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.8 (20.0-46.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52.6 (50.2\u0026ndash;59.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.6 (38.2\u0026ndash;50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53.7 (39.5\u0026ndash;59.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0.0-5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.2 (21.6\u0026ndash;25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6 (4.3\u0026ndash;13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.8 (5.7\u0026ndash;15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDβH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.5 (0-13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.0 (38.3\u0026ndash;43.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.6 (11.9\u0026ndash;40.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.6 (20.4\u0026ndash;45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSudomotor nerve fibre density, nm/\u0026micro;m\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7 (0.5-2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.9 (1.6\u0026ndash;2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.1 (2.1\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.8 (2.5\u0026ndash;3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6 (0.0-0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.3 (1.2\u0026ndash;1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.7\u0026ndash;1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.6 (1.4\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eSBP, systolic blood pressure; HR, heart rate; NA, noradrenaline; PNFD, pilomotor nerve fibre density; SNFD, sudomotor nerve fibre density.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePlasma noradrenaline\u003c/h2\u003e \u003cp\u003eSeventeen patients had plasma noradrenaline levels measured: 12 with MSA, all of whom had nOH, and five patients with PD, three with nOH and two without nOH. Patients with MSA had normal supine noradrenaline (256 [240\u0026ndash;303] pg/ml), with minimal rise on tilt (11 [5\u0026ndash;12] pg/ml). In comparison, patients with PD with nOH had significantly lower supine noradrenaline (158 [154\u0026ndash;190] pg/ml, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.04), with modest rise on tilt (38 [22\u0026ndash;55] pg/ml). Patients with PD without nOH had normal supine noradrenaline (232 [224\u0026ndash;239] pg/ml) and preserved rise on tilt (93 [80\u0026ndash;106] pg/ml) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePostganglionic sudomotor function and cutaneous somatic and autonomic innervation\u003c/h2\u003e \u003cp\u003eOur group recently reported that postganglionic sudomotor function and cutaneous sudomotor innervation was reduced in patients with MSA and PD compared to healthy controls, with greater impairments in patients with MSA.\u003csup\u003e7\u003c/sup\u003e In this subset of patients who had cardiovascular autonomic testing, we had similar results, with more impaired sweat production/cm\u003csup\u003e2\u003c/sup\u003e, sweat output/gland, sweat gland density, and cholinergic sudomotor innervation in patients with MSA and PD compared to controls, with the MSA patients showing reduced sweat gland density and cholinergic sudomotor innervation compared to patients with PD (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). There was no difference in postganglionic sudomotor function between patients with and without nOH (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostganglionic sudomotor function and cutaneous innervation in MSA and PD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c8\" namest=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSA (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePD (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCTRL (n\u0026thinsp;=\u0026thinsp;100) \u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eANOVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCTRLvs MSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCTRL vs PD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMSA vs PD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical details\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (55\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (58\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (54\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (F/M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12/25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49/51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlands/cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (18\u0026ndash;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (37\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (62\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutput/gland, nL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1 (1.4\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.5 (2.5\u0026ndash;4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.4 (7.7\u0026ndash;13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSweat output, nL/cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (22\u0026ndash;139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e153 (102\u0026ndash;261)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e591 (363\u0026ndash;871)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin biopsies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIENFD, f/mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3 (1.4-5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.8 (5.3\u0026ndash;8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.1 (10.5\u0026ndash;14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePilomotor nerve density, f/mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.8 (22.0-50.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.7 (38.2\u0026ndash;65.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (66\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8 (0.0-17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.1 (2.6\u0026ndash;21.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.3 (52.4\u0026ndash;69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDβH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.6 (0.4\u0026ndash;30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.6 (20.4\u0026ndash;44.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (49.5\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSudomotor nerve density, nm/\u0026micro;m\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2 (0.6\u0026ndash;3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.9 (2.3\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6 (3.1\u0026ndash;3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8 (0.3\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6 (1.1\u0026ndash;1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.1 (1.9\u0026ndash;2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u0026dagger; DST data available for 15 healthy controls.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostganglionic sudomotor function and cutaneous innervation in patients with and without OH\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c8\" namest=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOH (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo OH (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCTRL\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eANOVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCTRL vs OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCTRLvs No OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo OH vs OH\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlands/cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (21\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (30\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (62\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutput/gland, nL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0 (2.3\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0 (2.2\u0026ndash;4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.4 (7.7\u0026ndash;13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSweat output, nL/cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113 (62\u0026ndash;166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119 (28\u0026ndash;190)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e591 (363\u0026ndash;871)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin biopsies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIENFD, f/mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.7 (1.3\u0026ndash;5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4 (5.1\u0026ndash;10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.1 (10.5\u0026ndash;14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePilomotor nerve density, f/mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.6 (23.6\u0026ndash;48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.1 (44.2\u0026ndash;61.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (66\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.8 (0-7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.8 (6.5\u0026ndash;23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.3 (52.4\u0026ndash;69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDβH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.6 (0.4\u0026ndash;21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.1 (28.4\u0026ndash;45.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (49.5\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSudomotor nerve density, nm/\u0026micro;m\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (0.7\u0026ndash;3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8 (2.2\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6 (3.1\u0026ndash;3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9 (0.1\u0026ndash;1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6 (1.4\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.1 (1.9\u0026ndash;2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u0026dagger; DST data available for 15 healthy controls.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIntraepidermal nerve fibre density was reduced in nOH (2.7 [1.3\u0026ndash;5.4] fibres/mm) and non-OH groups (7.4 [5.1\u0026ndash;10.0] fibres/mm) compared to controls (12.1 [10.5\u0026ndash;14.0] fibres/mm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001), without significant difference between the nOH and non-OH groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.25). Pilomotor adrenergic innervation was significantly reduced in the nOH group (10.6 [0.4\u0026ndash;21.4] fibres/mm) compared to controls (52.0 [49.5\u0026ndash;55.0 fibres/mm], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;.001), (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Sudomotor cholinergic innervation was lowest in the nOH group (0.9 [0.1\u0026ndash;1.3] fibres/mm), followed by the non-OH group (1.6 [1.4\u0026ndash;1.8] fibres/mm) then the control group (2.1 [1.9\u0026ndash;2.7] fibres/mm), with significant differences between all groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;.01).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCorrelations between OH, cutaneous autonomic denervation, patient reported outcomes, disease severity, and disease duration\u003c/h2\u003e \u003cp\u003eThere was a strong correlation between the severity of nOH as measured by the fall in systolic blood pressure at 5 minutes standing and pilomotor adrenergic innervation (ρ=-0.54, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.003). The fall in systolic blood pressure on standing also correlated significantly with patient reported autonomic symptoms on the COMPASS-31 (ρ\u0026thinsp;=\u0026thinsp;0.55, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.002), and disease severity as measured by the Hoehn-Yahr scale (ρ\u0026thinsp;=\u0026thinsp;0.50, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.004) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDisease duration correlated with the fall in systolic blood pressure on standing (ρ\u0026thinsp;=\u0026thinsp;0.59, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001), intraepidermal innervation (ρ=-0.41, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.002), pilomotor adrenergic innervation, ρ=-0.41, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.006), sudomotor cholinergic innervation, ρ=-0.51, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001), and Hoehn-Yahr grade (ρ=-0.46, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001).\u003c/p\u003e \u003cp\u003eSupine noradrenaline did not correlate with any quantitative cardiovascular or sudomotor testing parameters or cutaneous innervation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBox 1. Illustrative clinical cases\u003c/em\u003e\u003c/p\u003e \u003cp\u003e1. A 66-year-old man with MSA, neurogenic OH and cardiovascular autonomic failure had a normal supine plasma noradrenaline level (224pg/ml) and cardiac MIBG suggesting preserved postganglionic innervation. However, we found severe postganglionic sudomotor dysfunction and cutaneous somatic and autonomic denervation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Our study findings and this case highlight how postganglionic autonomic denervation may not occur in a uniform fashion within the disease cohort and individual patients.\u003c/p\u003e \u003cp\u003e2. A 55-year-old man with a 2-year history of PD, longstanding constipation, and occasional episodes of orthostatic intolerance increasing over the previous year had a minimal fall in blood pressure on standing with good compensatory heart rate rise (9/7mmHg, 25bpm), preserved pressor responses with isometric exercise (22mmHg; 16bpm), HR\u003csub\u003eDB\u003c/sub\u003e (12bpm) and Valsalva ratio (1.92). However, beat-to-beat blood pressure recording during the Valsalva manoeuvre showed reduced phase II late recovery and phase IV overshoot indicating early adrenergic failure. We suggest that patients with evolving symptoms should undergo comprehensive testing at a specialist autonomic laboratory including analysis of Valsalva maneuver to exclude mild emerging adrenergic dysfunction in absence of overt neurogenic OH.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study has revealed insights into neurogenic OH and cardiovascular autonomic failure in MSA and PD with clinically relevant implications. In most patients with MSA and PD, nOH does not occur in isolation, but in the context of more generalised impairment of other autonomic reflexes, in keeping with more widespread cardiovascular autonomic failure. Furthermore, our results confirm previous studies showing nOH contributes significantly to functional disability in PD and MSA.\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn a subgroup of patients emerging autonomic cardiovascular dysfunction might be present in the absence of overt nOH as illustrated by case 2 (Box1). NOH was associated with cutaneous adrenergic denervation, with significant correlations between the severity of nOH, cutaneous adrenergic denervation, patient reported symptoms, and Hoehn-Yahr grade, in both MSA and PD. To our knowledge, this is the first study demonstrating an association between cutaneous adrenergic denervation and orthostatic hypotension in PD and MSA. While cutaneous adrenergic denervation is unlikely to contribute significantly to impairment of systemic blood pressure regulation, we hypothesize that it may reflect more widespread peripheral adrenergic denervation. In healthy individuals, a series of central and peripheral autonomic networks are activated to maintain blood pressure and organ perfusion on orthostasis. In MSA, the underlying pathophysiology of neurogenic orthostatic hypotension has previously been thought to be predominantly through dysfunction of central autonomic networks, in contrast to dysfunction of peripheral postganglionic autonomic nerves in PD. Our study suggests postganglionic adrenergic denervation may contribute to the pathophysiology of nOH in patients with MSA as well as patients with PD, with potential impact on responses to therapeutic agents.\u003c/p\u003e \u003cp\u003eWe found a reduction in cutaneous adrenergic pilomotor innervation in patients with nOH compared to healthy controls, with no significant differences between the MSA with nOH and PD with nOH subgroups on post-hoc analysis. Our results are in keeping with a previous study by Gibbons et al, who compared the cutaneous innervation of 28 patients with PD with and without autonomic failure to 23 healthy controls and found patients with autonomic failure had reduced pilomotor and sudomotor innervation compared to controls. Our results may appear to contradict Donadio et al\u0026rsquo;s study that reported predominantly somatic fibre involvement with preserved autonomic innervation in MSA-P and more prominent autonomic denervation in PD with nOH.\u003csup\u003e27\u003c/sup\u003e However, closer analysis of the supplementary data from their study shows intraepidermal and sudomotor innervation at the distal leg was reduced in both MSA-P and PD\u0026thinsp;+\u0026thinsp;nOH patients compared to controls, with pilomotor innervation reduced in PD\u0026thinsp;+\u0026thinsp;nOH compared to both MSA-P and controls. Our cohort of patients with PD was significantly younger than theirs (median 65 [IQR 58\u0026ndash;74] years compared to mean 74\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 6.7 years) and we studied autonomic innervation using pan-neuronal, cholinergic, and adrenergic specific markers, so the studies are not directly comparable.\u003c/p\u003e \u003cp\u003ePost mortem studies have shown a loss of sympathetic preganglionic cells in the intermediolateral cell column of the thoracolumbar spinal cord in PD and MSA patients with autonomic failure compared to patients without autonomic failure and normal controls, \u003csup\u003e28\u003c/sup\u003e but a loss of postganglionic cardiac adrenergic fibres in PD patients only.\u003csup\u003e29\u003c/sup\u003e In vivo cardiac scintigraphy studies have also demonstrated cardiac uptake of noradrenaline analogues tends to be spared in MSA compared to PD,\u003csup\u003e4, 30, 31\u003c/sup\u003e although these studies do not always reliably distinguish between individuals with MSA and PD.\u003csup\u003e5, 32\u003c/sup\u003e The differences in noradrenergic innervation at other bodily sites as assessed by \u003csup\u003e18\u003c/sup\u003eF-dopamine positron emission topographic scans and postmortem neurochemical data suggests that the difference between patients with Lewy body synucleinopathies, including patients with PD, and MSA is cardioselective; and there were no differences between norepinephrine levels in the sympathetic ganglia and a number of other organs studied.\u003csup\u003e33\u003c/sup\u003e In our study, cardiovascular autonomic testing did not differ significantly between MSA with nOH and PD with nOH subgroups, in agreement with previous reports,\u003csup\u003e5, 34\u003c/sup\u003e suggesting that cardiovascular autonomic testing on its own cannot reliably distinguish between patients with MSA with nOH and PD with nOH. Interestingly, while there were no significant subgroup differences, the MSA with nOH patients had the most severe nOH with standing and diminished blood pressure response to isometric exercise, whereas the PD with nOH patients had the most diminished heart rate response to isometric exercise and lowest Valsalva ratio, perhaps reflecting greater cardiac adrenergic denervation.\u003c/p\u003e \u003cp\u003eIn our study, supine noradrenaline levels were significantly higher in MSA vs PD with nOH subgroups, in keeping with previous studies,\u003csup\u003e35, 36\u003c/sup\u003e and in fact, supine noradrenaline was the only biomarker to differ significantly amongst the MSA and PD with nOH subgroups. The relationship between plasma noradrenaline levels and sympathetic innervation and activity is complex, and resting plasma supine noradrenaline levels are likely to reflect both production from postganglionic pre-synaptic terminals, cellular reuptake, metabolism and storage. Peripheral adrenergic denervation is likely to contribute to abnormal responses to physiological and pharmacological stimuli, including novel therapeutic agents for nOH that aim to enhance availability of noradrenaline.\u003csup\u003e37\u0026ndash;41\u003c/sup\u003e Previous studies using surrogate markers of postganglionic autonomic denervation to try predict responses to novel agents for nOH have generated conflicting results. Palma et al\u0026rsquo;s study of 20 patients with nOH found supine noradrenaline levels predicted pressor response to droxidopa, a pro-drug of noradrenaline, whereas Shibao at al\u0026rsquo;s larger study of 99 patients with nOH found neither plasma noradrenaline nor cardiac innervation on MIBG were good predictors for response to noradrenaline reuptake inhibitor atomoxetine.\u003csup\u003e38, 40\u003c/sup\u003e In our study, plasma noradrenaline did not correlate with cutaneous adrenergic innervation, suggesting it may be oversimplistic to use plasma noradrenaline as a single biomarker to estimate global postganglionic adrenergic denervation.\u003c/p\u003e \u003cp\u003eIn this exploratory multicentre study, we chose to study 3-mm skin distal leg biopsies, for which there is excellent safety data previously reported, with no serious side effects reported in over 35000 biopsies performed over 15 years across 10 laboratories.\u003csup\u003e24\u003c/sup\u003e We chose to quantify cutaneous sudomotor and pilomotor autonomic innervation as our group and others have previously established and validated methods to quantify innervation to these autonomic adnexa.\u003csup\u003e24, 25, 42\u003c/sup\u003e The variability and complexity of cutaneous vasculature and its innervation has limited previous attempts to quantify vascular innervation. Sohn et al recently outlined a method of quantifying cutaneous vessel innervation in 20 diabetic patients and 19 controls, and had similar findings to our study, showing individuals with nOH had lower vascular innervation than those without nOH, with significant correlations between neurovascular density and cardiovascular autonomic biomarkers, including blood pressure drop during head-up tilt and blood pressure overshoot on phase IV of the Valsalva manoeuvre, and autonomic symptom scores.\u003csup\u003e43\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne of the strengths of our study is that patients were systematically assessed with combination of cardiovascular, sudomotor and morphology testing and with good correlations seen between functional study and patient\u0026rsquo;s outcome measures.\u003c/p\u003e \u003cp\u003eOne of the limitations of our study is that none of the patients underwent post-mortem to confirm the clinical diagnosis, and there is overlap between the clinical criteria of MSA and PD with nOH. Nevertheless, all patients were assessed by neurologists with movement disorders and autonomic expertise and followed up for two years from initial recruitment, with exclusion of subjects who had an alternative clinical diagnosis on follow up.\u003c/p\u003e \u003cp\u003eIn summary, in our cohort of patients with PD and MSA, nOH was associated with cutaneous adrenergic denervation, with significant corelations between severity of nOH, cutaneous adrenergic denervation, patient reported symptoms and Hoehn-Yahr grade. Postganglionic autonomic denervation may contribute to the pathophysiology of nOH and autonomic failure in both PD and MSA and might influence response to therapeutic agents for nOH.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eThe authors are grateful to Laura Watson and Scott Johnstone from the Autonomic Unit at the National Hospital for Neurology and Neurosurgery for their assistance in the analysis of plasma catecholamine levels and cardiovascular autonomic data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor Roles\u003c/p\u003e\n\u003cp\u003eSK: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data\u003c/p\u003e\n\u003cp\u003eVP: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data\u003c/p\u003e\n\u003cp\u003eEV: Drafting/revision of the manuscript for content, including medical writing for content; Analysis or interpretation of data\u003c/p\u003e\n\u003cp\u003eGC: Major role in the acquisition of data; Analysis or interpretation of data\u003c/p\u003e\n\u003cp\u003eFV: Major role in the acquisition of data\u003c/p\u003e\n\u003cp\u003eAS: Major role in the acquisition of data\u003c/p\u003e\n\u003cp\u003eIB: Major role in the acquisition of data\u003c/p\u003e\n\u003cp\u003eFM: Drafting/revision of the manuscript for content, including medical writing for content\u003c/p\u003e\n\u003cp\u003eLS: Drafting/revision of the manuscript for content, including medical writing for content\u003c/p\u003e\n\u003cp\u003eMN: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data\u003c/p\u003e\n\u003cp\u003eVI: Drafting/revision of the manuscript for content, including medical writing for content; Major role in the acquisition of data; Study concept or design; Analysis or interpretation of data\u003c/p\u003e\n\u003ch3\u003eFunding Sources\u003c/h3\u003e\n\u003cp\u003eThis study was financed by Italian Ministry of Health \u0026ldquo;Ricerca Finalizzata 2013\u0026rdquo; \u0026ndash; project code PE-2013-02359028. Dr S Koay was supported by the Guarantors of Brain Entry Fellowship. Dr V Iodice is supported by National Institute for Health Research University College London Hospitals Biomedical Research Centre.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eFull Financial Disclosures of all Authors for the Past Year: \u003c/h3\u003e\n\u003cp\u003eDr F Manganelli has received honoraria from Sobi, Alnylam, Pfizer and Csl Behring. The other authors have no financial disclosures to declare. Dr V Iodice has received honoraria from Theravance Biopharma\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003ePotential conflicts of Interest\u003c/h3\u003e\n\u003cp\u003eThe authors have no potential conflicts of interest to declare relevant to the research in the submitted manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBannister R, Iodice V, Vichayanrat E, Mathias CJ (2013) Clinical features and evaluation of the primary autonomic failure syndromes. In: Bannister R, Mathias CJ (eds) Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford University Press\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLow PA, Reich SG, Jankovic J et al (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710\u0026ndash;719\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Pablo-Fernandez E, Tur C, Revesz T, Lees AJ, Holton JL, Warner TT (2017) Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease. JAMA Neurol 74:970\u0026ndash;976\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696\u0026ndash;702\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLipp A, Sandroni P, Ahlskog JE et al (2009) Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch Neurol 66:742\u0026ndash;750\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProvitera V, Nolano M, Caporaso G et al (2014) Postganglionic sudomotor denervation in patients with multiple system atrophy. Neurology 82:2223\u0026ndash;2229\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProvitera V, Iodice V, Manganelli F et al (2022) Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease: A Morpho-functional Study. Neurology\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiley DE, Chelimsky TC (2003) Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson\u0026rsquo;s disease. J Neurol Neurosurg Psychiatry 74:56\u0026ndash;60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoon EA, Fealey RD, Sletten DM et al (2017) Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction. Mov Disord 32:397\u0026ndash;404\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePostuma RB, Berg D, Stern M et al (2015) MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 30:1591\u0026ndash;1601\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670\u0026ndash;676\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf 42:377\u0026ndash;381\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Minor BL et al (2019) The REDCap consortium: Building an international community of software platform partners. J Biomed Inf 95:103208\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17:427\u0026ndash;442\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBakkers M, Merkies IS, Lauria G et al (2009) Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 73:1142\u0026ndash;1148\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSletten DM, Suarez GA, Low PA, Mandrekar J, Singer W (2012) COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc 87:1196\u0026ndash;1201\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheshire WP, Freeman R, Gibbons CH et al (2021) Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology. Clin Neurophysiol 132:666\u0026ndash;682\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeurology TCCotAASatAAo (1996) Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 46:1470\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNorcliffe-Kaufmann L, Kaufmann H, Palma JA et al (2018) Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 83:522\u0026ndash;531\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNorcliffe-Kaufmann L, Palma JA, Kaufmann H (2018) A validated test for neurogenic orthostatic hypotension at the bedside. Ann Neurol 84:959\u0026ndash;960\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathias C, Low DA, Iodice V, Vichayanrat E, Bannister R (2013) Investigation of autonomic disorders. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edn. Oxford University Press, Oxford, pp 259\u0026ndash;289\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProvitera V, Nolano M, Caporaso G, Stancanelli A, Santoro L, Kennedy WR (2010) Evaluation of sudomotor function in diabetes using the dynamic sweat test. Neurology 74:50\u0026ndash;56\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNolano M, Provitera V, Estraneo A et al (2008) Sensory deficit in Parkinson's disease: evidence of a cutaneous denervation. Brain 131:1903\u0026ndash;1911\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLauria G, Hsieh ST, Johansson O et al (2010) European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 17:903\u0026ndash;912 e944-909\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNolano M, Provitera V, Caporaso G, Stancanelli A, Vitale DF, Santoro L (2010) Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. Neurology 75:1089\u0026ndash;1097\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNolano M, Caporaso G, Manganelli F et al (2022) Phosphorylated alpha-Synuclein Deposits in Cutaneous Nerves of Early Parkinsonism. J Parkinsons Dis 12:2453\u0026ndash;2468\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonadio V, Incensi A, Rizzo G et al (2020) Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson's Disease with Orthostatic Hypotension. Mov Disord\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOppenheimer DR (1980) Lateral horn cells in progressive autonomic failure. J Neurol Sci 46:393\u0026ndash;404\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrimo S, Uchihara T, Nakamura A et al (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease. Brain 131:642\u0026ndash;650\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLenka A, Lamotte G, Goldstein DS (2021) Cardiac (18)F-Dopamine PET Distinguishes PD with Orthostatic Hypotension from Parkinsonian MSA. Mov Disord Clin Pract 8:582\u0026ndash;586\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBraune S, Reinhardt M, Schnitzer R, Riedel A, Lucking CH (1999) Cardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy. Neurology 53:1020\u0026ndash;1025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkowronek C, Zange L, Lipp A (2019) Cardiac 123I-MIBG Scintigraphy in Neurodegenerative Parkinson Syndromes: Performance and Pitfalls in Clinical Practice. Front Neurol 10:152\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLamotte G, Holmes C, Sullivan P, Lenka A, Goldstein DS (2020) Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies. Ann Clin Transl Neurol 7:2450\u0026ndash;2460\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeys F, Fanciulli A, Ndayisaba JP, Granata R, Struhal W, Wenning GK (2020) Cardiovascular autonomic function testing in multiple system atrophy and Parkinson's disease: an expert-based blinded evaluation. Clin Auton Res 30:255\u0026ndash;263\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolinsky R, Kopin I, Ebert M, Weise V (1981) Pharmacologic distinction different orthostatic hypotension Syndr Neurol 31:1\u0026ndash;7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldstein D, Polinsky R, Garty M et al (1989) Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 26:558\u0026ndash;563\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkamoto LE, Shibao CA, Gamboa A et al (2019) Synergistic Pressor Effect of Atomoxetine and Pyridostigmine in Patients With Neurogenic Orthostatic Hypotension. Hypertension. ;73:235\u0026ndash;241\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShibao CA, Palma JA, Celedonio JE, Martinez J, Kaufmann H, Biaggioni I (2021) Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension. Hypertension 78:525\u0026ndash;531\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShibao C, Raj SR, Gamboa A et al (2007) Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension 50:47\u0026ndash;53\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalma JA, Norcliffe-Kaufmann L, Martinez J, Kaufmann H (2018) Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension. Neurology 91:e1539\u0026ndash;e1544\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaufmann H, Vickery R, Wang W et al (2021) Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial. Clin Auton Res 31:699\u0026ndash;711\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGibbons CH, Illigens BM, Wang N, Freeman R (2010) Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve 42:112\u0026ndash;119\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSohn E, Suh BC, Wang N, Freeman R, Gibbons CH (2020) A novel method to quantify cutaneous vascular innervation. Muscle Nerve 62:492\u0026ndash;501\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"orthostatic hypotension, autonomic failure, Parkinson’s Disease, Multiple System Atrophy, punch skin biopsy","lastPublishedDoi":"10.21203/rs.3.rs-4405619/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4405619/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eCardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling in Parkinson’s disease (PD) and multiple system atrophy (MSA). Recent studies have shown evidence of postganglionic denervation in MSA as well as PD.\u003c/p\u003e\n\u003cp\u003eObjectives\u003c/p\u003e\n\u003cp\u003eTo characterise the relationship between nOH, autonomic failure and markers of postganglionic denervation in PD and MSA.\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eWe assessed 57 patients (37 PD, 20 MSA, 18 females, median 64[IQR 59-70] years) with autonomic cardiovascular testing, plasma noradrenaline levels, dynamic sweat testing, skin biopsies for quantification of intraepidermal, pilomotor and sudomotor innervation and COMPASS-31 autonomic symptom questionnaires.\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003e78% with MSA and 36% with PD had nOH≥ 20/10mmHg. Overall, compared to patients without nOH, patients with nOH demonstrated greater 1) cardiovascular autonomic failure, with significantly reduced responses to isometric exercise, deep breathing and Valsalva ratio, 2) intraepidermal, pilomotor and sudomotor denervation, 3) autonomic symptoms and Hoehn-Yahr grade. Quantitative cardiovascular biomarkers including nOH severity correlated with autonomic denervation, patient symptoms and Hoehn-Yahr grade (ρ≥0.50).\u003c/p\u003e\n\u003cp\u003eCompared to PD, MSA patients had worse nOH, pressor responses to isometric exercise, sudomotor dysfunction and cutaneous denervation, with higher supine noradrenaline, but subgroup analysis showed only supine noradrenaline differed significantly between MSA and PD with nOH subgroups (\u003cem\u003eP\u003c/em\u003e=.04).\u003c/p\u003e\n\u003cp\u003eConclusions\u003c/p\u003e\n\u003cp\u003eNOH was associated with cutaneous denervation in both PD and MSA, with significant correlations between quantitative cardiovascular autonomic biomarkers, cutaneous denervation, and Hoehn-Yahr grade. Postganglionic denervation may contribute to autonomic failure in PD and MSA and affect responses to therapeutic agents for nOH.\u003c/p\u003e","manuscriptTitle":"Cardiovascular autonomic failure correlates with cutaneous autonomic devervation in PD and MSA","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 21:50:42","doi":"10.21203/rs.3.rs-4405619/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-05-31T13:07:29+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-20T11:44:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-14T11:39:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2024-05-13T12:07:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d84d7d3a-70ca-4e31-918d-751eb749449f","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-15T15:58:52+00:00","versionOfRecord":{"articleIdentity":"rs-4405619","link":"https://doi.org/10.1007/s10286-025-01154-4","journal":{"identity":"clinical-autonomic-research","isVorOnly":false,"title":"Clinical Autonomic Research"},"publishedOn":"2025-09-12 15:57:09","publishedOnDateReadable":"September 12th, 2025"},"versionCreatedAt":"2024-06-04 21:50:42","video":"","vorDoi":"10.1007/s10286-025-01154-4","vorDoiUrl":"https://doi.org/10.1007/s10286-025-01154-4","workflowStages":[]},"version":"v1","identity":"rs-4405619","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4405619","identity":"rs-4405619","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}