The Effects of Multimodal Exercise on Sleep Quality and Architecture, Motor Function, Cognition, Fatigue, and Systemic Inflammation in Corticobasal Syndrome: A Case Report.

The Effects of Multimodal Exercise on Sleep Quality and Architecture, Motor Function, Cognition, Fatigue, and Systemic Inflammation in Corticobasal Syndrome: A Case Report. | 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 Case Report The Effects of Multimodal Exercise on Sleep Quality and Architecture, Motor Function, Cognition, Fatigue, and Systemic Inflammation in Corticobasal Syndrome: A Case Report. Jacopo Cristini, Freddie Seo, Ashanté Bon, Lynden Rodrigues, Kira Sikorska, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6696024/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Oct, 2025 Read the published version in Physical Therapy → Version 1 posted You are reading this latest preprint version Abstract Importance. Corticobasal syndrome (CBS) is a rare tauopathy, with a complex pathophysiology that usually includes neuroinflammation. Parkinsonism, cognitive impairments, and sleep disturbances are common in CBS, although alterations in sleep architecture remain poorly characterized. Regular exercise has been recommended in CBS to manage gait dysfunction, balance issues, and cognitive decline. However, to our knowledge, no studies examined the effects of regular exercise on sleep quality, sleep architecture and systemic inflammation in CBS. Objective. To describe the effects of a 12-week training program in CBS. Methods. An individual with CBS “On” antiparkinsonian medications was assessed before and after a 12-week multimodal training program. Cardiorespiratory fitness level (V̇O2peak) was assessed with a symptom-limited cardiopulmonary exercise test and strength with a sub-maximal 1-RM test. Subjective and objective sleep quality were assessed using the Parkinson’s Disease (PD) Sleep Scale-2 and actigraphy, respectively. Sleep architecture was evaluated with polysomnography. Cognition and motor function were assessed with the Scale for Outcomes in PD-Cognition (SCOPA-COG) and MDS-UPDRS-III, respectively. Fatigue was assessed with the PD Fatigue Scale. Concentrations of inflammatory cytokines interleukin (IL)1β, IL6, IL10, tumor necrosis factor (TNF)α, and C-reactive protein (CRP) were measured from serum collected after a 12-hour fasting period. Results. Following the training program (34 sessions; 25.35 hours), we observed improvements in fitness, objective sleep quality and architecture, cognition and a reduction in systemic inflammation. Conversely, motor function deteriorated, and the participant reported diminished subjective sleep quality and increased fatigue. Conclusions. Our results suggest that exercise may improve specific clinical outcomes in CBS. However, it had no positive effects on motor signs, subjective sleep quality and fatigue, which worsened. Controlled studies are warranted to confirm and expand our observations. Impact. To our knowledge, this is the first case report describing the effects of a training program on sleep architecture and systemic inflammation in CBS. Corticobasal syndrome Sleep architecture Cognition Motor function Regular Exercise. Figures Figure 1 Introduction Corticobasal syndrome (CBS) is a rare Parkinsonian disorder that belongs to the group of tauopathies, in which neuroinflammation contributes to its pathophysiology[ 1 – 3 ]. CBS is characterized by marked asymmetry, rigidity, dystonia and apraxia, as well as cortical sensory and cognitive deficits[ 2 , 4 ]. Sleep quality and architecture (i.e., the fundamental structure of normal sleep and the cyclical pattern of its various stages) are also affected in CBS; however, these aspects have not been extensively investigated. Small sample studies and case series have shown that sleep disorders, such as insomnia, restless leg syndrome, periodic limb movements, and sleep-wake cycle disturbances are common in CBS[ 5 – 10 ]. Additionally, alterations in sleep quality and architecture in these patients include reductions in total sleep time, sleep efficiency, non-rapid eye movement (NREM) and REM sleep[ 5 , 7 , 10 ]. To our knowledge, no studies have quantified alterations in micro-sleep architecture (i.e., transient, dynamic events and rhythms in neural electrical activity that occur within and across sleep stages) in CBS or examined whether sleep alterations may be linked to cognitive and motor decline, as seen in other neurodegenerative disorders[ 11 , 12 ]. Finally, little evidence exists regarding blood markers of systemic inflammation in CBS, despite the important contribution of (neuro)inflammation to tau pathophysiology. More importantly, consistent evidence indicates that both regular exercise[ 13 ] and sleep quality[ 14 ] can positively influence systemic inflammation in different (clinical) populations. Based on results from case reports in CBS[ 15 – 18 ] and other tauopathies[ 19 ], exercise has been recommended as an important component to counter gait and balance disturbances as well as cognitive deterioration. Moreover, exercise can enhance sleep quality and architecture in conditions with pathophysiological similarities to CBS, such as Parkinson's (PD) and Alzheimer's disease (AD), with multimodal training approaches potentially inducing the largest benefits[ 20 – 22 ]. Therefore, evidence that can confirm and expand previously reported cross-sectional findings and longitudinal changes following regular exercise in this rare condition has important clinical implications. Here, we present a case report describing baseline and longitudinal changes in sleep quality, sleep architecture, cognition, motor function, fatigue and markers of systemic inflammation in an individual with CBS following 12 weeks of multimodal training. Methods Research ethic approval was granted by the Comité d’Éthique de la Recherche (CÉR) CISSS de Laval (Project number: MP-50-2022-1584). This case report is reported following the CARE guidelines[ 23 ]. Role of the Funding Source The funders played no role in the design, conduct, or reporting of this study. Case Description and Examination One male individual who was initially diagnosed with PD and subsequently re-diagnosed with CBS (Table 1 ) gave informed consent to participate in the study. The participant was evaluated on anti-parkinsonian medications at the same time of the day (~ 1 hour) at baseline (T0) and after 12 weeks of multimodal training (T1). The evaluations were conducted over two days, separated by approximately seven days at both time points. Blinded assessors conducted motor and cognitive evaluations (see below). The participant did not change medications during the study period. Table 1 Characteristics of the participant at baseline and post-training changes. Baseline (T0) Post-Intervention (T1) Changes Age 50.3 years Weight (BMI) 72.3 kg (23.1 kg/m 2 ) 68.2 kg (21.8 kg/m 2 ) -4.1 kg Disease duration 0.5 year Levodopa equivalent daily doses 600 mg 600 mg No change Pro oxazepam 15 mg 15 mg No change MDS-UPDRS III 31 42 + 11 (deterioration) • Rigidity 9 12 + 3 (deterioration) • Tremor 4 9 + 5 (deterioration) • Bradykinesia 18 19 + 1 (deterioration) • Axial 0 2 + 2 (deterioration) SCOPA-COG 25 34 + 9 (improvement) • Memory and learning 11 16 + 5 (improvement) • Attention 4 4 No change • Executive functions 0 9 + 9 (improvement) • Visuospatial functions 10 5 -5 (deterioration) RBDSQ-1 Item 0 0 No change PDSS-2 10 15 + 5 (deterioration) BDI-2 11 14 + 3 (deterioration) PD Fatigue Scale 2.38 3.00 + 0.62 (deterioration) CPET • Test duration 12:00 min 14:00 min + 2:00 min • V̇O2peak 30.9 ml*kg − 1 *min − 1 31.7 ml*kg − 1 *min − 1 + 0.8 ml*kg − 1 *min − 1 • Peak power output (W/kg) 155 W (2.14 W/kg) 165 W (2.42 W/kg) + 10 W (+ 0.28 W/kg) • Heart rate max (bpm) 159 bpm 163 bpm + 4 bpm • Rate of perceive exertion 7/10 9/10 Sub-maximal 1-RM test • Leg extension 58.4 kg 100 kg + 41.6 kg • Chest press 76.4 kg 90.7 kg + 14.3 kg • Lat machine 94.1 kg 100 kg + 5.9 kg • Leg curl 67.1 kg NA Inflammatory biomarkers • IL1β 0.52 pg/ml 0.51 pg/ml -0.01 pg/ml • IL6 NA Δ 2.13 pg/ml NA • IL10 2.07 pg/ml 7.12 pg/ml + 5.05 pg/ml • TNFα 13.46 pg/ml 12.58 pg/ml -0.88 pg/ml • CRP 4972.84 ng/ml 4761.86 ng/ml -210.98 ng/ml Footnote : Δ = value lower than standard curve; BDI-2 = Beck Depression Inventory – 2; CPET = cardiopulmonary exercise testing; NA = not applicable; RBDSQ-1 = The REM sleep behavior disorder screening questionnaire – 1 item. *Table 1 should be placed here Therapeutic intervention The multimodal training combined resistance and cardiovascular training and was conducted at moderate to vigorous intensities for ~ 45 minutes, 3 times per week, over a 12-week period. Resistance training targeted large muscle groups (i.e., chest, back, quadriceps, and hamstrings) and was performed with resistance machines. Cardiovascular training was performed on a total body recumbent stepper, involving the upper and lower extremities. Each training session included five minutes of warm-up, followed by resistance training, cardiovascular training, and five minutes of cool-down. Training intensity and progression were tailored to the participant’s fitness level (see below). A detailed description of the intervention is reported elsewhere[ 24 ]. Outcomes measures Functional fitness measures Cardiorespiratory fitness level (V̇O 2peak ) and muscle strength were assessed with a symptom-limit cardiopulmonary exercise test (CPET; Quark CPET, Cosmed Srl, Italy) on a recumbent stepper and a sub-maximal 1-RM test, respectively. A detailed description of the functional fitness measures is reported elsewhere[24]. Sleep quality and architecture Sleep quality was assessed subjectively with the PD Sleep Scale-2 (PDSS-2) and objectively through actigraphy (Actiwatch Spectrum Plus; Philips Respironics, Bend, USA) worn on the non-dominant wrist for ~ 7 days, during which the participant also completed a sleep diary. Actiware software (v6.3; Philips Respironics, Bend, USA) was implemented to automatically score the recording using an activity count threshold of 20, a minimum of 10 minutes of immobility, and rest durations of ≥ 30 minutes for major sleep bouts and ≥ 15 minutes for minor sleep bouts (up to 75 minutes)[ 25 ]. Subsequently, all recordings were visually inspected, and the onset and offset of rest periods were cross-checked against the sleep diary. It should also be noted that actigraphy was used to monitor sleep patterns during the days preceding the overnight sleep evaluation conducted at our facilities. During this overnight evaluation, sleep architecture was assessed with polysomnography (Grael v2, Compumedics Limited, Abbotsford, Victoria, Australia). Specifically, electroencephalography (EEG) was conducted using a standard montage (10–20 international system) with frontal (F3-M2, F4-M1), central (C3-M2, C4-M1), parietal (P3-M2, P4-M1), and occipital (O1-M2, O2-M1) electrodes referenced to the mastoids. Electro-oculography and electromyography for chin muscle tone and tibialis anterior muscle were also collected. Signals were digitized at a sampling rate of 256 Hz (Profusion Sleep version 5, Compumedics Limited). An expert sleep technician, blinded to the study, manually scored the sleep recordings following AASM guidelines using 30-second epochs[ 26 ]. Artifacts were detected by an automatic algorithm[ 27 ] and visually verified. In addition to macro-sleep architecture parameters, micro-sleep architecture (i.e., sleep slow wave and spindle features) was examined during artifact-free NREM sleep stages 2–3 using Snooz Toolbox[ 27 ]. The same toolbox was implemented to conduct EEG power spectral analysis of low-frequency slow waves (≤ 4 Hz), slow oscillation (< 1 Hz) and delta waves (1–4 Hz) throughout the sleep cycles. Sleep outcomes and methodologies implemented to analyze the EEG signal can be found in Supplemental materials 1 & 2 . Cognition, motor function and fatigue Cognition and motor function were assessed with the Scale for Outcomes in PD-Cognition (SCOPA-COG)[ 28 ] and Movement Disorders Society Unified PD Rating Scale part III (MDS-UPDRS III)[ 29 ], respectively. Fatigue was assessed with the PD Fatigue Scale[ 30 , 31 ]. Systemic inflammation The concentrations of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)α, and C-reactive protein (CRP) were measured from serum collected in the morning after a 12-hour fasting period. Blood samples were collected using a Vacutainer serum separator tube, allowed to clot for one hour at room temperature, cooled at ~ 4°C for 30 minutes, and centrifuged at 2200g for 15 minutes. The resulting sera were aliquoted into 250 µL cryovials, stored at -80°C (Thermo Fisher Scientific, Waltham, USA), and analyzed using Millipore Sigma kits (HSCTMAG-28SK and HCVD3MAG-67K). Results The participant completed all the evaluations and 34 training sessions (total training time: 25h 21min; average rate of perceived exertion during training = 16/20) without experiencing any adverse events. Tables 1 and 2 show baseline and post-training outcomes. After the exercise program, cardiorespiratory fitness level (+ 0.8 ml*kg − 1 *min − 1 ) and sub-maximal strength (Table 1 ) improved. The participant reported a subjective reduction in sleep quality ( PDSS-2 : 10/60 to 15/60) post intervention. Despite this reduction in subjective sleep quality, actigraphy and polysomnography showed improvements in several sleep outcomes after the exercise program (Table 2 a). That is, actigraphy results showed an improvement in total sleep time (383.4 ± 65.0 to 433.3 ± 82.3 min), sleep efficiency (81.8 ± 9.7 to 90.6 ± 3.9%) and sleep onset latency (16.6 ± 16.4 to 2.5 ± 4.1 min). Additionally, they showed that there was a reduction in daily activity counts (222.9 ± 38.8 AC/min to107.5 ± 60.1 AC/min), suggesting a reduction in daily physical activity levels post-treatment. This reduction in physical activity levels might partially be explained by changes in physical activity associated with seasonal temperature changes[ 32 ], as the baseline and post-exercise evaluations took place in July (average 23.6℃) and November (average 4.9℃;), respectively. Table 2 a. Actigraphy and macro-sleep architecture outcomes at baseline and after 12 weeks of training. Actigraphy Baseline (T0) Post-Intervention (T1) Nights recorded 9 6 TST (avg ± sd) 383.4 ± 65.0 min 433.3 ± 82.3 min WASO (avg ± sd) 31.3 ± 13.1 min 29.4 ± 14.7 min SOL (avg ± sd) 16.6 ± 16.4 min 2.5 ± 4.1 min Sleep efficiency (avg ± sd) 81.8 ± 9.7% 90.6 ± 3.9% Sleep fragmentation (avg ± sd) 5.8 ± 5.7% 6.5 ± 3.2% Daily Activity Count (avg ± sd) 222.9 ± 38.8 AC/min 107.5 ± 60.1 AC/min Polysomnography: Sleep architecture Baseline Post-Intervention TIB 271 min 487.5 min TST 193 min 461 min Sleep efficiency 71.2% 94.6% SOL 33 min 9 min REM latency 167 min 158 min WASO 78 min 26.5 min N1 (min) 8.5 min 17 min N2 (min) 162 min 334.5 min N3 (min) 3.5 min 4.5 min NREM (min) 174 min 356 min REM (min) 19 min 105 min Wake (%) 28.8% 5.4% N1 (%) 4.4% 3.7% N2 (%) 83.9% 72.6% N3 (%) 1.8% 1.0% NREM (%) 90.2% 77.2% REM (%) 9.8% 22.8% Footnote: SOL = sleep onset latency; TIB = time in bed; TST = total sleep time; WASO = wake after sleep onset. *Table 2 a should be placed here Table 2 b. Slow waves and spindle features at baseline and after 12 weeks of training. Slow waves and spindle features Baseline Post-Intervention Slow wave (count) Frontal: 1846 count Central: 1008 count Parietal: 373 count Total: 3234 count Frontal: 1407 count Central: 628 count Parietal: 215 count Total: 2259 count Slow wave density (count/min) Frontal: 5.6 count/min Central: 3.0 count/min Parietal: 1.1 count/min Total: 2.8 count/min Frontal: 2.1 count/min Central: 0.9 count/min Parietal: 0.3 count/min Total: 1.0 count/min Slow wave amplitude (µV) Frontal: 102.3 µV Central: 98.8 µV Parietal: 93.4 µV Total: 96.3 µV Frontal: 100.2 µV Central: 96.3 µV Parietal: 91.1 µV Total: 94.5 µV Slow wave slope (min-to-max; µV/sec) Frontal: 358.2 µV/sec Central: 356.8 µV/sec Parietal: 306.8 µV/sec Total: 319.9µV/sec Frontal: 271.6 µV/sec Central: 246.8 µV/sec Parietal: 202.6 µV/sec Total: 224.5 µV/sec Slow wave frequency (Hz) Frontal: 1.4 Hz Central: 1.5 Hz Parietal: 1.3 Hz Total: 1.3 Hz Frontal: 1.1 Hz Central: 1.0 Hz Parietal: 0.9 Hz Total: 1.0 Hz Slow wave transition frequency (Hz) Frontal: 1.7 Hz Central: 1.8 Hz Parietal: 1.6 Hz Total: 1.6 Hz Frontal: 1.4 Hz Central: 1.3 Hz Parietal: 1.1 Hz Total: 1.2 Hz Spindle (count) Frontal: 513 count Central: 171 count Parietal: 77 count Total: 770 count Frontal: 2720 count Central: 1777 count Parietal: 1279 count Total: 5927 count Spindle density (count/min) Frontal: 1.6 count/min Central: 0.5 count/min Parietal: 0.2 count/min Total: 0.6 count/min Frontal: 4.0 count/min Central: 2.6 count/min Parietal: 1.9 count/min Total: 2.2 count/min Spindle amplitude (µV) Frontal: 29.9 µV Central: 25.9 µV Parietal: 24.0 µV Total: 25.9 µV Frontal: 30.2 µV Central: 25.4 µV Parietal: 23.0 µV Total: 24.7 µV Spindle frequency (Hz) Frontal: 12.5 Hz Central: 12.7 Hz Parietal: 13.4 Hz Total: 13.0 Hz Frontal: 12.6 Hz Central: 13.1 Hz Parietal: 13.6 Hz Total: 13.1 Hz *Table 2 b should be placed here Consistent with the actigraphy results, polysomnography results showed an increase in total sleep time (195.0 to 462.5 min), sleep efficiency (71.2 to 94.6%), N2 (162 to 334.5 min), REM (19 to 105 min) and a reduction in sleep onset latency (33.0 to 9.0 min). Furthermore, while no major changes in N1% (4.4 to 3.7%) and N3% (1.8 to 1.0%) were found, there was a reduction in N2% (83.9 to 72.6%) and wake time (28.8 to 5.4%), as well as an increase in REM% (9.8 to 22.8%). It should be noted that sleep stage N3 was extremely short and did not change post-exercise (Table 2 a). Hypnograms can be found in Supplemental material 3 . Sleep spindles and slow wave features (i.e., micro-sleep architecture) are reported in Table 2 b, and power spectral analysis results are shown in Fig. 1 . Sleep spindle density increased (average across channels: 0.58 to 2.20 count/min) post-exercise. In contrast, slow wave density (average across channels: 2.8 to 1.0 count/min) as well as slow wave slope, frequency, and transition frequency decreased. These changes in slow waves indicate potential (post-exercise) modifications not only in slow wave density but also in morphology. Finally, there was an overall reduction in low-frequency slow wave power across sleep cycles post-exercise (Fig. 1 a). Importantly, however, this overall reduction was specific to delta wave power (Fig. 1 b) and did not occur for slow oscillation, whose power increased after exercise (Fig. 1 c). A similar power reduction was observed for fast delta waves power (2–4 Hz[ 33 ]; Supplemental material 4 ). *Figure 1 should be placed here Following the training program, an overall improvement in cognition ( SCOPA-COG : 25/43 to 34/43) was observed. However, the improvement was in memory/learning and executive functions domains while a worsening in visuospatial functions was detected. Conversely, the participant experienced a deterioration in motor signs ( MDS-UPDRS III : 31/132 to 42/132) and fatigue ( PD Fatigue Scale : 2.38/5 to 3/5). Finally, peripheral TNFα and CRP blood concentrations decreased, while IL10 increased post intervention (Table 1 ). Discussion The participant reported relatively good satisfaction with their subjective sleep perception at baseline. However, there were marked alterations in objective sleep quality and architecture, confirming previously observed sleep disturbances in CBS[ 5 , 7 , 9 , 10 ]. That is, our participant showed reduced sleep time and efficiency, NREM and REM sleep, and nearly absent N3 (i.e., slow wave sleep). Furthermore, we quantified important sleep slow wave and spindle density deteriorations, with values markedly lower than those reported in neurotypical adults[ 34 , 35 ] and, in case of sleep spindles, even lower than those reported in PD[ 36 , 37 ]. However, the deterioration of these neural oscillations was broadly comparable to that observed in other tauopathies, such as AD[ 12 ]. Notably, following the 12-week multimodal training program, we observed improvements in multiple sleep outcomes measured objectively both with actigraphy over several days in the participant’s home setting as well as with polysomnography. However, we cannot rule out the possibility that a first-night effect could have biased the polysomnography outcomes. These results suggest that our participant experienced a significant improvement in objective sleep quality, particularly in sleep efficiency[ 38 ], following the training program. Conversely, we observed a deterioration in self-reported subjective sleep quality post-exercise intervention. This deterioration is well above the minimal clinically important difference (MCID; 2.07 points) established for PD [ 39 ] and suggests a discrepancy between subjective and objective sleep measures. The reasons for the observed decline in subjective sleep quality remain unclear. Potential explanations include sleep misperception (already evident at baseline; PDSS-2 = 10/60), increased awareness/expectations following the intervention, a slight worsening of fatigue and depressive symptoms (Table 1 ), or a combination of these factors[ 40 – 44 ]. However, this discrepancy is not novel, it has been observed repeatedly in other (clinical) populations, and it underlies the importance of combining objective and subjective sleep measures to capture all the dimensions of sleep[ 20 , 21 , 45 ]. Additionally, it reinforces the notion that a combination of different interventions (e.g., exercise and sleep hygiene) might be required to improve all the dimensions of sleep[ 20 , 21 , 42 ]. In addition to improvements in objective sleep quality, we observed changes in features of micro-sleep architecture and low-frequency slow wave power. Specifically, sleep spindle density, which was particularly low at baseline[ 35 ], markedly increased following the training program, corroborating similar positive effects observed in PD after a comparable training intervention[ 46 ]. Notably, overall post-training sleep spindle density reached values typically observed in neurotypical adult individuals (i.e., ~ 2–3/min)[ 35 ]. It would be important to determine whether the observed increase in sleep spindle density is solely the results of longer sleep duration and time spent in sleep stage N2 during the second evaluation or linked to other mechanisms[ 35 , 47 ]. Conversely, we observed a reduction in slow wave count/density following the training program, suggesting that exercise was ineffective at increasing this specific sleep feature in our participant. It is also important to note that slow wave density was markedly low at baseline compared to previously published data from neurotypical adults in their middle age[ 34 ] but similar to what reported in PD[ 37 ]. These results expand prior research in CBS, suggesting an early disruption of slow waves and spindles presumably induced by neurodegeneration within sleep-regulatory brain structures observed in tauopathy[ 5 , 7 , 10 , 48 ]. Critically, regular exercise may improve some (i.e., spindles) of those relevant neural oscillations in CBS. The reduction in slow wave (count/density) was paralleled by a reduction in low-frequency slow waves power, particularly during the first two sleep cycles after the training program (Fig. 1 a). However, this reduction appeared to be specific to the delta power (Fig. 1 c) while slow oscillations power increased (Fig. 1 b), a finding that is consistent with the changes also observed in slow wave morphology (frequency/transition frequency; Table 2 b). Slow oscillations and delta waves are thought to be regulated and respond differently to homeostatic sleep pressure (i.e., the need for sleep accumulates with prolonged wakefulness and dissipates during sleep)[ 33 , 49 – 52 ]. Given that during the days leading up to the second polysomnography evaluation, the participant experienced a substantial improvement in objective sleep quality and a potential overall reduction in levels of physical activity measured with actigraphy (Table 1 ), one could speculate that an overall reduction in homeostatic sleep pressure might cause the reduction in (fast) delta power. In any event, the effects of regular exercise on those power frequencies and their clinical relevance in CBS need to be investigated further. At baseline, the participant scored 25 on the SCOPA-COG, which is slightly above the established cut-off (< 25) for identifying mild cognitive impairment in PD[ 53 ], indicating some cognitive dysfunction. Executive and visuospatial dysfunctions are early, key cognitive alterations that can be implemented as a criterion for diagnosing CBS[ 54 ]. Our longitudinal finding suggests that exercise, as observed in other neurodegenerative disorders[ 55 , 56 ], can ameliorate overall cognitive function in CBS[ 19 ]. However, a closer analysis indicates that the overall cognitive enhancement was domain-specific (i.e., executive function and memory/learning domains), while some aspects of cognition (i.e., visuospatial functions) kept deteriorating. It would be tempting to speculate that this overall cognitive improvement was linked to better sleep (e.g., sleep spindle density and slow oscillation power)[ 11 , 12 , 37 , 57 – 62 ]. Controlled studies are required to determine whether regular exercise improves specific cognitive domains in CBS and whether changes in sleep architecture mediate this positive effect[ 61 ]. We also observed increased fatigue and a marked deterioration in motor signs. The perceived increase in fatigue suggests that exercise is not always effective at improving this detrimental feature common in Parkinsonian syndromes[ 63 – 65 ] and could be related to the observed deterioration in other non-motor symptoms (i.e., subjective sleep quality and depression)[ 43 , 44 ]. Similarly, the motor decline, which was well above the MCID (4.63 points) to detect worsening in PD[ 66 ], indicates that exercise was ineffective. This finding contrasts with the positive effects of regular exercise on motor function in PD[ 67 , 68 ], and several concomitant factors could partially explain this deterioration. These may include the potential progression of the disease, poor response to levodopa in CBS, well-established limitations of the MDS-UPDRS III, and the type of training modality used[ 2 , 4 , 19 , 69 – 72 ]. It would also be crucial to determine whether this motor deterioration resulted from increased fatigue[ 43 , 44 ], which our intervention might have triggered. This hypothesis, however, contrasts with the fitness improvements observed after the training program, the fact that the intervention was tailored and progressive, and previous research findings in PD[ 73 ]. Another important contributor to the motor deterioration might be linked to the abnormal sleep architecture observed in our participant, who showed minimal, almost absent, N3 sleep (time and %) and slow wave density already at baseline. As delta wave activity (i.e., power) can predict motor progression in PD[ 11 , 74 ], it is crucial to investigate whether similar associations can be observed in other neurodegenerative disorders, including CBS over longer period of time. Finally, the systemic inflammatory profile of our participant may have improved following the training program. We could speculate that this anti-inflammatory effect was driven by exercise[ 13 ], improved sleep quality[ 14 ], or both mechanisms. Notably, previous evidence suggests that exercise may enhance sleep quality and architecture in neurological disorders such as PD and AD by reducing inflammation[ 22 ]. Thus, future studies, including a non-exercise control condition or multiple baseline evaluations, should determine whether exercise improves systemic inflammation in CBS and whether this change leads to or results from better sleep. Limitations We acknowledge that this case report has limitations. First, although our results align with previous findings in this clinical population[ 19 ], they cannot be generalized to all individuals with CBS. Second, the lack of a control condition limits the strength of our findings and conclusions. We interpreted our results considering MCID and established cut-off values to address this limitation. Finally, the absence of follow-up prevents us from assessing whether and for how long the observed benefits of exercise were sustained. In summary, this case report supports the notion that objective sleep quality, sleep architecture, and cognitive function are markedly altered in CBS. It further suggests that moderate-to-vigorous exercise is feasible and can improve fitness, objective sleep quality and architecture, overall cognition, and systemic inflammation in an individual with CBS. However, despite the 12-week exercise intervention, subjective sleep quality, sleep slow waves, motor signs and fatigue worsened. These findings confirm and expand previous reports in CBS and may support the notion that sleep and exercise play a crucial role in the clinical trajectory of Parkinsonian syndromes. Controlled trials are warranted to corroborate our observations and interpretations. Declarations Authors’ contributions MR and JCC conceived the study. JCC, AB, FS, and LR organized and executed the study. JCC and MR analyzed and interpreted the data. JCC wrote the first draft of the manuscript. All authors contributed to the writing of the manuscript and critically reviewed it. All authors approved the final version of the manuscript. Acknowledgements The authors would like to thank the participant for his time and effort in contributing to this study and Sonia Frenette for her help with data analysis. Funding The work was supported by a Canadian Institutes of Health Research (CIHR) Project Grant (02109PJT468982-MOV-CFAA-244681). JCC received funding from the Brain Canada Next Gen Award in Parkinson’s Disease Research, and the Fonds de recherche du Quebec (FRQS) (doctoral scholarships). MR was supported FRQS Salary Award (Junior 2). Ethics approval and consent to participate Research ethic approval was granted by the Comité d’Éthique de la Recherche (CÉR) CISSS de Laval (Project number: MP-50-2022-1584). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. 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Nat Rev Neurosci 20(12):746–762 Bouchard M et al (2021) Sleeping at the switch. eLife 10:e64337 Campbell IG et al (2006) Homeostatic behavior of fast fourier transform power in very low frequency non-rapid eye movement human electroencephalogram. Neuroscience 140(4):1395–1399 Isella V et al (2013) Diagnosis of possible Mild Cognitive Impairment in Parkinson's disease: Validity of the SCOPA-Cog. Parkinsonism Relat Disord 19(12):1160–1163 Koga S et al (2022) Neuropathology and emerging biomarkers in corticobasal syndrome. J Neurol Neurosurg Psychiatry, : p. jnnp-2021-328586. Paillard T, Rolland Y, de Barreto P (2015) Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review. jcn, 11(3): pp. 212–219 Murray DK et al (2014) The effects of exercise on cognition in Parkinson's disease: a systematic review. Transl Neurodegener 3(1):5 Amara A et al (2022) Spindles and Slow Waves Predict Parkinson’s Disease-Mild Cognitive Impairment. Memon AA et al (2022) Effects of exercise on sleep spindles in Parkinson's disease. Front Rehabil Sci 3:952289 Park I et al (2021) Exercise improves the quality of slow-wave sleep by increasing slow-wave stability. Sci Rep 11(1):4410 Schreiner SJ et al (2021) Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease. Front Neurol 12:618101 Sharon O et al (2024) Tau pathology leads to lonely non-traveling slow waves that mediate human memory impairment Wood KH et al (2021) Slow Wave Sleep and EEG Delta Spectral Power are Associated with Cognitive Function in Parkinson's Disease. J Parkinsons Dis 11(2):703–714 Winward C et al (2012) Weekly exercise does not improve fatigue levels in Parkinson's disease. Mov Disord 27(1):143–146 Folkerts A-K et al (2023) Physical Exercise as a Potential Treatment for Fatigue in Parkinson’s Disease? A Systematic Review and Meta-Analysis of Pharmacological and Non-Pharmacological Interventions. J Parkinson’s Disease 13(5):659–679 van der Kolk NM et al (2019) Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial. Lancet Neurol 18(11):998–1008 Horváth K et al (2015) Minimal clinically important difference on the Motor Examination part of MDS-UPDRS. Parkinsonism Relat Disord 21(12):1421–1426 Wang J et al (2025) Optimal dose and type of exercise to improve motor symptoms in adults with Parkinson's disease: A network meta-analysis. Journal of Science and Medicine in Sport Zhen K et al (2022) A systematic review and meta-analysis on effects of aerobic exercise in people with Parkinson’s disease. npj Parkinson's Disease 8(1):146 Evers LJW et al (2019) Measuring Parkinson's disease over time: The real-world within-subject reliability of the MDS-UPDRS. Mov Disord 34(10):1480–1487 Regnault A et al (2019) Does the MDS-UPDRS provide the precision to assess progression in early Parkinson's disease? Learnings from the Parkinson's progression marker initiative cohort. J Neurol 266(8):1927–1936 Tosin MHS et al (2021) Does MDS-UPDRS Provide Greater Sensitivity to Mild Disease than UPDRS in De Novo Parkinson's Disease? Mov Disord Clin Pract 8(7):1092–1099 Lamb R et al (2016) Progressive Supranuclear Palsy and Corticobasal Degeneration: Pathophysiology and Treatment Options. Curr Treat Options Neurol 18(9):42 Archer T, Fredriksson A, Johansson B (2011) Exercise alleviates Parkinsonism: clinical and laboratory evidence. Acta Neurol Scand 123(2):73–84 Schreiner SJ et al (2019) Slow-wave sleep and motor progression in Parkinson disease. Ann Neurol 85(5):765–770 Supplementary Material Supplementary Material 1 to 3 are not available with this version. Additional Declarations The authors declare no competing interests. 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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-6696024","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":458516955,"identity":"150ee153-c4d7-43be-9184-b4b17e122d6b","order_by":0,"name":"Jacopo 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07:19:23","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6696024/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6696024/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1093/ptj/pzaf130","type":"published","date":"2025-10-23T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83337287,"identity":"933a0641-0023-4e60-ade6-0b48584d652c","added_by":"auto","created_at":"2025-05-23 09:27:38","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":254509,"visible":true,"origin":"","legend":"\u003cp\u003ePower spectral analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1a.\u003c/strong\u003e \u003cstrong\u003eLow-frequency slow wave power\u003c/strong\u003e - \u003cstrong\u003eT0\u003c/strong\u003e:\u003cstrong\u003e \u003c/strong\u003ecycle 1 = 259.6 µV\u003csup\u003e2\u003c/sup\u003e; cycle 2 = 174.6 µV\u003csup\u003e2\u003c/sup\u003e. \u003cstrong\u003eT1\u003c/strong\u003e: cycle 1 = 202.4 µV\u003csup\u003e2\u003c/sup\u003e; cycle 2 = 116.5 µV\u003csup\u003e2\u003c/sup\u003e; cycle 3 = 67.8 µV\u003csup\u003e2\u003c/sup\u003e; cycle 4 = 75.6 µV\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1b.\u003c/strong\u003e \u003cstrong\u003eSlow oscillation power\u003c/strong\u003e - \u003cstrong\u003eT0\u003c/strong\u003e:\u003cstrong\u003e \u003c/strong\u003ecycle 1 = 51.8 µV\u003csup\u003e2\u003c/sup\u003e; cycle 2 = 39.3 µV\u003csup\u003e2\u003c/sup\u003e. \u003cstrong\u003eT1\u003c/strong\u003e: cycle 1 = 70.4 µV\u003csup\u003e2\u003c/sup\u003e; cycle 2 = 49.2 µV\u003csup\u003e2\u003c/sup\u003e; cycle 3 = 20.2 µV\u003csup\u003e2\u003c/sup\u003e; cycle 4 = 19.3 µV\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1c.\u003c/strong\u003e \u003cstrong\u003eDelta power\u003c/strong\u003e - \u003cstrong\u003eT0\u003c/strong\u003e:\u003cstrong\u003e \u003c/strong\u003ecycle 1 = 207.8 µV\u003csup\u003e2\u003c/sup\u003e; cycle 2 = 135.3 µV\u003csup\u003e2\u003c/sup\u003e. \u003cstrong\u003eT1\u003c/strong\u003e: cycle 1 = 132.0 µV\u003csup\u003e2\u003c/sup\u003e; cycle 2 = 67.3 µV\u003csup\u003e2\u003c/sup\u003e; cycle 3 = 47.6 µV\u003csup\u003e2\u003c/sup\u003e; cycle 4 = 56.3 µV\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e","description":"","filename":"floatimage118.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6696024/v1/e859c465cd5098b70954478e.jpeg"},{"id":94444635,"identity":"ae53fe1f-4d9c-43b9-8ea7-a547632b109b","added_by":"auto","created_at":"2025-10-27 14:32:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1526552,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6696024/v1/90bb1d12-8587-45c4-a07e-e077af2e6c63.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eThe Effects of Multimodal Exercise on Sleep Quality and Architecture, Motor Function, Cognition, Fatigue, and Systemic Inflammation in Corticobasal Syndrome: A Case Report.\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCorticobasal syndrome (CBS) is a rare Parkinsonian disorder that belongs to the group of tauopathies, in which neuroinflammation contributes to its pathophysiology[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CBS is characterized by marked asymmetry, rigidity, dystonia and apraxia, as well as cortical sensory and cognitive deficits[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Sleep quality and architecture (i.e., the fundamental structure of normal sleep and the cyclical pattern of its various stages) are also affected in CBS; however, these aspects have not been extensively investigated. Small sample studies and case series have shown that sleep disorders, such as insomnia, restless leg syndrome, periodic limb movements, and sleep-wake cycle disturbances are common in CBS[\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, alterations in sleep quality and architecture in these patients include reductions in total sleep time, sleep efficiency, non-rapid eye movement (NREM) and REM sleep[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. To our knowledge, no studies have quantified alterations in micro-sleep architecture (i.e., transient, dynamic events and rhythms in neural electrical activity that occur within and across sleep stages) in CBS or examined whether sleep alterations may be linked to cognitive and motor decline, as seen in other neurodegenerative disorders[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Finally, little evidence exists regarding blood markers of systemic inflammation in CBS, despite the important contribution of (neuro)inflammation to tau pathophysiology. More importantly, consistent evidence indicates that both regular exercise[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and sleep quality[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] can positively influence systemic inflammation in different (clinical) populations.\u003c/p\u003e \u003cp\u003eBased on results from case reports in CBS[\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and other tauopathies[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], exercise has been recommended as an important component to counter gait and balance disturbances as well as cognitive deterioration. Moreover, exercise can enhance sleep quality and architecture in conditions with pathophysiological similarities to CBS, such as Parkinson's (PD) and Alzheimer's disease (AD), with multimodal training approaches potentially inducing the largest benefits[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, evidence that can confirm and expand previously reported cross-sectional findings and longitudinal changes following regular exercise in this rare condition has important clinical implications. Here, we present a case report describing baseline and longitudinal changes in sleep quality, sleep architecture, cognition, motor function, fatigue and markers of systemic inflammation in an individual with CBS following 12 weeks of multimodal training.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e Research ethic approval was granted by the Comit\u0026eacute; d\u0026rsquo;\u0026Eacute;thique de la Recherche (C\u0026Eacute;R) CISSS de Laval (Project number: MP-50-2022-1584). This case report is reported following the CARE guidelines[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eRole of the Funding Source\u003c/h2\u003e \u003cp\u003eThe funders played no role in the design, conduct, or reporting of this study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase Description and Examination\u003c/h3\u003e\n\u003cp\u003eOne male individual who was initially diagnosed with PD and subsequently re-diagnosed with CBS (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) gave informed consent to participate in the study. The participant was evaluated on anti-parkinsonian medications at the same time of the day (~\u0026thinsp;1 hour) at baseline (T0) and after 12 weeks of multimodal training (T1). The evaluations were conducted over two days, separated by approximately seven days at both time points. Blinded assessors conducted motor and cognitive evaluations (see below). The participant did not change medications during the study period.\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\u003eCharacteristics of the participant at baseline and post-training changes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline (T0)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-Intervention (T1)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChanges\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.3 years\u003c/p\u003e \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\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight (BMI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.3 kg (23.1 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.2 kg (21.8 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-4.1 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease duration\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 year\u003c/p\u003e \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\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLevodopa equivalent daily doses\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e600 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e600 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePro oxazepam\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMDS-UPDRS III\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;11 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eRigidity\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;3 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eTremor\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;5 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eBradykinesia\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;1 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eAxial\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;2 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSCOPA-COG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;9 (improvement)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eMemory and learning\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;5 (improvement)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eAttention\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eExecutive functions\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;9 (improvement)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eVisuospatial functions\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-5 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRBDSQ-1 Item\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePDSS-2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;5 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBDI-2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;3 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePD Fatigue Scale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;0.62 (deterioration)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCPET\u003c/b\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\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eTest duration\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12:00 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14:00 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;2:00 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eV̇O2peak\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.9 ml*kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e*min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.7 ml*kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e*min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;0.8 ml*kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e*min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003ePeak power output (W/kg)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e155 W (2.14 W/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e165 W (2.42 W/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;10 W (+\u0026thinsp;0.28 W/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eHeart rate max (bpm)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159 bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e163 bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;4 bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eRate of perceive exertion\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSub-maximal 1-RM test\u003c/b\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\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eLeg extension\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.4 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;41.6 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eChest press\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.4 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90.7 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;14.3 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eLat machine\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94.1 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;5.9 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eLeg curl\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.1 kg\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInflammatory biomarkers\u003c/b\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\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eIL1β\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.52 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.01 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eIL6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003csup\u003eΔ\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.13 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eIL10\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.07 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.12 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;5.05 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eTNFα\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.46 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.58 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.88 pg/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; \u003cem\u003eCRP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4972.84 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4761.86 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-210.98 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFootnote\u003c/b\u003e: \u003csup\u003e\u003cb\u003eΔ\u003c/b\u003e\u003c/sup\u003e = value lower than standard curve; \u003cb\u003eBDI-2\u003c/b\u003e\u0026thinsp;=\u0026thinsp;Beck Depression Inventory \u0026ndash; 2; \u003cb\u003eCPET\u003c/b\u003e\u0026thinsp;=\u0026thinsp;cardiopulmonary exercise testing; \u003cb\u003eNA\u003c/b\u003e\u0026thinsp;=\u0026thinsp;not applicable; \u003cb\u003eRBDSQ-1\u003c/b\u003e\u0026thinsp;=\u0026thinsp;The REM sleep behavior disorder screening questionnaire \u0026ndash; 1 item.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e*Table 1 should be placed here\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eTherapeutic intervention\u003c/h2\u003e \u003cp\u003eThe multimodal training combined resistance and cardiovascular training and was conducted at moderate to vigorous intensities for ~\u0026thinsp;45 minutes, 3 times per week, over a 12-week period. Resistance training targeted large muscle groups (i.e., chest, back, quadriceps, and hamstrings) and was performed with resistance machines. Cardiovascular training was performed on a total body recumbent stepper, involving the upper and lower extremities. Each training session included five minutes of warm-up, followed by resistance training, cardiovascular training, and five minutes of cool-down. Training intensity and progression were tailored to the participant\u0026rsquo;s fitness level (see below). A detailed description of the intervention is reported elsewhere[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes measures\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFunctional fitness measures\u003c/h2\u003e \u003cp\u003eCardiorespiratory fitness level (V̇O\u003csub\u003e2peak\u003c/sub\u003e) and muscle strength were assessed with a symptom-limit cardiopulmonary exercise test (CPET; Quark CPET, Cosmed Srl, Italy) on a recumbent stepper and a sub-maximal 1-RM test, respectively. A detailed description of the functional fitness measures is reported elsewhere[24].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSleep quality and architecture\u003c/h3\u003e\n\u003cp\u003eSleep quality was assessed subjectively with the PD Sleep Scale-2 (PDSS-2) and objectively through actigraphy (Actiwatch Spectrum Plus; Philips Respironics, Bend, USA) worn on the non-dominant wrist for ~\u0026thinsp;7 days, during which the participant also completed a sleep diary. Actiware software (v6.3; Philips Respironics, Bend, USA) was implemented to automatically score the recording using an activity count threshold of 20, a minimum of 10 minutes of immobility, and rest durations of \u0026ge;\u0026thinsp;30 minutes for major sleep bouts and \u0026ge;\u0026thinsp;15 minutes for minor sleep bouts (up to 75 minutes)[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Subsequently, all recordings were visually inspected, and the onset and offset of rest periods were cross-checked against the sleep diary. It should also be noted that actigraphy was used to monitor sleep patterns during the days preceding the overnight sleep evaluation conducted at our facilities. During this overnight evaluation, sleep architecture was assessed with polysomnography (Grael v2, Compumedics Limited, Abbotsford, Victoria, Australia). Specifically, electroencephalography (EEG) was conducted using a standard montage (10\u0026ndash;20 international system) with frontal (F3-M2, F4-M1), central (C3-M2, C4-M1), parietal (P3-M2, P4-M1), and occipital (O1-M2, O2-M1) electrodes referenced to the mastoids. Electro-oculography and electromyography for chin muscle tone and tibialis anterior muscle were also collected. Signals were digitized at a sampling rate of 256 Hz (Profusion Sleep version 5, Compumedics Limited). An expert sleep technician, blinded to the study, manually scored the sleep recordings following AASM guidelines using 30-second epochs[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Artifacts were detected by an automatic algorithm[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and visually verified. In addition to macro-sleep architecture parameters, micro-sleep architecture (i.e., sleep slow wave and spindle features) was examined during artifact-free NREM sleep stages 2\u0026ndash;3 using Snooz Toolbox[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The same toolbox was implemented to conduct EEG power spectral analysis of low-frequency slow waves (\u0026le;\u0026thinsp;4 Hz), slow oscillation (\u0026lt;\u0026thinsp;1 Hz) and delta waves (1\u0026ndash;4 Hz) throughout the sleep cycles. Sleep outcomes and methodologies implemented to analyze the EEG signal can be found in \u003cb\u003eSupplemental materials 1\u003c/b\u003e \u0026amp; \u003cb\u003e2\u003c/b\u003e.\u003c/p\u003e\n\u003ch3\u003eCognition, motor function and fatigue\u003c/h3\u003e\n\u003cp\u003eCognition and motor function were assessed with the Scale for Outcomes in PD-Cognition (SCOPA-COG)[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and Movement Disorders Society Unified PD Rating Scale part III (MDS-UPDRS III)[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], respectively. Fatigue was assessed with the PD Fatigue Scale[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSystemic inflammation\u003c/h2\u003e \u003cp\u003eThe concentrations of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)α, and C-reactive protein (CRP) were measured from serum collected in the morning after a 12-hour fasting period. Blood samples were collected using a Vacutainer serum separator tube, allowed to clot for one hour at room temperature, cooled at ~\u0026thinsp;4\u0026deg;C for 30 minutes, and centrifuged at 2200g for 15 minutes. The resulting sera were aliquoted into 250 \u0026micro;L cryovials, stored at -80\u0026deg;C (Thermo Fisher Scientific, Waltham, USA), and analyzed using Millipore Sigma kits (HSCTMAG-28SK and HCVD3MAG-67K).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe participant completed all the evaluations and 34 training sessions (total training time: 25h 21min; average rate of perceived exertion during training\u0026thinsp;=\u0026thinsp;16/20) without experiencing any adverse events. Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e show baseline and post-training outcomes. After the exercise program, cardiorespiratory fitness level (+\u0026thinsp;0.8 ml*kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e*min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and sub-maximal strength (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) improved. The participant reported a subjective reduction in sleep quality (\u003cb\u003ePDSS-2\u003c/b\u003e: 10/60 to 15/60) post intervention. Despite this reduction in subjective sleep quality, actigraphy and polysomnography showed improvements in several sleep outcomes after the exercise program (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). That is, actigraphy results showed an improvement in total sleep time (383.4\u0026thinsp;\u0026plusmn;\u0026thinsp;65.0 to 433.3\u0026thinsp;\u0026plusmn;\u0026thinsp;82.3 min), sleep efficiency (81.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 to 90.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9%) and sleep onset latency (16.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 to 2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 min). Additionally, they showed that there was a reduction in daily activity counts (222.9\u0026thinsp;\u0026plusmn;\u0026thinsp;38.8 AC/min to107.5\u0026thinsp;\u0026plusmn;\u0026thinsp;60.1 AC/min), suggesting a reduction in daily physical activity levels post-treatment. This reduction in physical activity levels might partially be explained by changes in physical activity associated with seasonal temperature changes[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], as the baseline and post-exercise evaluations took place in July (average 23.6℃) and November (average 4.9℃;), respectively.\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\u003ea. Actigraphy and macro-sleep architecture outcomes at baseline and after 12 weeks of training.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eActigraphy\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline (T0)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-Intervention (T1)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNights recorded\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTST (avg\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e383.4\u0026thinsp;\u0026plusmn;\u0026thinsp;65.0 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e433.3\u0026thinsp;\u0026plusmn;\u0026thinsp;82.3 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWASO (avg\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.3\u0026thinsp;\u0026plusmn;\u0026thinsp;13.1 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.4\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOL (avg\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep efficiency (avg\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep fragmentation (avg\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaily Activity Count (avg\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e222.9\u0026thinsp;\u0026plusmn;\u0026thinsp;38.8 AC/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107.5\u0026thinsp;\u0026plusmn;\u0026thinsp;60.1 AC/min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePolysomnography: Sleep architecture\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ePost-Intervention\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e271 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e487.5 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e193 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e461 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep efficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREM latency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e167 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e158 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWASO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.5 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1 (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2 (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e334.5 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN3 (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.5 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNREM (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e174 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e356 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREM (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWake (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN3 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNREM (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREM (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFootnote: SOL\u003c/b\u003e\u0026thinsp;=\u0026thinsp;sleep onset latency; \u003cb\u003eTIB\u003c/b\u003e\u0026thinsp;=\u0026thinsp;time in bed; \u003cb\u003eTST\u003c/b\u003e\u0026thinsp;=\u0026thinsp;total sleep time; \u003cb\u003eWASO\u003c/b\u003e\u0026thinsp;=\u0026thinsp;wake after sleep onset.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003ch2\u003e*Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea should be placed here\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eb. Slow waves and spindle features at baseline and after 12 weeks of training.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSlow waves and spindle features\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-Intervention\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow wave (count)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 1846 count\u003c/p\u003e \u003cp\u003eCentral: 1008 count\u003c/p\u003e \u003cp\u003eParietal: 373 count\u003c/p\u003e \u003cp\u003eTotal: 3234 count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 1407 count\u003c/p\u003e \u003cp\u003eCentral: 628 count\u003c/p\u003e \u003cp\u003eParietal: 215 count\u003c/p\u003e \u003cp\u003eTotal: 2259 count\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow wave density (count/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 5.6 count/min\u003c/p\u003e \u003cp\u003eCentral: 3.0 count/min\u003c/p\u003e \u003cp\u003eParietal: 1.1 count/min\u003c/p\u003e \u003cp\u003eTotal: 2.8 count/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 2.1 count/min\u003c/p\u003e \u003cp\u003eCentral: 0.9 count/min\u003c/p\u003e \u003cp\u003eParietal: 0.3 count/min\u003c/p\u003e \u003cp\u003eTotal: 1.0 count/min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow wave amplitude (\u0026micro;V)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 102.3 \u0026micro;V\u003c/p\u003e \u003cp\u003eCentral: 98.8 \u0026micro;V\u003c/p\u003e \u003cp\u003eParietal: 93.4 \u0026micro;V\u003c/p\u003e \u003cp\u003eTotal: 96.3 \u0026micro;V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 100.2 \u0026micro;V\u003c/p\u003e \u003cp\u003eCentral: 96.3 \u0026micro;V\u003c/p\u003e \u003cp\u003eParietal: 91.1 \u0026micro;V\u003c/p\u003e \u003cp\u003eTotal: 94.5 \u0026micro;V\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow wave slope (min-to-max; \u0026micro;V/sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 358.2 \u0026micro;V/sec\u003c/p\u003e \u003cp\u003eCentral: 356.8 \u0026micro;V/sec\u003c/p\u003e \u003cp\u003eParietal: 306.8 \u0026micro;V/sec\u003c/p\u003e \u003cp\u003eTotal: 319.9\u0026micro;V/sec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 271.6 \u0026micro;V/sec\u003c/p\u003e \u003cp\u003eCentral: 246.8 \u0026micro;V/sec\u003c/p\u003e \u003cp\u003eParietal: 202.6 \u0026micro;V/sec\u003c/p\u003e \u003cp\u003eTotal: 224.5 \u0026micro;V/sec\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow wave frequency (Hz)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 1.4 Hz\u003c/p\u003e \u003cp\u003eCentral: 1.5 Hz\u003c/p\u003e \u003cp\u003eParietal: 1.3 Hz\u003c/p\u003e \u003cp\u003eTotal: 1.3 Hz\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 1.1 Hz\u003c/p\u003e \u003cp\u003eCentral: 1.0 Hz\u003c/p\u003e \u003cp\u003eParietal: 0.9 Hz\u003c/p\u003e \u003cp\u003eTotal: 1.0 Hz\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow wave transition frequency (Hz)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 1.7 Hz\u003c/p\u003e \u003cp\u003eCentral: 1.8 Hz\u003c/p\u003e \u003cp\u003eParietal: 1.6 Hz\u003c/p\u003e \u003cp\u003eTotal: 1.6 Hz\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 1.4 Hz\u003c/p\u003e \u003cp\u003eCentral: 1.3 Hz\u003c/p\u003e \u003cp\u003eParietal: 1.1 Hz\u003c/p\u003e \u003cp\u003eTotal: 1.2 Hz\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpindle (count)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 513 count\u003c/p\u003e \u003cp\u003eCentral: 171 count\u003c/p\u003e \u003cp\u003eParietal: 77 count\u003c/p\u003e \u003cp\u003eTotal: 770 count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 2720 count\u003c/p\u003e \u003cp\u003eCentral: 1777 count\u003c/p\u003e \u003cp\u003eParietal: 1279 count\u003c/p\u003e \u003cp\u003eTotal: 5927 count\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpindle density (count/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 1.6 count/min\u003c/p\u003e \u003cp\u003eCentral: 0.5 count/min\u003c/p\u003e \u003cp\u003eParietal: 0.2 count/min\u003c/p\u003e \u003cp\u003eTotal: 0.6 count/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 4.0 count/min\u003c/p\u003e \u003cp\u003eCentral: 2.6 count/min\u003c/p\u003e \u003cp\u003eParietal: 1.9 count/min\u003c/p\u003e \u003cp\u003eTotal: 2.2 count/min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpindle amplitude (\u0026micro;V)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 29.9 \u0026micro;V\u003c/p\u003e \u003cp\u003eCentral: 25.9 \u0026micro;V\u003c/p\u003e \u003cp\u003eParietal: 24.0 \u0026micro;V\u003c/p\u003e \u003cp\u003eTotal: 25.9 \u0026micro;V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 30.2 \u0026micro;V\u003c/p\u003e \u003cp\u003eCentral: 25.4 \u0026micro;V\u003c/p\u003e \u003cp\u003eParietal: 23.0 \u0026micro;V\u003c/p\u003e \u003cp\u003eTotal: 24.7 \u0026micro;V\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpindle frequency (Hz)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrontal: 12.5 Hz\u003c/p\u003e \u003cp\u003eCentral: 12.7 Hz\u003c/p\u003e \u003cp\u003eParietal: 13.4 Hz\u003c/p\u003e \u003cp\u003eTotal: 13.0 Hz\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrontal: 12.6 Hz\u003c/p\u003e \u003cp\u003eCentral: 13.1 Hz\u003c/p\u003e \u003cp\u003eParietal: 13.6 Hz\u003c/p\u003e \u003cp\u003eTotal: 13.1 Hz\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e*Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb should be placed here\u003c/h2\u003e \u003cp\u003eConsistent with the actigraphy results, polysomnography results showed an increase in total sleep time (195.0 to 462.5 min), sleep efficiency (71.2 to 94.6%), N2 (162 to 334.5 min), REM (19 to 105 min) and a reduction in sleep onset latency (33.0 to 9.0 min). Furthermore, while no major changes in N1% (4.4 to 3.7%) and N3% (1.8 to 1.0%) were found, there was a reduction in N2% (83.9 to 72.6%) and wake time (28.8 to 5.4%), as well as an increase in REM% (9.8 to 22.8%). It should be noted that sleep stage N3 was extremely short and did not change post-exercise (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Hypnograms can be found in \u003cb\u003eSupplemental material 3\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003cp\u003eSleep spindles and slow wave features (i.e., micro-sleep architecture) are reported in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb, and power spectral analysis results are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Sleep spindle density increased (average across channels: 0.58 to 2.20 count/min) post-exercise. In contrast, slow wave density (average across channels: 2.8 to 1.0 count/min) as well as slow wave slope, frequency, and transition frequency decreased. These changes in slow waves indicate potential (post-exercise) modifications not only in slow wave density but also in morphology. Finally, there was an overall reduction in low-frequency slow wave power across sleep cycles post-exercise (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Importantly, however, this overall reduction was specific to delta wave power (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) and did not occur for slow oscillation, whose power increased after exercise (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). A similar power reduction was observed for fast delta waves power (2\u0026ndash;4 Hz[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]; \u003cb\u003eSupplemental material 4\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e*Figure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e should be placed here\u003c/h2\u003e \u003cp\u003eFollowing the training program, an overall improvement in cognition (\u003cb\u003eSCOPA-COG\u003c/b\u003e: 25/43 to 34/43) was observed. However, the improvement was in memory/learning and executive functions domains while a worsening in visuospatial functions was detected. Conversely, the participant experienced a deterioration in motor signs (\u003cb\u003eMDS-UPDRS III\u003c/b\u003e: 31/132 to 42/132) and fatigue (\u003cb\u003ePD Fatigue Scale\u003c/b\u003e: 2.38/5 to 3/5). Finally, peripheral TNFα and CRP blood concentrations decreased, while IL10 increased post intervention (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe participant reported relatively good satisfaction with their subjective sleep perception at baseline. However, there were marked alterations in objective sleep quality and architecture, confirming previously observed sleep disturbances in CBS[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. That is, our participant showed reduced sleep time and efficiency, NREM and REM sleep, and nearly absent N3 (i.e., slow wave sleep). Furthermore, we quantified important sleep slow wave and spindle density deteriorations, with values markedly lower than those reported in neurotypical adults[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] and, in case of sleep spindles, even lower than those reported in PD[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. However, the deterioration of these neural oscillations was broadly comparable to that observed in other tauopathies, such as AD[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Notably, following the 12-week multimodal training program, we observed improvements in multiple sleep outcomes measured objectively both with actigraphy over several days in the participant\u0026rsquo;s home setting as well as with polysomnography. However, we cannot rule out the possibility that a first-night effect could have biased the polysomnography outcomes. These results suggest that our participant experienced a significant improvement in objective sleep quality, particularly in sleep efficiency[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], following the training program.\u003c/p\u003e \u003cp\u003eConversely, we observed a deterioration in self-reported subjective sleep quality post-exercise intervention. This deterioration is well above the minimal clinically important difference (MCID; 2.07 points) established for PD [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] and suggests a discrepancy between subjective and objective sleep measures. The reasons for the observed decline in subjective sleep quality remain unclear. Potential explanations include sleep misperception (already evident at baseline; \u003cb\u003ePDSS-2\u003c/b\u003e\u0026thinsp;=\u0026thinsp;10/60), increased awareness/expectations following the intervention, a slight worsening of fatigue and depressive symptoms (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), or a combination of these factors[\u003cspan additionalcitationids=\"CR41 CR42 CR43\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. However, this discrepancy is not novel, it has been observed repeatedly in other (clinical) populations, and it underlies the importance of combining objective and subjective sleep measures to capture all the dimensions of sleep[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Additionally, it reinforces the notion that a combination of different interventions (e.g., exercise and sleep hygiene) might be required to improve all the dimensions of sleep[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to improvements in objective sleep quality, we observed changes in features of micro-sleep architecture and low-frequency slow wave power. Specifically, sleep spindle density, which was particularly low at baseline[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], markedly increased following the training program, corroborating similar positive effects observed in PD after a comparable training intervention[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Notably, overall post-training sleep spindle density reached values typically observed in neurotypical adult individuals (i.e., ~\u0026thinsp;2\u0026ndash;3/min)[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. It would be important to determine whether the observed increase in sleep spindle density is solely the results of longer sleep duration and time spent in sleep stage N2 during the second evaluation or linked to other mechanisms[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConversely, we observed a reduction in slow wave count/density following the training program, suggesting that exercise was ineffective at increasing this specific sleep feature in our participant. It is also important to note that slow wave density was markedly low at baseline compared to previously published data from neurotypical adults in their middle age[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] but similar to what reported in PD[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These results expand prior research in CBS, suggesting an early disruption of slow waves and spindles presumably induced by neurodegeneration within sleep-regulatory brain structures observed in tauopathy[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Critically, regular exercise may improve some (i.e., spindles) of those relevant neural oscillations in CBS.\u003c/p\u003e \u003cp\u003eThe reduction in slow wave (count/density) was paralleled by a reduction in low-frequency slow waves power, particularly during the first two sleep cycles after the training program (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). However, this reduction appeared to be specific to the delta power (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003ec) while slow oscillations power increased (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eb), a finding that is consistent with the changes also observed in slow wave morphology (frequency/transition frequency; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Slow oscillations and delta waves are thought to be regulated and respond differently to homeostatic sleep pressure (i.e., the need for sleep accumulates with prolonged wakefulness and dissipates during sleep)[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Given that during the days leading up to the second polysomnography evaluation, the participant experienced a substantial improvement in objective sleep quality and a potential overall reduction in levels of physical activity measured with actigraphy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), one could speculate that an overall reduction in homeostatic sleep pressure might cause the reduction in (fast) delta power. In any event, the effects of regular exercise on those power frequencies and their clinical relevance in CBS need to be investigated further.\u003c/p\u003e \u003cp\u003eAt baseline, the participant scored 25 on the SCOPA-COG, which is slightly above the established cut-off (\u0026lt;\u0026thinsp;25) for identifying mild cognitive impairment in PD[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], indicating some cognitive dysfunction. Executive and visuospatial dysfunctions are early, key cognitive alterations that can be implemented as a criterion for diagnosing CBS[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Our longitudinal finding suggests that exercise, as observed in other neurodegenerative disorders[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e], can ameliorate overall cognitive function in CBS[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, a closer analysis indicates that the overall cognitive enhancement was domain-specific (i.e., executive function and memory/learning domains), while some aspects of cognition (i.e., visuospatial functions) kept deteriorating. It would be tempting to speculate that this overall cognitive improvement was linked to better sleep (e.g., sleep spindle density and slow oscillation power)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan additionalcitationids=\"CR58 CR59 CR60 CR61\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Controlled studies are required to determine whether regular exercise improves specific cognitive domains in CBS and whether changes in sleep architecture mediate this positive effect[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe also observed increased fatigue and a marked deterioration in motor signs. The perceived increase in fatigue suggests that exercise is not always effective at improving this detrimental feature common in Parkinsonian syndromes[\u003cspan additionalcitationids=\"CR64\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e] and could be related to the observed deterioration in other non-motor symptoms (i.e., subjective sleep quality and depression)[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Similarly, the motor decline, which was well above the MCID (4.63 points) to detect worsening in PD[\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e], indicates that exercise was ineffective. This finding contrasts with the positive effects of regular exercise on motor function in PD[\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e], and several concomitant factors could partially explain this deterioration. These may include the potential progression of the disease, poor response to levodopa in CBS, well-established limitations of the MDS-UPDRS III, and the type of training modality used[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR70 CR71\" citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. It would also be crucial to determine whether this motor deterioration resulted from increased fatigue[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], which our intervention might have triggered. This hypothesis, however, contrasts with the fitness improvements observed after the training program, the fact that the intervention was tailored and progressive, and previous research findings in PD[\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. Another important contributor to the motor deterioration might be linked to the abnormal sleep architecture observed in our participant, who showed minimal, almost absent, N3 sleep (time and %) and slow wave density already at baseline. As delta wave activity (i.e., power) can predict motor progression in PD[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e], it is crucial to investigate whether similar associations can be observed in other neurodegenerative disorders, including CBS over longer period of time.\u003c/p\u003e \u003cp\u003eFinally, the systemic inflammatory profile of our participant may have improved following the training program. We could speculate that this anti-inflammatory effect was driven by exercise[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], improved sleep quality[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], or both mechanisms. Notably, previous evidence suggests that exercise may enhance sleep quality and architecture in neurological disorders such as PD and AD by reducing inflammation[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Thus, future studies, including a non-exercise control condition or multiple baseline evaluations, should determine whether exercise improves systemic inflammation in CBS and whether this change leads to or results from better sleep.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eWe acknowledge that this case report has limitations. First, although our results align with previous findings in this clinical population[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], they cannot be generalized to all individuals with CBS. Second, the lack of a control condition limits the strength of our findings and conclusions. We interpreted our results considering MCID and established cut-off values to address this limitation. Finally, the absence of follow-up prevents us from assessing whether and for how long the observed benefits of exercise were sustained.\u003c/p\u003e \u003cp\u003eIn summary, this case report supports the notion that objective sleep quality, sleep architecture, and cognitive function are markedly altered in CBS. It further suggests that moderate-to-vigorous exercise is feasible and can improve fitness, objective sleep quality and architecture, overall cognition, and systemic inflammation in an individual with CBS. However, despite the 12-week exercise intervention, subjective sleep quality, sleep slow waves, motor signs and fatigue worsened. These findings confirm and expand previous reports in CBS and may support the notion that sleep and exercise play a crucial role in the clinical trajectory of Parkinsonian syndromes. Controlled trials are warranted to corroborate our observations and interpretations.\u003c/p\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMR and JCC conceived the study. JCC, AB, FS, and LR organized and executed the study. JCC and MR analyzed and interpreted the data. JCC wrote the first draft of the manuscript. All authors contributed to the writing of the manuscript and critically reviewed it. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the participant for his time and effort in contributing to this study and Sonia Frenette for her help with data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by a Canadian Institutes of Health Research (CIHR) Project Grant (02109PJT468982-MOV-CFAA-244681). JCC received funding from the Brain Canada Next Gen Award in Parkinson\u0026rsquo;s Disease Research, and the Fonds de recherche du Quebec (FRQS) (doctoral scholarships). MR was supported FRQS Salary Award (Junior 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch ethic approval was granted by the Comit\u0026eacute; d\u0026rsquo;\u0026Eacute;thique de la Recherche (C\u0026Eacute;R) CISSS de Laval (Project number: MP-50-2022-1584).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo disclosure to report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAli F, Josephs KA (2018) Corticobasal degeneration: key emerging issues. 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Ann Neurol 85(5):765\u0026ndash;770\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Supplementary Material","content":"\u003cp\u003eSupplementary Material 1 to 3 are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Corticobasal syndrome, Sleep architecture, Cognition, Motor function, Regular Exercise.","lastPublishedDoi":"10.21203/rs.3.rs-6696024/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6696024/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eImportance.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorticobasal syndrome (CBS) is a rare tauopathy, with a complex pathophysiology that usually includes neuroinflammation. Parkinsonism, cognitive impairments, and sleep disturbances are common in CBS, although alterations in sleep architecture remain poorly characterized. Regular exercise has been recommended in CBS to manage gait dysfunction, balance issues, and cognitive decline. However, to our knowledge, no studies examined the effects of regular exercise on sleep quality, sleep architecture and systemic inflammation in CBS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo describe the effects of a 12-week training program in CBS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn individual with CBS “On” antiparkinsonian medications was assessed before and after a 12-week multimodal training program. Cardiorespiratory fitness level (V̇O2peak) was assessed with a symptom-limited cardiopulmonary exercise test and strength with a sub-maximal 1-RM test. Subjective and objective sleep quality were assessed using the Parkinson’s Disease (PD) Sleep Scale-2 and actigraphy, respectively. Sleep architecture was evaluated with polysomnography. Cognition and motor function were assessed with the Scale for Outcomes in PD-Cognition (SCOPA-COG) and MDS-UPDRS-III, respectively. Fatigue was assessed with the PD Fatigue Scale. Concentrations of inflammatory cytokines interleukin (IL)1β, IL6, IL10, tumor necrosis factor (TNF)α, and C-reactive protein (CRP) were measured from serum collected after a 12-hour fasting period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing the training program (34 sessions; 25.35 hours), we observed improvements in fitness, objective sleep quality and architecture, cognition and a reduction in systemic inflammation. Conversely, motor function deteriorated, and the participant reported diminished subjective sleep quality and increased fatigue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur results suggest that exercise may improve specific clinical outcomes in CBS. However, it had no positive effects on motor signs, subjective sleep quality and fatigue, which worsened. Controlled studies are warranted to confirm and expand our observations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first case report describing the effects of a training program on sleep architecture and systemic inflammation in CBS.\u003c/p\u003e","manuscriptTitle":"The Effects of Multimodal Exercise on Sleep Quality and Architecture, Motor Function, Cognition, Fatigue, and Systemic Inflammation in Corticobasal Syndrome: A Case Report.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-23 09:27:33","doi":"10.21203/rs.3.rs-6696024/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d2cded7-f5b0-432d-bf7d-48a15d4341d5","owner":[],"postedDate":"May 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T13:11:55+00:00","versionOfRecord":{"articleIdentity":"rs-6696024","link":"https://doi.org/10.1093/ptj/pzaf130","journal":{"identity":"physical-therapy","isVorOnly":true,"title":"Physical Therapy"},"publishedOn":"2025-10-23 00:00:00","publishedOnDateReadable":"October 23rd, 2025"},"versionCreatedAt":"2025-05-23 09:27:33","video":"","vorDoi":"10.1093/ptj/pzaf130","vorDoiUrl":"https://doi.org/10.1093/ptj/pzaf130","workflowStages":[]},"version":"v1","identity":"rs-6696024","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6696024","identity":"rs-6696024","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}