Cerebral Autoregulation in Orthostatic Hypotension and Falls Among Older Adults: A Community-Based Exploratory Study

Cerebral Autoregulation in Orthostatic Hypotension and Falls Among Older Adults: A Community-Based Exploratory Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cerebral Autoregulation in Orthostatic Hypotension and Falls Among Older Adults: A Community-Based Exploratory Study Nor Izzati Saedon, James Frith, WAN AZMAN WAN AHMAD, MAW PIN TAN This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6460238/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Sep, 2025 Read the published version in Clinical Autonomic Research → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Orthostatic hypotension (OH) is prevalent in older adults and is often associated with falls. However, the presence or absence of symptoms in OH may be mediated by cerebral autoregulation, which helps maintain cerebral perfusion during blood pressure fluctuations. Methods: We recruited 40 older adults (aged ≥55 years) from the Malaysian Elders Longitudinal Research (MELoR) cohort. Participants underwent cerebral blood flow velocity monitoring using transcranial Doppler ultrasonography and beat-to-beat blood pressure recording. Three protocols were used: active stand, mental arithmetic, and Valsalva manoeuvre. Participants were categorized based on OH (≥30 mmHg systolic drop) and fall history into four groups. Cerebrovascular resistance (CVR) was derived and analyzed. Results: Participants with OH but no history of falls demonstrated preserved autoregulatory responses, as reflected by adaptive reductions in CVR. In contrast, fallers—regardless of OH status—had impaired CVR modulation. Significant group differences were found during the active stand test at 165s and 180s (p<0.05). Conclusion: Preserved cerebral autoregulation may protect older adults with OH from symptomatic manifestations such as falls. Targeting cerebral autoregulation could offer novel approaches for preventing falls in this population. Orthostatic hypotension cerebral autoregulation falls older adults cerebral blood flow Figures Figure 1 Figure 2 Figure 3 1. Introduction Orthostatic hypotension (OH), defined as a sustained drop in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg upon standing, is a common and under-recognized clinical condition in older adults. It affects up to 30% of the community-dwelling older population and is associated with adverse outcomes such as falls, fractures, cognitive impairment, and increased mortality. Given the global aging demographic, understanding the mechanisms that underlie the variability in symptom manifestation among those with OH is of increasing public health relevance. While OH is traditionally diagnosed through peripheral haemodynamic monitoring, there is growing interest in understanding the central nervous system's role in modulating its impact. One of the key physiological mechanisms in this context is cerebral autoregulation. Cerebral autoregulation refers to the brain's intrinsic ability to maintain a relatively constant cerebral blood flow (CBF) despite changes in systemic blood pressure, within a defined range of perfusion pressures. This protective mechanism ensures stable oxygen and nutrient delivery to brain tissue, safeguarding cognitive and motor functions. Aging and associated comorbidities, including diabetes, hypertension, and neurodegenerative diseases, are known to impair the efficiency of cerebral autoregulatory mechanisms. The interplay between impaired autoregulation and systemic hypotension could exacerbate cerebral hypoperfusion, leading to symptoms such as dizziness, syncope, and falls. However, not all individuals with OH report symptoms, suggesting that compensatory cerebrovascular mechanisms may modulate clinical expression. Previous studies have explored cerebral autoregulation in pathological states. For instance, Novak et al. showed variability in autoregulatory responses among patients with autonomic failure and OH, noting that symptoms were absent in those with preserved cerebrovascular adaptation despite hypotension. Similarly, Mankovsky et al. found that diabetic patients with autonomic neuropathy and OH exhibited impaired cerebral blood flow velocity regulation during postural changes. However, these studies were largely hospital-based and focused on select patient groups, limiting generalizability. Our study aims to bridge this gap by evaluating cerebral autoregulation in a population-based sample of older adults with and without OH, and with varying fall histories. We employed a series of challenge protocols to assess dynamic changes in cerebrovascular resistance (CVR) and explored their association with symptomatic expression, particularly falls. We hypothesize that preserved cerebral autoregulation differentiates asymptomatic from symptomatic OH and may serve as a potential therapeutic target in fall prevention strategies. 2. Materials and Methods Study Design and Setting This was a cross-sectional, observational study conducted at the University of Malaya Medical Centre in Kuala Lumpur, Malaysia. Ethical approval was obtained from the institutional review board, and all participants provided written informed consent prior to participation. The study was conducted in accordance with the Declaration of Helsinki. Participants and Recruitment Participants were drawn from the Malaysian Elders Longitudinal Research (MELoR) cohort, a community-based longitudinal study focusing on aging and functional health in older adults. Additional participants were recruited through outpatient clinics and local advertisements. Inclusion criteria included age ≥55 years, ability to provide informed consent, and physical capacity to undergo protocol assessments. Exclusion criteria were the presence of known focal neurological deficits, prior history of significant carotid stenosis, or the inability to obtain a suitable transtemporal window for transcranial Doppler (TCD) measurement. Clinical Assessment and Grouping Detailed Clinical interviews were conducted to document demographics, comorbidities, medication use, and history of falls within the previous 12 months. Falls were defined as any unexpected event resulting in the individual coming to rest on the ground, floor, or lower level. Orthostatic hypotension was diagnosed based on a systolic blood pressure reduction of ≥30 mmHg during the active stand test. Participants were categorized into four groups: Group 1: No OH, no falls Group 2: OH, no falls Group 3: No OH, with falls Group 4: OH, with falls Haemodynamic Monitoring Protocols All participants fasted for 10 hours before assessments and were instructed to continue taking prescribed medications. Continuous beat-to-beat blood pressure was monitored using a TaskForce® Monitor (CNSystems, Austria), utilizing the vascular unloading technique. The device was calibrated using oscillometric brachial blood pressure measurements. Cerebral blood flow velocity (CBFV) was assessed using a 2-MHz pulsed TCD probe (DWL DopplerBox®, Germany) to insonate the left middle cerebral artery via a transtemporal window. CBFV signals were synchronized with blood pressure and electrocardiogram (ECG) data. Cerebrovascular Resistance Calculation Cerebrovascular resistance (CVR) was derived from mean arterial pressure (MAP) and CBFV using the formula: CVR = MAP / CBFV Intracranial pressure was assumed to be stable and negligible across all participants. Experimental Challenge Protocols Three physiological challenge protocols were performed: Active Stand Test: After 5 minutes supine rest, participants stood upright within 3 seconds and remained standing for 3 minutes. CBFV and blood pressure data were collected throughout. Mental Arithmetic Test: Participants performed continuous serial subtractions from 100 in intervals of seven for 1 minute while seated. Valsalva Manoeuvre: Participants blew into a manometer to maintain 40 mmHg pressure for 15 seconds. Measurements were analyzed across the four standard phases of the Valsalva response. Data Analysis CBFV and blood pressure readings were extracted at predefined time points. MATLAB (MathWorks, USA) and SPSS (Version 26.0, IBM) were used for signal processing and statistical analysis. Analysis of variance (ANOVA) and linear regression were used to identify group differences and adjust for potential confounders such as age, sex, body mass index, and antihypertensive use. 3. Results A total of 40 participants were included in the final analysis. The distribution across the four groups was as follows: Group 1 (No OH, No Fall) – 22 participants (55%), Group 2 (OH, No Fall) – 8 participants (20%), Group 3 (No OH, Fall) – 6 participants (15%), and Group 4 (OH, Fall) – 4 participants (10%). Baseline demographic and clinical characteristics are summarized in Table 1.1. No statistically significant differences were found in age, gender, BMI, or cognitive scores across the groups. However, use of anti-Parkinsonian medication was more common in faller groups (p = 0.040). Haemodynamic Responses Across Protocols Haemodynamic variables collected during the active stand, mental arithmetic, and Valsalva manoeuvre protocols are presented in Table 1.2. During the active stand, a significant difference was observed in standing systolic blood pressure between groups (p = 0.036), with Group 2 and Group 4 displaying lower values compared to non-OH participant. Cerebrovascular Resistance Trends in Fig. 1 illustrates the mean CVR values across the 180-second active stand protocol. While Groups 1 and 2 demonstrated a relatively stable or slightly decreasing trend in CVR over time, Groups 3 and 4 exhibited minimal or no adaptive changes, indicating impaired autoregulatory capacity. Significant group differences in CVR were observed at the 165-second (p = 0.028) and 180-second (p = 0.023) time points during the active stand. These findings are detailed in Table 1.3. Notably, Group 3 (No OH, Fall) showed the greatest CVR reduction failure compared to Group 1. Mental Arithmetic and Valsalva Manoeuvre During the mental arithmetic test, CVR increased consistently in Group 1 and Group 2, reflecting intact cerebrovascular responsiveness to cognitive load. This pattern was disrupted in faller groups, which exhibited blunted or inconsistent CVR modulation (Fig. 2). In the Valsalva manoeuvre (Fig. 3), Group 2 exhibited a paradoxical rise in CVR during Phase 2B, contrasting with the expected drop seen in Group 1. This may indicate an enhanced baroreceptor-mediated vasoconstrictive response to counter intrathoracic pressure changes. Mean differences during each phase are reported in Table 1.3. Analysis of a multivariable regression model adjusting for age, standing systolic BP, and Parkinson’s medication use revealed that Group 2 had significantly lower CVR at 180 seconds compared to Group 1 (β = -0.213, 95% CI: 0.057–0.798, p < 0.05). Group 3 and 4 differences were not statistically significant after adjustment (Table 1.4). 4. Discussion This study explored the role of cerebral autoregulation in modulating symptomatic expression of orthostatic hypotension (OH) among older adults, particularly focusing on its relationship with falls. We observed that individuals with OH but no history of falls (Group 2) exhibited a preserved autoregulatory response, reflected by decreasing cerebrovascular resistance (CVR) over time during postural and cognitive challenges. In contrast, those who experienced falls (Groups 3 and 4) demonstrated impaired CVR modulation, regardless of the presence of OH. These findings underscore the potential for cerebral autoregulatory capacity to act as a buffer against symptomatic OH and fall risk. Our findings align with previous reports indicating that cerebral autoregulation remains an essential determinant of cerebral perfusion and symptomatology in older adults. Novak et al. showed that individuals with autonomic failure and OH who lacked symptoms had preserved cerebrovascular adaptability [ 1 ]. Similarly, Mankovsky et al. documented that diabetic patients with autonomic neuropathy exhibited altered CBFV responses during postural changes, consistent with impaired autoregulation [ 2 ]. What distinguishes our study is the community-based design and inclusion of asymptomatic individuals, broadening the generalizability of results. Most prior studies have relied on selected patient populations from neurology or cardiology clinics [ 3 , 4 ]. By utilizing challenge protocols—active stand, mental arithmetic, and Valsalva—we could assess dynamic cerebrovascular regulation in ecologically relevant scenarios. Mental arithmetic testing has been shown to elicit measurable changes in cerebral hemodynamics, offering a window into neurovascular reactivity [ 5 ]. The paradoxical increase in CVR during Phase 2B of the Valsalva manoeuvre in Group 2 is particularly noteworthy. While speculative, this may reflect an enhanced baroreceptor-mediated vasoconstrictive response to counter intrathoracic pressure increases, a mechanism that could preserve cerebral perfusion in OH. Similar autonomic adaptations have been suggested in younger adults with syncope resistance [ 6 ]. Although OH has been widely recognized as a fall risk factor, its predictive utility remains limited, with many asymptomatic cases [ 7 ]. Our study supports the idea that cerebral autoregulation may explain this discrepancy. Specifically, Group 3 (No OH, Fall) showed impaired CVR responses despite normotensive postural readings, indicating that impaired autoregulation can exist independently of OH. This is consistent with work by Finucane et al., who noted variability in symptomatic presentation among individuals with OH and highlighted cerebral perfusion metrics as more discriminative than peripheral blood pressure alone [ 8 ]. The study also identified an association between anti-Parkinsonian medication and fall risk, although this requires cautious interpretation given the small sample size. Parkinsonian syndromes are known to impair baroreflex sensitivity and cerebral vasomotor control [ 9 ], which may partly explain these findings. Our multivariate analysis further supports the hypothesis that preserved autoregulation, rather than systemic blood pressure alone, predicts functional resilience. After adjusting for age, standing BP, and medications, only Group 2 showed statistically significant CVR differences, reinforcing the protective effect of cerebral autoregulatory capacity. Limitations of this study include its small sample size and the reliance on transcranial Doppler, which provides blood flow velocity rather than absolute cerebral blood flow. Moreover, the cross-sectional nature of the data limits causal inference. Nonetheless, the findings provide a strong rationale for future studies and clinical applications. Assessment of cerebral autoregulation could be integrated into fall risk screening for older adults, especially those with OH. Interventions such as physical therapy, cardiovascular conditioning, and neurofeedback that enhance autoregulatory function may reduce fall risk and improve quality of life in this population. 5. Conclusion Our findings suggest that preserved cerebral autoregulation differentiates asymptomatic OH from symptomatic OH associated with falls. This autoregulatory integrity may play a protective role in older adults, mitigating the cerebral hypoperfusion effects of blood pressure fluctuations. By integrating cerebrovascular resistance assessments into clinical evaluations, healthcare providers may better identify those at elevated fall risk, even in the absence of overt OH. Future research should further explore interventions that support or enhance autoregulatory function to reduce morbidity among older populations. Declarations Author Contributions Nor I’zzati Saedon: Conceptualization, data collection, data analysis, manuscript drafting. Wan Azman Wan Ahmad: Cardiovascular supervision, critical manuscript review. James Frith: Methodological guidance, data interpretation, manuscript editing. Tan Maw Pin: Project oversight, conceptual development, final approval of manuscript. Funding This work was supported by the University of Malaya, Clinical and Health Sciences Research Grant (FRGS/1/2016/SKK02/UM/02/1). Acknowledgments We thank all participants and staff of the MELoR study for their valuable contributions. Special appreciation is extended to the technical teams involved in transcranial Doppler and cardiovascular assessments. Conflicts of Interest The authors declare no conflicts of interest. References Novak V, Novak P, Spies JM, Low PA. Autoregulation of cerebral blood flow in orthostatic hypotension. Stroke. 1998;29(1):104–11. Mankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension. Diabet Med. 2003;20(2):119–26. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21(2):69–72. Lipsitz LA. Orthostatic hypotension in the elderly. N Engl J Med. 1989;321(14):952–7. Ogoh S, Ainslie PN. Cerebral blood flow during exercise: mechanisms of regulation. J Appl Physiol. 2009;107(5):1370–80. Verheyden B, Liu J, Beckers F, Aubert AE, Flandre TD. Autonomic responses to head-up tilt in patients with vasovagal syncope. Clin Auton Res. 2008;18(3):130–6. Saedon NI, Frith J, Goh CH, Shahar S, Kamaruzzaman SB, Tan MP. Orthostatic blood pressure changes and physical, functional and cognitive performance: the MELoR study. Clin Auton Res. 2020;30(2):129–37. Finucane C, O’Connell MDL, Fan CW, Savva GM, Soraghan CJ, Nolan H, et al. Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA). Circulation. 2014;130(20):1780–9. Hauser RA, Isaacson SH, Barone P. Roles of the peripheral autonomic nervous system in Parkinson’s disease. Mov Disord. 2011;26(5):656–64. Tables Tables 1.1 to 1.4 are available in the Supplementary Files section Supplementary Files Tables.pdf Cite Share Download PDF Status: Published Journal Publication published 08 Sep, 2025 Read the published version in Clinical Autonomic Research → Version 1 posted Reviewers agreed at journal 06 May, 2025 Reviewers invited by journal 05 May, 2025 Editor assigned by journal 03 May, 2025 First submitted to journal 28 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6460238","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":452299453,"identity":"d6b7e8ec-864b-4b89-84dd-e18fcdea70fe","order_by":0,"name":"Nor Izzati Saedon","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBACNjBpYIPCJULLAYM0ErSAwQGGwyRo4eM//vDzh4LziWunHX7A8KHsMIPujARCDjuQLHHA4HbitttpBowzzh1mMLtBSAtjwwGolhwGZt42YrQwMzb/OGBwDqLlL1Fa2JjZgLYcgGhhJEoLDxubxRmDZGOQXw72nEvnMTvzAL8W+f7jj29U/LGT3XY7+eGDH2XWcmbHCdiCAg4AMQ+DAClaIID/AMlaRsEoGAWjYHgDABUORwtrZTg4AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-6634-7934","institution":"University of Malaya","correspondingAuthor":true,"prefix":"","firstName":"Nor","middleName":"Izzati","lastName":"Saedon","suffix":""},{"id":452299454,"identity":"1931a2b3-9e39-4ead-ab8d-2a62c0470be8","order_by":1,"name":"James Frith","email":"","orcid":"","institution":"Newcastle University","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Frith","suffix":""},{"id":452299455,"identity":"1748c54c-4a91-4fbb-8f9a-c0c87e20a734","order_by":2,"name":"WAN AZMAN WAN AHMAD","email":"","orcid":"","institution":"Universiti Malaya Fakulti Perubatan: Universiti Malaya Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"WAN","middleName":"AZMAN WAN","lastName":"AHMAD","suffix":""},{"id":452299456,"identity":"3ef55716-0b0e-4ab9-908f-65c513ad6064","order_by":3,"name":"MAW PIN TAN","email":"","orcid":"","institution":"Universiti Malaya Fakulti Perubatan: Universiti Malaya Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"MAW","middleName":"PIN","lastName":"TAN","suffix":""}],"badges":[],"createdAt":"2025-04-16 06:41:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6460238/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6460238/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10286-025-01152-6","type":"published","date":"2025-09-08T15:57:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82562034,"identity":"62f9f147-9288-43b0-844c-def5a9f80610","added_by":"auto","created_at":"2025-05-13 01:41:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84125,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6460238/v1/e6b04ee9e1b40f00ba424641.png"},{"id":82560298,"identity":"772c9c07-4b89-457d-ab0c-9c864a4dda1c","added_by":"auto","created_at":"2025-05-13 01:33:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":59041,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6460238/v1/820e4e73a8f69807a2f117d7.png"},{"id":82560300,"identity":"4f968227-4f60-4773-9eb0-06b97247b933","added_by":"auto","created_at":"2025-05-13 01:33:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52399,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6460238/v1/6a18eb31daaceed5b18d320b.png"},{"id":91359178,"identity":"ab14e62c-a2eb-4bf1-9484-a00fe7d5e5c9","added_by":"auto","created_at":"2025-09-15 16:05:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":440817,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6460238/v1/8049e31e-8bf8-4b6d-81f5-f40bd5ec3cc9.pdf"},{"id":82560304,"identity":"43f0a207-1e0f-44da-90db-33164c2f55f2","added_by":"auto","created_at":"2025-05-13 01:33:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":81248,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6460238/v1/1cc4c81cebde60c81e3fdf6c.pdf"}],"financialInterests":"","formattedTitle":"Cerebral Autoregulation in Orthostatic Hypotension and Falls Among Older Adults: A Community-Based Exploratory Study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOrthostatic hypotension (OH), defined as a sustained drop in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg upon standing, is a common and under-recognized clinical condition in older adults. It affects up to 30% of the community-dwelling older population and is associated with adverse outcomes such as falls, fractures, cognitive impairment, and increased mortality. Given the global aging demographic, understanding the mechanisms that underlie the variability in symptom manifestation among those with OH is of increasing public health relevance.\u003c/p\u003e \u003cp\u003eWhile OH is traditionally diagnosed through peripheral haemodynamic monitoring, there is growing interest in understanding the central nervous system's role in modulating its impact. One of the key physiological mechanisms in this context is cerebral autoregulation. Cerebral autoregulation refers to the brain's intrinsic ability to maintain a relatively constant cerebral blood flow (CBF) despite changes in systemic blood pressure, within a defined range of perfusion pressures. This protective mechanism ensures stable oxygen and nutrient delivery to brain tissue, safeguarding cognitive and motor functions.\u003c/p\u003e \u003cp\u003eAging and associated comorbidities, including diabetes, hypertension, and neurodegenerative diseases, are known to impair the efficiency of cerebral autoregulatory mechanisms. The interplay between impaired autoregulation and systemic hypotension could exacerbate cerebral hypoperfusion, leading to symptoms such as dizziness, syncope, and falls. However, not all individuals with OH report symptoms, suggesting that compensatory cerebrovascular mechanisms may modulate clinical expression.\u003c/p\u003e \u003cp\u003ePrevious studies have explored cerebral autoregulation in pathological states. For instance, Novak et al. showed variability in autoregulatory responses among patients with autonomic failure and OH, noting that symptoms were absent in those with preserved cerebrovascular adaptation despite hypotension. Similarly, Mankovsky et al. found that diabetic patients with autonomic neuropathy and OH exhibited impaired cerebral blood flow velocity regulation during postural changes. However, these studies were largely hospital-based and focused on select patient groups, limiting generalizability.\u003c/p\u003e \u003cp\u003eOur study aims to bridge this gap by evaluating cerebral autoregulation in a population-based sample of older adults with and without OH, and with varying fall histories. We employed a series of challenge protocols to assess dynamic changes in cerebrovascular resistance (CVR) and explored their association with symptomatic expression, particularly falls. We hypothesize that preserved cerebral autoregulation differentiates asymptomatic from symptomatic OH and may serve as a potential therapeutic target in fall prevention strategies.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eStudy Design and Setting\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis was a cross-sectional, observational study conducted at the University of Malaya Medical Centre in Kuala Lumpur, Malaysia. Ethical approval was obtained from the institutional review board, and all participants provided written informed consent prior to participation. The study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eParticipants and Recruitment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants were drawn from the Malaysian Elders Longitudinal Research (MELoR) cohort, a community-based longitudinal study focusing on aging and functional health in older adults. Additional participants were recruited through outpatient clinics and local advertisements. Inclusion criteria included age \u0026ge;55 years, ability to provide informed consent, and physical capacity to undergo protocol assessments. Exclusion criteria were the presence of known focal neurological deficits, prior history of significant carotid stenosis, or the inability to obtain a suitable transtemporal window for transcranial Doppler (TCD) measurement.\u003c/p\u003e\n\u003cp\u003eClinical Assessment and Grouping Detailed\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical interviews were conducted to document demographics, comorbidities, medication use, and history of falls within the previous 12 months. Falls were defined as any unexpected event resulting in the individual coming to rest on the ground, floor, or lower level. Orthostatic hypotension was diagnosed based on a systolic blood pressure reduction of \u0026ge;30 mmHg during the active stand test. Participants were categorized into four groups:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eGroup 1: No OH, no falls\u003c/li\u003e\n \u003cli\u003eGroup 2: OH, no falls\u003c/li\u003e\n \u003cli\u003eGroup 3: No OH, with falls\u003c/li\u003e\n \u003cli\u003eGroup 4: OH, with falls\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eHaemodynamic Monitoring Protocols\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll participants fasted for 10 hours before assessments and were instructed to continue taking prescribed medications. Continuous beat-to-beat blood pressure was monitored using a TaskForce\u0026reg; Monitor (CNSystems, Austria), utilizing the vascular unloading technique. The device was calibrated using oscillometric brachial blood pressure measurements.\u003c/p\u003e\n\u003cp\u003eCerebral blood flow velocity (CBFV) was assessed using a 2-MHz pulsed TCD probe (DWL DopplerBox\u0026reg;, Germany) to insonate the left middle cerebral artery via a transtemporal window. CBFV signals were synchronized with blood pressure and electrocardiogram (ECG) data.\u003c/p\u003e\n\u003cp\u003eCerebrovascular Resistance Calculation Cerebrovascular resistance (CVR) was derived from mean arterial pressure (MAP) and CBFV using the formula: CVR = MAP / CBFV Intracranial pressure was assumed to be stable and negligible across all participants.\u003c/p\u003e\n\u003cp\u003eExperimental Challenge Protocols\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThree physiological challenge protocols were performed:\u003c/p\u003e\n\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eActive Stand Test: After 5 minutes supine rest, participants stood upright within 3 seconds and remained standing for 3 minutes. CBFV and blood pressure data were collected throughout.\u003c/li\u003e\n \u003cli\u003eMental Arithmetic Test: Participants performed continuous serial subtractions from 100 in intervals of seven for 1 minute while seated.\u003c/li\u003e\n \u003cli\u003eValsalva Manoeuvre: Participants blew into a manometer to maintain 40 mmHg pressure for 15 seconds. Measurements were analyzed across the four standard phases of the Valsalva response.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eData Analysis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCBFV and blood pressure readings were extracted at predefined time points. MATLAB (MathWorks, USA) and SPSS (Version 26.0, IBM) were used for signal processing and statistical analysis. Analysis of variance (ANOVA) and linear regression were used to identify group differences and adjust for potential confounders such as age, sex, body mass index, and antihypertensive use.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eA total of 40 participants were included in the final analysis. The distribution across the four groups was as follows: Group 1 (No OH, No Fall) \u0026ndash; 22 participants (55%), Group 2 (OH, No Fall) \u0026ndash; 8 participants (20%), Group 3 (No OH, Fall) \u0026ndash; 6 participants (15%), and Group 4 (OH, Fall) \u0026ndash; 4 participants (10%). Baseline demographic and clinical characteristics are summarized in Table\u0026nbsp;1.1. No statistically significant differences were found in age, gender, BMI, or cognitive scores across the groups. However, use of anti-Parkinsonian medication was more common in faller groups (p\u0026thinsp;=\u0026thinsp;0.040). Haemodynamic Responses Across Protocols Haemodynamic variables collected during the active stand, mental arithmetic, and Valsalva manoeuvre protocols are presented in Table\u0026nbsp;1.2. During the active stand, a significant difference was observed in standing systolic blood pressure between groups (p\u0026thinsp;=\u0026thinsp;0.036), with Group 2 and Group 4 displaying lower values compared to non-OH participant. Cerebrovascular Resistance Trends in Fig.\u0026nbsp;1 illustrates the mean CVR values across the 180-second active stand protocol. While Groups 1 and 2 demonstrated a relatively stable or slightly decreasing trend in CVR over time, Groups 3 and 4 exhibited minimal or no adaptive changes, indicating impaired autoregulatory capacity.\u003c/p\u003e \u003cp\u003eSignificant group differences in CVR were observed at the 165-second (p\u0026thinsp;=\u0026thinsp;0.028) and 180-second (p\u0026thinsp;=\u0026thinsp;0.023) time points during the active stand. These findings are detailed in Table\u0026nbsp;1.3. Notably, Group 3 (No OH, Fall) showed the greatest CVR reduction failure compared to Group 1. Mental Arithmetic and Valsalva Manoeuvre During the mental arithmetic test, CVR increased consistently in Group 1 and Group 2, reflecting intact cerebrovascular responsiveness to cognitive load. This pattern was disrupted in faller groups, which exhibited blunted or inconsistent CVR modulation (Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eIn the Valsalva manoeuvre (Fig.\u0026nbsp;3), Group 2 exhibited a paradoxical rise in CVR during Phase 2B, contrasting with the expected drop seen in Group 1. This may indicate an enhanced baroreceptor-mediated vasoconstrictive response to counter intrathoracic pressure changes. Mean differences during each phase are reported in Table\u0026nbsp;1.3. Analysis of a multivariable regression model adjusting for age, standing systolic BP, and Parkinson\u0026rsquo;s medication use revealed that Group 2 had significantly lower CVR at 180 seconds compared to Group 1 (β = -0.213, 95% CI: 0.057\u0026ndash;0.798, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Group 3 and 4 differences were not statistically significant after adjustment (Table\u0026nbsp;1.4).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study explored the role of cerebral autoregulation in modulating symptomatic expression of orthostatic hypotension (OH) among older adults, particularly focusing on its relationship with falls. We observed that individuals with OH but no history of falls (Group 2) exhibited a preserved autoregulatory response, reflected by decreasing cerebrovascular resistance (CVR) over time during postural and cognitive challenges. In contrast, those who experienced falls (Groups 3 and 4) demonstrated impaired CVR modulation, regardless of the presence of OH. These findings underscore the potential for cerebral autoregulatory capacity to act as a buffer against symptomatic OH and fall risk.\u003c/p\u003e \u003cp\u003eOur findings align with previous reports indicating that cerebral autoregulation remains an essential determinant of cerebral perfusion and symptomatology in older adults. Novak et al. showed that individuals with autonomic failure and OH who lacked symptoms had preserved cerebrovascular adaptability [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Similarly, Mankovsky et al. documented that diabetic patients with autonomic neuropathy exhibited altered CBFV responses during postural changes, consistent with impaired autoregulation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhat distinguishes our study is the community-based design and inclusion of asymptomatic individuals, broadening the generalizability of results. Most prior studies have relied on selected patient populations from neurology or cardiology clinics [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. By utilizing challenge protocols\u0026mdash;active stand, mental arithmetic, and Valsalva\u0026mdash;we could assess dynamic cerebrovascular regulation in ecologically relevant scenarios. Mental arithmetic testing has been shown to elicit measurable changes in cerebral hemodynamics, offering a window into neurovascular reactivity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe paradoxical increase in CVR during Phase 2B of the Valsalva manoeuvre in Group 2 is particularly noteworthy. While speculative, this may reflect an enhanced baroreceptor-mediated vasoconstrictive response to counter intrathoracic pressure increases, a mechanism that could preserve cerebral perfusion in OH. Similar autonomic adaptations have been suggested in younger adults with syncope resistance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough OH has been widely recognized as a fall risk factor, its predictive utility remains limited, with many asymptomatic cases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our study supports the idea that cerebral autoregulation may explain this discrepancy. Specifically, Group 3 (No OH, Fall) showed impaired CVR responses despite normotensive postural readings, indicating that impaired autoregulation can exist independently of OH. This is consistent with work by Finucane et al., who noted variability in symptomatic presentation among individuals with OH and highlighted cerebral perfusion metrics as more discriminative than peripheral blood pressure alone [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study also identified an association between anti-Parkinsonian medication and fall risk, although this requires cautious interpretation given the small sample size. Parkinsonian syndromes are known to impair baroreflex sensitivity and cerebral vasomotor control [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], which may partly explain these findings.\u003c/p\u003e \u003cp\u003eOur multivariate analysis further supports the hypothesis that preserved autoregulation, rather than systemic blood pressure alone, predicts functional resilience. After adjusting for age, standing BP, and medications, only Group 2 showed statistically significant CVR differences, reinforcing the protective effect of cerebral autoregulatory capacity.\u003c/p\u003e \u003cp\u003eLimitations of this study include its small sample size and the reliance on transcranial Doppler, which provides blood flow velocity rather than absolute cerebral blood flow. Moreover, the cross-sectional nature of the data limits causal inference. Nonetheless, the findings provide a strong rationale for future studies and clinical applications.\u003c/p\u003e \u003cp\u003eAssessment of cerebral autoregulation could be integrated into fall risk screening for older adults, especially those with OH. Interventions such as physical therapy, cardiovascular conditioning, and neurofeedback that enhance autoregulatory function may reduce fall risk and improve quality of life in this population.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eOur findings suggest that preserved cerebral autoregulation differentiates asymptomatic OH from symptomatic OH associated with falls. This autoregulatory integrity may play a protective role in older adults, mitigating the cerebral hypoperfusion effects of blood pressure fluctuations. By integrating cerebrovascular resistance assessments into clinical evaluations, healthcare providers may better identify those at elevated fall risk, even in the absence of overt OH. Future research should further explore interventions that support or enhance autoregulatory function to reduce morbidity among older populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eNor I\u0026rsquo;zzati Saedon: Conceptualization, data collection, data analysis, manuscript drafting.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Wan Azman Wan Ahmad: Cardiovascular supervision, critical manuscript review.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;James Frith: Methodological guidance, data interpretation, manuscript editing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Tan Maw Pin: Project oversight, conceptual development, final approval of manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the University of Malaya, Clinical and Health Sciences Research Grant (FRGS/1/2016/SKK02/UM/02/1).\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe thank all participants and staff of the MELoR study for their valuable contributions. Special appreciation is extended to the technical teams involved in transcranial Doppler and cardiovascular assessments.\u003c/p\u003e\n\u003cp\u003eConflicts of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNovak V, Novak P, Spies JM, Low PA. Autoregulation of cerebral blood flow in orthostatic hypotension. Stroke. 1998;29(1):104\u0026ndash;11.\u003c/li\u003e\n \u003cli\u003eMankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension. Diabet Med. 2003;20(2):119\u0026ndash;26.\u003c/li\u003e\n \u003cli\u003eFreeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21(2):69\u0026ndash;72.\u003c/li\u003e\n \u003cli\u003eLipsitz LA. Orthostatic hypotension in the elderly. N Engl J Med. 1989;321(14):952\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eOgoh S, Ainslie PN. Cerebral blood flow during exercise: mechanisms of regulation. J Appl Physiol. 2009;107(5):1370\u0026ndash;80.\u003c/li\u003e\n \u003cli\u003eVerheyden B, Liu J, Beckers F, Aubert AE, Flandre TD. Autonomic responses to head-up tilt in patients with vasovagal syncope. Clin Auton Res. 2008;18(3):130\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eSaedon NI, Frith J, Goh CH, Shahar S, Kamaruzzaman SB, Tan MP. Orthostatic blood pressure changes and physical, functional and cognitive performance: the MELoR study. Clin Auton Res. 2020;30(2):129\u0026ndash;37.\u003c/li\u003e\n \u003cli\u003eFinucane C, O\u0026rsquo;Connell MDL, Fan CW, Savva GM, Soraghan CJ, Nolan H, et al. Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA). Circulation. 2014;130(20):1780\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eHauser RA, Isaacson SH, Barone P. Roles of the peripheral autonomic nervous system in Parkinson\u0026rsquo;s disease. Mov Disord. 2011;26(5):656\u0026ndash;64.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1.1 to 1.4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Orthostatic hypotension, cerebral autoregulation, falls, older adults, cerebral blood flow","lastPublishedDoi":"10.21203/rs.3.rs-6460238/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6460238/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Orthostatic hypotension (OH) is prevalent in older adults and is often associated with falls. However, the presence or absence of symptoms in OH may be mediated by cerebral autoregulation, which helps maintain cerebral perfusion during blood pressure fluctuations.\u003c/p\u003e\n\u003cp\u003eMethods: We recruited 40 older adults (aged ≥55 years) from the Malaysian Elders Longitudinal Research (MELoR) cohort. Participants underwent cerebral blood flow velocity monitoring using transcranial Doppler ultrasonography and beat-to-beat blood pressure recording. Three protocols were used: active stand, mental arithmetic, and Valsalva manoeuvre. Participants were categorized based on OH (≥30 mmHg systolic drop) and fall history into four groups. Cerebrovascular resistance (CVR) was derived and analyzed.\u003c/p\u003e\n\u003cp\u003eResults: Participants with OH but no history of falls demonstrated preserved autoregulatory responses, as reflected by adaptive reductions in CVR. In contrast, fallers—regardless of OH status—had impaired CVR modulation. Significant group differences were found during the active stand test at 165s and 180s (p\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003eConclusion: Preserved cerebral autoregulation may protect older adults with OH from symptomatic manifestations such as falls. Targeting cerebral autoregulation could offer novel approaches for preventing falls in this population.\u003c/p\u003e","manuscriptTitle":"Cerebral Autoregulation in Orthostatic Hypotension and Falls Among Older Adults: A Community-Based Exploratory Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 01:33:43","doi":"10.21203/rs.3.rs-6460238/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-05-06T18:55:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-05T22:38:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-03T04:22:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2025-04-28T10:08:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c1b1db36-a177-4275-a432-97eeee39c8d6","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-15T16:04:30+00:00","versionOfRecord":{"articleIdentity":"rs-6460238","link":"https://doi.org/10.1007/s10286-025-01152-6","journal":{"identity":"clinical-autonomic-research","isVorOnly":false,"title":"Clinical Autonomic Research"},"publishedOn":"2025-09-08 15:57:06","publishedOnDateReadable":"September 8th, 2025"},"versionCreatedAt":"2025-05-13 01:33:43","video":"","vorDoi":"10.1007/s10286-025-01152-6","vorDoiUrl":"https://doi.org/10.1007/s10286-025-01152-6","workflowStages":[]},"version":"v1","identity":"rs-6460238","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6460238","identity":"rs-6460238","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}