To systematically evaluate the role of left atrial low-voltage areas (LVA) as a preoperative risk marker of atrial fibrillation/atrial tachycardia (AF/AT) recurrence following pulmonary vein isolation (PVI) in patients with non-valvular AF. A comprehensive literature search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted up to November 29, 2025, to identify eligible cohort studies assessing AF/AT recurrence outcomes in patients undergoing PVI. Random- or fixed-effects models were used to calculate pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup and meta-regression analyses were performed to explore the sources of heterogeneity. Study quality was assessed using the Newcastle-Ottawa Scale. A meta-analysis of 15 observational studies (n = 3,957) was performed to assess the association between LVA (defined as bipolar voltage < 0.5 mV) and post-PVI recurrence of AF/AT. LVA presence was significantly associated with an increased risk of AF/AT recurrence. The overall pooled estimate yielded an OR of 2.35 (95% CI: 1.86-2.97), while the adjusted OR following trim-and-fill correction for publication bias was 1.86 (95% CI: 1.47-2.36). Subgroup analysis revealed that LVA had the strongest association with AF/AT recurrence in mixed AF cohorts (paroxysmal and persistent AF), with a pooled OR of 2.75 (95% CI: 2.01-3.77). In pure persistent AF cohorts, the association was attenuated (OR = 1.63, 95% CI: 1.20-2.21). Studies that stratified patients by LVA burden (high vs. low) demonstrated a stronger association with recurrence (pooled OR = 2.74, 95% CI: 2.01-3.74) compared to those using a simple presence/absence classification. LVA is associated with AF/AT recurrence after PVI, with both the presence of LVA and its extent (burden) independently influencing recurrence risk. This supports the use of LVA in preoperative risk stratification and individualized treatment strategies.

Pure autonomic failure (PAF) can be the prodromal presentation of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), although phenoconversion rates and predictors have not been systematically reported. To estimate phenoconversion rates for MSA, PD, and DLB separately and grouped as central α-synucleinopathies and identify clinical predictors of phenoconversion in patients with PAF. PubMed and Embase databases from inception to June 2025. Longitudinal studies including patients with confirmed PAF reporting data on incidence and/or predictors of phenoconversion. Studies were screened and data extracted by 2 independent investigators according to PRISMA guidelines. A meta-analysis was performed using generic inverse-variance random-effects models. PD, DLB, MSA, and central α-synucleinopathy phenoconversion incidence rates as per 100 person-years were the main outcomes. Incidence rates were log transformed and pooled using a random-effects meta-analysis. Clinical predictors of phenoconversion were reported as secondary outcomes. Prediction intervals and meta-regression explored study-level moderators. A total of 9 studies comprising 900 individuals with PAF (mean [SD] age at onset, 63.1 [4.3] years; 63.8% male) were included. During the mean (SD) 6.4 (2.0) years of follow-up, 270 of 900 individuals with PAF (30%) experienced phenoconversion to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD) with a pooled incidence rate of 5.09 per 100 person-years (95% CI, 3.79-6.85; approximately 5% per year). Phenoconversion rates for MSA (pooled incidence rate, 1.96; 95% CI, 1.29-2.99) were highest in the first years of follow-up, whereas Lewy body disorders showed more constant phenoconversion rates (DLB pooled incidence rate, 1.56; 95% CI, 0.94-2.61; PD pooled incidence rate, 1.35; 95% CI, 0.75-2.41). Hyposmia was the only predictor with diagnostic value to distinguish between those with phenoconversion to PD and DLB (hyposmia pooled risk ratio, 1.88; 95% CI, 1.26-2.97) and MSA, although rapid eye movement sleep behavior disorder (RBD) and subtle motor signs were consistent predictors of phenoconversion to any central α-synucleinopathy. Heterogeneity was partly explained by follow-up duration. Findings of this systematic review and meta-analysis suggest that PAF may be a prodromal presentation of PD, DLB, or MSA with phenoconversion incidence rates similar to those of RBD. A combination of clinical (RBD, subtle motor signs, hyposmia) and in-development biomarkers may help refine the phenoconversion trajectories of people with PAF providing an invaluable opportunity for early diagnosis and intervention.

Differential patterns of central synucleinopathy and catecholaminergic abnormalities in Lewy body diseases and multiple system atrophy.

We reported a middle-aged man who initially presented with anhidrosis for 20 years and subsequently developed severe orthostatic hypotension, gastrointestinal dysmotility, and urogenital dysfunction. Due to progressive symptom aggravation, he was hospitalized and underwent comprehensive clinical assessment, neurophysiological studies, autonomic function tests, and multidisciplinary team (MDT) evaluation. The final diagnosis was pure autonomic failure (PAF). This case describes in detail the patient's long diagnostic course, differential diagnostic reasoning, the pivotal role of MDT management, and individualized treatment strategies and outcomes. The report aims to enhance the understanding of primary autonomic disorders characterized by neurogenic orthostatic hypotension for physicians, emphasizing the importance of systematic etiological screening and multidisciplinary collaboration in rare disease diagnosis and management to reduce misdiagnosis and improve prognosis and quality of life.

BackgroundLewy Body pathology can be detected by alpha-synuclein-Seed Amplification Assay (αSyn-SAA) in cerebrospinal fluid (CSF) with high sensitivity and specificity in cohort studies. Yet, little is known about the results that can be expected from αSyn-SAA in CSF in samples outside cohort studies as obtained in clinical routine.ObjectiveThis study analyzed the concordance of αSyn-SAA findings in CSF with clinical diagnosis in patients from clinical routine with diverse neurologic and psychiatric conditions.MethodsIn this cross-sectional study, CSF from patients who underwent lumbar puncture for therapeutic or diagnostic purposes were tested in αSyn-SAA. Analysis included binary αSyn-SAA findings, data collected during neurological examination, and structured medical history.ResultsAll 356 participants (Mean Age 67.1 years, SD = 16.2; 55.9% male) were included in the primary analysis, including 90 patients with Parkinsonian syndromes, 139 with predominant cognitive disorders, 25 with other movement disorders, 35 with inflammatory or (para)neoplastic syndromes, and 67 with further diseases. αSyn-SAA was positive in all samples from patients with Parkinson's disease (41), dementia with Lewy bodies (30), pure autonomic failure (4), and in a subset of patients with Alzheimer's disease (13/46), normal pressure hydrocephalus (7/14) and others.ConclusionsαSyn-SAA findings show high concordance with a clinical diagnosis of PD and DLB. Findings are comparable to results from well-characterized cohort studies, supporting potential diagnostic value in future clinical routine. Challenges may result from the fact that αSyn-SAA detect LB co-pathology that is known from neuropathological studies for several neurodegenerative diseases.

Parkinson's disease (PD) and associated synucleinopathies are preceded by a prolonged prodromal phase during which neurodegenerative processes evolve years before the onset of motor or cognitive symptoms. Identifying biologically specific and accessible biomarkers during this window is critical for early diagnosis, risk stratification, and the development of disease-modifying therapies. Increasing evidence supports the skin as a key peripheral tissue involved in synucleinopathy, offering a minimally invasive source for in vivo detection of pathological α-synuclein. This review summarizes current evidence on skin-derived biomarkers across the prodromal continuum of PD, with particular emphasis on skin biopsy-based detection of phosphorylated α-synuclein and α-synuclein seed amplification assays (SAAs). Findings in high-risk prodromal phenotypes, including idiopathic REM sleep behavior disorder (iRBD) and pure autonomic failure (PAF), are critically reviewed. Emerging data suggest that cutaneous α-synuclein pathology may precede nigrostriatal dopaminergic degeneration and may predict phenoconversion to overt synucleinopathies. Important knowledge gaps are highlighted, including the lack of data in other prodromal phenotypes such as hyposmia. Overall, skin-based biomarkers appear to represent promising, scalable tools for biological diagnosis, prognostication, and enrichment of prodromal PD cohorts in clinical trials.

Liquid chromatography with electrochemical detection (LC-ED) after batch alumina extraction has been the mainstay for assaying levels of catecholamines and related 3,4-dihydroxy compounds (catechols) as part of the clinical laboratory workup of patients with neurogenic orthostatic hypotension, especially in the setting of the autonomic synucleinopathies Parkinson disease with orthostatic hypotension (PD + OH), pure autonomic failure (PAF), and multiple system atrophy (MSA). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is faster and measures catechols and non-catechol metabolites simultaneously but has not yet been validated sufficiently against LC-ED or used to assess catechol vs. non-catechol neurochemical abnormalities in autonomic synucleinopathies. We measured plasma catechols by LC-MS/MS and LC-ED in patients with PAF, PD + OH, or MSA and healthy controls. Cardiac sympathetic neuroimaging by 18F-dopamine positron emission tomography (PET) was used to indicate myocardial norepinephrine (NE) content in the same subjects. Across 41 participants (12 PAF, 9 PD + OH, 10 MSA, 10 controls) individual values for plasma 3,4-dihydroxyphenylglycol (DHPG), NE, and 3,4-dihydroxyphenylalanine (DOPA) by LC-MS/MS correlated positively with values by LC-ED (r = 0.97, 0.98, and 1.00, p < 0.0001 each). The PAF group had low mean NE, DHPG, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, epinephrine, and metanephrine compared to the PD + OH group, while cardiac PET did not separate the 2 groups. We therefore conclude that LC-MS/MS validly assays plasma catechols. Several catechol and non-catechol biomarkers of generalized catecholamine deficiency separate PAF from PD + OH but not PD + OH from MSA, while 18F-dopamine PET separates PAF and PD + OH from MSA but not PAF from PD + OH. Combining LC-MS/MS with cardiac sympathetic neuroimaging efficiently differentiates among these conditions.

Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing.

Quality of life and disability in pure autonomic failure: More than a prodromal synucleinopathy.

BackgroundIodine‐131‐meta‐iodobenzylguanidine (131I‐MIBG) cardiac scintigraphy is a nuclear medicine technique used to assess the function of the sympathetic nervous system in the heart. Decreased myocardial 131I‐MIBG uptake has been reported in some patients with neurodegenerative diseases. The purpose of this study was to compare sympathetic denervation in the myocardium across various neurodegenerative diseases.MethodWe recruited 222 patients with Parkinson's Disease (PD), 37 with Parkinson's Disease Dementia (PDD), 10 with Dementia with Lewy Bodies (DLB), 116 with Multiple System Atrophy (MSA), 14 with Pure Autonomic Failure (PAF), 9 with Progressive Supranuclear Palsy (PSP), and 63 with Parkinsonian Syndrome (PDS). The heart‐to‐mediastinum ratio (H/M ratio) at 15 minutes and 4 hours post‐injection of 131I‐MIBG cardiac scintigraphy was calculated and compared among the neurodegenerative disease groups mentioned above.ResultPatients with PD, PDD, and DLB had significantly lower H/M ratios for both early and delayed images than those with PAF, MSA, PSP, and PDS (p < 0.05). Moreover, patients with PDD and DLB demonstrated significantly reduced H/M ratios in both imaging sessions compared to those with PD (p < 0.05). However, no significant differences were observed between the PDD and DLB groups.Conclusion131I‐MIBG cardiac scintigraphy is a valuable research tool for enhancing our understanding of autonomic nervous system involvement in neurodegenerative diseases. Patients with PDD and DLB showed lower cardiac MIBG uptake than those with PD. Our findings indicate a novel perspective on the potential differences in pathological changes among PD, PDD, and DLB.

Abstract Background A transient drop of blood pressure (BP) shortly after moving from seated or supine position to standing is a physiologic occurrence that most often goes unnoticed. However, near-syncope or falls may occur if the BP drop is sufficiently severe (usually considered a systolic BP drop ≥40mmHg) in which case it is termed 'initial' or 'immediate' orthostatic hypotension (iOH). In health, the BP drop in iOH is accompanied by an increased heart rate (HR) that contributes to hemodynamic recovery. However, while in patients with major autonomic disturbances such as those with Pure Autonomic Failure (PAF) a limited chronotropic compensation may be expected to aggravate iOH severity, the impact of a diminished HR response has yet to be systematically studied. Purpose To evaluate the relationship between magnitude of BP drop and compensatory HR changes during active standing in PAF patients compared to healthy controls, expressed as the normalized HR response per mmHg of systolic BP drop (ΔHR/ΔSBP). Methods The study cohort comprised PAF patients (n=14) and healthy controls (n=24) undergoing autonomic evaluation. Continuous beat-to-beat HR and BP were monitored during a standardized active standing test. Changes in systolic BP (SBP), heart rate (HR), and the ratio of HR change normalized per mmHg BP drop (ΔHR/ΔSBP) were compared between groups. Statistical analysis was performed using t-test for normally distributed data and Mann-Whitney U test for non-normally distributed data, with p&amp;lt;0.05 considered statistically significant. Results Both PAF patients and controls exhibited significant immediate BP drop from baseline values with active standing, with PAF patients tending to show a more pronounced decline in SBP compared to controls (ΔSBP: -38±16 vs -33±14 mmHg, p=0.38). However, despite the greater SBP fall, PAF patients had a lesser HR response (ΔHR: +8±9 vs +19±11 bpm, p=0.01) compared to controls. Consequently, the ΔHR/ΔSBP ratio was significantly lower in PAF patients (PAF: 0.25±0.27 vs. Controls: 0.81±1.27 bpm/mmHg, p=0.01) (Figure). The interquartile range was also markedly different between PAF patients (0.14, 0.25) and controls (0.33, 0.58), indicating a consistently impaired chronotropic response in PAF. Conclusion Our findings reveal that PAF patients exhibit significantly impaired HR compensation in iOH relative to the magnitude of orthostatic BP drop when compared to healthy controls. This diminished chronotropic response may be due to impaired baroreflex-mediated feedback and likely contributes to the symptom burden associated with orthostatic intolerance in PAF. Further, the ΔHR/ΔSBP ratio provides a quantitative assessment that may be a useful additional tool to assess severity of cardiovascular autonomic disturbance in a range of symptomatic patients.Figure 1

Background/Introduction: Immediate/Initial orthostatic hypotension (iOH) presents as an abnormal transient blood pressure (BP) decrease immediately upon assuming upright posture, with prompt recovery. The pathophysiology underlying this BP drop and subsequent recovery is incompletely understood. Hypothesis: We hypothesized that the initial BP nadir is determined primarily by gravitational forces and therefore should be similar in healthy subjects (Controls) and individuals exhibiting pure autonomic failure (PAF), whereas recovery time is more likely determined by reflex sympathetic activation, and thus would be expected to be delayed in PAF. Methods: Autonomic testing was undertaken in 116 healthy individuals (age 36±14.3 years) and 35 PAF patients in whom iOH was measurable (age 67±13 years). Continuous non-invasive beat-to-beat BP and ECG recordings were obtained with subjects seated and then during movement to Active Standing (AS). We measured initial systolic BP drop (ΔSBP), time to BP nadir, recovery time (seconds from nadir to 90% of baseline), heart rate increment (ΔHR), and the ΔHR/ΔSBP ratio. Data underwent Shapiro-Wilk normality testing followed by parametric or non-parametric analyses as appropriate. Results: Initial systolic BP decrements with AS were comparable in Controls and PAF patients (-33±14 mmHg vs -36.4±21, p=0.38) despite significantly different baseline SBP values (126±18mmHg vs 142±22, p&lt;0.01). Conversely, compared to Controls, Recovery time was significantly prolonged in PAF (38.6±14.2 vs 18.7±6.3 seconds, p&lt;0.001). Further, compensatory HR response initiated by BP drop was markedly attenuated in PAF (+8±9 vs +19±11 bpm, p&lt;0.01), yielding significantly reduced ΔHR/ΔSBP ratios (0.22±0.25 vs 0.76±0.58 bpm/mmHg, p&lt;0.01). Conclusion: These findings provide physiological evidence that in iOH, BP decrease is driven principally by gravitational hydrostatic effect whereas BP recovery kinetics are importantly determined by autonomic tone, most likely baroreflex-mediated sympathetic activation, and thus are delayed in PAF.

Establish the minimally clinically important difference (MCID) for the Orthostatic Hypotension Questionnaire (OHQ). Neurogenic orthostatic hypotension (nOH) causes disabling symptoms that impair daily function and quality of life. The OHQ is a validated patient-reported outcome with a symptom assessment (OHSA) and daily activity scale (OHDAS), widely used in clinical trials, despite the MCID being unestablished. We analyzed data from two phase 3, randomized placebo-controlled trials (SEQUOIA and REDWOOD), evaluating ampreloxetine for symptomatic nOH in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure. Using anchor-based and distribution-based methods, we calculated the MCID for the total OHQ score, OHSA and OHDAS composite subscales, and for the single dizziness/lightheadedness question (OHSA1). The analysis included 184 subjects from SEQUOIA and 128 from REDWOOD. The total OHQ MCID for improvement was a reduction of 0.9-1.2 points and for worsening was an increase of 0.7-1.1 points. The MCID for the OHSA composite ranged from a reduction of 0.9-1.3 points for improvement and an increase of 0.7-1.1 points for worsening. For the single-item OHSA1, the MCID was a reduction of 2.0-3.0 points for improvement and an increase of 1.0 point for worsening. Owing to poor correlation with the symptom-based anchors, a reliable MCID for the OHDAS component was not established. These MCID thresholds for the OHQ, OHSA and OHSA item 1 alone, enhance the interpretability of scores and support their use in evaluating clinical benefit.

Lewy body diseases (LBDs) feature profound myocardial depletion of the sympathetic neurotransmitter norepinephrine. In addition to sympathetic neuronal loss, the norepinephrine deficiency may reflect decreased vesicular sequestration of cytoplasmic catecholamines in dysfunctional but living nerve terminals. To evaluate intraneuronal vesicular storage in patients with LBDs, we retrospectively analyzed multitracer PET data using 18F-6-fluorodopamine (18F-DA, a sympathetic neuroimaging agent) and 11C-methylreboxetine (11C-MRB, a ligand for the cell membrane norepinephrine transporter). If there were a vesicular storage defect, then the decrease in 18F-DA-derived radioactivity would be greater than the decrease in 11C-MRB-derived radioactivity. Methods: Twenty-three patients with Parkinson disease or the Lewy body form of pure autonomic failure and 15 controls underwent 18F-DA dynamic scanning (9 frames; last frame, 10-min duration with midpoint at 25 min) and on a separate day underwent 11C-MRB PET for 45 min (dynamic for 30 min, then a static 15-min frame with midpoint at 38 min). Results: All patients in the LBD group had interventricular septal 18F-DA-derived radioactivity below the range of values in the control group (mean decrease, 75%; P < 0.0001). The LBD group also had a mean decrease of 37% in 11C-MRB-derived radioactivity from the control group in the static frame with midpoint at 38 min (P < 0.0001). At all time points after tracer administration, septal myocardial 18F-DA/11C-MRB ratios were lower in the LBD group (by 68% at 25 min; P < 0.0001). Conclusion: LBDs entail substantially decreased vesicular storage in cardiac sympathetic nerves. This abnormality has direct implications for disease-modifying treatment and prevention strategies, since extant but dysfunctional ("sick-but-not-dead") neurons may be salvageable.

Crosstalk between bladder-cardiovascular autonomic nervous system in synucleinopathies.

Autonomic dysfunction is a common feature of synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). Orthostatic hypotension (OH) and supine hypertension (SH) are hallmark manifestations of cardiovascular autonomic dysfunction that are increasingly recognized as contributors to long-term adverse clinical outcomes such as accelerated cognitive decline, motor symptom exacerbation, and end-organ damage. Several atypical presentations of OH, including coat-hanger pain, cognitive fluctuation, postural instability, fatigue, exertional dyspnea, and falls, commonly overlap with motor and non-motor features of synucleinopathies. This clinical overlap highlights the need for heightened awareness of the diverse and often subtle manifestations of OH in affected individuals. Although the general management of OH has been addressed in prior literature, a dedicated framework tailored to the pathophysiological and clinical nuances specific to synucleinopathies remains lacking. SH, despite its high prevalence and significant prognostic implications, has received minimal attention in existing reviews and is often overlooked in clinical practice. Given the growing recognition of cardiovascular autonomic dysfunction as a potentially modifiable contributor to disease progression and patient quality of life, a focused updated review is warranted to inform clinical decision-making and guide future research in this evolving area. This narrative review comprehensively discusses the approach to OH and SH in the context of synucleinopathies. The key topics addressed are the pathophysiology of OH and SH in synucleinopathies, diagnostic criteria and types of OH, diagnostic criteria of SH, and management strategies (non-pharmacological, pharmacological, and novel/experimental).

Harlequin syndrome is a rare autonomic disorder characterized by unilateral facial flushing and contralateral anhidrosis. We sought to delineate underlying causes, clinical presentations, and autonomic testing profiles of patients with Harlequin syndrome. Retrospective chart review was performed of the Mayo Clinic electronic health record for patients with a Harlequin syndrome diagnosis from 1998 to 2024. Clinical, laboratory, imaging, and autonomic function testing results, including autonomic reflex screen (ARS) and thermoregulatory sweat test (TST), were reviewed. Of 51 patients with Harlequin syndrome, 39 (76%) were women. Median age of onset was 52years (range 8-73years). Harlequin syndrome was often idiopathic (N = 19; 37%), followed by postsurgical (N = 9; 17%), neoplasm (N = 5; 9.8%), trauma (N = 4; 7.8%), small fiber neuropathy (N = 4; 7.8%), systemic causes (N = 3; 5.9%), autoimmune (N = 3; 5.9%), pure autonomic failure (N = 2; 3.9%), and multiple sclerosis (N = 1; 2%). Pupil abnormalities were found in 13 patients (25.5%) with abnormal muscle stretch reflexes in 17 (33.3%). Headache was a comorbidity in 20 patients (39%). Of those with postsurgical onset, various surgeries preceded Harlequin syndrome onset, including heart, lung, and neck operations. Onset was acute or subacute in the majority of postsurgical patients (57%), while insidious onset was most common in nonsurgical patients (89%; p = 0.001). Median anhidrosis on TST was 9% (range 0.6-63%; N = 27). Median composite autonomic severity score was 1 (interquartile range (IQR) 0-3; N = 31). Harlequin syndrome commonly has an insidious onset and occurs without an identifiable cause, which could be considered primary Harlequin syndrome. Secondary Harlequin syndrome can occur following surgeries in the vicinity of sympathetic pathways, which most commonly leads to an acute or subacute presentation.

ABSTRACTBackgroundPure autonomic failure (PAF) presents with autonomic failure without other neurological features. A third develop central neurological features, fulfilling criteria for multiple system atrophy (MSA) and Lewy body diseases (LBD), including Parkinson's disease and Dementia with Lewy bodies. We hypothesized multimodal autonomic biomarkers would identify differences between PAF, MSA, and LBD, and predict phenoconversion in patients presenting with PAF.MethodsThis observational cohort study included 391 alpha‐synucleinopathy patients evaluated with cardiovascular autonomic testing, plasma noradrenaline, pupillometry, autonomic symptom, and quality‐of‐life questionnaires. PAF patients were monitored for the emergence of central neurological features. Logistic regression modeling was used to identify autonomic biomarkers at initial assessment that predicted future phenoconversion.ResultsPatients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD. 50/194 (26%) with PAF phenoconverted to MSA or LBD after a median of 13 years, with normal pupils, heart rate response to deep breathing ≥ 10 bpm, and supine plasma noradrenaline ≥ 200 pg/mL predicting future phenoconversion to MSA or LBD, with younger age at presentation and higher supine plasma noradrenaline levels associated with conversion to MSA.ConclusionIn patients presenting with PAF, normal pupillary function and supine plasma noradrenaline levels with intact cardiovagal responses were red flags for future phenoconversion. Younger patients with higher supine plasma noradrenaline levels were more likely to convert to MSA rather than LBD. A non‐invasive multimodal autonomic assessment can help differentiate between alpha‐synucleinopathies and predict phenoconversion from PAF to MSA or LBD.

ABSTRACTObjectiveReliable biomarkers are essential for tracking disease progression and advancing treatments for multiple system atrophy (MSA). In this study, we propose the MSA Atrophy Index (MSA‐AI), a novel composite volumetric measure to distinguish MSA from related disorders and monitor disease progression.MethodsSeventeen participants with an initial diagnosis of probable MSA were enrolled in the longitudinal bioMUSE study and underwent 3T MRI, biofluid analysis, and clinical assessments at baseline, 6, and 12 months. Final diagnoses were determined after 12 months using clinical progression, imaging, and fluid biomarkers. Ten participants retained an MSA diagnosis, while five were reclassified as either Parkinson disease (PD, n = 4) or dementia with Lewy bodies (DLB, n = 1). Cross‐sectional comparisons included additional MSA cases (n = 26), healthy controls (n = 23), pure autonomic failure (n = 23), PD (n = 56), and DLB (n = 8). Lentiform nucleus, cerebellum, and brainstem volumes were extracted using deep learning‐based segmentation. Z‐scores were computed using a normative dataset (n = 469) and integrated into the MSA‐AI. Group differences were tested with linear regression; longitudinal changes and clinical correlations were assessed using mixed‐effects models and Spearman correlations.ResultsMSA patients exhibited significantly lower MSA‐AI scores compared to all other diagnostic groups (p < 0.001). The MSA‐AI effectively distinguished MSA from related synucleinopathies, correlated with baseline clinical severity (ρ = −0.57, p < 0.001), and predicted disease progression (ρ = −0.55, p = 0.03). Longitudinal reductions in MSA‐AI were associated with worsening clinical scores over 12 months (ρ = −0.61, p = 0.01).InterpretationThe MSA‐AI is a promising imaging biomarker for diagnosis and monitoring disease progression in MSA. These findings require validation in larger, independent cohorts.

Alpha-synucleinopathies, including Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), and Pure Autonomic Failure (PAF), are associated with autonomic dysfunctions such as orthostatic hypotension (OH) and supine hypertension (SH). SH, characterized by elevated supine blood pressure, carries significant cardiovascular and cognitive risks, yet its prevalence in α-synucleinopathies remains inadequately defined. We aimed to conduct a systematic review and meta-analysis to assess the prevalence of SH in α-synucleinopathies. We systematically searched PubMed, Embase, and Web of Science databases for studies reporting SH prevalence in patients with α-synucleinopathies. A random-effects model estimated prevalence, stratified by disease type, study design, SH definition, OH presence, and disease duration. Sensitivity analyses were applied to explore sources of variability. Nineteen studies involving 4973 patients were included. The overall SH prevalence was 30.4% (95% CI: 26.4-34.7; I2 = 87.6%). In PD, SH prevalence was 28.3% (95% CI: 24.0-32.9; I2 = 86.4%), with OH significantly increasing prevalence (33.9% vs. 21.3%, P = 0.0341). In MSA, SH prevalence was 31.1% (95% CI: 25.9-36.9; I2 = 30.5%), with OH similarly associated with higher SH prevalence (46.5% vs. 19.8%, P = 0.0023). In DLB, the pooled SH prevalence was 48.7% (95% CI: 39.5-58.1; I2 = 11.9%). For PAF, a single study reported a prevalence of 48.4% (95% CI: 35.7-61.2). SH is highly prevalent across α-synucleinopathies, with variability by disease type and OH presence. Standardizing diagnostic criteria and investigating its clinical implications are essential to enhance management strategies.