Faculty Bibliography

BACKGROUND:The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated. OBJECTIVE:To evaluate the diagnostic performance of the PP-MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. METHODS:Seventy-six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP-MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. RESULTS:Thirty-eight participants met PP-MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. CONCLUSIONS:The PP-MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

PURPOSE/OBJECTIVE:To review the cardiovascular effects of pharmacologic dopamine receptor modulation in humans, organized by receptor subtype. METHODS:Narrative review of human pharmacological, genetic, and clinical evidence linking dopamine receptor agonism and antagonism to blood pressure and heart rate changes in healthy volunteers and in patients with Parkinson disease, autonomic failure, psychiatric disorders, and selected cardiovascular conditions. RESULTS:Dopaminergic receptor agonism generally lowers blood pressure, with the magnitude of hypotension tracking with intrinsic activity: full orthosteric agonists (bromocriptine, ropirinole, apomorphine) carry the highest risk of orthostatic hypotension, and partial agonists (tavapadon) produce attenuated but clinically relevant hypotension. Dopamine D3-preferring agents (PF-592379, mesdopetam, cariprazine) have neutral cardiovascular effects in short-term trials. Levodopa-induced orthostatic hypotension arises from at least five converging mechanisms whose clinical impact is amplified by underlying neurogenic orthostatic hypotension. A notable exception is mevidalen, a centrally acting dopamine D1 positive allosteric modulator that paradoxically raises blood pressure. Despite murine knockout models consistently predicting that dopamine receptor deletion produces hypertension, pharmacological antagonism in humans does not reliably raise blood pressure: dopamine D1, D2, and D3 antagonists show largely neutral cardiovascular profiles, while antipsychotic-associated orthostatic hypotension is driven primarily by α1-adrenergic blockade. CONCLUSIONS:The cardiovascular response to dopaminergic agents depends on receptor selectivity, intrinsic activity, and baroreflex integrity. The discrepancy between murine-knockout-predicted hypertension and human pharmacological neutrality with antagonists, and the hypertensive effects of dopamine D1 positive allosteric modulators, represent key unresolved questions.

Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of <30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.

We report a 71-year-old woman who developed disabling orthostatic tremor and severe orthostatic hypertension following cosmetic neck lift surgery. Autonomic testing demonstrated exaggerated pressor responses and excessive orthostatic catecholamine release, consistent with sympathoadrenal overactivation due to impaired carotid baroreflex function. This case highlights a potential autonomic complication of aesthetic neck surgery.

PURPOSE/OBJECTIVE:The Unified Multiple System Atrophy Rating Scale (UMSARS) is widely used as an outcome measure in MSA trials, but it has limitations for clinical trial use. To address these, we developed the Multiple System Atrophy Combined Outcome Assessment (MuSyCA), a comprehensive multimodal tool for disease-modifying MSA trials. The purpose of this manuscript is to describe the development and validation plan for MuSyCA, with emphasis on its structure, intended use, and assessment of reliability, validity, and sensitivity in tracking disease progression. METHODS:The development of MuSyCA followed a multistep process. Candidate outcome assessments were identified through systematic literature review and analysis of longitudinal data from large MSA cohorts. Content was refined through multiple Delphi-like consensus rounds involving MSA experts, patient advocacy groups representatives, and industry stakeholders. Cognitive interviews conducted in 20  patients with MSA evaluated the clarity and clinical relevance of patient- and clinician-reported outcomes; feedback was incorporated into a subsequent version of the MuSyCA. Validation is ongoing and includes assessment of construct validity, internal consistency, test-retest reliability, and responsiveness. Longitudinal analyses to determine sensitivity to change over time are ongoing. RESULTS:MuSyCA combines patient- and clinician-reported outcomes, biomarkers (neurofilament light chain, neuroimaging), and performance-based measures to capture subjective and objective aspects of MSA progression, enhancing its utility  to detect treatment effects in clinical trials. MuSyCa is not intended to be used in clinical practice. CONCLUSIONS:MuSyCA offers a multidimensional approach to MSA assessment, supporting precise, disease-relevant evaluations in trials of putative disease-modifying therapies. Its validation will provide a standardized multimodal outcome measure, advancing MSA therapeutic development.

OBJECTIVE:To determine the test performance of cutaneous phosphorylated alpha-synuclein (P-SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. METHODS:This is the first subgroup analysis of the Synuclein-One study, a prospective, blinded study evaluating P-SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control (N = 151) and DLB (N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P-SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40-99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. RESULTS:After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P-SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. INTERPRETATION/CONCLUSIONS:In this prospective, blinded, cross-sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P-SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P-SYN detected. These results support a role for skin biopsy detection of P-SYN in patients with DLB. TRIAL REGISTRATION/BACKGROUND:NCT04700722.

BACKGROUND:Pain affects up to 87% of people with multiple system atrophy (MSA), but it remains unclear which types of pain contribute most to the overall burden. OBJECTIVE:To estimate the frequency of different types of pain in MSA individuals. METHODS:In 2023, individuals with MSA completed a web-based survey that included the King's Parkinson's Disease Pain Questionnaire (KPPQ) and additional questions addressing pain related to MSA core features (eg, coat-hanger pain, pain due to bladder-issues, cold extremities, bruises, and pressure sores). Respondents were matched by age, gender, and disease duration with historical cohorts of individuals with Parkinson's disease (PD) and healthy controls (n = 96 each) who had previously completed the KPPQ. RESULTS:One hundred and fifty-seven MSA individuals with pain completed the survey. The most frequently reported KPPQ types of pain were nocturnal pain (73%), musculoskeletal pain (63%), and fluctuation-related pain (62%). Common additional pain sources included coat-hanger pain (59%), cold extremities (48%), and bruises (44%). All KPPQ pain types were significantly more frequent in MSA than in healthy controls, except for musculoskeletal pain (63% vs. 66%, P = 0.722). Compared with PD, MSA individuals reported less musculoskeletal (63% vs. 78%, P = 0.023), but more orofacial pain (32% vs. 12%, P < 0.001) on the KPPQ. CONCLUSIONS:MSA is associated with both non-specific and disease-related pain types, which may be neuropathic, nociceptive, nociplastic, or mixed in nature. These findings inform the development of tailored tools for identifying distinct pain sources in MSA, as each may require a specific therapeutic approach, including targeted treatment of motor and non-motor symptoms. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.