Goldstein, David S.

Abstract 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.

Abstract We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3–10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6–22 and HR: 3.6, 95% CI: 1.1–12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2–6), trouble swallowing (HR 2.5, 95% CI: 1.4–4.5) and changes in speech (HR:2.4, 95% CI:1.1–4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1–5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2–38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6–46), preserved olfaction (HR: 8.7, 95% CI: 1.7–45), anhidrosis (HR: 1.8, 95% CI: 1–3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1–2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4–26). Patients with PAF have an estimated 12% (95% CI: 9–15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

ABSTRACT Background Parkinson's disease with orthostatic hypotension (PD + OH) can be difficult to distinguish clinically from the parkinsonian form of multiple system atrophy (MSA‐P). Previous studies examined cardiac sympathetic neuroimaging to differentiate PD from MSA but without focusing specifically on PD + OH versus MSA‐P, which often is the relevant differential diagnostic issue. Objective To investigate the utility of cardiac sympathetic neuroimaging by 18 F‐dopamine positron emission tomographic (PET) scanning for separating PD + OH from MSA‐P. Methods Cardiac 18 F‐dopamine PET data were analyzed from 50 PD + OH and 68 MSA‐P patients evaluated at the NIH Clinical Center from 1990 to 2020. Noradrenergic deficiency was defined by interventricular septal 18 F‐dopamine‐derived radioactivity <6000 nCi‐kg/cc‐mCi in the 5′ frame with mid‐point 8′ after initiation of 3′ tracer injection. Results 18 F‐Dopamine PET separated the PD + OH from the MSA‐P group with a sensitivity of 92% and specificity of 96%. Conclusion Cardiac 18 F‐dopamine PET scanning efficiently distinguishes PD + OH from MSA‐P.

Objective Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Methods Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. Results We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; −44 ± 25 vs −21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one‐third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy ( p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. Interpretation A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522–531

ObjectiveTo define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.MethodsOne hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy‐four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests.ResultsAt enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had autonomic failure for 5 ± 7 years. Within 4 years of follow‐up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell.InterpretationPatients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287–297

Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean ± sem, 0.40 ± 0.09 vs. 1.08 ± 0.18 pmol·100 g−1·min−1, P &lt; 0.05) and arterial norepinephrine concentrations (0.92 ± 0.10 vs. 1.23 ± 0.08 nmol·liter−1, P &lt; 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.

Abstract —According to the “epinephrine hypothesis,” circulating epinephrine taken up by sympathetic nerves is coreleased with norepinephrine during sympathetic stimulation and binding of coreleased epinephrine to presynaptic β-adrenoceptors augments exocytotic release of norepinephrine, contributing to high blood pressure. This study examined whether infusion of a physiologically active amount of epinephrine affects subsequent vascular responses and the estimated rate of entry of norepinephrine into regional venous plasma (norepinephrine spillover). Each of 3 experiments included intravenous infusion of 3 H-norepinephrine, measurements of forearm vascular resistance, and intra-arterial infusion of epinephrine (3 ng/min per deciliter forearm volume). In experiment 1, subjects underwent lower body negative pressure (LBNP−25 mm Hg) before and after intra-arterial epinephrine; in experiment 2, LBNP and intra-arterial yohimbine before and after intra-arterial epinephrine; and in experiment 3, intravenous nitroprusside before and after intra-arterial epinephrine. In all subjects, intra-arterial epinephrine produced ipsilateral pallor and decreased forearm vascular resistance. Ipsilateral venous epinephrine increased by 10-fold. Epinephrine did not affect forearm vasoconstrictor responses to LBNP or vasodilator responses to intra-arterial yohimbine or intravenous nitroprusside; did not affect venous norepinephrine levels or norepinephrine spillover during LBNP, yohimbine, LBNP during yohimbine, or nitroprusside; and did not increase venous epinephrine levels during any of these manipulations. Loading of forearm sympathetic terminals with epinephrine therefore does not augment subsequent neurogenic vasoconstriction or norepinephrine release in the human forearm in response to sympathetic stimulation. The findings are inconsistent with the epinephrine hypothesis.