Goldstein, David S.

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.

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.