Survival in synucleinopathies: A prospective cohort study

Abstract

Objectives: Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) involve cytoplasmic deposition of α-synuclein and are considered to be synucleinopathies. Approximately 40% of patients with PD, most patients with MSA, and all patients with PAF have neurogenic orthostatic hypotension (OH). This study compared long-term survival in these synucleinopathies.

Methods: In this prospective cohort study, survival data were obtained for 97.6% of 206 referred patients evaluated between 1994 and 2014 (47 PD + OH, 54 PD no OH, 15 cerebellar MSA [MSA-C], 57 parkinsonian MSA [MSA-P], 28 PAF). Individual diagnoses were confirmed by clinical criteria and results of pharmacologic, neurochemical, and neuroimaging tests of sympathetic noradrenergic innervation. The Cox proportional hazard model was used to calculate hazard ratios (HRs) from symptom onset and from time of evaluation to death.

Results: Patients with MSA-C or MSA-P had shorter survival from symptom onset than did patients with PD + OH (age- and sex-adjusted HR = 6.1, 5.6; p < 0.0001 each), PAF (HR = 10.8, 9.9; p < 0.0001 each) or PD no OH (HR = 14.9, 13.6; p < 0.0001 each). Among parkinsonian patients who died, median times from motor onset to death were 7.5 years in MSA-P, 11.6 years in PD + OH, and 15.8 years in PD no OH. Probabilities of survival for 10 years from onset of relevant symptoms were 0.39 in MSA-C, 0.33 in MSA-P, 0.74 in PD + OH, 0.87 in PAF, and 0.93 in PD no OH.

Conclusions: In synucleinopathies, survival depends on the particular disease, with the risk of death greater in MSA-P than in PD + OH and in PD + OH than in PD no OH.

Figure 1. Patterns of brain and cardiac catecholaminergic abnormalities

(A) Decreased putamen ¹⁸F-DOPA–derived radioactivity and decreased left ventricular myocardial ¹⁸F-dopamine–derived radioactivity. (B) Normal putamen ¹⁸F-DOPA–derived radioactivity and normal left ventricular myocardial ¹⁸F-dopamine–derived radioactivity. (C) Decreased putamen ¹⁸F-DOPA–derived radioactivity and normal left ventricular myocardial ¹⁸F-dopamine–derived radioactivity. (D) Normal putamen ¹⁸F-DOPA–derived radioactivity and decreased left ventricular myocardial ¹⁸F-dopamine–derived radioactivity.

Figure 2. Clinical laboratory distinctions among autonomic synucleinopathies

In PAF, the putamen to occipital cortex ratio of ¹⁸F-DOPA–derived radioactivity (PUT:OCC) is normal, while interventricular septal myocardial ¹⁸F-dopamine–derived radioactivity is decreased. In PD + OH, the PUT:OCC ratio is normal, while interventricular septal myocardial ¹⁸F-dopamine–derived radioactivity is decreased. In MSA-P, the PUT:OCC ratio is decreased, while septal ¹⁸F-dopamine–derived radioactivity is normal. In MSA-C, both the PUT:OCC ratio and septal ¹⁸F-dopamine–derived radioactivity are normal. In the panel for MSA-P, the arrow indicates a patient with definite MSA-P who had putamen dopamine and myocardial norepinephrine depletion without Lewy bodies. MSA-C = cerebellar multiple system atrophy; MSA-P = parkinsonian multiple system atrophy; OH = orthostatic hypotension; PAF = pure autonomic failure; PD = Parkinson disease.

Figure 3. Survival plots and numbers of at-risk patients in α-synucleinopathies

Displayed are survival probabilities expressed as a function of years since symptom onset (A and B) or initial evaluation at the NIH Clinical Center (C and D). (A and C) Kaplan-Meier plots and numbers of at-risk living patients. (B and D) Survival plots after adjustment for age and sex. “Censored” at-risk patients were alive as of the indicated years. MSA-C = cerebellar multiple system atrophy; MSA-P = parkinsonian multiple system atrophy; OH = orthostatic hypotension; PAF = pure autonomic failure; PD = Parkinson disease.

Figure 4. Survival plots and numbers of at-risk patients based on patterns of catecholaminergic abnormalities

(A) Kaplan-Meier plots and numbers of at-risk living patients. (B) Survival plots after adjustment for age and sex.