[Skip to Content]
[Skip to Content Landing]
Original Investigation
January 14, 2019

Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease

Author Affiliations
  • 1Reta Lila Weston Institute of Neurological Studies, University College London Queen Square Institute of Neurology, London, England
  • 2Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, London, England
JAMA Neurol. 2019;76(4):470-479. doi:10.1001/jamaneurol.2018.4377
Key Points

Question  Does clinical subtyping of Parkinson disease at diagnosis estimate disease progression and neuropathology?

Findings  In this cohort study, clinical subtyping of 111 autopsy-confirmed patients with Parkinson disease based on motor symptoms, rapid eye movement sleep behavior disorder, and autonomic and cognitive dysfunction at diagnosis showed different disease course and survival rates across subtypes. Parkinson subtypes were associated with different rates of Lewy pathology and Alzheimer disease–related neuropathology progression.

Meaning  Clinical subtyping in Parkinson disease is feasible in clinical practice and provides accurate estimation of disease progression and survival; different neuropathologies are important determinants of clinical subtypes and contribute to the clinical heterogeneity.

Abstract

Importance  Clinical subtyping of Parkinson disease at diagnosis is useful in estimating disease course and survival. Severity and rate of progression of neuropathologies are important determinants of clinical Parkinson subtypes.

Objective  To provide longitudinal clinical disease-course data and neuropathologic correlation for newly proposed Parkinson disease subtypes.

Design, Setting, and Participants  Retrospective cohort study of consecutive patients with autopsy-confirmed Parkinson disease who were regularly seen throughout their disease course by hospital specialists in the United Kingdom and donated their brain at death to the Queen Square Brain Bank between January 2009 and December 2017. Patients with additional neuropathologic diagnoses, monogenic forms of parkinsonism, or insufficiently detailed clinical information were excluded. Based on severity of motor symptoms, rapid eye movement sleep behavior disorder, and autonomic and cognitive function at diagnosis, patients were classified adapting a subtyping classification into mild-motor predominant, intermediate, or diffuse malignant subtypes.

Main Outcomes and Measures  Time from diagnosis to disease milestones (recurrent falls, wheelchair dependence, dementia, and care home placement) and death were compared between subtypes, and their risk was estimated using Cox hazard regression models. Severity and distribution of Lewy pathology and Alzheimer disease–related pathology were assessed using staging systems.

Results  From a total of 146 patients, 111 patients were included (67 men [60.4%]; mean [SD] age at diagnosis, 62.5 [11.5] years). The diffuse malignant subtype had earlier development of milestones and reduced survival. Cox proportional hazard regression showed an increased adjusted risk of any disease milestone (hazard ratio, 10.90; 95% CI, 5.51-21.58; P < .001) and death (hazard ratio, 3.65; 95% CI, 1.98-6.75; P < .001) in the diffuse malignant group. Age at diagnosis was the only additional variable with statistical significance (adjusted hazard ratio for death, 1.14; 95% CI, 1.11-1.17; P <.001). Staging of Lewy pathology and Alzheimer disease–related pathology did not differ between subtypes, although they showed different rates of progression, and the latter was associated with age at death.

Conclusions and Relevance  Parkinson clinical subtypes at diagnosis may estimate disease course and survival, which may be useful in providing a more accurate prognosis in individual patients in clinical practice and helping to stratify subgroups in clinical trials. Different severity and progression of neuropathologies are important determinants of Parkinson subtypes, and age at diagnosis should be included in future subtype classifications.

×