Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease

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.

Figure 1.. Kaplan-Meier Curves of Cumulative Probability of Survival and Cumulative Risk of Disease Milestones, Including First Disease Milestone, Regular Falls, Wheelchair Use, Dementia, and Care Placement, Among Parkinson Disease Subtypes

DM indicates diffuse malignant; IM, intermediate; MMP, mild-motor–predominant.

Figure 2.. Clinical Heterogeneity of Parkinson Disease (PD)

A schematic representation of the clinical course illustrating symptom severity over time for different PD subtypes. In the early-middle stages, PD has a very heterogeneous course, with different rates of progression and levels of disability among Parkinson subtypes. In the final stages of the disease, there is an exponential clinical progression, with all patients with PD reaching a similar end point characterized by severe disability followed by death at the same age.

Figure 3.. Neuropathological Heterogeneity of Parkinson Disease (PD)

Factors contributing to neuropathologic heterogeneity in PD. Lewy pathology seems directly associated with the duration of the disease in a proportion of patients with slow clinical and pathologic progression. Other factors may modulate this association, and Parkinson subtypes seem to have a different neuropathologic progression rate because all cases reach advanced stages despite significant differences in disease duration. Distribution of Lewy pathology is also variable, and at least a proportion of those patients presenting with early dementia show diffuse neocortical Lewy pathology since the onset compared with the typical caudo-rostral pattern of progression seen in most patients. Other comorbid pathologies are likely to contribute to the clinical heterogeneity. Particularly important in elderly patients is the presence of Alzheimer disease pathology, which is directly associated with age at death.