Parkinson disease clinical subtypes: key features & clinical milestones

Abstract

Objectives: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones.

Methods: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality.

Results: LCA identified distinct subtypes: "motor only" (N = 63) characterized by primary motor deficits; "psychiatric & motor" (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; "cognitive & motor" (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the "cognitive & motor" subtype. Surprisingly, mortality risk was similarly elevated for both "cognitive & motor" and "psychiatric & motor" subtypes compared to the "motor only" subtype (relative risk = 3.15, 2.60).

Interpretation: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes.

Figure 1

PD Clinical Subtypes. (A) LCA analysis identified three distinct PD subtypes based on the pattern of scores across motor, cognitive and psychiatric domains. Discriminant analyses achieved significant subtype separation and 98.3% classification accuracy based on discriminant functions 1 and 2, which accounted for 60.5% and 39.5% of the variance, respectively. Group centroid represents the standardized mean scores for that subtype on function 1 and 2. (B) Subtypes differed across motor, cognitive, and psychiatric measures. Values represent z‐scores for each measure (indicator). Higher scores represent worse function for motor and psychiatric measures; lower scores represent worse function for cognitive domains. PIGD = postural instability and gait difficulty. Significant subtype differences for all measures, except tremor (P = 0.40) and memory (P = 0.11).

Figure 2

PD subtypes predict conversion to dementia and mortality. Graphs represent Kaplan‐Meier and Cox regression survival plots where “+” indicates censoring and a vertical drop indicates occurrence of an event, either conversion to dementia (panel A) or mortality (panel B). (A1) Top graph represents the Kaplan‐Meier curve for rate of dementia conversion for each subtype without covariates. Table indicates number of participants for each subtype at risk of conversion across time. (A2) Bottom graph represents the Cox regression curves predicting dementia conversion rates for each subtype, accounting for education, sex, age, symptom duration, and CDR score at initial visit, showing a clear difference in conversion rates between the “cognitive & motor” subtypes and both “motor only” and “psychiatric & motor” subtypes. (B1) Kaplan–Meier curves for mortality of each subtype without covariates. Table indicates the number of participants for each subtype at risk of mortality across time. (B2) Bottom graph represents Cox regression curves predicting mortality rates for each subtype, accounting for age, sex, and symptom duration at initial visit, showing similar mortality rates between “cognitive & motor” and “psychiatric & motor” subtypes that are greater than the mortality rate of the “motor only” subtype