Cognitive decline before diagnosis of Parkinson's disease

Anette Schrag and colleagues assessed the usefulness of several demographic, clinical, and biomarker variables to predict cognitive impairment in patients with newly diagnosed Parkinson’s disease, and systematically selected the best predictors to construct a prediction model. The study provides important hints about the underlying mechanisms of cognitive decline in Parkinson’s disease. The underlying pathological mechanisms of Parkinson’s disease dementia are highly heterogeneous, and the duration of parkinsonism before dementia can be associated with different patterns of neuropathology: patients who develop dementia in the first 10 years after diagnosis generally have a mix of Alzheimer’s disease pathology and synucleinopathy, whereas patients with longstanding parkinsonism prior to dementia tend to have a more pure synucleinopathy. However, little is known about the pathological mechanisms that drive cognitive decline in Parkinson’s disease before parkinsonism is diagnosed, a stage at which patients might still respond to putative disease-modifying interventions. In the 2015 Movement Disorder Society clinical diagnostic criteria for Parkinson’s disease, dementia before parkinsonism was removed as an exclusion criterion, and we subsequently4 showed that subtle cognitive decline can start as early as 6 years before parkinsonism diagnosis in patients with Parkinson’s disease. Since Schrag and colleagues aimed to predict incident cognitive impairment after diagnosis of Parkinson’s disease, they excluded patients with poor cognitive functioning at diagnosis. Moving forward, however, that specific subgroup of patients could be crucial to elucidate the exact underlying pathological mechanisms of cognitive decline in Parkinson’s disease. Future observational studies aiming to quantify the contribution of various pathologies to cognitive decline in Parkinson’s disease should include patients irrespective of their cognitive status. This will also accelerate the shift towards a pathological mechanism-based classification of patients with Parkinson’s disease, which could enable targeted selection of patients for putative disease-modifying trials.

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