In vivo assessment of multiple neurodegenerations and cognitive impairment in Parkinson disease

Objectives To investigate the prevalence of caudate nucleus dopaminergic and cortical cholinergic deficits, and amyloidopathy in cognitive impairment in Parkinson disease (PD).

Methods PD subjects (n=143, 106M), age 65.5±7.4 years, Hoehn and Yahr stage 2.4±0.6, underwent [¹¹C]PMP acetylcholinesterase and [¹¹C]DTBZ dopaminergic PET imaging and cognitive assessment. A subset of 61 subjects completed also [¹¹C]PiB β-amyloid PET imaging. Abnormal innervation was defined with a 5th percentile cut-off from normative data. Relative frequency of significant degenerations was determined for consecutive 0.5 z-score ranges of cognitive impairment based on global cognitive z-scores ranging from no or minimal (z >-0.5) to more severe cognitive impairment (z ≤ -2).

Results Caudate nucleus dopaminergic denervation was relatively frequent in the subgroup with no or minimal cognitive changes (63.4%) and trended higher in the more severe cognitive impairment range (χ²=7.9, P=0.096). Cortical cholinergic denervation frequency increased from 24.7% in the best to 85.7% in the lowest z-score group (χ²=23.2, P=0.0001). The frequency of subjects with increased cortical β-amyloid deposition remained relatively stable across the cognitive spectrum (ranging from 29.6% to 42.9% (χ²=2.2, P=0.70), but increased striatal β-amyloid deposition frequency demonstrated an increasing trend from 3.7% to 42.9% (χ²=8.6, P=0.07). Stepwise regression using global cognitive z-scores as the outcome variable showed significant regressor effects for cortical cholinergic denervation (F=7.77, P=0.0076) and increased striatal β-amyloid (F=5.15, P=0.028).

Conclusions Caudate nucleus dopaminergic denervation is common in PD subjects with no to minimal cognitive impairment. Cortical cholinergic denervation becomes increasingly more frequent with greater cognitive decline in the majority of subjects. Combined presence of striatal and cortical amyloidopathy has increasing but moderate prevalence with more severe cognitive decline.

Research Support NIH P01 NS015655, R01 NS070856, Department of Veterans Affairs and the Michael J. Fox Foundation.