Presence of cerebral amyloid modulates phenotype and pattern of neurodegeneration in early Parkinson's disease

Abstract

Objective: To evaluate the frequency of cerebral amyloid in early Parkinson's disease (ePD) and provide a multimodal assessment of the influence of cerebral amyloid on disease phenotype.

Methods: We performed a multicentre cohort study of the Parkinson's Progression Markers Initiative (PPMI), including 369 drug-naïve patients with ePD and 174 healthy controls (HC). Cerebrospinal fluid (CSF) amyloid-β levels were transformed using the linear regression procedure. A cut-off of >198 pg/mL was used to define amyloid-negative (PD-) and amyloid-positive (PD+) subgroups. Grey matter (GM) density and hippocampal volume from the MRI was measured using Advanced Normalisation Tools (ANTs). We compared demographic, genetic, CSF, behavioural, functional and imaging modalities across ePD- and ePD+ groups.

Results: We observed that 16.5% of ePD have CSF evidence of amyloidosis. PD+ was significantly older than PD-, had a higher frequency of APOE e4 alleles and all CSF measures (total-tau, phosphorylated-tau and α-synuclein) were reduced. PD+ had reduced cognitive performance relative to PD- on Symbol-Digit Matching, Verbal Category Fluency and Delayed Recall tests. Imaging analysis in a subset of individuals (PD+ =43; PD- =241) revealed overlapping GM atrophy relative to HC in medial temporal, frontal and brainstem structures. Direct comparisons revealed PD+ GM reductions predominantly located in the frontal cortex while PD- had GM reductions in subcortical structures. These observations remain when controlling for age and APOE e4 allele status.

Conclusions: Cerebral amyloid in ePD yields a unique phenotype across all measured modalities that is consistent with a synergistic interaction between α-synuclein and amyloid pathology. Amyloid status should be considered when screening these individuals for trials involving disease-modifying agents.

Figure 1

Regions of reduced grey matter for amyloid-negative early Parkinsons disease (ePD−; blue) and amyloid-positive ePD (ePD+; red) relative to amyloid-negative healthy controls (p<0.05 threshold-free cluster enhancement family-wise error-corrected). Magenta indicates regions of overlapping ePD− and ePD+ reduced GM relative to healthy controls.

Figure 2

Regions of reduced grey matter for amyloid-negative early Parkinsons disease (ePD−; blue) and amyloid-positive ePD (ePD+; red) relative to each other in direct comparisons (p<0.05 threshold-free cluster enhancement family-wise error-corrected).

Figure 3

Regions of reduced grey matter associated with an interaction between amyloid status (positive and negative) by group (early Parkinsons disease and healthy controls) (p<0.05 threshold-free cluster enhancement family-wise error-corrected).