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Research paper
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.

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