Journal
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
Volume 87, Issue 10, Pages 1112-1122Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jnnp-2015-312690
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Funding
- Alzheimer's Association [BAND-14-338181]
- Michael J. Fox Foundation [BAND-14-338181]
- Weston Brain Institute [BAND-14-338181]
- National Institutes of Health [AG043503]
- Michael J. Fox Foundation for Parkinson's Research
- AbbVie
- Avid Radiopharmaceuticals
- Biogen
- Bristol-Myers Squib
- Covance
- GE Healthcare
- Genentech
- GlaxoSmithKline
- Lilly
- Lundbeck
- Merck
- Meso Scale Discovery
- Pfizer
- Piramal
- Roche
- Servier
- UCB
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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-naive patients with ePD and 174 healthy controls (HC). Cerebrospinal fluid (CSF) amyloid-beta 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 a-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 alpha-synuclein and amyloid pathology. Amyloid status should be considered when screening these individuals for trials involving disease-modifying agents.
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