QUANTIFICATION OF PATHOLOGICAL LESIONS DETECTS CLINICOPATHOLOGICAL PHENOTYPES OF MIXED AD/LBD

Abstract

Dementing disorders are defined neuropathologically by their most prevalent pathology. However, some brains of demented subjects show high burdens of neuropathological hallmark lesions of more than one disease. Cases that neuropathologically fulfil criteria for both Alzheimer's disease (AD) and Lewy body disease (LBD - Dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD)) are classified as mixed AD/LBD. Using semi-quantitative scoring, no differences were detected in mixed AD/LBD between cases that presented clinically with AD or LBD. We investigated whether a quantitative approach could reveal differences in the amounts of AD and LBD pathology in mixed AD/LBD cases. 19 mixed AD/LBD cases, which presented clinically as AD (n=8), DLB (n=8) or PDD (n=3), 5 pure AD and 5 pure DLB cases (mean age 75.26 +/- 9.1 years) were stained for antibodies against tau, β amyloid and α-synuclein and percentage burden of each pathology was quantified in neocortical, limbic and brainstem regions. Differences in the burden of pathology between clinically AD and LBD in various regions were detected quantitatively, as a significant increase in the amount of tau pathology was observed in the hippocampus (p<0.05), striatum (p<0.05), neocortex (p<0.05) and locus coeruleus (p<0.01) in clinically AD compared to LBD patients, respectively. When compared against the PDD phenotype, clinically AD cases have greater burden of tau pathology in the majority of areas analysed. Of note, we found an increase of α-synuclein in the substantia nigra of clinically AD and DLB cases compared to clinically PDD cases. When comparing neuropathologically mixed AD/LBD with pure AD and DLB cases we observed an increase in all 3 protein aggregates in the substantia nigra in the mixed AD/LBD group. Moreover, we found a significant correlation between hyperphosphorylated tau and α synuclein (p<0.01 and R 2 =0.616) in mixed AD/LBD group. Our findings suggest that cases neuropathologically diagnosed as mixed AD/LBD can be separated into different clinico-pathological phenotypes when quantitative neuropathological methods are applied. However, the question whether clinical diagnosis reflects the primary underlying pathology, which may be confounded by concomitant pathologies, warrants further investigation.