The effect of Lewy body (co-)pathology on the clinical and imaging phenotype of amnestic patients.

Abstract

Lewy body (LB) pathology is present as a co-pathology in ∼50% of patients with Alzheimer's disease (AD) and may even represent the main neuropathologic substrate in a subset of patients with amnestic impairments. However, the degree to which LB pathology affects regional neurodegeneration patterns and clinical trajectories among amnestic patients is not well understood. We studied 865 patients from the Alzheimer's Disease Neuroimaging Initiative cohort with clinical diagnoses of amnestic mild cognitive impairment (n = 661) or AD dementia (n = 211), who had CSF and FDG-PET data available. CSF samples were analysed for peptide levels of amyloid-β1-42 and p-tau181, and αSyn positivity was evaluated using a novel α-synuclein seed amplification assay. Based on positive/negative results on the different biomarkers, subjects were classified as 'AD-LB-' (n = 304), 'AD+LB-' (n = 335), 'AD+LB+' (n = 158) and 'AD-LB+' (n = 68). We analysed group differences in regional FDG-PET patterns, demographics, APOE4 genotype, baseline and longitudinal domain-specific cognitive profiles (memory versus executive function/visuospatial performance), and risk for developing hallucinations. AD+LB+ showed worse global cognition (Mini-Mental State Examination: P = 0.005) and declined faster (P < 0.001) than AD+LB-, but both groups exhibited similar memory-predominant cognitive profiles. In FDG-PET, AD+LB+ showed more severe hypometabolism compared to AD+LB-, but both groups were characterized by largely identical patterns of temporo-parietal hypometabolism. By contrast, AD-LB+ were less globally impaired (P < 0.001) but characterized by a markedly more dysexecutive and visuospatial profile (P < 0.003) and a strikingly different posterior-occipital pattern of hypometabolism. APOE4 positivity was similar between AD+LB+ and AD+LB- (72% versus 75%, P = 0.28) but lower in AD-LB+ (28%, P < 0.001). On a group level, AD+LB+, AD+LB- and AD-LB+ showed similar risks of developing hallucinations, but patients with LB-like posterior-occipital hypometabolism had a significantly higher risk compared to those showing an AD-typical temporo-parietal pattern (hazard ratio = 2.58, P = 0.004). In conclusion, LB co-pathology in AD was associated with more severe hypometabolism and faster cognitive decline, but did not affect the regional hypometabolic pattern or cognitive profile. By contrast, patients with relatively pure LB pathology showed a more executive/visuospatial-predominant cognitive profile and a distinct posterior-occipital hypometabolism pattern characteristic for LB disease. These findings indicate that the presence of LB pathology may have different consequences for the clinical phenotype depending on AD co-morbidity, which may have critical implications for accurate diagnosis and prognosis of patients presenting with amnestic syndromes.