Investigating Heterogeneity and Neuroanatomic Correlates of Longitudinal Clinical Decline in Atypical Alzheimer Disease

Abstract

Objective:To compare rates of longitudinal change in neurological and neuropsychological test performance between the logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) variants of atypical Alzheimer’s disease (AD) and use unbiased principal component analysis to assess heterogeneity in patterns of change and relationships to demographics and concurrent brain atrophy.Methods:Patients with posterior cortical atrophy (PCA) or logogenic progressive aphasia (LPA) that were positive for amyloid and tau AD biomarkers and had undergone serial neurological and neuropsychological assessments and structural MRI were identified. Rates of change in 13 clinical measures were compared between groups in a case-control design, and principal component analysis was used to assess patterns of clinical change unbiased by clinical phenotype. Components were correlated with rates of regional brain atrophy using tensor-based morphometry.Results:Twenty-eight PCA patients and 27 LPA patients were identified. LPA showed worse baseline performance and faster rates of decline in naming, repetition and working memory, as well as faster rates of decline in verbal episodic memory, compared to PCA. Conversely, PCA showed worse baseline performance in tests of visuospatial and perceptual function and on the Clinical dementia rating scale, and faster rates of decline in visuoperceptual function, compared to LPA. The principal component analysis showed that patterns of clinical decline were highly heterogeneous across the cohort, with 10 principal components required to explain over 90% of the variance. The first principal component reflected overall severity, with higher scores in LPA than PCA reflecting faster decline in LPA and was related to left temporoparietal atrophy. The second and third principal components were not related to clinical phenotype but showed some relationship to regional atrophy. No relationships were identified between the principal components and age, sex, disease duration, amyloid PET findings or apolipoprotein genotype.Conclusion:Longitudinal patterns of clinical decline differ between LPA and PCA but are heterogeneous and related to different patterns of topographic spread. PCA is associated with a more slowly progressive course than LPA.

APOE ε4 influences within and between network functional connectivity in posterior cortical atrophy and logopenic progressive aphasia

“…Indeed, we observed faster declines in memory performance over the first year from diagnosis in LPA compared to PCA. 44 We also observed greater disruption within the language network in APOE ε4 carriers compared to non-carriers in LPA, suggesting that APOE may influence connectivity throughout the temporal lobe. This finding brings up the possibility that APOE may influence the phenotypical presentation of the disease in LPA and could theoretically influence patterns of clinical decline in these patients.…”

“…Longitudinal follow‐up will be needed to test this hypothesis. Indeed, we observed faster declines in memory performance over the first year from diagnosis in LPA compared to PCA 44 . We also observed greater disruption within the language network in APOE ε4 carriers compared to non‐carriers in LPA, suggesting that APOE may influence connectivity throughout the temporal lobe.…”

“…In fact, the visual network also showed reduced connectivity to the DMN and language network in LPA. This could reflect clinical overlap between both phenotypes, as visuospatial difficulties have been reported to develop in LPA 44,55 . This overlap could be intensified in the presence of the APOE ε4 genotype.…”

“…This could reflect clinical overlap between both phenotypes, as visuospatial difficulties have been reported to develop in LPA. 44,55 This overlap could be intensified in the presence of the APOE ε4 genotype. In contrast to, these reductions in between-network connectivity, we found evidence for an increase in connectivity between the visual and memory networks.…”

Deficient Novelty Detection and Encoding in Early Alzheimer’s Disease: An ERP Study

“…But histologically defined AD is heterogeneous (Jellinger, 2021 ). It appears unlikely that patients with a non-amnestic variant of AD, e.g., posterior cortical atrophy or logopenic progressive aphasia, who lack the initial memory impairment observed in our patients (Whitwell et al, 2022 ), would present the same EEG alterations. It is also possible that non-AD amnesia (e.g., hypoxic encephalopathy) would induce similar results.…”