Abdi, Zeinab; (2023) Posterior cortical atrophy, a pathological characterisation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction Posterior cortical atrophy (PCA) is a neurodegenerative syndrome, typically caused by Alzheimer’s disease (AD), and with a predominantly young age of onset. It is a clinico-radiological diagnosis, characterised by higher order visual and spatial difficulties, reflecting differential involvement of the “posterior” cortical brain regions, namely the occipital and parietal cortices, compared with relatively preserved episodic memory difficulties observed in typical AD (TAD) and associated with the medial temporal region. This study characterised the neuropathological substrates of PCA in comparison with TAD, with the aim of furthering the understanding of the biological basis of phenotypical heterogeneity in AD. Materials and methods Immunohistochemistry for Aβ, tau, the microglial markers CD68, CR3-43 and Iba1, α-synuclein (α-syn) and TDP-43 was carried out on 26 PCA and 27 age and gender-matched TAD cases at the Queen Square Brain Bank (QSBB). Aβ, tau and the three microglial markers were quantified in the frontal, temporal, parietal and occipital cortices whereas α-syn and TDP-43 was assessed based on commonly used staging criteria. Results There was a higher load of Aβ and tau in the parietal region of PCA compared to TAD. In the PCA compared to the TAD group, there were significant increases in tau load in parietal and frontal relative to temporal regions. There was no difference in CAA severity between PCA and TAD. There was a significantly lower temporal CD68 load in the TAD compared with the PCA group, in the context of the temporal TAD region having the highest tau load across the four regions. There was also a significantly lower frontal CD68 load in PCA compared with TAD. Findings regarding α-syn and TDP-43 were mixed. There were no differences in α-syn severity using the formal staging criteria, but higher overall incidence of α-syn in PCA compared with TAD was observed. There was lower severity of TDP-43 in PCA compared with TAD but no difference in incidence overall. There was no association between ApoE4 carrier status and AD pathology load, microglial load, CAA severity or non-AD co-pathology presence in the PCA or TAD. Conclusions This thesis has demonstrated distribution of AD-pathology in keeping with the PCA clinical phenotype, with observation of higher Aβ and tau loads in the parietal region of PCA compared to TAD. The higher frontal tau load observed in PCA, is in line with in-vivo evidence of the frontal cortex in atypical AD as vulnerable to tau deposition over time. Observation of lower CD68, a marker of activated phagocytic microglia and high tau in the temporal region of the TAD group suggests a differential regional neuroinflammatory response in PCA and TAD. This finding in the context of higher overall circularity, indicates a more activated microglia phenotype and perhaps a more robust immune environment in PCA, compared with a more dysfunctional and depressed immune response in TAD, particularly in the temporal region. The co-pathology findings of higher α-syn frequency in PCA compared with TAD raise questions regarding the potential role of α-syn in the clinical phenotype of PCA.

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