Medial Temporal Lobe Does Not Tell The Whole Story: Episodic Memory In ‘atypical’ Variants Of Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia, which is globally epidemic and well-known by the general public. Episodic memory, a conscious recollection of a particular event in spatial and temporal context, is the most prominent deficit in the early stage of clinical amnestic AD, and reflected by the shrinkage of structures in medial temporal lobe (MTL), including the hippocampus. According to Braak staging, tangles begin in the transentorhinal cortex of the MTL, which then spreads to hippocampal subfields, and later to neocortical areas. Cases that are less recognized by the general public are patients with the atypical variants of AD. Interestingly, many of the atypical cases of AD appear to share the same histopathological features with clinical amnestic AD. According to the diagnostic criteria for these atypical variants of AD, episodic memory should be relatively preserved. However, inconsistent reports on the episodic memory performance and the hippocampal involvement in these atypical cases pose challenges for accurately diagnosing these patients. The two kinds of atypical variants of AD that I focused here are logopenic variant of Primary Progressive Aphasia (lvPPA) and posterior cortical atrophy (PCA). The overarching theme of my thesis is to examine 1) whether the atypical cases of AD have episodic memory difficulty, and if so, 2) what brain areas are responsible for this difficulty. Chapter 2 and 3 of the current thesis show that 1) episodic memory difficulty is observed in lvPPA and PCA cases and 2) this impairment is modulated by deficit in other cognitive domains and associated with disease in non-MTL brain regions. This would be consistent with the ‘hippocampal-sparing’ hypothesis that not all AD histopathology begins in the MTL, and these hippocampal-sparing conditions suggest that additional mechanisms must be considered in the genesis of spreading pathology in AD

Neural Correlates of Verbal Episodic Memory and Lexical Retrieval in Logopenic Variant Primary Progressive Aphasia

Objective: Logopenic variant primary progressive aphasia (lvPPA) is commonly associated with Alzheimer's disease (AD) pathology. But lvPPA patients display different cognitive and anatomical profile from the common clinical AD patients, whose verbal episodic memory is primarily affected. Reports of verbal episodic memory difficulty in lvPPA are inconsistent, and we hypothesized that their lexical retrieval impairment contributes to verbal episodic memory performance and is associated with left middle temporal gyrus atrophy.Methods: We evaluated patients with lvPPA (n = 12) displaying prominent word-finding and repetition difficulties, and a demographically-matched cohort of clinical Alzheimer's disease (AD, n = 26), and healthy seniors (n = 16). We assessed lexical retrieval with confrontation naming and verbal episodic memory with delayed free recall. Whole-brain regressions related naming and delayed free recall to gray matter atrophy. Medial temporal lobe (MTL) subfields were examined using high in-plane resolution imaging.Results: lvPPA patients had naming and delayed free recall impairments, but intact recognition memory. In lvPPA, delayed free recall was related to naming; both were associated with left middle temporal gyrus atrophy but not MTL atrophy. Despite cerebrospinal fluid evidence consistent with AD pathology, examination of MTL subfields revealed no atrophy in lvPPA. While AD patients displayed impaired delayed free recall, this deficit did not correlate with naming. Regression analyses related delayed free recall deficits in clinical AD patients to MTL subfield atrophy, and naming to left middle temporal gyrus atrophy.Conclusion: Unlike amnestic AD patients, MTL subfields were not affected in lvPPA patients. Verbal episodic memory deficit observed in lvPPA was unlikely to be due to a hippocampal-mediated mechanism but appeared to be due to poor lexical retrieval. Relative sparing of MTL volume and intact recognition memory are consistent with previous reports of hippocampal-sparing variant cases of AD pathology, where neurofibrillary tangles are disproportionately distributed in cortical areas with relative sparing of the hippocampus. This suggests that AD neuropathology in lvPPA may originate in neuronal networks outside of the MTL, which deviates from the typical Braak staging pattern of spreading pathology in clinical AD