In vivo and post-mortem memory circuit integrity in frontotemporal dementia and Alzheimer’s disease

Abstract

Behavioural variant frontotemporal dementia can present with episodic memory deficits as severe as those in Alzheimer's disease. Little is known of the integrity of grey matter areas and white matter tracts of the Papez memory circuit in these diseases. The integrity of the Papez circuit (hippocampus, fornix, mammillary bodies, anterior thalamus, cingulate cortex) was investigated in vivo and at post-mortem in behavioural variant frontotemporal dementia and Alzheimer's disease cohorts using voxel-based morphometry, diffusion tensor imaging and manual volumetric tracing. Our findings indicate that behavioural variant frontotemporal dementia and Alzheimer's disease show similar degrees of hippocampal atrophy in vivo, but patients with behavioural variant frontotemporal dementia show greater hippocampal atrophy at post-mortem, with the frontotemporal lobar degeneration with TDP-43 inclusions subtype being particularly affected. Cingulate cortex findings show an expected atrophy pattern with behavioural variant frontotemporal dementia being affected more anteriorly and Alzheimer's disease showing more posterior atrophy. More importantly, subcortical Papez circuit regions (fornix and anterior thalamus) were affected in behavioural variant frontotemporal dementia only, with atrophy in these regions determining the degree of amnesia in behavioural variant frontotemporal dementia. Hippocampal atrophy does not appear to be an efficient diagnostic marker for underlying behavioural variant frontotemporal dementia or Alzheimer's disease pathology, although for behavioural variant frontotemporal dementia, episodic memory deficits in conjunction with marked hippocampal atrophy emerge as potential biomarkers for frontotemporal lobar degeneration with TDP-43 inclusions pathology. Sub-regions of the Papez circuit were differentially affected in behavioural variant frontotemporal dementia and Alzheimer's disease with subcortical regions determining the degree of episodic memory deficits in behavioural variant frontotemporal dementia. Subcortical atrophy should be taken into account when establishing whether the severe amnesia observed in a patient is likely to be due to behavioural variant frontotemporal dementia or Alzheimer's disease pathology.

Prospective Memory Impairments in Alzheimer’s Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates

“…Hippocampal atrophy is well documented in bvFTD [32] and has been shown to correlate robustly with episodic memory dysfunction in this group [6]. Accordingly, compromised PM performance in bvFTD may reflect disruption of the retrospective memory search processes required to retrieve the intended action, a process which is mediated by the hippocampus [56].…”

“…Importantly, given mounting evidence pointing to the involvement of the hippocampus in the genesis of EM dysfunction in bvFTD [6,32], we predicted that the hippocampus would represent a common neural correlate across the two disease syndromes.…”

Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease Regardless of Amnesia?

“…In more details, the preservation of episodic memory in bvFTD has been recently challenged by an increasing number of independent studies showing that bvFTD patients can present with similar levels of amnesia as Alzheimer's disease, [4,5] with both manifesting a combination of frontally mediated and storagebased memory impairment. Although previous studies have suggested that prefrontal cortex degeneration might be the greatest determinant of amnesia in bvFTD, [21,22] more recent evidence suggest that bvFTD patients also show severe atrophy of the medial temporal lobes, including the hippocampus as well as the entire Papez circuit.…”

“…Although previous studies have suggested that prefrontal cortex degeneration might be the greatest determinant of amnesia in bvFTD, [21,22] more recent evidence suggest that bvFTD patients also show severe atrophy of the medial temporal lobes, including the hippocampus as well as the entire Papez circuit. [4,6] One of the only studies that cross-correlated episodic memory performance with grey matter intensity in bvFTD and Alzheimer's disease showed that posterior parietal and cingulate regions were implicated exclusively in Alzheimer's disease while temporal poles and medial frontal regions were involved specifically in bvFTD. [8] Although the profile of cortical involvement in episodic amnesia is different in bvFTD and Alzheimer's disease, current available episodic memory assessments (i.e.…”

“…[1,2] However, increasing evidence suggest that bvFTD patients can show episodic memory deficits, [3] with a subgroup of bvFTD patients being impaired to a similar level as Alzheimer's disease, even in biologically and pathologically confirmed cases. [4,5] Similarly, on a neural level, memory-related structures of the limbic system are found to be affected up to a similar degree as Alzheimer's disease in bvFTD. [3,[6][7][8] By contrast, social cognition assessments have emerged as powerful new tools to distinguish both diseases in a clinical setting, when CSF biomarkers or amyloid imaging are not available.…”