Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer’s disease

Abstract

Objective: We previously found temporoparietal “Alzheimer-typical” atrophy in patients with the behavioral variant of Alzheimer's disease (bvAD) with relative sparing of frontal regions. Here, we aimed to understand the pathophysiological mechanisms of bvAD based on alternative neuroimaging markers. Methods: We retrospectively included 150 participants at the University of California San Francisco and University of Berkeley, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other groups on glucose metabolism and metabolic connectivity on [18F]FDG-PET, and subcortical gray matter volumes and white matter hyperintensity volumes (WMHV) on MRI. A receiver-operating-characteristic-analysis was performed to determine the measures yielding the highest contrast between groups. Results: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD compared to tAD, partially overlapping with bvFTD. Metabolic connectivity analyses indicated greater anterior default mode network (DMN) involvement in bvAD compared to tAD, mimicking bvFTD. Analyses of subcortical volume and WMHV showed no relevant group differences. The top-3 discriminative measures for bvAD vs. bvFTD were: metabolism in posterior (bvAD<bvFTD), anterior DMN (bvAD>bvFTD) and parietal cortex (bvAD<bvFTD; AUC: 0.80-0.91, p<0.01), while the top-3 discriminators for bvAD vs. tAD were amygdalar volume (bvAD>tAD), anterior DMN (bvAD<tAD) and salience network metabolism (bvAD<tAD; AUC: 0.66-0.75, p<0.05). Conclusion: Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD.

Heterogeneous distribution of tau pathology in the behavioral variant of Alzheimer’s disease

“…Importantly, most bvAD cases did not show prominent tau uptake in medial prefrontal and insular regions, which are affected in bvFTD and constitute key regions of the salience network 31 36,37 , rather than from frontal neocortical pathology. However, except for the amygdala, we previously observed no differences in gray matter volumes or patterns of white matter hyperintensities between bvAD and typical AD that are of relevance for behavior 3 . In addition, the current study showed no differences in postmortem tau pathology in subcortical regions between bvAD and typical AD, supporting the notion that these structures may not be disproportionally affected in bvAD.…”

“…However, given the demonstrated right hemispheric dominance in bvFTD 45 and suggested dominance in bvAD 3,5,13 as well as established relationships between right frontal areas and behavioral deficits like apathy, disinhibition and aberrant motor behavior 46 , it is unlikely that this affected our results. Fourth, the comparison of the frontal pole in the postmortem study against the medial and lateral prefrontal cortices in the tau PET study may introduce a bias, as these regions have been differentially implicated in behavioral disturbances 47 .…”

“…In addition, the current study showed no differences in postmortem tau pathology in subcortical regions between bvAD and typical AD, supporting the notion that these structures may not be disproportionally affected in bvAD. Alternatively, the explanation may lie in functional rather than structural mechanisms, as behavior may rely on complex integrated networks across the brain and we previously showed alterations in metabolic connectivity of the anterior default mode network in bvAD 3 . In addition, analogous to reports of participants with the logopenic variant of progressive aphasia showing learning disabilities in their medical history 38 The fact that the regional distribution of tau pathology did not show a strong consistent concordance with the clinical features of bvAD raises questions about the relationship between tau and behavior in AD, as bvAD patients represent the extreme of behavioral deficits on the clinical spectrum of AD.…”

“…Individuals with the behavioral variant of Alzheimer's disease (bvAD, previously referred to as "frontal AD") experience early prominent behavioral symptoms and personality changes, such as disinhibition, compulsive behaviors and loss of empathy 1,2 . These individuals are clinically reminiscent of behavioral variant frontotemporal dementia (bvFTD), but have AD as the primary pathology and resemble patients with "typical" AD (tAD) neuroanatomically, as atrophy and hypometabolic patterns in bvAD predominantly occur in temporoparietal regions 1,3 . Imaging and pathological investigations (mostly case reports or small cohort studies based on the low prevalence of this phenotype 1 ) have provided mixed results regarding the involvement of the frontal cortex in bvAD [4][5][6][7][8] .…”

Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

“…Autopsy studies assessing the distribution of amyloid-β and tau in behavioural/dysexecutive AD are small (n≤6) and report conflicting results [9][10][11] . Subsequent larger studies did not identify substantial frontal atrophy 8,12 , leading to the designation of "behavioural/dysexecutive AD" over "frontal variant AD" 8 . However, these larger studies have not assessed the distribution amyloid-β or tau pathology 8,12 , which could be related to clinical presentation and anticipate focal neurodegeneration in these individuals 13 .…”