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

Abstract

Background We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. Methods We retrospectively included 150 participants, 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 diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. 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 than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvAD<bvFTD), MRI posterior-DMN-ratios (bvAD<bvFTD), MRI salience-network-ratios (bvAD>bvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD<tAD), FDG anterior-DMN-ratios (bvAD<tAD, AUC range 0.71–0.84, all p < 0.05). Conclusions Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD.

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

“…The anterior cingulate cortex and frontal insula are constituents of the brain's salience network, 38 also vulnerable in bvFTD. 39 A recent study has identified metabolic dysfunction in the frontal insula in patients with behavioral/dysexecutive AD compared to those with typical AD, 12 further corroborating the relationship between the brain's salience network and behavioral symptoms in neurodegenerative diseases including bvFTD and AD.…”

“…It is also possible that a more sensitive measure of neurodegeneration such as [ 18 F]FDG-PET may capture topographic differences in cortical neurodegeneration not observed in our study. 12 Longitudinal analysis may clarify atrophy patterns in behavioral/dysexecutive AD as neurodegeneration follows tau-PET uptake 13 , 40 and correlates with neurofibrillary tangle distribution at autopsy. 41 …”

“…The most important limitation is the lack of consensus classification guidelines for behavioral/dysexecutive AD. Currently, classification of behavioral/dysexecutive AD is based on consensus judgement of a clinical team, 8 , 12 which can lead to variability between centers. This stands in contrast to other focal cortical AD syndromes with established clinical and imaging guidelines such as lvPPA 16 and PCA.…”

“…Based on their behavioral and executive dysfunction with relative preservation of other cognitive domains, the 15 remaining patients with biomarker evidence of AD (amyloid+/tau+) were classified as having behavioral/dysexecutive AD following a consensus meeting of dementia specialists and neuropsychologists. As consensus clinical criteria for this syndrome do not exist, we based our study's criteria on the criteria from the largest study on behavioral/dysexecutive AD 8 and subsequent studies that have also used these same methods, 12 with the additional criteria that participants had a clinical history compatible with possible bvFTD. 15 Of the 15 patients with amyloid+/tau+ behavioral/dysexecutive AD, 4 were referred to the memory center with a diagnosis of bvFTD, 3 were referred requesting a differential diagnosis of bvFTD vs frontal AD, 3 were referred with a diagnosis of “atypical dementia,” 3 were referred with clinical diagnosis of AD with predominance of dysexecutive cognitive impairment, and 2 were referred with a clinical diagnosis of AD with predominance of behavioral changes.…”

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