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

Abstract

ObjectiveTo determine the associations between amyloid-PET, tau-PET and atrophy with the behavioural/dysexecutive presentation of Alzheimer's disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 cases of behavioural/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 disease severity- and age-matched amnestic AD patients and a group of 131 cognitively unimpaired (CU) elderly individuals. All subjects were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioural/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the ROC curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate and frontal insular cortices were best able to differentiate between behavioural/dysexecutive and amnestic AD (AUC = 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioural/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

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

“… 9 Furthermore, a group study (n=15) combining cases with behavioural and dysexecutive AD suggested frontal involvement of tau pathology measured with PET, in the absence of marked frontal brain atrophy. 28 Our extended case series shows that patients with bvAD are primarily characterised by a classical temporoparietal pattern of tau, with, in some cases, pronounced involvement of (mostly lateral) frontal areas, which did not strongly depend on disease severity or age of onset. 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 29 that regulates complex social behaviours.…”

Provisional research criteria for the behavioral variant of Alzheimer’s disease A systematic review and meta-analysis

“…Table-2 provides an overview of neuroimaging studies in bvAD. Structural MRI studies (number of studies [“k”]=6, number of participants [“n”]=92) showed temporoparietal 23 , frontotemporal and insular 17,24,25 , or frontoparietal 26 predominant atrophy patterns across bvAD patients. bvAD did not differ from tAD in three studies 23,26,27 , and showed moderately more involvement of frontal regions in bvAD compared to tAD in three other studies 17,24,25 .…”

“…Structural MRI studies (number of studies [“k”]=6, number of participants [“n”]=92) showed temporoparietal 23 , frontotemporal and insular 17,24,25 , or frontoparietal 26 predominant atrophy patterns across bvAD patients. bvAD did not differ from tAD in three studies 23,26,27 , and showed moderately more involvement of frontal regions in bvAD compared to tAD in three other studies 17,24,25 . Studies assessing glucose metabolism with [ 18 F]FDG-PET or perfusion with SPECT (k=7, n=88) also showed heterogeneous results, ranging from a predominantly temporoparietal hypometabolic pattern 27,28 to a mixed frontal and temporoparietal 15,16,29,30 or predominantly frontal pattern 31 .…”

“…Amyloid-PET studies (k=2, n=28) showed no differences in amyloid-β burden or distribution between bvAD and tAD patients. 26,31 For tau-PET (k=2, n=22), one study showed a temporoparietal pattern with higher uptake in anterior regions in bvAD compared to tAD 26 , whereas another study showed heterogeneous patterns across bvAD patients 32 . Findings on functional connectivity (k=3, n=54) and white matter hyperintensities (k=1, n=29) in bvAD are presented in Table-S6 .…”

“…Some studies (mainly case studies or case series) showed anterior neurodegenerative patterns that resemble bvFTD, but most group studies showed either a mix of anterior and posterior involvement or a posteriorpredominant pattern. 17,[23][24][25][26][27][28]36,37 Contrary to PCA and lvPPA, we therefore did not incorporate MRI, CT, SPECT or [ 18 F]FDG-PET read-outs into the core bvAD research criteria, but only added them as supportive features. Fourth, evidence of amyloid-β pathology provided by PET, CSF or plasma biomarkers can upgrade the diagnosis from "clinical bvAD" to "possible bvAD".…”