Presymptomatic cortical thinning in familial Alzheimer disease

Abstract

Objective:To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration.Methods:We recruited 43 FAD mutation carriers—36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)—and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2.9) follow-up scans approximately annually. Cortical thickness was measured using FreeSurfer. A cortical thinning signature was identified from symptomatic FAD participants. We then examined cortical thickness changes in this signature region in presymptomatic carriers and assessed associations with cognitive performance.Results:The cortical signature included 6 regions: entorhinal cortex, inferior parietal cortex, precuneus, superior parietal cortex, superior frontal cortex, and supramarginal gyrus. There were significant differences in mean cortical signature thickness between mutation carriers and controls 3 years before predicted symptom onset. The earliest significant difference in a single region, detectable 4 years preonset, was in the precuneus. Rate of change in cortical thickness became significantly different in the cortical signature at 5 years before predicted onset, and in the precuneus at 8 years preonset. Baseline mean signature thickness predicted rate of subsequent thinning and correlated with presymptomatic cognitive change.Conclusions:The FAD cortical signature appears to be similar to that described for sporadic AD. All component regions showed significant presymptomatic thinning. A composite signature may provide more robust results than a single region and have utility as an outcome measure in presymptomatic trials.

Cognitive Impairment Correlates Linearly with Mean Flow Velocity by Transcranial Doppler below a Definable Threshold

“…Affected cognitive functions overlap with those in the current study, including tests of memory and executive function. These investigators also showed a linear correlation between lower flow and cortical thinning, a marker also associated with cognitive impairment [25,26]. This correlation was also demonstrated in patients with carotid disease [27].…”

Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria

“…On the other hand, lower 5‐HIAA levels correlated also with a large cluster of atrophy in the precuneus, which is a multimodal cortical hub integrating information from temporal, occipital, and parietal lobes . The precuneus is a very vulnerable region of the aging brain, as its atrophy and dysfunction has been associated with early phases of Alzheimer's disease . Thus, the association between GM atrophy of this specific area with lower 5‐HIAA/5‐HTP CSF levels might reflect the interaction of chronic serotonin depletion specifically present in PKU patients and the time‐dependent changes in the human brain.…”

Cortical microstructure in young onset Alzheimer's disease using neurite orientation dispersion and density imaging

“…Five of the ROIs were chosen on the basis of being early sites of neuropathological change in AD. These included four regions that comprise the Mayo Clinic cortical signature of AD (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, and fusiform gyrus) (Jack et al, ; Schwarz et al, ), all of which have been implicated to undergo grey matter atrophy at a relatively early stage of AD (Braak and Braak, ; Dickerson et al, ; Jack et al, ; Petersen et al, ; Weston et al, ) and the precuneus, which has been reported to undergo more pronounced atrophy in YOAD patients (Ishii et al, ; Karas et al, ; Möller et al, ). To investigate if cortical NODDI metrics are potentially a more sensitive marker of AD pathology than cortical macrostructural metrics, the precentral gyrus (primary motor cortex) was included as a ROI.…”

“…To provide a mask for field map processing a total intracranial mask (Malone et al, 2015) generated from SPM12 (http://www.fil.ion.ucl.ac.uk/spm) segmentation was propagated from the T1 to diffusion volumes by a union of direct affine transformation and nonlinear transformation to provide maximal coverage before and after susceptibility correction. Structural T1 to diffusion b 5 0 and diffusion to field map magnitude registration was carried out using Niftyreg ( all of which have been implicated to undergo grey matter atrophy at a relatively early stage of AD (Braak and Braak, 1991;Dickerson et al, 2011;Jack et al, 2017;Petersen et al, 2016;Weston et al, 2016) and the precuneus, which has been reported to undergo more pronounced atrophy in YOAD patients (Ishii et al, 2005;Karas et al, 2007;M€ oller et al, 2013). To investigate if cortical NODDI metrics are potentially a more sensitive marker of AD pathology than cortical macrostructural metrics, the precentral gyrus (primary motor cortex) was included as a ROI.…”