Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations

Abstract

Background Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer’s disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer’s disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. Methods Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. Results MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. Conclusions Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.

The thalamus as a putative biomarker in neurodegenerative disorders

“…In familial AD, thalamic atrophy (Lee et al, 2013;Ryan et al, 2013) and increased fractional anisotropy of the thalamus bilaterally (Ryan et al, 2013) have been reported in the presymptomatic stage of disease, consistent with amyloid imaging studies demonstrating that amyloid deposition first occurs in the striatum and thalamus in pre-symptomatic cohorts (see Knight et al, 2011). Longitudinal studies of thalamic morphology in both sporadic and familial AD are warranted.…”

“…In terms of structural MRI, meta-analyses have reported thalamic atrophy in schizophrenia (Adriano et al, 2010) and major depressive disorder (Du et al, 2012), but not in bipolar disorder (Hallahan et al, 2011). Thalamic atrophy has been reported in both sporadic AD (De Jong et al, 2008) and the presymptomatic stage of familial AD (Lee et al, 2013;Ryan et al, 2013), as well as in progressive supranuclear palsy (PSP) (Whitwell et al, 2011), FTD (Cardenas et al, 2007;Chow et al, 2008) and HD (Kassubek et al, 2005).…”

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

“…Changes to the gross structure and size of the striatum occur early during progression of both familial (early onset) and more common sporadic (late onset) forms of AD (Cho et al, 2013;de Jong et al, 2011;de Jong et al, 2008;Pievani et al, 2013). Indeed, brain imaging has revealed that structural changes of both the striatum and the hippocampus are evident at pre-and early-symptomatic stages in carriers of familial AD-causing mutations (Cash et al, 2013;Lee et al, 2013;Ryan et al, 2013) and that the striatum in particular is the site of the earliest amyloid accumulations in familial AD (Klunk et al, 2007;Knight et al, 2011). In view of the major roles of the human striatum and hippocampus in higher cognition, testing the hypothesis that neurogenesis defects contribute to the early striatal and hippocampal changes occurring in human AD represents an important challenge.…”

What dementia reveals about proverb interpretation and its neuroanatomical correlates

“…All algorithms used in creating TBM Jacobian maps, including linear registration, non-linear registration, and linear regression algorithms, were developed at the Laboratory of NeuroImaging (LONI) at UCLA and have been successfully used in previous studies measuring brain volumetric changes in neurodegenerative disorders (Hua et al, 2008;Lee et al, 2013), and were implemented using the LONI Pipeline (Dinov et al, 2010).…”