Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes

Abstract

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.

Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

“…Interestingly, Compta et al. observed a reverse relationship in the PD-D group, where increased CSF α -synuclein was associated with atrophy in the parahippocampal gyrus and precuneus, both of which are commonly implicated in preclinical and established stages of dementia (Mak et al., 2017, Villemagne and Chételat, 2016). However, the correlations did not persist after adjusting for CSF tau, suggesting that any effects of CSF α -synuclein may be mediated through tau (Compta et al., 2014).…”

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

“…We also observed a significant association between accelerated DNAm age (based on the Hannum epigenetic age clock) and two MRI measures (Supplementary have been associated with aging and symptomatic neurodegeneration and could be chance findings. Alternatively, epigenetic aging associated with increased FA and decreased MD could be linked with comparable findings in presymptomatic carriers of familial AD mutations, where it has been suggested that such findings could reflect earlier axonal insults in the pathway toward subsequent neurodegeneration such as neuroinflammatory changes leading to neuronal and glial swelling [42,43]. Nevertheless most studies indicated no change or decreased FA and increased MD in preclinical familial AD [42].…”

“…Alternatively, epigenetic aging associated with increased FA and decreased MD could be linked with comparable findings in presymptomatic carriers of familial AD mutations, where it has been suggested that such findings could reflect earlier axonal insults in the pathway toward subsequent neurodegeneration such as neuroinflammatory changes leading to neuronal and glial swelling [42,43]. Nevertheless most studies indicated no change or decreased FA and increased MD in preclinical familial AD [42]. No associations were observed between the Horvath epigenetic clock and any of the imaging variables tested and neither of the epigenetic clocks were associated with cognitive function or presence of cognitive impairment.…”

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

“…Brain damage associated to AD starts decades before the symptomatic onset and clinical diagnose, which has led to consider AD as a continuum (Dubois et al, 2016;Jack et al, 2018). In this line, studies performed on AD risk population such as carriers of apolipoprotein E (APOE)-ε4 or rs405509 alleles have detected brain differences between these subjects and control subjects in elderly Reiter et al, 2017;Shu et al, 2015) and middle-age healthy population (Cacciaglia et al, 2018;Habib et al, 2017;Mak et al, 2017;ten Kate et al, 2016).…”