Subcortical Shape Changes, Hippocampal Atrophy and Cortical Thinning in Future Alzheimer's Disease Patients

Abstract

Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59–82, 47.8% female), future converters at baseline (n = 10, age range 66–84, 90% female) and at time of conversion (age range 68–87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61–81, 47.8% female; n = 10, age range 66–82, 80% female; n = 10, age range 68–82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease.

Subcortical amyloid load is associated with shape and volume in cognitively normal individuals

“…This concurs with the occurrence of significant amounts of Aβ in the thalamus of AD (Braak & Braak, ). Shape abnormalities in the thalamus associated with Aβ have also been reported in cognitively normal individuals (Schroeder et al, ) as well as in MCI patients who showed cognitive worsening over a 2‐year period (Kalin et al, ). Interestingly, we also found that some of the surface change in the thalamus were also due to changes in shape only (i.e., surface remains abnormal even when analyses were corrected for size and global scalings), particularly in regions which did not show surface changes when investigating the effect of local volume change.…”

“…A vertex‐based surface approach was used to investigate Aβ‐associated local surface changes in subcortical structures and whether these changes related more to local volume or shape. Surface‐based approaches have proven efficient in the detection of subtle surface abnormalities in subcortical structures in AD, MCI, and cognitively normal individuals (Csernansky et al, ; de Flores et al, ; Kalin et al, ; Leh et al, ; Schroeder et al, ). Unlike our previous analyses using subcortical overall volumes, we found that subcortical regional PiB retention values were associated with the surface of the bilateral hippocampus and thalamus and the right pallidum.…”

“…Several studies have used other morphometric approaches to investigate the surface in the hippocampus (Csernansky et al, ; de Flores et al, ; Kalin et al, ; Tang et al, ), which revealed local modifications that did not necessarily translate into changes in the overall size of the structures (Patenaude, Smith, Kennedy, & Jenkinson, ). Such approaches have mainly revealed inward surface displacement in regions corresponding to the CA1 subfield and subiculum in AD and MCI patients (de Flores et al, ; Kalin et al, ) but also surface changes in the amygdala and the lateral ventricles (Tang et al, ). In cognitively normal individuals, surface deformation has also been found in association to Aβ burden in the hippocampal head and body and in the thalamus (Achterberg et al, ; Carmichael et al, ; Csernansky et al, ; Schroeder et al, ).…”

“…However, the association between baseline amyloidosis and longitudinal change in hippocampal volume in cognitively normal individuals remains unclear. Several studies have used other morphometric approaches to investigate the surface in the hippocampus (Csernansky et al, 2005;de Flores et al, 2015;Kalin et al, 2017;Tang et al, 2014), which revealed local modifications that did not necessarily translate into changes in the overall size of the structures (Patenaude, Smith, Kennedy, & Jenkinson, 2011). Such approaches have mainly revealed inward surface displacement in regions corresponding to the CA1 subfield and subiculum in AD and MCI patients (de Flores et al, 2015;Kalin et al, 2017) but also surface changes in the amygdala and the lateral ventricles (Tang et al, 2014).…”

Differentiation drives widespread rewiring of the neural stem cell chaperone network

“…We next examined how aging affects TRiC and sHSPs levels in the brain. Proteostat staining of aged brain sections compared to young counterparts indicated that the increase in Proteostat + inclusions was not restricted to aged NSPCs (Figures 1D-G, S1C), but was widespread in other regions; particularly the cortex and striatum (Figures 7A, B; S7A), areas typically affected in age-related proteopathies (Kalin et al, 2017; Rub et al, 2016). We observed a decline in TRiC protein levels in Sox2 + cells of the aged SGZ stem cell niche compared to those of young adult mice; both in vivo in mouse brain sections (Figures 7C, S7B) and in vitro in isolated NSPCs (Figures 7D).…”