Aims

Post-mortem work has shown local accumulation of amyloid-beta, p-tau in the nucleus basali of Meynert (NbM), which leads to cholinergic deficiency in Alzheimer’s disease (AD). In MRI, NbM volume loss and microstructural alterations have been reported in AD. We aim to investigate the effect of neuropathological hallmarks in the NbM on MRI-measured NbM volume and structural connectivity in AD.

Methods

Twenty AD and eleven age- and gender-matched non-neurological control donors underwent post-mortem in-situ 3T MRI: T1-w for NbM delineation and DTI (fractional anisotropy, FA, and mean diffusivity, MD) for quantifying the integrity of the NbM and the projections. NbM sections of 20 μm were immunohistochemically stained for ChAT, amyloid-beta, and p-tau, and analyzed with ImageJ for their area %-load. Group comparisons were assessed using non-parametric tests and MRI-pathology associations with linear mixed models.

Results

AD cases showed lower NbM volume (p=0.003) and higher MD (p=0.003), as well as higher amyloid-beta (p=0.003) and p-tau (p=0.004) load than controls. In addition, AD cases showed higher MD in frontal (p=0.017) and temporal (p=0.039) projections.

For MRI-pathology associations in combined groups, NbM atrophy associated with less ChAT load (r=0.58,p=0.005), and lower FA associated with higher amyloid-beta load (r=0.47,p=0.032) in the NbM. MD of parietal and temporal projections associated with NbM ChAT load (r=0.44,p=0.013;r=0.3,p=0.007), and FA of temporal projections (r=0.26,p=0.029) with NbM p-tau load.

Conclusions

Our results indicate that cholinergic degeneration due to AD pathology is not restricted to the NbM, but further impacts its projections to the cortex, which can be captured by diffusion MRI.

Aims

Alzheimer’s disease (AD) is characterized by cortical atrophy on MRI and abnormal depositions of amyloid-beta, p-tau and inflammation pathologically. However, the relative contribution of these pathological hallmarks to cortical atrophy, widely used as MRI biomarker in AD, is yet to be defined. The aim of this study is to determine the independent and combined contributions of the pathological hallmarks to cortical thickness in AD descents.

Methods

Twenty pathologically confirmed AD donors and ten age-matched controls underwent post-mortem in-situ 3T 3DT1 MRI, from which cortical thickness was calculated with Freesurfer. Upon subsequent autopsy, 12 cortical regions from the right and 9 from the left hemisphere were dissected and immunostained for amyloid-beta, p-tau, CD68 and C4b complement, and area %load was calculated. MRI-pathology associations were assessed with linear mixed models.

Results

A region-wide positive association between amyloid-beta load and cortical thickness was found in AD cases (r=0.17,p=0.012). In contrast, region-specific negative associations between p-tau and cortical thickness were found in frontal (r=-0.91,p<0.001), parietal (r=-0.71,p<0.001) and medial temporal regions (r=-0.89,p<0.001). CD68 load contributed to the correlation with cortical thickness in the parietal region even when controlling for p-tau (r=-0.55,p=0.048).

Conclusions

Our results show that amyloid-beta and p-tau burden contribute to cortical thickness differently: while amyloid-beta contributes to a cortical thickening diffusely, p-tau strongly contributes to cortical thinning in specific regions. Moreover, reactive microglia load contributes to cortical thinning in the inferior parietal gyrus, independently of the underlying pathology.

Aims

Hippocampal atrophy is the most established structural imaging biomarker for Alzheimer’s disease (AD). Nevertheless, some argue that hippocampal diffusion is a more sensitive imaging marker. We addressed the pathological sensitivity of hippocampal MRI volume and diffusivity vis-à-vis, and determined the relative contribution of AD related pathological proteins in hippocampal sub-regions.

Methods

Ten clinically amnestic and pathological confirmed AD, and ten age- and gender matched control decedents underwent post-mortem in-situ 3T MRI; 3DT1 for FSL FIRST hippocampus segmentation, and DTI to obtain mean diffusivity (MD). At autopsy, hippocampal tissue was dissected and processed for Aβ and p-tau immunohistochemistry, and area % immunoreactivity in hippocampal sub-regions was calculated. MRI-pathology associations were assessed with linear mixed models and with partial correlations, corrected for age, gender and post-mortem delay.

Results

Compared to controls, AD donors showed significantly increased hippocampal MD (p<0.021), but not decreased volume (p=0.195) which was more sensitive to within-group variation. Hippocampal MD associated with Braak stage (r=0.54, p=0.033) and Thal phase (r=0.51, p=0.045), volume was not significant due to within-group variation in disease duration. In whole-group analysis, p-tau contributed to hippocampal volume (p<0.001), while both Aβ (p=0.014) and p-tau (p<0.001) contributed to hippocampal MD. Regionally, hippocampal volume was associated with Aβ in CA4, CA1 and subiculum (0.03<p<0.05), and with p-tau in DG, CA4, CA3 and CA2 (0.001<p<0.05). Hippocampal MD associated with Aβ and p-tau in all subregions (0.001<p<0.05).

Conclusions

Hippocampal MD showed to be a more robust measure with greater sensitivity to (sub-regional) AD related pathological load than hippocampal volume.

Aims

Axons are crucial for impulse transmission, transportation of organelles, and clearance of proteins necessary for neuronal and synaptic survival. In Parkinson’s disease (PD), axonal degeneration occurs early and contributes to spread of pathology. The aim of this study is to assess features of axonal degeneration and protein aggregation in the anterior insular sub-regions in PD and dementia with Lewy bodies (DLB).

Methods

The post-mortem anterior insula was collected from 25 PD, PD dementia (PDD), and DLB donors. Axonal loss was evaluated using modified Bielschowsky silver staining and unbiased stereology. Pathology load was semi-quantified on sections stained for α-synuclein, hyperphosphorylated (HPF)-tau, and amyloid-β proteins. For cytoskeletal damage, immunofluorescent multi-labelling with neurofilament (NFL), myelin, and α-synuclein was analyzed using confocal laser-scanning microscopy. Parametric tests and linear mixed model were used for data analysis.

Results

The anterior agranular insula showed a significantly higher load of α-synuclein (t(21)=5.3;p<0.001), HPF-tau pathology (t(19)=5.1;p<0.001) and axonal loss (t(23)=-5.7;p<0.001) compared to the anterior dysgranular insula. The dysgranular insula alternatively showed a significant higher load of amyloid-β pathology (t(9)=-2.5;p=0.03). In mixed model analysis, HPF-tau significantly contributed to axonal loss (b=-3.45x10^-5;F(1,42)=4.2;p=0.046). NFL showed fragmentation and swellings; while myelin showed axon-myelin disruption in both sub-regions. The DLB group showed most severe axonal loss, cytoskeletal damage and protein aggregates.

Conclusions

The agranular and dysgranular insular sub-regions were differentially vulnerable to axonal loss and pathological aggregates, most pronounced in DLB. Our results highlight the selective vulnerability of the anterior insula to various converging pathologies disrupting axonal integrity, potentially contributing to non-motor deficits in PD and DLB.