We found a significant association of higher numbers of MBI to lower brain weight and to poorer ante-mortem global cognitive performance measured by the CASI. The association with lower CASI score was partially mediated through lower brain weight. While NP were not significant correlates or mediators of BW, NFT were associated with BW, especially in demented decedents. In models containing MBI, NFT and NP, only NFT and MBI were significantly and independently correlated with CASI score.
There were differences in the magnitude of these associations between those who had vs. those who did not have an ante-mortem diagnosis of dementia. Compared to the D
group, in the ND group
, MBI were more strongly associated with brain weight. Consistent with these observations, we also found MBI were more strongly associated with a lower CASI score in ND
. In contrast, among those who were diagnosed with dementia, more NFT were significantly associated with lower BW and CASI score in models that included both the cerebrovascular and Alzheimer lesions. NFT also marginally influenced the association of MBI to lower brain weight and to lower CASI scores(efigure 6
Autopsy studies are by definition cross-sectional and cannot provide information on the temporal changes in the brain. Never-the-less, as other autopsy studies (1
), our analyses may provide clues to the staging of lesions linked to dementia and to what is often considered normal aging-related declines in cognitive function. In this context, our data are consistent with the emerging hypothesis-generating model of late onset Alzheimer’s disease (16
) published by Jack and colleagues. In this model brain changes evolve progressively from accumulating NP, NFT and decline in neuronal and synaptic reserves, evident as loss of brain tissue. Our findings that NFT are strongly related to brain weight and ante-mortem cognitive function in those with a dementia diagnosis are consistent with the proposal that NFT formation occurs downstream in the cascade, and is therefore the most strongly related to ante-mortem dementia.
We found MBI pathology is a significant and independent factor contributing to low brain weight, particularly in those who did not have an ante-mortem diagnosis of dementia. This suggests consequent vascular changes may occur relatively earlier in the trajectory to dementia. However, our non-demented group performed from good to poor on the CASI and may include subjects with insufficient data to support a diagnosis of dementia. Results for the demented group do suggest MBI are modestly associated with cognitive function, particularly when the models are adjusted for the variation in NFT. This increase in the statistical significance of MBI to the CASI score may reflect several different pathologic profiles. For instance, there is a wide distribution of NFT across subjects, so when we control for that variation, other factors contributing to cognitive function can be detected. There may also be a sub-group of subjects with a high MBI and low NFT load in the demented group.
One question that is currently debated is whether vascular damage initiates the cascade of neurodegeneration, plays a role in the progression of neurodegeneration, or adds to the pathology underlying cognitive impairment and dementia. The widely distributed vascular damage captured in MBI count could lead to ischemia, with attendant inflammation, oxidative stress, energy imbalance, glucocorticoid-mediated effects(17
). It has been proposed, for instance, that APP is produced, or deposited, as an acute response to damage, which may be vascular (20
). However, other data suggest vascular lesions contribute additively to the clinical presentation of dementia(6
). Our findings suggest there may be multiple roles for vascular damage depending on the stage of disease. The role and position in the trajectory of dementia of vascular damage is critical to understand from both pathophysiologic and prevention perspectives. Studying the in vivo trajectory to dementia, although greatly aided by the imaging of amyloid deposition, remains difficult in the absence of bio-imaging biomarkers of microvascular disease, NFT and the other pathologies contributing to late-life dementia. However, these data suggest interventions to reduce vascular damage at an earlier, and possibly also a later stage of dementia may be beneficial to the clinical presentation.
The generalizability of these results should be taken into account. Our sample is based on Japanese American men. Possibly the results are modified by factors such as the type of education, cognitive reserve, the extent of unmeasured pathology in the brain or life style factors specific to this group. Possibly associations in women compared to men may differ for reasons that are under study. Second, we only examined a global measure of cognitive function in relation to a global measure of lesion load. More targeted examination of specific cognitive tests in relation to specific brain areas would be important to our understanding of how vascular lesions influence cognitive function.