The human brain undergoes non-uniform changes during aging. The substantia nigra (SN), the source of major dopaminergic pathways in the brain, is particularly vulnerable to changes in the progression of several age-related neurodegenerative diseases. To establish normative data for high-resolution imaging, and to further clinical and anatomical studies we analyzed SNs from 15 subjects aged 50-91 cognitively normal human subjects without signs of parkinsonism. Complete brains or brainstems with substantia nigra were formalin-fixed, celloidin-mounted, serially cut and Nissl-stained. The shapes of all SNs investigated were reconstructed using fast, high-resolution computer-assisted 3D reconstruction software. We found a negative correlation between age and SN volume (p = 0.04, rho = -0.53), with great variability in neuronal numbers and density across participants. The 3D reconstructions revealed SN inter- and intra-individual variability. Furthermore, we observed that human SN is a neuronal reticulum, rather than a group of isolated neuronal islands. Caution is required when using SN volume as a surrogate for SN status in individual subjects. The use of multimodal sequences including those for fiber tracts may enhance the value of imaging as a diagnostic tool to assess SN in vivo. Further studies with a larger sample size are needed for understanding the structure-function interaction of human SN.

Objective

We conducted a clinicopathologic study in a large population with very low levels of education to determine whether very few years of education could contribute to cognitive reserve and modify the relation of neuropathologic indices to dementia.

Methods

In this cross-sectional study, we included 675 individuals 50 years of age or older from the Brazilian Aging Brain Study Group. Cognitive abilities were evaluated through a structured interview with an informant at the time of autopsy, including the Clinical Dementia Rating (CDR) scale. Neuropathologic examinations were performed using immunohistochemistry and following internationally accepted criteria. Multivariate linear regression models were conducted to determine whether the association between cognitive abilities (measured by CDR sum of boxes) and years of education was independent of sociodemographic variables and neuropathologic indices, including neuritic plaques, neurofibrillary tangles, lacunar infarctions, small-vessel disease, and Lewy bodies. In addition, interaction models were used to examine whether education modified the relation between neuropathologic indices and cognition.

Results

Mean education was 3.9 ± 3.5 years. Formal education was associated with a lower CDR sum of boxes (β = -0.197; 95% confidence interval -0.343, -0.052; p = 0.008), after adjustment for sociodemographic variables and neuropathologic indices. Furthermore, education modified the relationship of lacunar infarcts with cognitive abilities (p = 0.04).

Conclusions

Even a few years of formal education contributes to cognitive reserve.