Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices

Abstract

The number of Thioflavine S-positive neurofibrillary tangles (NFT) and neuritic plaques (NP) was determined in visual and auditory cortical regions of 8 patients with Alzheimer's disease. On both a regional and laminar basis, NFT exhibited very distinctive and consistent distribution patterns. The mean (+/- SEM) number of NFT in a 250-micron- wide cortical traverse was very low in area 17, primary visual cortex (0.9 +/- 1.0), increased 20-fold in the immediately adjacent visual association cortex of area 18 (19.7 +/- 3.6), and showed a further doubling in area 20, the higher-order visual association cortex of the inferior temporal gyrus (35.5 +/- 8.8). Similar differences in NFT number were present between primary auditory (1.6 +/- 0.5) and auditory association (18.9 +/- 5.4) regions. On a laminar basis, NFT were predominantly present in layers III and V, although there were striking regional differences in the proportion of NFT in these 2 layers. Layer III contained 79% of the NFT in layers III and V in area 18, 41% in area 20, and only 27% in area 22. In contrast, NP showed different, and less specific, regional and laminar distribution patterns. Total NP number was similar in the 3 visual areas, although there were marked regional differences in the type of NP present. Nearly 80% of the NP in area 17 was of the NPc type (i.e., contained a dense, brightly fluorescent core), whereas over 70% of the NP in both areas 18 and 21 was of the NPnc type (i.e., lacked a dense, brightly fluorescent core). NP were present in every cortical layer but were most numerous in layers III and IV. The distinctive distribution patterns of NFT are very similar to the regional and laminar locations of long corticocortical projection neurons in homologous regions of monkey neocortex. This association suggests that NFT reside in the cell bodies of a subpopulation of pyramidal neurons, namely, those that furnish long corticocortical projections. In contrast, the distribution patterns of NP suggest that multiple neuronal systems contribute to their formation.

Diffusion Tensor Imaging of Normal-Appearing White Matter in Mild Cognitive Impairment and Early Alzheimer Disease: Preliminary Evidence of Axonal Degeneration in the Temporal Lobe

“…27,28 Early microscopic studies have described the intracellular and extracellular features of AD in limbic and neocortical brain regions, [29][30][31][32] and more recent MR imaging studies have demonstrated volumetric changes in corresponding gray matter regions of AD brains. 1,[33][34][35][36] However, relatively little attention has been directed toward abnormalities in cerebral white matter in AD.…”

“…This finding is consistent with the known propensity for early degeneration of temporal lobe structures such as the hippocampal formation, parahippocampal gyrus, and entorhinal cortex in AD. 1,3,[30][31][33][34] Furthermore, because DA is more strongly related to axonal pathology and DR is more strongly related to demyelination, 18,19 the changes in temporal white matter directional diffusivities of MCI (2DA) may reflect early axonal damage, and the directional diffusivity changes in temporal white matter of AD (2DA, 1DR) may reflect complete loss of myelinated axons as would be seen in wallerian degeneration. Lesser changes in directional diffusivities were also observed in the frontal and parietal white matter of MCI and AD subjects but were not observed in the occipital white matter.…”

Sensory cortical interactions in aging, mild cognitive impairment, and Alzheimer’s disease

“…The cognitive deficits in AD may be related to a possible disconnection between cortical areas due to pathology affecting neurons that provide long corticocortical connections [13,17,19,22,23]. MCI is considered a risk factor for the development of AD [26], which suggests that less extensive cortical disconnection, relative to AD, may contribute to the memory dysfunction in MCI.…”

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

“…Hyperphosphorylation induces aggregation and then fibrillation, which in humans can progress to NFT formation. In AD, NFTs are selective to the association cortex (7,8), where they specifically target pyramidal cells with the most extensive corticocortical connections (9). For example, layer III pyramidal cells of the dorsolateral prefrontal association cortex (dlPFC) have extensive corticocortical connections and are afflicted early and severely in AD (9).…”

“…For example, layer III pyramidal cells of the dorsolateral prefrontal association cortex (dlPFC) have extensive corticocortical connections and are afflicted early and severely in AD (9). In contrast, primary sensory cortices (e.g., visual area V1) have very few NFTs even in late-stage disease (7,8). Although this pattern of degeneration has been recognized for decades, it has not been known why extensively interconnected pyramidal cells in association cortex are selectively afflicted and why advancing age is such a high risk factor for their degeneration.…”