Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late‐onset sporadic Alzheimer's disease

Abstract

To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i-NFT) and extracellular NFT (e-NFT) in 22 patients with late-onset sporadic Alzheimer's disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin-eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i-NFT and e-NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e-NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e-NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e-NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e-NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression.

Compensatory Changes in the Noradrenergic Nervous System in the Locus Ceruleus and Hippocampus of Postmortem Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

“…The reduction in ␣ 1D -AR mRNA cannot be attributed to the cell loss documented in the CA1 in AD (Simic et all., 1997;Bobinski et al, 1998;Fukutani et al, 2000;Price et al, 2001;Rossler et al, 2002) because ␣ 2A -AR mRNA expression was unchanged in the same region, in the same subjects. It is possible that these different ␣-AR subtypes are expressed in different neurons and the neurons expressing ␣ 1D -AR mRNA are lost in AD and DLB.…”

“…Perhaps the loss of ␣ 2C -AR mRNA in AD and DLB subjects in the hippocampus contributes to these behavior symptoms. The loss of ␣ 2C -AR mRNA in the GCL or CA3 cannot be attributed to neuronal loss in AD because these regions do not demonstrate any degree of loss (Simic et al, 1997;Bobinski et al, 1998;Fukutani et al, 2000;Price et al, 2001;Rossler et al, 2002), and the expression of ␣ 2A -AR mRNA in the same regions was unchanged in AD and DLB.…”

Spatial patterns of mammalian brain aging: Distribution of cathepsin D–immunoreactive cell bodies and dystrophic dendrites in aging dogs resembles that in Alzheimer's disease

“…Neurofibrillary tangles, a defining feature of Alzheimer's disease (AD), occur earlier and with much greater frequency in the superficial layers of perirhinal and entorhinal cortex than in most areas of neocortex (Brun and Gustafson, 1976;Ball, 1977;Braak andBraak, 1985, 1991;Arnold et al, 1991;Casanova et al, 1993;Arendt et al, 1998;Braak et al, 2000). Regional differentiation is also well documented for the hippocampus, where tangles are significantly more frequent in CA1 than in CA3 neurons (Braak and Braak, 1991;Bobinski et al, 1996;Corder et al, 2000;Fukutani et al, 2000). Aberrant swellings of the initial segments of axons ("meganeurites"), a feature that occurs with increasing frequency in human brains beginning at about age 50, also show a striking regional selectivity (e.g., layer III but not layer V of the frontal cortex), which matches well with the distribution of tangles (Braak, 1984).…”

P2‐231: Systematic Comparison of Different Techniques to Measure Hippocampal Subfield Volumes in ADNI2

“…AD is characterized by a well-defined progression of its histopathological hallmarks amyloid plaques and neurofibrillary tangles. Particularly the latter has been shown to be closely associated with cognitive performance and neuron loss within the hippocampus and mesio-temporal lobe (Giannakopoulos et al, 1996;Giannakopoulos et al, 2007;Fukutani et al, 2000). The earliest site of neurofibrillary tangle accumulation in the preclinical state of AD is the trans-entorhinal cortex (BA 35) followed by the entorhinal cortex.…”

“…The hippocampus is not a homogeneous structure but consists of several histologically and functionally specialized but nonetheless tightly interconnected subfields: the subiculum (SUB) which is subdivided into the prosubiculum, subiculum proper, pre-and parasubiculum, the cornu ammonis sectors (CA) 1-3 and the dentate gyrus (DG) (Duvernoy et al, 2013). Animal and histopathological studies have shown that different pathological conditions affect subfields differently, e.g., Alzheimer's disease and hypoxia damage CA1, schizophrenia CA2, traumatic brain injury and post-traumatic stress syndrome CA3 and temporal lobe epilepsy damages the dentate gyrus (e.g., West et al, 1994;Fukutani et al, 2000;Bluemcke et al, 1999;Lucassen et al, 2006;Baldwin et al, 1997;Bluemcke et al, 2007). These observations suggest that subfield specific information might allow for a better differentiation of different disease processes and consequently for an earlier diagnosis than total hippocampal volume (Small, 2014).…”