Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing.

Upon activation by calcineurin, the nuclear factor of activated T-cells (NFAT) translocates to the nucleus and guides the transcription of numerous molecules involved in inflammation and Ca 2ϩ dysregulation, both of which are prominent features of Alzheimer's disease (AD). However, NFAT signaling in AD remains relatively uninvestigated. Using isolated cytosolic and nuclear fractions prepared from rapid-autopsy postmortem human brain tissue, we show that NFATs 1 and 3 shifted to nuclear compartments in the hippocampus at different stages of neuropathology and cognitive decline, whereas NFAT2 remained unchanged. NFAT1 exhibited greater association with isolated nuclear fractions in subjects with mild cognitive impairment (MCI), whereas NFAT3 showed a strong nuclear bias in subjects with severe dementia and AD. Similar to NFAT1, calcineurin-A␣ also exhibited a nuclear bias in the early stages of cognitive decline. But, unlike NFAT1 and similar to NFAT3, the nuclear bias for calcineurin became more pronounced as cognition worsened. Changes in calcineurin/NFAT3 were directly correlated to soluble amyloid-␤ (A␤ (1-42) ) levels in postmortem hippocampus, and oligomeric A␤, in particular, robustly stimulated NFAT activation in primary rat astrocyte cultures. Oligomeric A␤ also caused a significant reduction in excitatory amino acid transporter 2 (EAAT2) protein levels in astrocyte cultures, which was blocked by NFAT inhibition. Moreover, inhibition of astrocytic NFAT activity in mixed cultures ameliorated A␤-dependent elevations in glutamate and neuronal death. The results suggest that NFAT signaling is selectively altered in AD and may play an important role in driving A␤-mediated neurodegeneration.

IntroductionNeuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer’s disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions.ResultsHere we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD + HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer’s Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and CD68 (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD + HS-aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB.ConclusionsWe conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes.

We evaluated the association between mini-mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression-based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimer's disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high-functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP-43-related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.

Abstract:The p38 mitogen-activated protein kinase is a stress-activated enzyme responsible for transducing inflammatory signals and initiating apoptosis. In the Alzheimer's disease (AD) brain, increased levels of phosphorylated (active) p38 were detected relative to age-matched normal brain. Intense phospho-p38 immunoreactivity was associated with neuritic plaques, neuropil threads, and neurofibrillary tangle-bearing neurons. The antibody against phosphorylated p38 recognized many of the same structures as an antibody against aberrantly phosphorylated, paired helical filament (PHF) tau, although PHF-positive tau did not cross-react with the phosphop38 antibody. These findings suggest a neuroinflammatory mechanism in the AD brain, in which aberrant protein phosphorylation affects signal transduction elements, including the p38 kinase cascade, as well as cytoskeletal Alzheimer's disease (AD) is a progressive dementing disorder characterized by selective neuron loss in the limbic system and association regions of the neocortex. The characteristic histopathologic alterations in AD are neuritic or senile plaques (SPs) composed largely of amyloid P-peptides (AP) and neuronal aggregates of abnormally phosphorylated cytoskeletal proteins [neurofibrillary tangles (NFTs)] (GrundkeIqbal et al., 1986). Brain regions affected by AD also demonstrate hallmarks of inflammation, including elevated levels of proinflammatory cytokines (particularly interleukin-1 and -6), complement, and acutephase reactants (Rogers et a]., 1996); higher than normal levels of lipid, protein, and DNA oxidation (Smith et al., 1991;Mecocci et al., 1993;Smith et al., 1997;Hensley et al., 1998); and proliferation of microglial cells, which are functionally similar to monocytes (Itagaki et al., 1989). Epidemiological data indicate that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) diminishes risk for AD (Carpenter et al., 1993), and clinical studies indicate that the antioxidant a-tocopherol as well as NSAIDs may slow the progression of the disease (Rich et al., 1995;Sano et al., 1997). Recent models for AD pathogenesis therefore propose that atypical forms of inflammation, perhaps initiated by an immune response to plaque deposition, engender oxidative stress and neuronal damage in sensitive brain regions. The principal weakness of the neuroinflammatory model is that specific biochemical mechanisms have not been discovered that might explain precisely how an inflammatory process can propagate chronically in the AD brain.Because inflammation is fundamentally an autocrine or paracrine process involving cytokine-mediated activation of gene expression in target cells, we reasoned that dysfunction of specific signal transduction pathways responsible for cytokine-, AP-, or oxidant-stimulated gene induction might engender chronic inflammatory and oxidative processes in AD. We now report evidence that the p38 mitogen-activated protein (MAP) kinase pathway, a major proinflammatory signal transduction pathway activated by oxidants, cytokines, and ...