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Results for “AD pathology”

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PubMed2000

MR imaging of the hippocampus in normal pressure hydrocephalus: correlations with cortical Alzheimer's disease confirmed by pathologic analysis.

BACKGROUND AND PURPOSE: MR studies have shown hippocampal atrophy to be a sensitive diagnostic feature of Alzheimer's disease (AD). In this study, we measured the hippocampal volumes of patients with a clinical diagnosis of normal pressure hydrocephalus (NPH), a potentially reversible cause of dementia when shunted. Further, we examined the relationship between the hippocampal volumes and cortical AD pathologic findings, intracranial pressure, and clinical outcomes in cases of NPH. METHODS: We measured hippocampal volumes from 37 patients with a clinical diagnosis of NPH (27 control volunteers and 24 patients with AD). The patients with NPH underwent biopsy, and their clinical outcomes were followed for a year. RESULTS: Compared with those for control volunteers, the findings for patients with NPH included a minor left-side decrease in the hippocampal volumes (P < .05). Compared with those for patients with AD, the findings for patients with NPH included significantly larger hippocampi on both sides. Although not statistically significant, trends toward larger volumes were observed in patients with NPH who had elevated intracranial pressure, who benefited from shunting, and who did not display cortical AD pathologic findings. CONCLUSIONS: Measurements of hippocampal volumes among patients with a clinical diagnosis of NPH have clear clinical implications, providing diagnostic discrimination from AD and possibly prediction of clinical outcome after shunting.

Aged↗

PubMedDate not supplied

Degenerative and protective signaling mechanisms in the neurofibrillary pathology of AD.

Attention has focussed on the molecular alterations in neurofibrillary tangles (NFT) in Alzheimer's disease (AD) with the presumption that the events leading to the alterations are involved in the neurodegenerative mechanism. Here I propose that some of the manifestations of NFT result from activation of neuroprotective signaling cascades such as those induced by neurotrophic factors. Increasing data implicate free radicals and calcium in the mechanism of neuronal injury (including cytoskeletal pathology) and death in AD. Increased accumulation of beta-amyloid peptide (A beta), reduced energy availability, and increased oxidative processes are among the age-associated changes in AD that appear to be upstream to increases in cellular free radicals and calcium. Neurotrophic factors influence the expression of gene products known to stabilize calcium homeostasis, suppress free radical accumulation, and protect neurons against AD-relevant insults. The events leading to the cytoskeletal alterations in NFT are not clear although some of the alterations can be induced by excitotoxic and metabolic insults. On the other hand, kinases activated by neurotrophic factors may contribute to tau hyperphosphorylation during brain development and in AD. Activities in both degenerative and protective signaling pathways are subject to modification by aging, and by genetic and environmental factors, suggesting that the multiple cytoskeletal alterations in NFT probably result from concurrent activation of both neurodegenerative and neuroprotective cascades.

Aged↗

PubMed2004

PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations.

Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by gamma-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.

Alzheimer Disease↗

PubMed1993

Proline-directed kinase systems in Alzheimer's disease pathology.

Immunohistochemical analysis was used to assess the distribution of the proline-directed kinase, cdc2, in Alzheimer's disease (AD) pathology. A robust signal was most prominent in the neurofibrillary tangle (NFT) of affected neurons that also contained abnormally phosphorylated tau protein. Biochemical analysis identified a pool of cdc2 in bovine brain microtubules that contain normal tau. These results strongly support the hypothesis that cdc2 is involved in the abnormal phosphorylation of tau in AD pathology and they raise important issues regarding regulation of tau phosphorylation in normal and diseased neurons.

Aged↗

PubMed2006

Investigation of Alzheimer's disease-related pathology in community dwelling older subjects who committed suicide.

BACKGROUND: Older people have a higher risk of completed suicide than any other age group worldwide. The contribution of neurodegenerative disease to this risk remains controversial. AIMS: To investigate prevalence of Alzheimer's disease-related (AD) pathology in older suicide victims. METHODS: Ratings of AD pathology using Braak and CERAD protocols were compared in 143 community-dwelling suicide victims aged 65 years or more and 59 motor vehicle accident victims autopsied at the request of an Australian Coroner's Court. RESULTS: There were no significant differences in plaque score or neurofibrillary tangle staging between suicide and control groups. None of the subjects with a history of dementia had neuropathologically confirmed AD. CONCLUSIONS: Our study is the second and largest investigation of the prevalence of AD neuropathology in the elderly suicide population. Unlike the previous study, we did not find an increased prevalence of AD neuropathology despite a history of dementia in 6.3%, implicating other pathologies such as Lewy Body or Vascular dementia in the aetiology of dementia in elderly suicide victims.

Accidents, Traffic↗

PubMed2006

Prevalence and impact of cerebrovascular pathology in Alzheimer's disease and parkinsonism.

OBJECTIVE: To study the prevalence and impact of cerebrovascular lesions (CVL) in Alzheimer's disease (AD) and their effects on cognitive impairment. MATERIAL AND METHODS: In study I, the prevalence of vascular lesions in a prospective series of 244 autopsy-proved AD cases (mean age 83.1+/-8.4 years) and 230 age-matched non-demented controls was examined using immunochemistry and current morphological diagnostic criteria. In study II, in 100 consecutive autopsy cases (mean age 84.3+/-9.3 years), the incidence of general and capillary cerebral amyloid angiopathy (CAA, CapCAA) was examined. RESULTS: In study I, AD cases showed significantly more frequent CVL than age-matched controls without differences in the Braak stages, but the severity of CAA was significantly higher in AD brain with associated vascular lesions. In study II, CAA was more frequent in demented than in non-demented patients, but did neither correlate with high-grade AD pathology nor with clinical dementia, whereas CapCAA correlated with both dementia and high Braak stages; the severity of both types of CAA showed only low correlation with each other. CONCLUSIONS: The present data and other studies confirm the importance of CVL in AD and Parkinson's disease without considerable impact on cognitive impairment in progressed stages of AD, and the close association of CapCAA but not of general CAA with clinical dementia and AD pathology.

Age Factors↗

PubMed2001

Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization.

Mental function has as its cerebral basis a specific dynamic structure. In particular, cortical and limbic areas involved in "higher brain functions" such as learning, memory, perception, self-awareness and consciousness continuously need to be self-adjusted even after development is completed. By this lifelong self-optimization process, the cognitive, behavioural and emotional reactivity of an individual is stepwise remodelled to meet the environmental demands. While the presence of rigid synaptic connections ensures the stability of the principal characteristics of function, the variable configuration of the flexible synaptic connections determines the unique, non-repeatable character of an experienced mental act. With the increasing need during evolution to organize brain structures of increasing complexity, this process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. These mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodelling according to experience, are accompanied, however, by increasing inherent possibilities of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time provide the basis for a variety of neuropsychiatric disorders. It is the objective of the present paper to outline the hypothesis that it might be the disturbance of structural brain self-organization which, based on both genetic and epigenetic information, constantly "creates" and "re-creates" the brain throughout life, that is the defect that underlies Alzheimer's disease (AD). This hypothesis is, in particular, based on the following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated with aberrant sprouting at both the presynaptic (axonal) and postsynaptic (dendritic) site. (3) The spatial and temporal distribution of AD pathology follows the pattern of structural neuroplasticity in adulthood, which is a developmental pattern. (4) AD pathology preferentially involves molecules critical for the regulation of modifications of synaptic connections, i.e. "morphoregulatory" molecules that are developmentally controlled, such as growth-inducing and growth-associated molecules, synaptic molecules, adhesion molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc. (5) Life events that place an additional burden on the plastic capacity of the brain or that require a particularly high plastic capacity of the brain might trigger the onset of the disease or might stimulate a more rapid progression of the disease. In other words, they might increase the risk for AD in the sense that they determine when, not whether, one gets AD. (6) AD is associated with a reactivation of developmental programmes that are incompatible with a differentiated cellular background and, therefore, lead to neuronal death. From this hypothesis, it can be predicted that a therapeutic intervention into these pathogenetic mechanisms is a particular challenge as it potentially interferes with those mechanisms that at the same time provide the basis for "higher brain function".

Alzheimer Disease↗

PubMed2002

Caspase-cleaved amyloid precursor protein in Alzheimer's disease.

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.

Aged↗

PubMed2001

Isolation of hNap1BP which interacts with human Nap1 (NCKAP1) whose expression is down-regulated in Alzheimer's disease.

We previously reported the isolation of a novel apoptosis-related gene, human Nap1 (HGMW-approved symbol NCKAP1), the expression of which was strongly down-regulated in sporadic Alzheimer's disease (AD). Human Nap1 proved to be an orthologue of rat Nap1 which binds to the adaptor molecule Nck in signal transduction. In order to further elucidate the function of human Nap1, we performed yeast two-hybrid screening. As a result of screening, we discovered a protein designated hNap1BP (human Nap1 binding protein) which is a member of the tyrosine kinase-binding protein family. In addition, hNap1BP bound to the SH3 domain of c-Abl and Nck. hNap1BP is expressed ubiquitously in various tissues like human Nap1, and intriguingly these genes are co-expressed in hippocampus and cerebral cortex in mouse brain where AD pathological features are strongly evident. Further functional analysis of hNap1BP may clarify its contribution to AD pathology.

3T3 Cells↗

PubMed2003

Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome.

Aged individuals with Down syndrome (DS) develop senile plaques and neurofibrillary tangles consistent with Alzheimer disease (AD). Prior to or in parallel with AD pathology, compensatory growth responses may occur. Immunohistochemistry and confocal microscopy studies in the hippocampus from 15 individuals ranging in age from 5 months to 67 years compared markers of normal and abnormal tau accumulation (phosphorylated tau [AT8, MC-1], tau-1, N-terminal tau) with the extent and location of neuronal growth marker immunoreactivity (BDNF, GAP-43, MAP-2). In middle age (30-40 years), prior to entorhinal neuron loss, the earliest tau accumulation occurred in the outer molecular layer (OML), which was consistent with both pathological and compensatory fetal tau expression. These events were followed at a later age, associated with entorhinal neuron loss, by an increase in GAP-43. Hilar neurons exhibiting a sprouting morphology were also noted. Age-dependent observations in the DS brain in the current study parallel hippocampal compensatory responses described in entorhinal cortex lesion studies in rodents. Thus, compensatory growth responses may occur in DS prior to extensive AD pathology and may be one mechanism underlying observations in PET studies of hypermetabolism in the entorhinal cortex of individuals with DS.

Adolescent↗

PubMed2002

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice.

We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD brain biopsy, human short postmortem brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5 kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG), and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice compared to age-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC, and C57B6/SJL Tg (+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kb) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg (+) mouse tissues, and in age-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8-OHG, and COX in the same cellular compartment. Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage.

Alzheimer Disease↗

PubMed1997

Lewy bodies and progressive dementia: a critical review and meta-analysis.

Researchers disagree as to whether Lewy body disease (LBD) constitutes a variant of Alzheimer's (AD) or Parkinson's disease (PD), or alternatively, whether it is an independent disease process. The neuropathological, genetic, and clinical characteristics of LBD are reviewed and compared to those of AD and PD. Data for 150 cases of LBD reported in the literature were compiled and grouped according to neuropathological status. Patients with pure LBD (with limited or no concurrent AD pathology) tend to present at a younger age with extrapyramidal signs followed by dementia, whereas patients with mixed LBD-AD (concurrent LB and AD pathology) are somewhat older and tend to present with dementia. The cognitive profile of LBD patients, and the relationships among LBD, AD, and PD remain unclear due to methodological limitations and the paucity of studies comparing the groups directly.

Aged↗

PubMed2000

Activated microglia in dementia with Lewy bodies.

To investigate the role of cerebral inflammation in dementia with Lewy bodies (DLB), activated microglial cells were quantified in postmortem brain tissue. Patients with pure DLB (LB but no AD pathology) had significantly greater numbers of cells than nondemented control subjects, but fewer than patients with either pure AD or DLB combined with AD. There was a positive correlation between the numbers of activated microglia and LB in different brain regions. This study demonstrates the presence of significant inflammation in DLB, even in the absence of AD pathology.

Aged↗

PubMed1998

Abnormalities of neural circuitry in Alzheimer's disease: hippocampus and cortical cholinergic innervation.

Severe pathology in Alzheimer's disease (AD) results in marked disruption of cortical circuitry. Formation of neurofibrillary tangles, neuronal loss, decrease in dendritic extent, and synaptic depletion combine to halt communication among various cortical areas, resulting in anatomic isolation and fragmentation of many cortical zones. The clinical manifestation of this disruption is severe and debilitating cognitive dysfunction, often accompanied by psychiatric and behavioral disturbances and a diminished ability to perform activities of daily living. However, different cortical circuits are not equally vulnerable to AD pathology. In particular, two cortical systems that appear to be involved in the neural processing of memory are selectively vulnerable to degeneration in AD. One consists of connections between the hippocampus and its neighboring cortical structures within the temporal lobe. The second is the cortical cholinergic system that originates in neurons within the basal forebrain and innervates the entire cortical mantle. The circuitry in these systems shows early and severe degenerative changes in the course of AD. The selective vulnerability of these circuits is the probable reason for the early and marked loss of memory observed in these patients. This review presents current knowledge of the general pattern of cortical circuitry, followed by a summary of abnormalities of this circuitry in AD. The cortical circuits that exhibit selective pathology in AD are described in greater detail. Therapeutic implications of the abnormal circuitry in AD are also discussed. For therapies to be effective, early diagnosis of AD is necessary. Future efforts at AD therapy must be combined with an equally intense effort to develop tools capable of early diagnosis of AD, preferably at a preclinical stage before the onset of cognitive symptoms.

Alzheimer Disease↗

PubMed2006

Increase in core body temperature of Alzheimer's disease patients as a possible indicator of chronic neuroinflammation: a meta-analysis.

BACKGROUND: Neuroinflammation contributes to the pathogenesis of Alzheimer's disease (AD). Increased pro-inflammatory cytokine levels have been reported in the brain and cerebro-spinal fluid of individuals affected by this neurodegenerative disorder. These same cytokines, including interleukin -1, interleukin-6 and tumor necrosis factor-alpha, are also believed to be involved in thermoregulation. Furthermore, their effects are thought to be mediated through the induction of cyclooxygenases resulting in increased production of inflammatory prostaglandins. Such increases have been observed in AD brains. We hypothesized that these increased levels of inflammatory mediators could lead to an increase in core body temperature in AD patients. OBJECTIVE: To determine whether clinical signs of AD are accompanied by an increase in core body temperature. METHODS: Analysis of the scientific literature identified six studies that used continuous rectal measurements of core body temperature in AD and control patients. Meta-analysis was performed on these published data. RESULTS: Meta-analysis showed that the mean core body temperature in AD patients was significantly increased by 0.10 degrees C when compared to healthy elderly subjects. The two-sided p value was 0.0355, and the 95% confidence interval was 0.0068-0.1950. The severity of AD pathology did not appear to contribute significantly (p = 0.235) to the heterogeneity in the core body temperature among different groups of AD patients. CONCLUSION: The significant increase in core body temperature in AD patients could be a direct consequence of local inflammatory reactions in the brain. Although the changes observed are probably too small to be of any diagnostic value, these observations lend further support to the neuroinflammatory hypothesis of AD pathology.

Alzheimer Disease↗

PubMed1994

Increased immunoreactivity for Jun- and Fos-related proteins in Alzheimer's disease: association with pathology.

The protein products of the Jun and Fos immediate early gene (IEG) families are cooperative transcriptional regulatory factors implicated in regulating the expression of many genes. The levels of a variety of proteins such as the amyloid precursor protein and basic fibroblast growth factor are altered in Alzheimer's disease (AD), thus the events regulating these changes are of interest. Both of these genes contain an activator protein-1 consensus sequence which may be responsive to regulation by immediate early genes. In order to evaluate the potential involvement of IEGs in AD pathology, we have examined Jun- and Fos-related protein immunoreactivity in control and AD brain. Specifically, we investigated the correspondence of immunoreactivity for Jun and Fos proteins with immunoreactivity for paired helical filament-1 (PHF-1), a marker for neurofibrillary tangles which recognizes abnormally phosphorylated tau, glial fibrillary acidic protein (GFAP), and thioflavine staining in double-labeling experiments. An intensification of both Jun and Fos immunoreactivity was observed in AD cases; in addition, both Jun and Fos immunoreactivity were colocalized with PHF-1 in some neurons in AD brain. Jun and Fos immunoreactivity were also colocalized with GFAP-positive astrocytes distributed in the cortex of AD and control cases, and surrounding thioflavine-stained plaques in AD brain. These observations suggest that members of the Jun and Fos IEG families may play a role in AD pathology.

Aged↗

PubMed2003

G-protein alpha-subunit levels in hippocampus and entorhinal cortex of brains staged for Alzheimer's disease neurofibrillary and amyloid pathologies.

G-protein alpha-subunits (Galphao, Galphai, Galphas, Galphaq) and adenylyl cyclase (AC) I and II isoforms were quantified in hippocampus and entorhinal cortex from 22 cases staged for Alzheimer's disease (AD) pathologies according to Braak and Braak. Hippocampal Galphai levels declined significantly with neurofibrillary staging, whereas AC I levels in this region increased. Significant amyloid stage-related reductions of Galphai were seen in both the hippocampus and entorhinal cortex. The hippocampus also showed a significant reduction of Galphao with amyloid staging. It is concluded that levels of inhibitory G-protein subunits Galphao, and in particular Galphai, decrease in parallel to the extent of AD pathology.

Adolescent↗

PubMed2026

Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.

Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.

Humans↗