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PubMed2004

Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy.

OBJECTIVE: To examine the clinical, genetic, and neuropathologic features of posterior cortical atrophy (PCA). DESIGN/METHODS: Using a broad definition of PCA as a syndrome with the insidious onset of visual dysfunction in the absence of primary ophthalmologic causes, the authors identified and then reviewed the presenting signs and symptoms, ApoE genotypes, tau haplotypes, and neuropathologic findings when available of PCA cases from two dementia research centers collected over the past 14 years. RESULTS: The authors identified 40 PCA cases. Their mean age at symptom onset was 60.5 +/- 8.9 years. There were twice as many women as men in the series. The principal types of visual impairment were simultanagnosia (82%) and visual field defect (47.5%). Acalculia, alexia, and anomia were also common. Insight was preserved in almost all (95%) early in the disorder. Neither apoE epsilon4 nor tau haplotype frequencies were different from typical Alzheimer disease (AD). Nine patients had died and underwent postmortem examination. Seven autopsied cases had AD pathology but when compared to typical AD, the neurofibrillary tangle (NFT) densities were significantly higher in Brodmann areas 17 and 18 (p < 0.05) and significantly lower in the hippocampus (p < 0.05). Two cases had corticobasal degeneration with maximal involvement of tau positive glial pathology in the posterior parietal lobe and Brodmann areas 17 and 18. CONCLUSIONS: PCA is a distinctive dementia syndrome in which the most pronounced pathologic involvement is in the occipitoparietal regions independent of the specific underlying pathology. AD was the most common pathologic cause, but its regional distribution differed from typical AD.

Adult↗

PubMed2002

Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis.

In addition to pathology in the gray matter, there are also abnormalities in the white matter in Alzheimer's disease (AD). Sulfatide species are a class of myelin-specific sphingolipids and are involved in certain diseases of the central nervous system. To assess whether sulfatide content in gray and white matter in human subjects is associated with both the presence of Alzheimer's disease (AD) pathology as well as the stage of dementia, we analyzed the sulfatide content of brain tissue lipid extracts by electrospray ionization mass spectrometry from 22 subjects whose cognitive status at time of death varied from no dementia to very severe dementia. All subjects with dementia had AD pathology. The results demonstrate that: (i) sulfatides were depleted up to 93% in gray matter and up to 58% in white matter from all examined brain regions from AD subjects with very mild dementia, whereas all other major classes of lipid (except plasmalogen) in these subjects were not altered in comparison to those from age-matched subjects with no dementia; (ii) there was no apparent deficiency in the biosynthesis of sulfatides in very mild AD subjects as characterized by the examination of galactocerebroside sulfotransferase activities in post-mortem brain tissues; (iii) the content of ceramides (a class of potential degradation products of sulfatides) was elevated more than three-fold in white matter and peaked at the stage of very mild dementia. The findings demonstrate that a marked decrease in sulfatides is associated with AD pathology even in subjects with very mild dementia and that these changes may be linked with early events in the pathological process of AD.

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PubMed1997

High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy.

From the somewhat conflicting published data on apolipoprotein E (apoE) genotype in hemorrhage due to cerebral amyloid angiopathy (CAA), it is unclear whether apoE genotype influences the risk of CAA-related hemorrhage independently of its association with concomitant Alzheimer's disease (AD). We determined the apoE genotypes of 36 patients presenting with cerebral hemorrhage associated with histologically confirmed CAA. The frequency of apoE epsilon 2 was 0.25 and the frequency of apoE epsilon 4 was 0.18. Patients with CAA-related hemorrhage and concomitant AD pathology (CERAD criteria, n = 17) had a high apoE epsilon 4 frequency, close to that in AD cases without hemorrhage. Patients in whom CAA-related hemorrhage occurred in the absence of significant AD pathology (n = 13) had an apoE epsilon 4 frequency somewhat lower than non-AD controls without hemorrhage. However, in CAA-related hemorrhage, the apoE epsilon 2 frequency was high regardless of whether significant AD pathology was present. We conclude that whereas possession of apoE epsilon 2 may be a risk factor for cerebral hemorrhage due to CAA, apoE epsilon 4 is a risk factor for concomitant AD but not an independent risk factor for CAA-related hemorrhage.

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PubMed1991

Tyrosine phosphorylation systems in Alzheimer's disease pathology.

Immunohistochemical techniques have been used to assess the distribution of phosphotyrosine-containing compartments in Alzheimer's disease (AD) pathology. Elevated levels of phosphotyrosine are apparent in the somatodendritic compartment of tangle-bearing neurons, in the neuritic plaque (NP) and in dystrophic neurites coursing through the neuropil. The only neuronal staining observed in non-AD tissue is in developing neurites. This suggests that some neuronal elements involved in AD pathology may be recapitulating a developmental profile or, alternately, that elevated phosphotyrosine levels may reflect a role for tyrosine kinase/phosphatase systems in the degeneration process directly. Cells in the neuritic plaque which strongly resemble microglia also contain elevated levels of phosphotyrosine compared to non-activated ramified microglia in the same tissue section. Thus, tyrosine phosphorylation systems may be involved in the response of microglia to degeneration in AD pathology. Implications of these results are discussed.

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PubMed2003

Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology--a pilot study.

Data on the relationship between cerebral amyloid angiopathy (CAA) ("congophilic angiopathy") and Alzheimer's disease (AD) pathology are conflicting. In the present study, CAA and capillary CAA (CapCAA) ("dyshoric angiopathy") were examined in the frontal cortex of 100 human brains obtained at autopsy from both male and female, demented and non-demented patients (mean age +/- SD 84.3+/-9.3 years); 50 brains with high (mean 5.0) and 50 with low (mean 2.4) Braak stages. CAA was assessed according to the method of Olichney et al. [25]; CapCAA was grouped into four grades by counting the affected capillaries in 10 high power fields. General CAA was present in 61% (87.5% demented, 55.6% non-demented; 70% with high and 52% low Braak stages). CAA did not correlate with either clinical diagnosis of dementia or high-grade AD pathology; CapCAA showed a low correlation with dementia and a medium positive correlation with high Braak stages. The severity of both lesions did not correlate with clinical dementia; whereas that of CAA showed low correlation with CERAD, Braak, and NIA-Reagan-Institute criteria, the severity of CapCAA correlated significantly with all three AD criteria. The presence and severity of CAA and CapCAA showed only low correlation, suggesting a different pathogenesis of these types of lesion. Since CapCAA represents insoluble amyloid peptide (Abeta) deposits in and around capillaries, its correlation with neuritic AD pathology supports the concept of neuronal origin of Abeta via drainage from interstitial fluid from the central nervous system to capillary walls. Studies to answer the question whether CapCAA represents an epiphenomenon or an indicator of a pathogenic association between tau cytopathology and Abeta deposition in capillaries are in progress.

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PubMed2000

Prevention and reduction of AD-type pathology in PDAPP mice immunized with A beta 1-42.

In AD certain brain structures contain a pathological density of A beta protein deposited into plaques. The effect of genetic mutations found in early onset AD patients was an overproduction of A beta 42, strongly suggesting that overproduction of A beta 42 is associated with AD. We hypothesized that an immunological response to A beta 42 might alter its turnover and metabolism. Young PDAPP transgenic mice were immunized with A beta 1-42, which essentially prevented amyloid deposition; astrocytosis was dramatically reduced and there was reduction in A beta-induced inflammatory response as well. A beta 1-42 immunization also appeared to arrest the progression of amyloidosis in older PDAPP mice. A beta immunization appears to increase clearance of amyloid plaques, and may therefore be a novel and effective approach for the treatment of AD.

Alzheimer Disease↗

PubMed1987

Neuropathological substrates of Alzheimer's disease and Parkinson's disease.

The pathology of Alzheimer's disease (AD) and Parkinson's disease (PD) is characterized by degeneration of certain vulnerable neuronal populations that display several types of cytoskeletal abnormalities (Alzheimer-type lesions and Lewy bodies, respectively). These may serve as diagnostic markers, although they can be found in both types of disorders and, less frequently, in brains of normal aged individuals. AD pathology shows a preponderance for hippocampal, neocortical, and forebrain cholinergic systems; the hallmark of PD is damage to the nigrostriatal dopaminergic system. Both disorders show frequent involvement of subcortical projection systems that can be similar in quality and distribution, with similar multiple neuromediator dysfunction. The results of morphometric studies of some subcortical nuclei in AD and PD are reported and related with neurochemical data. In addition to classical forms of AD and PD, both types of lesions can coexist suggesting an increased risk of PD in patients with AD and vice versa. The basis for an association between the two disorders is unknown. Many AD cases with signs of PD have additional PD pathology, while cortical Alzheimer lesions may be seen in demented PD patients. However, dementia in PD does not imply coexistent cortical AD pathology; prominent subcortical lesions alone, or in combination with cortical AD pathology, may occur. AD and PD may show some differences in the primary locus of degenerative changes in specific cortical and subcortical neuronal systems, but the causative factors, mutual relations, and relative contributions to the clinical syndromes remain to be elucidated.

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PubMed2006

It may take inflammation, phosphorylation and ubiquitination to 'tangle' in Alzheimer's disease.

Neurofibrillary tangles (NFT) are one of the pathologic hallmarks of Alzheimer's disease (AD). Their major component is tau, a protein that becomes hyperphosphorylated and accumulates into insoluble paired helical filaments. During the course of the disease such filaments aggregate into bulky NFT that get ubiquitinated. What triggers their formation is not known, but neuroinflammation could play a role. Neuroinflammation is an active process detectable in the earliest stages of AD. The neuronal toxicity associated with inflammation makes it a potential risk factor in the pathogenesis of chronic neurodegenerative diseases, such as AD. Determining the sequence of events that lead to this devastating disease has become one of the most important goals for AD prevention and treatment. In this review we focus on three topics relevant to AD pathology and to NFT formation: (1) what triggers CNS inflammation resulting in glia activation and neuronal toxicity; (2) how products of inflammation might change the substrate specificity of kinases/phosphatases leading to tau phosphorylation at pathological sites; (3) the relationship between the ubiquitin/proteasome pathway and tau ubiquitination and accumulation in NFT. The overall aim of this review is to provide a challenging and sometimes provocative survey of important contributions supporting the view that CNS inflammation might be a critical contributor to AD pathology. Neuronal cell death resulting from neuroinflammatory processes may have devastating effects as, in the vast majority of cases, neurons lost to disease cannot be replaced. In order to design therapies that will prevent endangered neurons from dying, it is critical that we learn more about the effects of neuroinflammation and its products.

Alzheimer Disease↗

PubMed1995

Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the aged population.

We have investigated the effect of genotypes of apolipoprotein E (ApoE) on the pathologies found in Alzheimer's disease (AD) and its related gene expression in 38 aged human brains obtained from consecutive autopsied cases. ApoE2/3, -3/3, -3/4, and -4/4 were typed in those aged brains, with ApoE3/3 being most prevalent. The AD pathologies were undetectable in ApoE2/3 brains, but were frequently observed in the other ApoE groups. In ApoE3/3 brains, 55%, 34%, and 24% of the cortical sections examined showed senile plaques (SPs), neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA), respectively. In ApoE4/4 brains, the SP formation was significantly higher. The ApoE genotype neither affected ApoE, APP, or tau mRNA level, nor the differential expression of the latter two. These results suggest that ApoE4/4 accelerates and ApoE2/3 decelerates the development of the AD pathologies in the aged brain, but this is not through alterations of the APP and tau gene expression.

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PubMed1993

Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer's and Parkinson's disease patients.

In both Alzheimer's disease (AD) and Parkinson's disease (PD), neurofibrillary tangles (NFT), in contrast to amyloid deposits, show a hierarchical spreading pattern from the allocortex to isocortical association areas with early involvement of the entorhinal region, a major relay station between hippocampus and isocortex. Based on the distribution pattern of NFT in human brain, a neuropathological staging of neuritic AD pathology has been proposed. Comparative studies of this neuropathological staging of neuritic AD changes with psychometrically assessed intellectual status (mini-mental state) in prospective cohorts of 29 aged individuals and 28 PD patients showed a linear correlation of morphological AD staging with the psychostatus in both disorders. The pattern of neuronal degeneration associated with neuritic AD pathology in both AD and PD may be an important basis of cognitive decline in both disorders.

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PubMed1998

Reduction of O-linked N-acetylglucosamine-modified assembly protein-3 in Alzheimer's disease.

Abnormal protein processing and modification is associated with Alzheimer's disease (AD) pathology. The role of phosphorylation in AD has been studied extensively because the presumed abnormal phosphorylation of tau protein is believed to play a role in the formation of paired helical filaments. Glycosylation with O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues is a dynamic protein modification of intracellular proteins, and it shares similar features with protein phosphorylation. In this study, O-GlcNAc glycosylation of proteins from autopsied human brains with confirmed AD and non-AD age-matched controls was examined. O-GlcNAcylation was demonstrated by labeling protein extracts with [3H]galactose in the presence of galactosyltransferase and subsequent analyses of saccharide-protein linkage and saccharide structure. The number of O-GlcNAc-containing proteins and the overall O-GlcNAc level do not appear to be different between AD and control brain tissues. The only significant change observed is a marked reduction of O-GlcNAcylated clathrin assembly protein-3 (AP-3) in AD. The reduction is more evident in brain neocortical regions, and there appears to be a negative correlation between O-glycosylated AP-3 and the density of neurofibrillary tangles. These data suggest a possible association between the O-glycosylated AP-3 and AD pathology.

Acetylation↗

PubMed2006

Body mass index in older persons is associated with Alzheimer disease pathology.

OBJECTIVE: We examined the extent to which body mass index (BMI) in older persons is associated with common age-related neuropathologies known to contribute to dementia including Alzheimer disease (AD) pathology, cerebral infarction, and Lewy body disease. METHODS: We studied brain autopsies from 298 deceased Catholic clergy participating in the Religious Orders Study, a longitudinal clinical-pathologic investigation. BMI was assessed at annual clinical evaluations during an average follow-up of 4.9 years (SD = 2.7 years). Each person's average BMI, derived from all evaluations, was used in analyses. Multiple regression analyses were used to examine the relation of common postmortem neuropathologic findings to average BMI prior to death. RESULTS: Mean age at death was 85.7 years (SD = 6.8 years), and average BMI during the course of the study was 26.0 (SD = 5.1). A series of linear regression models was performed with average BMI as the outcome and controlling for age, sex, and education. Level of AD pathology was associated with BMI proximate to death (estimate = -1.15; SE = 0.42; p = 0.007). However, Lewy body pathology (estimate = -0.45; SE = 0.73; p = 0.53) and cerebral infarctions (estimate = -0.10; SE = 0.61; p = 0.88) were not associated with average BMI. The association of AD pathology with BMI was unchanged after controlling for dementia, chronic diseases, and physical activity. CONCLUSION: Body mass in old age is associated with Alzheimer disease pathology in persons with and without dementia.

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PubMed2002

Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis.

In the past, 'Alzheimer disease' (AD) referred to pathologic AD with clinical onset of dementia in the presenium, while 'senile dementia of the Alzheimer type' (SDAT) referred to senile onset AD. Because AD appears clinically homogeneous regardless of age of onset, the two subtypes in more recent years have not been distinguished. Pathologic differences have been noted, but synapse loss has not previously been compared between the two groups. Hypothesizing that synapse loss would be greater in presenile onset than senile onset AD, we compared synapse loss, as well as Alzheimer pathology in presenile and senile onset AD, using an ELISA method to quantify synaptophysin. Synaptophysin was significantly lower in presenile than senile AD in right frontal and bilateral parietal lobes. Neuritic plaque counts were significantly higher in presenile than senile AD in bilateral frontal and parietal lobes. Semi-quantitative evaluation of neurofibrillary tangles revealed significantly more tangles in bilateral frontal and parietal lobes in presenile than senile AD. Brain weight was significantly lower in presenile than senile AD. The differences in synapse loss and Alzheimer-type pathology in presenile and senile onset AD support the hypothesis that 'cognitive reserve' protects the human brain from neurodegenerative disease.

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PubMed2004

High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity.

One pathogenic characteristic of Alzheimer's disease (AD) is the formation of extracellular senile plaques with accumulated microglia. According to the amyloid hypothesis, the increase or accumulation of amyloid-beta (Abeta) peptides in the brain parenchyma is the primary event that influences AD pathology. Although the role of microglia in AD pathology has not been clarified, their involvement in Abeta clearance has been noted. High mobility group box protein-1 (HMGB1) is an abundant nonhistone chromosomal protein. We reported recently that HMGB1 was associated with senile plaques and the total protein level significantly increased in AD brain. In this study, diffuse HMGB1 immunoreactivity was observed around dying neurons in the kainic acid- and Abeta1-42 (Abeta42)-injected rat hippocampi. HMGB1 also colocalized with Abeta in the Abeta42-injected rats but not in transgenic mice, which show massive Abeta production without neuronal loss in their brains. Furthermore, coinjection of HMGB1 delayed the clearance of Abeta42 and accelerated neurodegeneration in Abeta42-injected rats. These results suggest that HMGB1 released from dying neurons may inhibit microglial Abeta42 clearance and enhance the neurotoxicity of Abeta42. HMGB1 may thus be another target in the investigation of a therapeutic strategy for AD.

Amyloid beta-Peptides↗

PubMed2006

Neuropathology of older persons without cognitive impairment from two community-based studies.

OBJECTIVE: To examine the relation of National Institute on Aging-Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). METHODS: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. RESULTS: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. CONCLUSIONS: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.

Age Factors↗

PubMed2003

Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains.

beta-Amyloid(1-42) (A beta 42), a major component of amyloid plaques, accumulates within pyramidal neurons in the brains of individuals with Alzheimer's disease (AD) and Down syndrome. In brain areas exhibiting AD pathology, A beta 42-immunopositive material is observed in astrocytes. In the present study, single- and double-label immunohistochemistry were used to reveal the origin and fate of this material in astrocytes. Our findings suggest that astrocytes throughout the entorhinal cortex of AD patients gradually accumulate A beta 42-positive material and that the amount of this material correlates positively with the extent of local AD pathology. A beta 42-positive material within astrocytes appears to be of neuronal origin, most likely accumulated via phagocytosis of local degenerated dendrites and synapses, especially in the cortical molecular layer. The co-localization of neuron-specific proteins, alpha 7 nicotinic acetylcholine receptor and choline acetyltransferase, in A beta 42-burdened, activated astrocytes supports this possibility. Our results also suggest that some astrocytes containing A beta 42-positive deposits undergo lysis, resulting in the formation of astrocyte-derived amyloid plaques in the cortical molecular layer in brain regions showing moderate to advanced AD pathology. These astrocytic plaques can be distinguished from those arising from neuronal lysis by virtue of their smaller size, their nearly exclusive localization in the subpial portion of the molecular layer of the cerebrocortex, and by their intense glial fibrillary acidic protein immunoreactivity. Overall, A beta 42 accumulation and the selective lysis of A beta 42-burdened neurons and astrocytes appear to make a major contribution to the observed amyloid plaques in AD brains.

Aged↗

PubMed2003

Regional distribution of alpha-synuclein pathology in unimpaired aging and Alzheimer disease.

The amygdaloid complex (AC) was found highly vulnerable to alpha-synuclein (alphaS) pathology in both familial and sporadic Alzheimer disease (AD), and recently, incidental Lewy bodies (LBs) were identified primarily in the lower brainstem. This challenges the traditional view that the substantia nigra (SN) is the region that is predominately affected in the spectrum of LB disorders. We examined the immunoreactivity of alphaS in the SN, the nucleus basalis of Meynert (nbM), and the AC in 904 subjects with or without concomitant AD pathology. AlphaS-positive structures were seen in at least one of the studied brain areas in 121 subjects (13%). The affected regions in the alphaS-positive subjects included the SN (89%), the nbM (73%), and the AC (67%). This study also included 82 sporadic AD patients diagnosed using CERAD criteria. AlphaS-positive structures were seen in 32% of the AD patients, with the SN and AC being equally affected. In a few subjects the AC was the only affected area. However, this was not inevitably associated with AD pathology, but was related to cognitive decline. Incidental LBs in the SN were described in the occasional subjects, with no alphaS pathology in the lower brainstem.

Adult↗

PubMed1997

The loss of GluR2(3) immunoreactivity precedes neurofibrillary tangle formation in the entorhinal cortex and hippocampus of Alzheimer brains.

Double-immunolabeling techniques were employed to examine the distribution of GluR2(3) subunits and markers of early cytoskeletal changes (mab MC1) within the entorhinal cortex (EC) and hippocampus of cases with varying degrees of Alzheimer disease (AD) pathology (stages I-VI by Braak and Braak). In addition near-adjacent tissue sections were double-immunolabeled using antibodies against GluR2(3) and a marker of normal neuronal cytoskeleton (MAP2). In those cases classified as stages I-II, most layer II neurons of the EC and pyramidal neurons in the CA1/subiculum were double-labeled with GluR2(3) and MAP2. An occasional MC1-labeled cell was observed, yet in no instance were these neurons double-labeled with GluR2(3). In cases with moderate AD pathology (stages III-IV), layer II of the EC and CA1/subiculum were characterized by a substantial loss of GluR2(3)-labeled neurons, while many were still immunoreactive to MAP2. Notably, the loss of GluR2(3) immunolabeling was accompanied by an increasing number of MC1-positive neurons. In no instance were GluR2(3) and MC1 co-localized within the same neuron. In cases with severe AD pathology (stages V-VI), the EC and CA1/subiculum were almost completely devoid of GluR2(3)-positive neurons. MAP2-labeled neurons also were reduced in number. In contrast, both regions contained an abundance of MC1-positive cells. That GluR2(3) and MC1 are not observed in the same neuron, together with the observation that the number of GluR2(3)-labeled neurons decreases as the number of MC1-positive cells increases, suggest that a loss of GluR2(3) immunolabeling precedes the appearance of MC1 immunolabeling.

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