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Journal ArticleDOI

Neuropathological stageing of Alzheimer-related changes.

01 Jan 1991-Acta Neuropathologica (Acta Neuropathol)-Vol. 82, Iss: 4, pp 239-259

TL;DR: The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations, permitting the differentiation of six stages.
Abstract: Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
Topics: Senile plaques (57%), Neurofibrillary tangle (54%), Braak staging (53%), Florbetaben (50%)
Citations
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Journal ArticleDOI
John Hardy1, Dennis J. Selkoe2Institutions (2)
19 Jul 2002-Science
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

11,721 citations


Journal ArticleDOI
Heiko Braak1, Kelly Del Tredici1, Udo Rüb1, Rob A.I. de Vos  +2 moreInstitutions (1)
TL;DR: This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
Abstract: Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.

7,329 citations


Cites methods from "Neuropathological stageing of Alzhe..."

  • ...The severity of co-occurring AD-related pathology was classified according to a procedure permitting differentiation of stages I–VI in the development of neurofibrillary changes and stages A–C in the evolution of -amyloid deposits (Table 2) [6,48]....

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Journal ArticleDOI
Bruce Fischl1, David H. Salat1, Evelina Busa1, Marilyn S. Albert1  +10 moreInstitutions (3)
31 Jan 2002-Neuron
Abstract: We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease.

5,983 citations


Journal ArticleDOI
TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.
Abstract: The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

4,847 citations


Cites background from "Neuropathological stageing of Alzhe..."

  • ...ries [68]) and the clinical syndrome of AD dementia (estimated prevalence from three epidemiological studies [69–71])....

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Journal ArticleDOI
William E. Klunk1, Henry Engler2, Agneta Nordberg3, Yanming Wang1  +17 moreInstitutions (3)
TL;DR: The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.
Abstract: This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

3,818 citations


References
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Journal ArticleDOI
01 Jul 1984-Neurology
TL;DR: The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information becomes available.
Abstract: Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.

25,936 citations


"Neuropathological stageing of Alzhe..." refers background in this paper

  • ...Insidious onset and continual progress of dementia in a state of clear consciousness characterize AD [37, 42, 54]....

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Journal ArticleDOI
Zaven S. Khachaturian1Institutions (1)
01 Nov 1985-JAMA Neurology
TL;DR: The purpose of the meeting was to identify the most important scientific research opportunities and the crucial clinical and technical issues that influence the progress of research on the diagnosis of AD.
Abstract: Early and accurate diagnosis of Alzheimer's disease (AD) has a major impact on the progress of research on dementia. To address the problems involved in diagnosing AD in its earliest stages, the National Institute on Aging, the American Association of Retired Persons, the National Institute of Neurological and Communicative Disorders and Stroke, and the National Institute of Mental Health jointly sponsored a workshop for planning research. The purpose of the meeting was to identify the most important scientific research opportunities and the crucial clinical and technical issues that influence the progress of research on the diagnosis of AD. The 37 participants included some of the most knowledgeable and eminent scientists and physicians actively involved in the study of AD. The participants were divided among six panels representing the disciplines of neurochemistry, neuropathology, neuroradiology, neurology, neuropsychology, and psychiatry. Within each of the panels, participants discussed specific areas of research requiring further

2,293 citations


Journal ArticleDOI
14 Sep 1984-Science
TL;DR: Examination of temporal lobe structures from Alzheimer patients reveals a specific cellular pattern of pathology of the subiculum of the hippocampal formation and layers II and IV of the entorhinal cortex that isolates the hippocampus from much of its input and output and probably contributes to the memory disorder in Alzheimer patients.
Abstract: Examination of temporal lobe structures from Alzheimer patients reveals a specific cellular pattern of pathology of the subiculum of the hippocampal formation and layers II and IV of the entorhinal cortex. The affected cells are precisely those that interconnect the hippocampal formation with the association cortices, basal forebrain, thalamus, and hypothalamus, structures crucial to memory. This focal pattern of pathology isolates the hippocampal formation from much of its input and output and probably contributes to the memory disorder in Alzheimer patients.

1,980 citations


Journal ArticleDOI
TL;DR: Data on the severity of the pathological involvement in different areas of the neocortex and the laminar distribution and the clustering of the tangles support the suggestion that the pathological changes in Alzheimer disease affect regions that are interconnected by well-defined groups of connections and that the disease process may extend along the connecting fibers.
Abstract: The numbers and distribution of the neurofibrillary tangles and neuritic plaques have been determined in several areas of the neocortex in brains affected by various degrees of severity of Alzheimer disease. The homotypical cortex of the "association" areas of the temporal, parietal, and frontal lobes are severely involved, whereas the motor, somatic sensory, and primary visual areas are virtually unaffected. The neurofibrillary tangles are mainly in the supra- and infragranular layers, particularly in layers III and V. In all areas except area 18 in the occipital lobe, there are approximately twice as many tangles in layer V as in layer III. The tangles are arranged in definite clusters, and those in the supra- and infragranular layers are in register. The neuritic plaques occur in all layers but predominantly affect layers II and III and do not show clustering. These data on the severity of the pathological involvement in different areas of the neocortex and the laminar distribution and the clustering of the tangles support the suggestion that the pathological changes in Alzheimer disease affect regions that are interconnected by well-defined groups of connections and that the disease process may extend along the connecting fibers. The invariable and severe involvement of the olfactory areas of the brain in this disease is in striking contrast to the minimal changes in the somatic sensory and primary visual areas and raises the possibility that the olfactory pathway may be initially involved.

966 citations


Journal ArticleDOI
TL;DR: The temporal lobe cortex and hippocampus were the areas most severely affected by the increased neurofibrillary tangle formation in senile dementia due to Alzheimer's disease.
Abstract: We have made a histological study of the cerebral cortex and hippocampus from 59 consecutively autopsied subjects, aged 51-102 years, prospectively assessed for the presence and extent (or absence) of dementia. Counts were obtained of the numbers of argyrophilic plaques and neurofibrillary tangles in each area examined. In demented patients without evidence of cerebrovascular disease, a highly significant correlation was found between the presence and severity of dementia and the number of neurofibrillary tangles in the cerebral cortex. A significant but much weaker and inconstant correlation was obtained between the presence and severity of dementia and the number of argyrophilic plaques present in the cortex. The temporal lobe cortex and hippocampus were the areas most severely affected by the increased neurofibrillary tangle formation in senile dementia due to Alzheimer's disease.

594 citations


"Neuropathological stageing of Alzhe..." refers background in this paper

  • ...NFT and NT, in contrast, exhibit a well-defined pattern [20, 30, 34, 60], permitting differentiation of stages....

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