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.

Neuropathological stageing of Alzheimer-related changes.

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.

/pdf/the-amyloid-hypothesis-of-alzheimer-s-disease-progress-and-211e4syver.pdf

The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

Staging of brain pathology related to sporadic Parkinson’s disease

Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.

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.

/pdf/toward-defining-the-preclinical-stages-of-alzheimer-s-4a348i45fl.pdf

Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Staging of Alzheimer's disease-related neurofibrillary changes.

Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories

The gradual intraneuronal accumulation of an insoluble fibrous material which partly consists of abnormally phosphorylated tau protein (neurofibrillary change) represents an important neuropathological hallmark of Alzheimer's disease. Neurofibrillary tangles and neuropil threads formed from this material develop in only a few types of cortical pyramidal cells. The first changes are seen in the entorhinal cortex. The destructive process then spreads into the hippocampal formation and eventually encroaches upon the isocortex. This sequence of events permits the distinction of six stages with a progressive increase in the severity of cortical destruction. The entorhinal region serves as an important interface between the isocortex and hippocampus. This interface function is markedly impaired due to the early deterioration of the entorhinal cortex. Severe entorhinal involvement is considered to represent the morphological counterpart of clinically incipient Alzheimer's disease. Similar changes are found in mentally impaired individuals suffering from Parkinson's disease or progressive supranuclear palsy.

Eva Braak

Papers

Neuropathological stageing of Alzheimer-related changes.

Staging of brain pathology related to sporadic Parkinson’s disease

Staging of Alzheimer's disease-related neurofibrillary changes.

Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories

Staging of Alzheimer-Related Cortical Destruction