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.

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

/pdf/national-institute-on-aging-alzheimer-s-association-5crbry24zc.pdf

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

/pdf/national-institute-on-aging-alzheimer-s-association-4honfkm34a.pdf

National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Summary Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and β-secretase and γ-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-β may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(03)00530-1.pdf

CSF markers for incipient Alzheimer's disease

The histologic diagnosis of Alzheimer9s disease (AD) might be aided if a more sensitive marker of aberrant A4 amyloid protein deposition were available. We screened a sample of aged brains, using immunocytochemical methods to detect the A4 protein deposition, and found that, in comparison with conventional histologic techniques (silver impregnation and Congo red), immunocytochemistry is more sensitive and allows an easier demarcation between “normal” and “abnormal.” If A4 protein deposition is accepted as a definitive marker for AD, then the age-related prevalence of AD increases dramatically. To what degree these prevalence rates are reflected in clinically detectable impairment of higher cortical function remains to be determined.

A4 amyloid protein deposition and the diagnosis of Alzheimer's disease Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques

Alzheimer’s disease affects 1% of the population of the Western world and 100% of aged individuals with Down’s syndrome. It is characterized by neuronal dysfunction and depositions of. amyloid A4 protein (β-protein) in the form of intracellular neurofibrillary tangles, extracellular plaques and cerebrovascular amyloid. Amyloid A4 is a self-aggregating protein that consists of 42–43 residues. “Reverse genetics” based on the sequence of amyloid A4 protein has indicated that the amyloid protein is encoded as part of a larger protein by a gene on chromosome 21. Recent cloning studies have indicated that the amyloid precursor gene encodes at least three alternatively spliced products.

Precursor of Alzheimer’s Disease (PAD) A4 Amyloid Protein

The major protein subunit of the amyloid fibril in Alzheimer’s disease is a small molecule of 42 residues (termed A4). It is derived from a larger precursor (PreA4), the gene for which is located on chromosome 21, in close proximity to the region involved in Down’s syndrome. The predicted structure of PreA4 suggests that it is an integral membrane glycoprotein. Knowledge of the mechanisms by which PreA4 is degraded to A4 may contribute to a better understanding of the cause of Alzheimer’s disease. Similarly, the amyloid fibril in the unconventional virus diseases is composed of the PrP molecule, which in turn is derived from a neuronal membrane glycoprotein. An understanding of the process by which the PrP molecule is converted into an amyloidogenic molecule may shed some light on the nature of the infectious unit.

The Molecular Basis of Cerebral Amyloidosis in Alzheimer’s Disease and the Unconventional Virus Diseases

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A4 amyloid protein deposition and the diagnosis of Alzheimer's disease Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques

Precursor of Alzheimer’s Disease (PAD) A4 Amyloid Protein

The Molecular Basis of Cerebral Amyloidosis in Alzheimer’s Disease and the Unconventional Virus Diseases