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.

Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.

https://jnnp.bmj.com/content/jnnp/55/3/181.full.pdf

Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

https://science.sciencemag.org/content/sci/274/5284/99.full.pdf

Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice

Objective. —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Data Sources. —Forty research teams contributed data onAPOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Main Outcome Measures. —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed forAPOEgenotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Results. —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). TheAPOE∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P Conclusions. —TheAPOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association betweenAPOE∈4 and AD in African Americans requires clarification, and the attenuated effect ofAPOE∈4 in Hispanics should be investigated further.

https://jamanetwork.com/journals/jama/articlepdf/418446/jama_278_16_041.pdf

Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis

The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.

/pdf/neuropathological-alterations-in-alzheimer-disease-2zexumi6x1.pdf

Neuropathological Alterations in Alzheimer Disease

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

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=NEUR&articleId=584730&pdfFileName=archneur_42_11_029.pdf

Diagnosis of Alzheimer's Disease

Studies of the central nervous system have a long history; however, it is only recently that we have begun to understand brain function in health and disease states. And, the topic of the aging brain has become a subject of intense study for a short period. At present, the process of normal aging is relatively poorly understood. Although there are a number of theories of aging, no single theory appears to account for most age-dependent brain changes. This review provides a re-evaluation of the "Calcium Hypothesis of Brain Aging" in light of new evidence which supports the proposition that cellular mechanisms, which maintain the homeostasis of cytosol Ca2+ concentration, play a key role in brain aging; and that sustained changes in [Ca2+]i homeostasis provide the final common pathway for age-associated brain changes. This revision of the calcium hypothesis suggests that there is a complex interaction between the amount of [Ca2+]i perturbation and the duration of such deregulation of Ca2+ homeostasis and it proposes that a small disturbance in Ca2+ homeostasis with a sustained increase in [Ca+]i over a long period has similar cell injuring consequences as that produced by a large increase in [Ca2+]i over a shorter period. Although there are several alternative mechanisms through which the regulation of cytosol [Ca2+]i can be disrupted (such as changes in ion channels, extrusion pumps, and sequestration), this review focuses on disruptions in energy metabolism and changes in the structure and function of membranes as the most likely antecedent events which lead to disruption of Ca2+ homeostasis. The principle purpose of this review is to identify scientific opportunities and stimulate further research into cellular mechanisms of brain aging.

The role of calcium regulation in brain aging: reexamination of a hypothesis.

Introduction A Synthesis of Critical Topics in Alzheimer's Disease, Z.S. Khachaturian and T.S. Radebaugh Overview and Historic Perspectives Current Research on Alzheimer's Disease in an Historical Perspective, R. Katzman A History of the Morphology of Alzheimer's Disease, R.D. Terry Epidemiology Putative Risk Factors for Alzheimer's Disease, R. Mayeux Descriptive Epidemiology of Alzheimer's Disease, D.A. Evans Methods of Screening for Survey Research on Alzheimer's Disease and Related Dementias, B.J. Gurland Diagnosis Differential Diagnosis of Alzheimer's Disease, J.C. Morris Clinical Assessment of Patient with Dementia, S. Gilman Heterogeneity of Alzheimer's Disease, A. Heyman The Use of Tests and Instruments in the Evaluation of Patients with Dementia, R.C. Mohs Biological Markers The Neuropathology of Alzheimer's Disease: Diagnostic Features and Standardization, S.S. Mirra and W.R. Markesbery Pathology, Neurobiology, and Animal Models of Alzheimer's Disease, J.C. Troncoso, B.J. Crain, S.S. Sisodia, and D.L. Price Neuroimaging Applications for the Study of Alzheimer's Disease, T.F. Budinger Cause(s) Intrinsic Biological Aging as Underlying Pathogenetic Mechanism, G.M. Martin Cerebral Metabolic Impairments, J.P. Blass The Metabolism of Apolipoprotein E and the Alzheimer's Diseases, A.D. Roses Neuroimmune Mechanisms in the Pathogenesis of Alzheimer's Disease, P.L. McGeer and E.G. McGeer Causes of Alzheimer's Disease, A.B. Young Trace Elements in Alzheimer's Disease, W.R. Markesbery Treatment Clinical Drug Trials in Alzheimer's Disease: Methodological Considerations, L.J. Thal Pharmacological Approaches to Behavioral Symptoms in Alzheimer's Disease, D. Galasko Treatment of Alzheimer's Disease, L. Shihabuddin and K.L. Davis Psychosocial Interventions, M.S. Mittelman and S.H. Ferris Care and Management Inappropriate Behavior, J. Cohen-Mansfield Managing Problems in Dementia Patients: Depression and Agitation, L. Teri Overview of Psychosocial Factors Contributing to Stress of Family Caregivers, K.C. Buckwalter The Influence of Social Context on the Caregiving Experience, R.J.V. Montgomery Care for Families Facing Alzheimer's Disease: Primary Care Practice Implications from Research, L.P. Gwyther Index

Zaven S. Khachaturian

Papers

Diagnosis of Alzheimer's Disease

The role of calcium regulation in brain aging: reexamination of a hypothesis.

Alzheimer's disease : cause(s), diagnosis, treatment, and care

Progress of research on Alzheimer's disease. Research opportunities for behavioral scientists.

Aluminum toxicity among other views on the etiology of Alzheimer disease