Neurofibrillary degeneration and cell loss in the nucleus basalis in comparison to cortical Alzheimer pathology.

Neurofibrillary tangle staging was compared in the nucleus basalis and cerebral cortex of Alzheimer's disease patients with and without Lewy body disease. In pure Alzheimer's disease, cholinergic nucleus basalis cell number, as determined from counts in serial forebrain sections, was 22-60% of control mean, with the majority of residual cells containing tangles. A comparison between control cell number and the combined number of tangles plus tangle-free neurons in pure Alzheimer's disease suggests that the majority of nucleus basalis neurons were lost through neurofibrillary degeneration. The staging of neurofibrillary degeneration in the nucleus basalis was discordant with cortical changes as some controls had more extensive tangle formation in the nucleus basalis than in the cerebral cortex. Patients having both Alzheimer's disease and Lewy body pathology had few or no tangles in the nucleus basalis despite greater loss of neurons than purely demented patients. The presence of concomitant pathology had a greater effect on nucleus basalis tangle burden than did cortical disease stage, suggesting dichotomous disease processes in the cerebral cortex and forebrain.

Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease.

Cortical atrophy and cell loss in the cholinergic nucleus basalis is a well-established characteristic of Alzheimer's disease; however, previous studies not have analysed cholinergic cell loss and cortical atrophy in concert. In autopsy brains from eight patients with Alzheimer's disease and 12 control subjects, the numbers of nucleus basalis neurons were determined from 50-microm serial Nissl-stained sections. Volumes of the cerebrum, cortical gray matter (total, lobar and subregional), white matter and deep gray structures were computed by point counting on black and white photographs of gapless 3-mm coronal slices of formalin-fixed brains. Cell loss in the nucleus basalis was found to range between 89% and 42% in Alzheimer's disease compared with controls. White matter volume was unchanged in absolute terms in Alzheimer's disease patients compared with controls, while cortical volume was significantly reduced. Gray matter atrophy was most prominent in temporal and frontal cortices. A highly significant linear relationship was found between cortical volume and nucleus basalis cell number in controls and Alzheimer's disease patients, with values for both groups on a single regression line. Whole brain and cerebral volumes were also highly correlated to nucleus basalis cell numbers in both groups. A quantitative analysis of plaque and tangle burden in cortical target areas of the nucleus basalis was performed. In contrast to the relationship with cortical volume, nucleus basalis cell number and neurofibrillary tangle number were not significantly correlated to the density of cortical histopathology. These results suggest that the volume of cortical gray matter is coupled to the number of nucleus basalis neurons. Compromised viability of nucleus basalis neurons may precede cortical volume loss as large numbers of neurofibrillary tangles, detected with nickel peroxidase staining, were found in this nucleus in all Alzheimer's disease cases, including those with minimal cell loss.

A novel nickel avidin-biotin-peroxidase method for histochemical visualization of neurofibrillary tangles, senile plaques, and neuropil threads.

A reliable new method was developed for detecting neurofibrillary tangles, senile plaques, and neuropil threads in human neural tissue. Excellent morphological definition of the pathological structures was achieved with this procedure without staining normal neuronal and glial elements. The technique was applied to cortical tissue from eight patients with Alzheimer's disease and three controls. Histological sections from these cases were incubated in an avidin-biotin-peroxidase complex solution containing 0.5% nickel ammonium sulfate, followed by visualization in 3,3'-diaminobenzidine and H2O2. Although the avidin-biotin system is routinely used in immunohistochemistry, no antibodies were employed in the present procedure. This technique has advantages over silver impregnation methods because it requires very little monitoring of critical steps and yields superior results. The method is suitable for processing large numbers of tissue sections per staining run, and the results are highly reproducible. These features are advantageous in research studies comparing the distribution of lesions in large numbers of cases. The precise mechanism of staining has not been determined; however, conditions such as nickel concentrations, pH, and avidin-biotin-peroxidase complex concentrations were varied to examine critical steps in the process.

Perivascular astrocytes within Alzheimer's disease plaques.

The association of astrocytes with plaques is a well-established feature of Alzheimer's disease (AD) and has generally been interpreted as a secondary reaction to amyloid deposition or neuronal degeneration. Astrocytes in brain tissue from six non-demented controls and six patients with AD were investigated using enhanced immunohistochemistry for glial fibrillary acid protein (GFAP) in serial sections from cortex, basal forebrain, amygdala, putamen and diencephalon. Astrocytes colocalized with all diffuse and non-diffuse plaques in AD and control brain tissue. All plaque-associated astrocytes contacted microvessels, and despite having greater numbers of hypertrophic and fine calibre processes, the cells maintained the perivascular arrangement characteristic of control brain tissue. These observations suggest that plaques form at the site of microvascular aberrations followed by reactive and degenerative changes in perivascular astrocytes.

Glial fibrillary acidic protein (GFAP) immunohistochemistry in human cortex: a quantitative study using different antisera.

Glial fibrillary acidic protein (GFAP) is the principal marker for brain astrocytes. The present study aims to examine the variability in GFAP immunohistochemistry in formalin-fixed human brain. Four commercially-available antisera were tested using standardised protocols in the cerebral cortex of three cases with prominent glial reactions and one control. GFAP immunoreactivity was largely confined to the pial surface and white matter in control cortex, with the number of astrocytic cell bodies and processes as well as intensity of staining markedly increased in damaged cortices. A dramatic difference in the pattern of GFAP staining using different antisera was observed and may account for discrepancies between past studies. This variance has important practical implications for the interpretation of results using GFAP immunohistochemistry in human tissue.

Unemployed youth and health: findings from the pilot phase of a longitudinal study.

Contemporary research perspectives on the impact of unemployment on health and well-being among young people have tended to focus on a rather narrow range of outcomes, typically those in the mental health domain. The impetus for the proposed longitudinal study, the main dimensions of which are described in this paper, reflects the need for a more comprehensive profiling of the health needs and experiences of young people if effective interventions tailored to their short and long term health needs are to be developed. The proposed study includes variables from a wide range of domains and adopts an interdisciplinary perspective. The feasibility of the approach, both in terms of establishing appropriately stratified samples and determining the acceptability and utility of the measures proposed has been examined during an extensive pilot phase. Findings from the database established during this phase are presented. These focus on multi-dimensional comparisons of health and well-being between employed and unemployed young people, the impact of socio-economic status of origin on cardiovascular and other indicators, and the correlates of health and well-being among the unemployed. The results point to the potential complexity of the influences on health status and behaviour and the need to develop comprehensive models of this for research and intervention purposes.

Use of microcomputers in medical practice management: a practical guide.

The decreasing cost and increasing availability of computers have created both concern and desire on the part of the non-computer professional. This article provides basic information to use in the selection of microcomputer hardware and software. It is slanted toward the small practitioner, one to four physicians, and provides practical guidelines, definitions, and examples relevant for a small practice.

Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus.

The present immunohistochemical study provides evidence that the kynurenine pathway is up-regulated in Alzheimer's disease (AD) brain, leading to increases in the excitotoxin quinolinic acid (QUIN). We show that the regulatory enzyme of the pathway leading to QUIN synthesis, indoleamine 2,3 dioxygenase (IDO) is abundant in AD compared with controls. In AD hippocampus, both IDO- and QUIN-immunoreactivity (-IR) was detected in cortical microglia, astrocytes and neurones, with microglial and astrocytic expression of IDO and QUIN highest in the perimeter of senile plaques. QUIN-IR was present in granular deposits within the neuronal soma of AD cortex and was also seen uniformly labelling neurofibrillary tangles. Our data imply that QUIN may be involved in the complex and multifactorial cascade leading to neuro-degeneration in AD. These results may open a new therapeutic door for AD patients.

Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon.

We have analyzed glial changes in forebrain and diencephalic regions in 19 alcoholics with different histories of chronic alcohol consumption and related medical complications including Wernicke's encephalopathy and alcoholic liver disease. Cases with postmortem evidence of hepatic encephalopathy were excluded. Two of the alcoholic patients had ceased drinking for several years prior to death. Brains were obtained postmortem and fixed in formalin. Serial 50 microns sections of the forebrain and diencephalon at 750 microns intervals were stained with standard histochemical stains (haematoxylin and eosin, luxol fast blue, cresyl violet and silver), as well as immunohistochemically for glial fibrillary acidic protein (GFAP). In control tissue, GFAP-positive astrocytes were intimately associated with ependymal, pial, and vascular surfaces. In alcoholic cases, the morphology of these cells was markedly changed showing enlargement of the cell bodies and beading of the cellular processes. In contrast to controls, GFAP-positive astrocytes were seen within and surrounding clusters of magnocellular neurons in the basal forebrain and hypothalamus. In thiamine-deficient alcoholics, glial scarring in the vicinity of the large branches of the cerebral arteries disrupted the normal forebrain architecture. A patchy loss of GFAP immunostaining was seen in most severe cases. A remarkable number of corpora amylacea also rimmed blood vessels, pial and ependymal surfaces in all alcoholics compared to controls. The beaded fibers were seen in alcoholics drinking at the time of death as well as in those who had ceased drinking alcohol several years prior to death. These results indicate that chronic alcoholics have prominent glial changes which persist despite the cessation of alcohol consumption and are not exclusive to alcoholics with liver pathology.

Mechanisms of cell death in cholinergic basal forebrain neurons in chronic alcoholics.

Tau immunoreactivity was examined in post mortem tissue from patients in three groups: neurologically-asymptomatic and neuropathologically normal alcoholics, alcoholics with Wernicke's Encephalopathy (WE) and age matched non-alcoholic controls. Tau-positive granular and fibrillary inclusions were frequently observed within the magnocellular neurons of the cholinergic nucleus basalis, within occasional nucleus basalis neurons in non-WE alcoholics, but not in controls. Tau immunoreactivity was not however observed in cortical, brainstem, diencephalic or non-cholinergic forebrain structures. Peroxidase activity was also examined within the nucleus basalis using diaminobenzidine as an indicator. The majority of neurons in the basal forebrain showed increased peroxidase activity in all WE alcoholics and in some nucleus basalis neurons of non-WE alcoholics, but was rarely seen in controls. Neighboring astrocytes also showed increased peroxidase activity. These results suggest a link between peroxidase activity and the abnormal accumulation of phosphorylated tau. The presence of tau in the nucleus basalis of alcoholics with WE suggests a thiamine-dependent mechanism in tau accumulation and cell death in the cholinergic basal forebrain.

Neurofibrillary tangles in chronic alcoholics.

Magnocellular neurons in the cholinergic nucleus basalis appear to be vulnerable in a variety of pathological conditions, including chronic alcoholism. While neurofibrillary degeneration of these neurons has been noted in a number of disorders characterized by dementia, the mechanism of cell death in thiamine-deficient chronic alcoholics has not been identified. In the present post-mortem investigation, multiple brain regions of seven thiamine-deficient chronic alcoholics, three neurologically asymptomatic chronic alcoholics and seven non-alcoholic age matched controls were screened for neurofibrillary pathology using both tau-immunohistochemistry and a modified Bielschowsky silver stain. In chronic alcoholics with thiamine deficiency, neurofibrillary pathology was found in the nucleus basalis, but not any other brain region. Neurofibrillary tangles were not seen in age-matched controls and were infrequent in alcoholics without neuropathological signs of thiamine-deficiency. Neurofibrillary tangles were most numerous in those cases with cell loss in the nucleus basalis. These findings suggest that neurodegeneration of the nucleus basalis in chronic alcoholics proceeds through the formation of neurofibrillary tangles.

Improved selectivity and sensitivity in the visualization of neurofibrillary tangles, plaques and neuropil threads.

Stain sensitivity is a key factor in estimating the frequency of plaques and neurofibrillary tangles in Alzheimer's disease (AD), making it essential that the sensitivity and selectivity of detection methods for identifying these lesions is maximized. Several new, improved techniques have recently been described, although these methods have not been compared quantitatively with those techniques currently recommended for use in standardized diagnostic protocols. In the present study, eight different stains were examined for their selectivity and sensitivity in detecting plaques and tangles in serial tissue sections from AD and control brains. Techniques compared were immunohistochemistry for tau and beta-amyloid, thioflavin S, nickel peroxidase method, and four silver impregnation techniques (Gallyas silver iodide, Campbell-Switzer-Martin, Garvey's modified Bielschowsky and methenamine silver methods). Among these eight staining techniques, the nickel peroxidase proved the most reliable method for the demonstration of the histopathological lesions of AD. This method labels all morphological types of plaques and tangles within a single tissue section, and provides several advantages for the analysis of lesion progression and distribution.

The nucleus basalis (Ch4) in the alcoholic Wernicke-Korsakoff syndrome: reduced cell number in both amnesic and non-amnesic patients.

BACKGROUND: The cholinergic nucleus basalis (Ch4) is an exclusive site of neurofibrillary degeneration in alcoholic patients with Wernicke's encephalopathy. AIM: To test the hypothesis that the loss of Ch4 neurons contributes to the memory disorder, Korsakoff's psychosis, commonly seen in Wernicke's encephalopathy. METHODS: Magnocellular basal forebrain neurons were quantified in alcoholic patients with Wernicke's encephalopathy, both with and without Korsakoff's psychosis, and neurologically asymptomatic alcoholic and non-alcoholic controls. Because amnesic and non-amnesic patients with Wernicke's encephalopathy share common periventricular lesions, both thiamine deficient groups as well as alcoholic patients with no neurological complications were included to determine the lesion specific to memory impairment. RESULTS: Ch4 cell number did not differ significantly between alcoholic and non-alcoholic controls and there was no correlation between cell number and lifetime alcohol intake. However, Ch4 cell number in all groups was significantly correlated with the volume of its major projection target, the cerebral cortex. Ch4 cell number in the non-amnesic Wernicke's encephalopathy group was significantly below controls (24%), with cell number in patients with Korsakoff's psychosis 21% below controls. There was considerable overlap in cell number between groups. On discriminant analysis, there was significantly greater cell loss in three non-amnesic patients with Wernicke's encephalopathy than in some patients with Korsakoff's psychosis. The nonamnesic patient with the greatest cell loss was impaired on attentional tasks. CONCLUSION: Whereas neurons in the nucleus basalis are at risk in thiamine deficient alcoholic patients, cell loss is minor and does not account for the profound memory disorder.