P.L. McGeer

Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

We detected large numbers of HLA-DR-positive reactive microglia (macrophages), along with Lewy bodies and free melanin, in the substantia nigra of all cases studied with Parkinsons disease (5) and parkinsonism with dementia (PD) (5). We found similar, but less extensive, pathology in the substantia nigra of six of nine cases of dementia of the Alzheimer type (DAT) but in only one of 11 age-matched nonneurologic cases. All dementia cases with a premortem diagnosis of DAT or PD showed large numbers of HLA-DR-positive reactive microglia and significant plaque and tangle counts in the hippocampus, as well as reduced cortical choline acetyltransferase activity. One of 11 nondemented controls showed mild evidence of similar cortical pathology. These data indicate that HLA-DR-positive reactive microglia are a sensitive index of neuropathologic activity. They suggest a frequent coexistence of DAT- and Parkinson-type pathology in elderly patients.

ENZYMES ASSOCIATED WITH THE METABOLISM OF CATECHOLAMINES, ACETYLCHOLINE AND GABA IN HUMAN CONTROLS AND PATIENTS WITH PARKINSON'S DISEASE AND HUNTINGTON'S CHOREA

—Tyrosine hydroxylase (TH), dopa decarboxylase (DDC), glutamic acid decarboxylase (GAD), choline acetyltransferase (CAT), and acetylcholinesterase (AChE) were measured in 18–55 areas of brain from humans post mortem. Individuals meeting sudden and unexpected death (22), patients dying in hospital with non–neurological illness (6), Parkinsons disease (12), Huntingtons chorea (8), terminal coma (6) or head injury (2) were included in the series. The absolute values obtained compared favourably with some previous human studies where high values for these enzymes were obtained, as well as with monkey and baboon data. The regional distributions of the enzymes were also comparable to those previously reported in human and animal studies. A number of important points with regard to human tissue seemed to emerge from the study. The mode of death was not a factor in enzyme levels in non–neurological and non‐coma cases. Post mortem delay did not seem to be a major factor either even though a substantial decline in GAD, TH and DDC could be demonstrated in rats left several hours between sacrifice and removal of the brain for assay. Age had a highly significant effect in certain areas of brain. The decline typically followed a curvilinear pattern (activity = A/age + B with the sharpest drops being in the younger age groups). DDC seemed to be the enzyme most severely affected by age but all the enzymes showed declines in certain brain areas, while in other areas there was no significant decline. All the enzymes were very depressed by coma from illness except AChE. TH and DDC in the brain stem were, however, not affected in the head injury cases. The Parkinsonian cases showed a sharply decreased TH activity in the substantia nigra, caudate and putamen. There were decreases in GAD in the globus pallidus (GP) and substantia nigra with marginal decreases in the neostriatum. CAT levels in the extrapyramidal nuclei were normal. In Huntingtons chorea there was a substantial decrease in GAD in all the extrapyramidal structures. There was a patchy loss of CAT in the neostriatum and locus coeruleus.

Aging, Alzheimer's disease, and the cholinergic system of the basal forebrain

All giant neurons of the medial basal forebrain stained for choline acetyltransferase (ChAT). Cell numbers declined from 400,000 to 475,000 in young controls to approximately 140,000 in elderly controls. Five senile dementia cases had counts ranging from 45,000 to 100,000 cells. ChAT levels in control frontal cortex decreased from 1.2 μmol/hr/100 mg protein at age 40 to 0.5 at age 95. Five senile dementia cases had levels ranging from 0.04 to 0.30. When the cholinergic cell count in the basal forebrain drops below about 100,000 cells, the level of cortical ChAT may be so low that clinical dementia appears.

Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K

The distribution of calbindin-D28K (CaBP)-positive neurons was investigated by immunohistochemistry in 4 controls, 5 cases of Parkinsons disease and a single case of strionigral degeneration. CaBP-positive neurons were preferentially localized to the mediodorsal portion of the substantia nigra pars compacta (SNC) in the beta layer, while CaBP-negative, melanin-positive neurons were concentrated in the ventrolateral SNC in the alpha layer. In Parkinsons disease and the case of strionigral degeneration, there was a relative sparing of the CaBP-positive neurons compared with CaBP-negative, pigmented neurons. These data imply that CaBP may confer some protection to SNC dopaminergic neurons against the pathological process which is responsible for Parkinsons disease and strionigral degeneration.

Expression of the histocompatibility glycoprotein HLA-DR in neurological disease

SummaryReactive microglia or macrophages expressing the histocompatibility glycoprotein HLA-DR were detected in many neurological diseases including Alzheimers, Parkinsons, Picks and Huntingtons diseases, parkinsonism-dementia of Guam, amyotrophic lateral sclerosis, Shy-Drager syndrome, multiple sclerosis and AIDS encephalopathy. Reactive astrocytes, also present in these conditions, were established as a population distinct from the HLA-DR positive microglia by double immunostaining for glial fibrillary acidic protein and HLA-DR. A distinctive pattern of HLA-DR positive cells was seen in each disease entity. Areas known to contain pathology always stained positively, and, in several cases, reactive microglia appeared in areas that would otherwise not have been suspected of being involved in the pathological process. HLA-DR staining, which outlines the surface membranes of positive cells, was so strong that lesioned areas could frequently be identified in sections with the naked eye. In adjacent sections stained with H&E or sections destained of HLA-DR and then restained with H&E, gliosis was often hard to identify except on close microscopic inspection. The results suggest that HLA-DR staining may be a valuable addition to standard neuropathological methods and might be useful in investigating diseases where pathology has not yet been identified.

On the source of gaba-containing terminals in the substantia nigra. Electron microscopic autoradiographic and biochemical studies

Gamma-aminobutyric acid ([3H]GABA) uptake into slices of caudate-putamen, globus pallidus and substantia nigra was studied by electron microscopic autoradiography. In the substantia nigra [3H]GABA uptake occured primarily into nerve terminals, while in the caudate-putamen and globus pallidus [3H]GABA was accumulated in both nerve terminals and cell bodies. Electrolytic lesions of the globus pallidus significantly reduced glutamic acid decar☐ylase activity (GAD) in the substantia nigra. Hemitransections at the level of the ventromedial hypothalamus reduced GAD in the substantia nigra but did not decrease GAD in the caudate-putamen or globus pallidus. Hemitransections at the level of the anterior commissure, which would sever any caudally directed projections from more than 60% of the caudate-putamen, did not reduce nigral GAD activity except in 3 animals where there was visible damage to the globus pallidus. These results point to the possible existence of a pallido-nigral pathway whose neurotransmitter is GABA.

Distribution of clusterin in Alzheimer brain tissue

The immunohistochemical distribution of clusterin (SP40,40, SGP-2) was determined in Alzheimer disease (AD) and normal human brain tissue and compared with the distributions of vitronectin, protectin and the complement membrane attack complex (MAC). Antibodies to all four proteins showed staining of dystrophic neurites and neuropil threads in AD tissue, and residual serum in normal tissue, but only antibodies to clusterin and vitronectin strongly stained amyloid deposits in senile plaques. The clusterin antibody also showed punctate staining of some normal appearing AD pyramidal neurons, and very scattered staining of intracellular neurofibrillary tangles. Clusterin, vitronectin and protectin are all believed to inhibit membrane insertion by the MAC, and these data are consistent with upregulation of all three proteins in response to MAC formation in AD, and with a neuronal origin of clusterin.

Choline acetyltransferase immunohistochemistry in brains of alzheimer's disease patients and controls ☆

Choline acetyltransferase (ChAT)-containing neuronal structures of the basal forebrain were studied by ChAT immunohistochemistry in the brains of persons dying with Alzheimers disease (SDAT), as well as age-matched controls dying without neurological disorder. A loss of greater than 50% in ChAT-containing neurons was found in the substantia innominata in the SDAT group. In contrast, there was no reduction in the number of ChAT-containing neurons of the putamen as compared with controls. The data confirm the reason for the reduction of ChAT as measured biochemically in the neocortex of SDAT cases, and support the cholinergic hypothesis of memory.

Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer's disease brain tissue

Cells expressing leucocyte common antigen (LCA) as well as T-cytotoxic-suppressor (T8) and T-helper-inducer (T4) antigens were detected in significant numbers in the hippocampus and temporal cortex of Alzheimer but not normal brain tissue. Leucocytes and reactive microglia strongly expressed LCA, as well as the class II major histocompatibility complex (MCH) glycoprotein HLA-DR, but astrocytes stained negatively. Such staining indicates the immunocompetent status of microglia, as well as their phenotypic linkage to blood borne mesodermal lines. T8 and T4 positive lymphocytes were detected in capillaries and the surrounding matrix in smaller numbers than LCA positive cells. The MHC class I (HLA-A,B,C) antigens were detected on capillaries in both Alzheimer and control tissue. The significance of LCA, T4 and T8 cells in Alzheimers disease is unknown but may be indicative of a cell mediated immune response in the disease.

Aging and brain enzymes

Abstract The activities of various enzymes involved in amine turnover were studied as a function of age (2–29 months) in rat caudate and whole brain minus caudate and cerebellum. The only significant changes with age (decreases) found were in tyrosine hydroxylase, choline acetylase and glutamic decarboxylase in the caudate nucleus. The sharp decrease in caudate tyrosine hydroxylase with age may be significant in behavioral and drug-tolerance changes in senility.