The AIDS dementia complex: II. Neuropathology

In order to define the histopathological substrate of the dementia that frequently complicates the acquired immune deficiency syndrome (AIDS), we analyzed the neuropathological findings in 70 autopsied adult AIDS patients, 46 of whom had suffered clinically overt dementia. Less than 10% of the brains were histologically normal. Abnormalities were found predominantly in the white matter and in subcortical structures, with relative sparing of the cortex. Their frequency and severity generally correlated well with the degree and duration of clinical dementia. Most commonly noted was diffuse pallor in the white matter, which in the pathologically milder cases was accompanied by scanty perivascular infiltrates of lymphocytes and brown-pigmented macrophages, and in the most advanced cases by clusters of foamy macrophages and multinucleated cells associated with multifocal rarefaction of the white matter. However, in nearly one third of the demented cases the histopathological findings were remarkably bland in relation to the severity of clinical dysfunction. In addition, similar mild changes were noted in over one half of the nondemented patients, consistent with subclinical involvement. Vacuolar myelopathy was found in 23 patients and was generally more common and severe in patients with advanced brain pathology. Evidence of cytomegalovirus (CMV) infection was noted in nearly one quarter of the brains and was associated with a relative abundance of microglial nodules, but correlated neither with the major subcortical neuropathology nor with the clinical dementia, indicating that CMV infection likely represented a second, superimposed process. This study establishes the AIDS dementia complex as a distinct clinical and pathological entity and, together with accumulating virological evidence, suggests that it is caused by direct LAV/HTLV-III brain infection.     

Neuropathological changes in early HIV-1 dementia

Early pathological abnormalities in human immunodeficiency virus (HIV-1)-related dementia have not been well documented. We report a homosexual man with fatigue and intermittent diarrhea in whom early HIV-1-related dementia was demonstrated during neurological screening in the Multicenter AIDS Cohort Study. Within 4 months he died of massive epistaxis, and the brain revealed astrocytosis of white matter and mild pallor of myelin staining in the absence of inflammation, multinucleated giant cells, and brain atrophy.     

Comparison of postmortem magnetic resonance imaging and neuropathologic findings in the cerebral white matter.

Two types of high-signal intensity abnormalities are frequently found bilaterally in the cerebral white matter of brains of elderly patients on T2-weighted magnetic resonance imaging (MRI) scans. One is located in the immediate periventricular region; the other, in the deep subcortical white matter (centrum semiovale). The diagnostic implications of this second type continue to be uncertain. To determine the neuropathologic correlates of these lesions, the brains from seven elderly patients were fixed in buffered formaldehyde solution, subjected to MRI scanning, and examined neuropathologically. Variable degrees of bilateral periventricular (subependymal) sharply defined areas of high-signal intensity were found in all the brains, and the larger of these showed corresponding areas of myelin pallor with gliosis and dilated perivascular spaces. Discrete bilateral patches of high-signal intensity were found in the centrum semiovale in five patients. Myelin and axon stains showed varying degrees of diffuse white matter pallor in many areas examined, both with and without these areas of high-signal intensity on MRI scans. Neither the myelin nor the axon stains showed discrete white matter abnormalities that corresponded to the MRI findings. We believe that these changes, so commonly found on MRI scans in the elderly, reflect actual changes in the white matter but that their nature and clinical significance need to be elucidated.     

Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation

We studied the brains of three patients with acquired immune deficiency syndrome (AIDS), all of whom developed subacutely progressive dementia unassociated with opportunistic infection or neoplasm in the central nervous system. Computed tomographic (CT) scans of the head revealed cortical atrophy, ventricular dilation, and diffuse hypodensity of the centrum semiovale. On microscopic examination, the cerebral and cerebellar white matter in all cases showed diffuse and focal, angiocentric regions of myelin pallor, focal vacuolization, and extensive gliosis. Variable axonal loss and axonal spheroids were evident. The microvasculature showed striking changes, including mural thickening, increased cellularity, and enlargement and pleomorphism of endothelial cells with variable numbers of macrophages and multinucleated giant cells (MNGC), which often contained hemosiderin pigment. Human immunodeficiency virus type 1 (HIV-1) antigens were identified immunocytochemically within perivascular macrophages and MNGC and in some microglial cells. We suggest that the morphologic abnormalities of the microcirculation may be associated with an alteration of the blood-brain barrier. The increased vascular permeability could contribute to damage and loss of the white matter including both myelin and axons, and result in subcortical cerebral atrophy. The HIV-1 infected cells present in relation to the microvasculature may play a role in mediating the vascular injury.     

Neuropathologic correlates of leuko-araiosis

We describe the pathologic findings in 17 persons with dementia, 12 of whom exhibited leuko-araiosis on computed tomographic scan. The presence of white matter pallor was confirmed on autopsy in 11 of these 12 cases, 9 with Alzheimer's disease and 2 with multi-infarct dementia. Two further patients, 1 with Alzheimer's disease and 1 with multi-infarct dementia, proved to have white matter changes on pathologic examination. White matter pallor coexisted with cerebral amyloid angiopathy in the brains of the patients with Alzheimer's disease. The presence of severe white matter pallor in patients with Alzheimer's disease correlated with early death, while the presence of cortical scars was associated with prolonged survival. Because early death in patients with Alzheimer's disease has been linked with severe pathologic and chemical changes, the presence of white matter pallor may be further evidence of a particularly severe process in patients with early onset of Alzheimer's disease.     

Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy

We have studied 12 patients with diffuse hemorrhagic cerebral amyloid angiopathy clinically and at postmortem examination. The brains in 8 patients had diffuse bilateral loss of myelin in the hemispheric white matter sparing the U fibers, corpus callosum, and internal capsules. The periventricular areas were predominantly affected. Microscopic examination of the white matter showed an association with subacute or chronic edematous lesions: spongiosis, swollen oligodendroglia, widening of the perivascular spaces with edema fluid or siderophages, hyalinization of the blood vessel walls, incomplete myelin loss, and astrocytic gliosis. Three of 8 autopsied patients had undergone computed tomographic examination, which showed bilateral hypodensity of the hemispheric white matter. The brains of 4 patients with illnesses of shorter duration showed only discrete but similar lesions in the centrum semiovale. These white matter changes are similar to those observed in Binswanger's subcortical encephalopathy. We suggest that a common mechanism of hypoperfusion of the distal white matter causes the leukoencephalopathy.     

Clinicopathologic study of progressive subcortical vascular encephalopathy of Binswanger type (PSVE)

To investigate the histopathological basis of white matter pallor on myelin staining in PSVE, the frontal white matter was examined by electron microscopy in 7 cases with PSVE. The number of nerve fibres per unit area of the white matter was significantly less in PSVE compared with that in the control group or in senile dementia of Alzheimer's type (SDAT). Nerve fibers in PSVE had a tendency to have thinner myelin sheaths than in the control group or in SDAT, but the difference was not significant. The white matter pallor in PSVE is mainly based on the loss of nerve fibres. The dementia in PSVE is probably related to the loss of nerve fibres in the cerebral white matter. A sum of oligodendrocytes and astrocytes per unit area decreased in the area with white matter pallor. Main stem of cerebral arteries, leptomeningeal arteries, medullary arteries in the cortex, and small arteries or arterioles in the cerebral white matter were studied pathologically in 22 elderly patients with PSVE. Not only the severe hyalinotic changes of arterioles in the cerebral white matter, but also the diffuse atherosclerotic lesions in main stem of cerebral arteries and/or the stenotic lesions in leptomeningeal arteries were the characteristic arterial changes of PSVE. Angionecrosis was observed in 70% of the PSVE patients. To substantiate my hypothesis that PSVE in the elderly can be induced by the repeated hypotension or the greater variability of the casual blood pressure in the hypertensives, I studied retrospectively the casual blood pressures in PSVE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunocytochemical quantitation of human immunodeficiency virus in the brain: Correlations with dementia

The pathogenesis of human immunodeficiency virus (HIV)-associated dementia is unclear, and the underlying pathological substrate has been a matter of debate. In a prospectively clinically characterized population of acquired immunodeficiency syndrome (AIDS) patients we investigated the relationship between the clinical syndrome of HIV-associated dementia and the presence and relative quantity of immunocytochemical Marchkers for HIV-1 (gp41 antibody), and for macrophages and microglia (HAM-56 antibody). Sections from the basal ganglia and frontal lobes from the brains of 51 patients were studied, and the data were stratified for severity of dementia (16 nondemented, 12 mildly demented, 23 severely demented), rate of dementia progression, duration of AIDS, use of antiretrovirals, and several other demographic features. We found a highly significant correlation between the degree of macrophage staining and the severity of dementia but only a borderline correlation between the presence and amount of gp41-positive cells and dementia. Several nondemented patients showed abundant gp41 immunoreactivity, and some severely demented showed little to no gp41 immunoreactivity. Other correlations with the immunostaining data, including antiretroviral use, were not significant. We conclude that the presence of macrophages and microglia is a better correlate with HIV-associated dementia than is the presence and amount of HIV-infected cells in the brain. These data support the concept that the pathogenesis of HIV-associated dementia is likely due to indirect effects of HIV-infection of the brain, possibly through the actions of macrophages and microglia.     

Tumor necrosis factor-α, microglia and astrocytes in AIDS dementia complex

The pathogenesis of HIV-associated cognitive changes is poorly understood. Cytokines such as tumor necrosis factor-α (TNF-α) have been postulated to contribute to the mechanism of the neurological complications of HIV infection. One of the effects of TNF-α is to induce astrocyte proliferation in vitro. The purpose of this study was to look for a correlation between the expression of TNF-α, astrogliosis and the degree of cognitive impairment in 12 prospectively assessed AIDS cases without focal brain lesion, 8 of whom were demented. They were compared with 6 control patients without neurological disease. Neuropathological examination showed myelin pallor in 5 of the 8 demented patients. TNF-α expression was detected by immunohistochemistry in the midfrontal cortex, subcortical and deep white matter, and basal ganglia. Not only perivascular macrophages but also some microglial and endothelial cells were labeled. Most TNF-α-positive cells were in close contact with glial fibrillary acidic protein-positive astrocytes. They were more numerous than gp41-positive cells. Their density increased with increasing cognitive impairment and in parallel to the astrogliosis in the frontal cortex, basal ganglia and deep white matter. These findings further support the hypotheses that lesions of the deep white matter, driven by TNF-α, are associated with cognitive alteration, and that indirect effects of HIV infection in the brain participate in the development of HIV-associated dementia through a diffuse immune activation, mediated by cytokines. Received: 22 May 1996 / Revised: 13 September 1996 / Accepted: 11 November 1996     

Cerebrospinal fluid myelin basic protein as predictive marker of demyelination in AIDS dementia complex

Myelin basic protein (MBP) was measured in cerebrospinal fluid (CSF) of patients with acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) in order to investigate the degree of white matter destruction. Results show that increased CSF levels of MBP were detected in all patients with severe ADC (10/10) and, less often, in subjects with mild (2/7) or moderate dementia (7/16). No evidence of MBP-elevated concentration was observed in 14 human immunodeficiency virus (HIV)-seropositive subjects without neurological disorders and in nine HIV-seronegative controls. Our findings suggest that the measurement of CSF MBP concentration may represent a predictive marker of myelin injury and neurologic damage during the course of ADC.     

Cerebral amyloid angiopathy in aged Chinese: a clinico-neuropathological study

To investigate the prevalence and clinico-neuropathological characteristics of cerebral amyloid angiopathy (CAA) in aged Chinese and its relationship to dementia and cerebrovascular lesions, we examined 362 archived brains of elderly with immunohistochemical staining for beta-amyloid peptide and Congo red, Bodian and Luxol fast blue stains. We found that: (1) CAA appeared in 31.7% examined brains without sexual preponderance, and the incidence increased with age; (2) the frontal lobe was most frequently involved in CAA, followed by occipital and parietal lobe; (3) subcortical white matter and cerebellum dentate nucleus areas may also be affected by CAA; (4) CAA has a close relationship to Alzheimer's disease and multiple cerebrovascular lesions; (5) CAA alone may result in dementia.     

Neuropathological investigation of cerebral white matter lesions caused by closed head injury

In order to ascertain whether there is widespread axonal disruption of cerebral white matter in the so‐called ‘diffuse axonal injury’ (DAI), a type of closed head injury, proposed by Adams et al. the author investigated his own cases clinicopathologically. Twenty‐six male autopsied cases of head injury, aged between 19 and 84, 15 of which had sustained road traffic accidents, were examined; the others were due to falling from heights and so on. The study group all belonged to non‐missile head injuries and included 12 cases of diffuse brain injury, as well as 14 cases of focal brain injury, according to the classification of Gennarelli et al. The survival time ranged from 2 h to 21 years. Formalin‐fixed brains were cut coronally so as to make paraffin‐embedded hemispheric sections. Then these sections were stained conventionally (HE, Bodian, Kluver‐Barrera and Holzer) and immunohistochemically (GFAP) to assess axonal decrease, myelin pallor and gliosis by the use of light microscopy. In the 13 chronic cases that died more than 1 month after the accidents, the intensities of gliosis, myelin pallor and axonal decrease tended to correlate with each other. In the 13 acute cases who died less than 1 month after their accident, the degree of axonal decrease in white matter seemed to correlate with the severity of myelin pallor. Regardless of types of trauma, however, axonal retraction balls, the so‐called hallmark of DAI, were found only with myelin pallor suggesting the presence of brain swelling after the injury. Therefore these findings indicate that it may be difficult to accept the notion of DAI, that is, the presence of axonal retraction balls without brain swelling. In addition, diffuse vascular injury (2 cases) as well as rarefaction of subcortical white matter (6 cases) were presented and their pathogenesis individually discussed based on a literature review.     

Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review

In the brains and spinal cords of 153 adult patients dying with acquired immunodeficiency syndrome (AIDS) at New York and Memorial Hospitals a subacute encephalitis with multinucleated cells was present in 28% of all patients. This encephalitis was characterized by multinucleated cells primarily located in the white matter and associated with myelin pallor and sparse infiltrates of rod cells, macrophages, gemistocytic astrocytes and lymphocytes. The incidence per 12 month period ranged from 0 to 43% and significantly increased between 1983-84 (14%) and 1984-85 (43%). Recent virologic and pathologic studies suggest that this encephalitis may be caused by direct LAV/HTLV-III infection of the central nervous system (CNS). Cytomegalovirus encephalomyelitis and toxoplasmosis were the most common opportunistic infections (26% and 10%, respectively). Progressive multifocal leukoencephalopathy, herpes simplex ventriculitis, varicella-zoster leukoencephalitis and fungal infections were infrequent (less than 3% each). A nonspecific encephalitis with microglial nodules and with mild white matter changes occurred in 17%, vacuolar myelopathy in 29% and CNS lymphoma in 6%. Less than 20% of patients had either normal brains or terminal metabolic encephalopathies. This survey shows that neuropathologic complications of AIDS are frequent. Infections are the most common complication and are caused by probable LAV/HTLV-III infection, or by opportunistic organisms.     

Decrease in nerve fibres in cerebral white matter in progressive subcortical vascular encephalopathy of binswanger type

Summary To study white matter changes in the frontal lobes and to investigate the histopathological basis for the dementia in progressive subcortical vascular encephalopathy (PSVE), the frontal white matter was examined by electron microscopy in seven cases with PSVE, and compared with that in a control group and in cases with senile dementia of Alzheimer's type (SDAT). The number of nerve fibres per unit selected area of the white matter was significantly less in PSVE compared with that in the control group or in SDAT. Nerve fibres in PSVE had a tendency to have thinner myelin sheaths than in the control group or in SDAT, but the difference was not significant. The pallor of the frontal white matter in PSVE is mainly based on the loss of nerve fibres, and may be in part based on the thin myelin sheaths. The dementia in PSVE is probably related to the loss of nerve fibres in the cerebral white matter.This work was supported in part by a Research Grant for Cardiovascular Diseases (A62-2) from the Ministry of Health and Welfare, Japan     

甲基维生素B12对拟血管性痴呆大鼠记忆功能及脑白质病理变化的影响

目的 观察甲基维生素B12对拟血管性痴呆大鼠记忆功能及脑白质病理变化的影响。方法 反复前脑缺血制备大鼠拟血管性痴呆模型，造模后甲基维生素B12治疗1周、2周、4周时Morris水迷宫检测大鼠学习记忆功能、LFB染色观察白质髓鞘变化、电镜下观察少突胶质细胞、髓鞘超微结构，并与假手术组及对照组对比。结果 治疗4周大鼠游迷宫时间明显短于对照组，造模2周、4周时LFB染色均可见白质髓鞘脱失，但治疗组明显较对照组轻。造模4周电镜下少突胶质细胞、髓鞘改变治疗组轻于对照组。结论 甲基维生素B12能改善拟血管性痴呆大鼠记忆功能，并能减轻脑白质病理变化。     

Quantitation of human immunodeficiency virus in brains of demented and nondemented patients with acquired immunodeficiency syndrome

We measured human immunodeficiency virus (HIV) DNA in brains of 15 patients who died with acquired immunodeficiency syndrome (AIDS). All had been followed prospectively prior to death; 7 were demented and 8 were not demented. HIV was detected in 13 of 15 brains by polymerase chain reaction (PCR) and in the remaining 2 by presence of viral RNA or viral antigen. Quantitative PCR showed a wide range in amounts of HIV DNA with no significant difference between brains of demented and nondemented patients. These results suggest that qualitative features of the virus, rather than increased virus load per se, may be responsible for the clinical differences between HIV-infected patients with and without dementia.     

Morphological spectrum, distribution and clinical correlation of white matter lesions in AIDS brains

This paper analyses the histopathological characteristics and the topographical distribution of 'pure' HIV-associated white matter lesions of the brain in 18 AIDS patients at autopsy; it includes a time-controlled correlation of neuropathology to clinical staging of the AIDS dementia complex. Three distinct lesion types can be delineated: 1 Vacuolar myelin damage (n = 15) in the hemispheric and interhemispheric white matter, in projection fibre tracts, and in intracerebral segments of cranial nerves III, VII, and VIII; 2 Angiocentric foci (n = 14), disseminated randomly in the white matter; 3 HIV leukoencephalopathy (n = 14), as previously defined, seen predominantly in the hemispheric white matter. As a sole lesion type, HIV leukoencephalopathy is found in two cases, while vacuolar myelin damage and angiocentric foci always occur in combination with one or both other types of pathology. Patients with advanced AIDS-dementia complex consistently show severe and combined white matter pathologies at autopsy. We conclude that, in addition to the previously defined features of diffuse HIV leukoencephalopathy, vacuolar myelin damage and angiocentric foci are significant and frequent components of white matter pathology in AIDS autopsies. This reflects the multitude of pathogenetic factors which co-operate in damaging the brain in AIDS. The advanced AIDS dementia complex correlates with the combined and severe white matter lesions.     

Programmed cell death in brains of HIV-1-positive AIDS and pre-AIDS patients

Neuropathological studies have revealed that the brains of HIV-1-infected AIDS patients show the typical encephalitis and, in addition, neuronal loss. More recently, this neuronal cell loss has been thought to take place via programmed cell death (apoptosis) which has been demonstrated by an in situ end labelling (ISEL) technique. In this study 54 brains of HIV-1-positive patients were investigated by the ISEL technique to investigate whether apoptosis is also present in the brains of patients at the asymptomatic stage. Of these, 10 patients suffered from HIV encephalitis (HIVE), 8 had AIDS without neuropathological disorders and 36 were HIV-1-positive pre-AIDS patients. Apoptotic cells were detected in 6 of the 10 HIVE, 1 of the 8 AIDS without central nervous system (CNS) disease and 4 of the 36 asymptomatic individuals. A difference seen between the AIDS and pre-AIDS cases was that, in the latter, apoptotic cells were found in the white matter in all 4 cases, while only 2 of these 4 showed apoptotic neurons. The presence of apoptotic cells in a number, albeit small, of brains of HIV-1-positive pre-AIDS individuals, combined with abnormalities described previously in the same group of patients gives further support to the opinion that brain damage already occurs during the early stages of HIV infection. Received: 19 June 1995 / Revised: 31 July 1995 / Accepted: 6 September 1995