I. Elovaara

CSF in Alzheimer's disease. Studies on blood-brain barrier function and intrathecal protein synthesis

Serum and cerebrospinal fluid (CSF) from 22 ambulatory and 10 institutionalised patients with Alzheimers disease (AD) and 22 age-matched controls were assayed nephelometrically for concentrations of IgG, IgA, IgM, haptoglobin, transferrin, prealbumin and albumin. The CSF/serum ratio and index were calculated for each protein. In the CSF of ambulatory patients IgG, transferrin and albumin were elevated while the institutionalised patients had higher IgG and IgA levels compared to the controls. The CSF haptoglobin was elevated in institutionalised AD patients compared to those who were ambulatory. The CSF/serum ratio for albumin was elevated in both groups. An increase in the IgG ratio was also found in both groups. The ratios for haptoglobin and prealbumin were markedly increased in the institutionalised patients. CSF indices gave no evidence for increased intrathecal synthesis of any of the proteins investigated. The increased CSF/serum ratios for IgG and albumin and also the higher CSF albumin in patients with AD suggest an increased blood-brain barrier permeability in this disease. The high prealbumin ratio may be related to amyloidogenesis often present in AD.

Cognitive changes as early signs of HIV infection

ABSTRACT‐ Neuropsychological examination was performed on 13 patients and 10 matched controls to assess the brain involvement of patients with human immunodeficiency virus (HIV) infection. HIV‐infected patients showed a significant decline in visuomotor, visuoconstructive and practical abilities as well as in motorfree visuospatial performance and repeating a long sentence. These findings could not be explained by the concomitant mental depression of these patients. Neither were they associated with any particular stage of HIV infection. The results suggest that mild cognitive changes may be detected even in the early stages of HIV infection, when examined by appropriate neuropsychological methods.

Radiological study of the brain at various stages of human immunodeficiency virus infection: early development of brain atrophy

SummaryOne hundred and one persons infected with human immunodeficiency virus (HIV-1), in whom other central nervous system infections or diseases were excluded, underwent brain CT and/or MRI at various stages of HIV-1 infection: 29 were asymptomatic (ASX), 35 had lymphadenopathy syndrome (LAS), 17 had AIDS-related complex (ARC), and 20 had AIDS. A control group of 32 HIV-1-seronegative healthy persons underwent brain MRI. The most common finding was brain atrophy, found in 9% of controls, and 31% of ASX cases, 29% of LAS, 59% of ARC and 70% of AIDS. Even the difference between the ASX or LAS groups and controls was significant. The changes were bilateral and symmetrical, and they were more severe at later stages of infection. Infratentorial atrophy was seen in the early stages; supratentorial atrophy became more pronounced at ARC, and generalized atrophy was typical of AIDS. Non-specific small hyperintense foci were found on MRI in 13% of controls and 6–15% of the infected groups. Larger, diffuse, bilateral white matter infiltrates were detected in 4 demented patients with AIDS. Four patients with AIDS and 1 with LAS had focal hyperintense lesions in the internal capsules, lentiform nuclei or thalamus, often bilateral on MRI. One patient with AIDS, examined with CT only, had low density in the lentiform nucleus. Loss of brain parenchyma can occur at an early stage of HIV-1 infection, and the atrophic process becomes more intense at later stages (ARC and AIDS). Parenchymal infiltration, seen as hyperintense areas on MRI, is most often associated with severe clinical symptoms, in the later stages of the disease.

Serum and Cerebrospinal Fluid Proteins and the Blood-Brain Barrier in Alzheimer’s Disease and Multi-Infarct Dementia

Serum concentrations of IgG, IgA, IgM, haptoglobin, transferrin, prealbumin and albumin quantitated nephelometrically in 22 patients with Alzheimers disease (AD), 29 patients with multi-infarct dementia (MID) and their age-matched controls were normal. Cerebrospinal fluid (CSF) albumin and CSF/serum ratio for albumin were higher in AD and MID patients compared to controls, but no significant differences were found between AD and MID. Patients with MID had elevated CSF IgG, IgA, IgM and prealbumin levels compared to controls and to AD. An increased CSF IgG index was found in 5 MID patients but none of the AD patients. Thus, the blood-brain barrier permeability is often increased in MID as well as in AD. There is no increased intrathecal IgG synthesis in AD but it may occur in MID.

Cognitive performance in HIV‐1 infection: relationship to severity of disease and brain atrophy

We examined cognitive performance in 72 HIV‐1 infected patients and 34 controls. None of the patients had opportunistic infections or unusual neoplasms of the central nervous system (CNS). Factors other than HIV‐1 known to cause cognitive decline were excluded from both groups. Cognitive functioning analysed with special emphasis on the severity of HIV infection was related to neuroradiological and immunological findings. In patients with AIDS‐related complex (CDC IVa) or AIDS (CDC IVc,d), a deterioration of memory as well as cognitive speed and flexibility was detected. Furthermore, memory deficits were associated with central cerebral and infratentorial atrophy in those patients, while no association was found between cognitive deficits and immunological abnormalities. Patients at CDC stages II or III showed slight association between altered cognitive speed and flexibility and elevated leukocyte count, suggesting a subclinical CNS disease already at early stages of HIV infection.

Glial filaments are a major brain fraction in infantile neuronal ceroid-lipofuscinosis

SummaryExtremely severe gliosis develops at the end stage of infantile neuronal ceroid-lipofuscinosis (INCL), a fatal encephalopathy characterized by accumulation of autofluorescent storage material in the brain and other tissues followed by a terminal subtotal neuronal and myelin loss. A major fraction of highly enriched intermediate filaments was obtained with a density gradient centrifugation method from INCL brain tissue, whereas the storage material represented only a minor fraction. SDS-polyacrylamide gel electrophoresis of the filament fraction showed a major protein with molecular weight of 51 kD and three to four polypeptides of 40–48 kD identified as glial fibrillary acidic protein (GFAP) and its degradation products by the immunoblotting technique with monoclonal antibodies against GFAP. Immunization experiments with the isolated INCL glial filament fraction produced antibodies reacting only with GFAP but not with other types of intermediate filament proteins, furthermore indicating a high content of GFAP in the isolated fraction. No significant amounts of vimentin or other types of intermediate filament proteins could be detected. These results document the extremely high content of glial filaments at the terminal stage of INCL and suggest that INCL brain may serve as a good human model for studies on the composition of glial filaments in vivo and on the pathogenesis of gliosis.

CSF and serum β‐2‐microglobulin in HIV infection related to neurological dysfunction

ABSTRACT— Elevated (< 2.2 mg/l) CSF β‐2‐microglobulin (β2m) level was found in 9 of 16 neurologically symptomatic patients but in only 4 of 21 who were neurologically symptom‐free (P < 0.01). Serum β2m concentration was elevated (<2.5 mg/l) in 12 of 16 neurologically symptomatic patients but in only 8 of 21 symptom‐free patients (P < 0.01). When the CSF and serum β2m levels were related to various stages of HIV infection, the highest mean values for both CSF and serum were found in patients with acquired immunodeficiency syndrome (AIDS), followed by lower values in AIDS‐related complex (ARC), lymphadenopathy syndrome (LAS), and asymptomatic seropositive individuals (ASX), in decreasing order of preference. Our results suggest that elevated β2m in CSF and serum is related to the stage of general HIV infection and that elevated CSF β2m in the presence of intact BBB may be useful in evaluating CNS involvement in HIV‐infected patients.

Dementia associated with human immunodeficiency virus: subcortical or cortical?

Two different types of dementia and corresponding neuropathological findings of patients with human immunodeficiency virus (HIV) infection are presented. In one case, “subcortical” dementia with slow movements and mental processes as well as problems in active recall but without focal defects corresponded to diffuse leukoencephalopathy. In another case, “cortical” dementia with impaired abstraction and memory as well as several focal defects corresponded to microglial nodules in cortical and in deep grey matter, with only a mild diffuse leukoencephalopathy. Thus, in contrast to earlier interpretations, subcortical dementia does not appear to be the only form of dementia in HIV‐infected patients, and cortical dysfunction may also occur.

EEG in Early HIV-1 Infection is Characterized by Anterior Dysrhythmicity of Low Maximal Amplitude

We analyzed the EEGs of 67 HIV-1-infected patients at various stages of the disease and of 35 HIV-1-seronegative controls. The most common EEG abnormality in HIV-1 infection was an increased amount of generalized episodic or persistent, predominantly anterior slow activity, associated with a low level of maximal amplitude. When compared to the controls, a lower maximal amplitude of dominant background activity (p less than 0.001), and more marked generalized (p less than 0.01) and anterior (p less than 0.001) disturbances were already seen in early stages of HIV-1 infection. EEG abnormalities were more severe in patients with advanced HIV-1 infection than in those at early infection (p less than 0.001 to p less than 0.05). The presence of a more marked, posteriorly (p less than 0.01) accentuated, generalized slow activity (p = 0.02) was found more often in patients with T-helper cell counts lower than 0.4 x 10(9) (p = 0.05) than in those with higher numbers of T-helper cells. No clear associations were found between the severity of EEG abnormalities and the duration of HIV-1 infection. Our results suggest that EEG is a sensitive method in detecting subclinical functional cerebral disturbances caused by HIV-1.

Immunocytochemical studies of Alzheimer neuronal perikarya with intermediate filament antisera

Isolated neuronal perikarya from the brains of patients with Alzheimers disease were examined in indirect immunofluorescence microscopy with different types of specific antisera against the subunit proteins of cytoskeletal intermediate filaments. From 30 to 50% of the neurofibrillary tangles were stained with antisera against each of the neurofilament triplet proteins, but not with antisera against glial fibrillary acidic protein, vimentin, desmin or cytokeratin. Polyacrylamide gel electrophoresis of Alzheimer perikaryal fractions showed polypeptide patterns markedly similar to control neuronal fractions. Our results thus suggest either that the Alzheimer neurofibrillary tangles and the antigenic neurofilament triplet protein fractions may contain related antigenic determinants or that unaffected perikaryal neurofilament material is associated with the tangles.