Posterior cortical brain dysfunction in cognitively impaired patients with Parkinson's disease--a rCBF scintigraphy study

Objectives –  The aim of the study was to visualize cortical function in Parkinson's patients with various degrees of cognitive impairment.
Materials and methods –  Thirty-seven patients with Parkinson's disease and three with Parkinson plus syndromes underwent cognitive assessment and rCBF using ^99mTC-HMPAO-SPECT.
Results –  Almost no regional reductions in cerebral blood flow were seen in patients without cognitive impairment ( n  = 16). Limited, mainly posterior, blood flow reductions were seen in patients with mild cognitive impairment ( n  = 14), whereas the reductions were extensive and bilaterally symmetric, involving both anterior and posterior brain regions in patients with dementia ( n  = 10).
Conclusions –  The findings suggest a widespread cortical, mainly posterior type of dysfunction and a relationship between the degree of cognitive impairment and the magnitude of the dysfunction.     

Altered levels of microtubule proteins in brains of Alzheimer's disease patients

Summary The amount of microtubule protein present in the total soluble protein from brains of Alzheimer's disease patients and from brains of non-Alzheimer age-matched controls, were determined by radioimmunoassay. No differences were found in the amount of tubulin or microtubule-associated protein MAP2 present in either group. However, the amount of tau protein or MAP1 from the brains of Alzheimer's disease patients was about half of that present in their control counterparts.Supported by Grants from the Comisión Asesora para el Desarrollo Tecnológico y Científico and Fondo de Investigaciones Sanitarias     

The topographic distribution of brain atrophy in cortical Lewy body disease: comparison with Alzheimer's disease

The topographic distribution of brain atrophy was quantified by image analysis of fixed coronal brain slices from four patients dying with cortical Lewy body disease (CLBD) all with Alzheimer-type pathology and compared to that in four other patients of similar age and gender dying with Alzheimer's disease (AD) alone. The pattern of atrophy in CLBD (+AD) was broadly similar to that in AD alone, suggesting that tissue loss was due mostly to parallel Alzheimer-type pathological changes and that the presence of Lewy bodies in cortical and subcortical neurones contributed little, if anything, to the overall degree of atrophy.     

Nocturnal sleep EEG in patients with HIV infection

Summary Nocturnal sleep was studied in 14 human immunodeficiency virus (HIV)-positive patients without opportunistic infections of the central nervous system. Seven patients had no bodily complaints at the time of the investigation. Patients exhibited an impaired nocturnal sleep with longer sleep onset latency, reduced total sleep time, reduced sleep efficiency, and more time spent awake and in stage 1. Stage 2 sleep was significantly decreased; in 2 cases, sleep spindle density was extremely low. REM latency was reduced and correlated negatively with depressive symptomatology, while the percentages of REM and slow wave sleep were normal. No significant differences in sleep parameters were present among patients in different stages of the illness, or between patients with and without bodily complaints. Ventricular size and sulcal width on computed tomography scans correlated with sleep variables indicating reduced sleep quality, and with REM density. Decreased tryptophan plasma levels were associated with shorter and less efficient sleep, and with reduced stage 2 sleep. The findings demonstrate that sleep EEG investigations can be valuable for detecting and monitoring central nervous system affection in HIV-positive individuals.This study was presented in part at the 10th Congress of the European Sleep Research Society, Strasbourg, France, 20–25 May 1990     

Alterations of nocturnal sleep in patients with HIV infection

Nocturnal sleep of 14 patients with HIV infection was characterized by longer sleep onset latency, shorter total sleep time, reduced sleep efficiency, more time spent awake and in Stage 1. There was significantly less sleep Stage 2 than in healthy controls. REM latency was slightly reduced and correlated negatively with depressive symptomatology, while percentages of REM and slow wave sleep were normal. Patients without complaints at the time of the investigation exhibited similar sleep abnormalities. The results stress the usefulness of polysomnography as a sensitive methodology for detection and monitoring of CNS affection in HIV positive patients.     

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

Aims: Microglia are involved in neurodegeneration, are prime targets for anti-inflammatory therapy and are potential biomarkers of disease progression. For example, positron emission tomography imaging employing radioligands for the mitochondrial translocator protein of 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) is being scrutinized to detect neuroinflammation in various diseases. TSPO is presumably present in activated microglia, but may be present in other neural cells. Methods: We sought to elucidate the protein expression in normal human central nervous system, several neurological diseases (HIV encephalitis, Alzheimer's disease, multiple sclerosis and stroke) and simian immunodeficiency virus encephalitis by performing immunohistochemistry with two anti-TSPO antibodies. Results: Although the overall parenchymal staining was minimal in normal brain, endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells were TSPO-positive. In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection. Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurones. Quantitative analysis demonstrated a significant increase in TSPO in the white matter of HIV encephalitis compared with brains without encephalitis. TSPO expression was also increased in simian immunodeficiency virus encephalitis. Conclusions: This report provides the first comprehensive immunohistochemical analysis of the expression of TSPO. The results are useful for informing the usage of positron emission tomography as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.     

Association of amyloid P component with complement proteins in neurologically diseased brain tissue

Amyloid P component (AP) was detected in a number of lesions in human brain associated with chronic degenerative disease. These lesions included diffuse and consolidated amyloid deposits, cerebral amyloid angiopathy, neurofibrillary tangles, neuropil threads and complement activated oligodendroglia. The staining for AP generally paralleled that for complement proteins C4d and C3d, suggesting that AP may serve as an adjuvant for phagocytosis.     

Analysis of oligoclonal antibody bands against individual HIV structural proteins in the CSF of patients infected with HIV

Summary Intrathecal antibody responses to HIV were investigated by a highly sensitive immunoblot assay. Serum and CSF specimens were tested for reactivity with the recombinant HIV gag proteins p15, p17 and p24 and with the recombinant transmembrane protein p41. Autochthonous production of virus-specific IgG to one or more HIV structural proteins was seen in 8 of 10 asymptomatic seropositive subjects, in 3 of 4 men with AIDS-related complex, and in 9 of 13 patients with AIDS. These results were consonant with an elevated CSF/serum antibody ratio to total HIV antigen. The high frequency of local HIV-specific antibody synthesis in seropositive individuals without related clinical symptoms indicates an early involvement of the CNS in HIV infections.     

Neuronal apoptosis in HIV infection in adults

Productive infection of the central nervous system by HIV predominantly involves the white matter and basal ganglia. Involvement of the cerebral cortex with neuronal loss is also described in AIDS patients but not in asymptomatic HIV-positive patients. The mechanism of neuronal damage is unknown. To enquire whether neuronal loss in AIDS may be due to an apoptotic process, we examined the cerebral cortex from 12 patients who died from AIDS using two different methods: in situ end labelling and gel electrophoresis of DNA to demonstrate DNA fragmentation. None of the patients had cerebral opportunistic infection or tumour. Four patients had no significant neuropathological changes, eight patients had variable cerebral atrophy and four of them also had productive HIV infection of the brain. These patients were compared with four HIV-positive asymptomatic patients, five seronegative asymptomatic controls, and two seronegative patients with Alzheimer's disease. We demonstrated neuronal apoptosis in the cortex in all AIDS patients, as well as in the Alzheimer's patients. Apoptosis was not observed in the asymptomatic cases whether seropositive or seronegative. Neuronal apoptosis was more severe in atrophic brains, and did not directly correlate with productive HIV infection, suggesting an indirect mechanism of neuronal damage is most likely.     

Myelin basic protein in the cerebrospinal fluid of patients infected with HIV

Summary The major pathological abnormalities of HIV encephalopathy are infiltrates of macrophages, multinucleated giant cells, microglial nodules and demyelination. Elevated myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) provide a marker for central nervous system demyelination. The purpose of this study was to investigate the possible role of CSF MBP as a useful and early marker for HIV encephalopathy. The CSF of 40 consecutive patients with HIV infection of various clinical stages was investigated, including 13 patients with clinical signs of HIV encephalopathy. CSF MBP was elevated in 2 patients (5.0 and 5.3 ng/ml), both of whom had moderate to severe HIV encephalopathy. The course of the disease was rapid in both patients. In the remaining 38 patients, CSF MBP levels were marginally elevated (n=12) or normal (n=26). Our results suggest that CSF MBP is not a sensitive marker for the diagnosis and evaluation of HIV encephalopathy, but may be an indicator of prognosis for the course of the disease. There were only few findings of elevated CSF MBP levels in patients with HIV encephalopathy in the current study, and this may be because the disorder progressed slowly in most patients. It is possible that CSF MBP levels in HIV encephalopathy may only be elevated with acute clinical deterioration but are normal in slowly progressive forms of demyelination, as seen in multiple sclerosis.     

Analyses of energy metabolism and mitochondrial genome in post-mortem brain from patients with Alzheimer's disease

Biochemical and mitochondrial DNA analyses were performed in post-mortem brain tissue from seven patients with dementia of Alzheimer's type and age- and sex-matched controls. We analysed all complexes of the respiratory chain in four regions, i.e. temporal, parietal, entorhinal cortex and hippocampus. Although enzymes representing complex II, III and IV were reduced in activity, succinate cytochrome c reductase was significantly reduced only in the parietal and temporal cortex. However, Southern blot analyses with two restriction enzymes excluded any deletions larger than 500 by in parietal and entorhinal cortex. It is concluded that there seems to be no specific respiratory chain defect in Alzheimer's disease.     

Increased GFAp levels in CSF as a marker of organicity in patients with Alzheimer's disease and other types of irreversible chronic organic brain syndrome

Summary Glial fibrillary acidic protein (GFAp), an astrocyte-specific protein, was determined in cerebrospinal fluid (CSF) of adults and children with global cognitive dysfunction. In children CSF-GFAp values were not closely associated with organic brain disease. However, GFAp values in CSF were increased in 65 of 121 samples of adults with dementia, independent of its cause. GFAp values were not correlated with the severity of the dementia. Increaed levels in the CSF are believed to indicate reactive gliosis in most patients with dementia, whereas GFAp levels in encephalitic patients normalize after clinical recovery.     

Expression of proinflammatory cytokines and its relationship with virus infection in the brain of macaques inoculated with macrophage‐tropic simian immunodeficiency virus

The pathogenesis of acquired immunodeficiency syndrome dementia complex (ADC) is still poorly understood. Many studies suggest that proinflammatory cytokines such as IL‐1β and TNF‐α released by microglia/macrophages or astrocytes play a role in CNS injury. A microscopic finding of a microglial nodule with multinucleated giant cells (MNGCs) is a histopathologic hallmark of ADC and named HIV encephalitis. However, in vivo expression of these cytokines in this microenvironment of HIV encephalitis is not yet clarified. One of the main reasons is complexities of brain pathology in patients who have died from terminal AIDS. In this study, we infected two macaques with macrophage‐tropic Simian immunodeficiency virus SIV239env/MERT and examined expression of TNF‐α and IL‐1β in inflammatory lesions with MNGCs and its relation to virus‐infected cells using immunohistochemistry. One macaque showed typical inflammatory lesions with MNGCs in the frontal white matter. Small microglial nodules were also detected in the basal ganglia and the spinal cord. SIVenv positive cells were detected mainly in inflammatory lesions, and seemed to be microglia/macrophages and MNGCs based on their morphology. Expression of IL‐1β and TNF‐α were detected in the inflammatory lesions with MNGCs, and these positive cells were found to be negative for SIVenv by double‐labeling immunohistochemistry or immunohistochemistry of serial sections. There were a few TNF‐α positive cells and almost no IL‐1β positive cells in the area other than inflammatory lesions. Another macaque showed scattered CD3+ cells and CD68+ cells in the perivascular regions of the white matter. SIVenv and TNF‐α was demonstrated in a few perivascular macrophages. These findings indicate that virus‐infected microglia/macrophages do not always express IL‐1β and TNF‐α, which suggests an indirect role of HIV‐1‐infected cells in cytokine‐mediated pathogenesis of ADC. Our macaque model for human ADC may be useful for better understanding of its pathogenesis.     

C-reactive protein and depression in persons with Human Immunodeficiency Virus infection: The Positive Living with HIV (POLH) Study

BackgroundHuman Immunodeficiency Virus (HIV) infection has been frequently associated with chronic inflammation as well as depression. C-reactive protein (CRP) is positively associated with depression in people without HIV infection. We tested the hypothesis of an independent relationship between CRP and depression in a cohort of HIV-positive people.MethodsA cross-sectional survey was conducted among 316 HIV-positive people (181 men and 135 women) aged 18–60 years residing in the Kathmandu Valley, Nepal. The latex agglutination turbidimetric method was used to measure serum CRP concentrations and the Beck Depression Inventory (BDI)-I method was used to measure depression, with a cut off of ⩾20 indicating likely depression. The relationship between CRP concentrations and depression symptoms was assessed using both multiple linear regression analysis and multiple logistic regression analysis, with adjustment for potential socio-demographic, cardiovascular, life-style, and HIV-related clinical and treatment confounding factors.ResultsTwenty-six percent participants (men: 23%; women: 29%) met criteria for depression. In multiple regression analysis, the authors observed a linear relation between serum CRP concentrations and BDI score (beta for 1 unit change in ln(CRP) = 1.13, p = 0.001) in HIV-positive participants. In a logistic regression analysis, participants with serum CRP levels > 3 mg/L had a 2.3-fold higher odds of depression symptoms compared to those with serum CRP level ⩽ 3 mg/L (p = 0.005). In analyses stratified by sex, associations were stronger in men than in women. For example, CRP > 3 mg/L was associated with a 3.6-fold higher odds of depression in men (p = 0.002), while in women the odds ratio was 1.7 (p = 0.33).ConclusionWe found a linear relationship between serum CRP concentrations and depression symptoms score in HIV-positive people, and evidence that risk of depression is elevated among HIV-positive men with a high level of inflammation (CRP > 3 mg/L). Further prospective study to confirm the role of inflammation in depression among HIV-positive people is warranted.     

Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains

The small heat shock protein family (sHsp) comprises molecular chaperones able to interact with incorrectly folded proteins. Alzheimer's disease (AD) is characterized by pathological lesions such as senile plaques (SPs), cerebral amyloid angiopathy (CAA) and neurofibrillary tangles (NFTs), predominantly consisting of the incorrectly folded proteins amyloid-beta (Abeta) and tau respectively. The aim of this study was to investigate the association of the chaperones Hsp20, HspB2, alphaB-crystallin and Hsp27 with the pathological lesions of AD brains. For this purpose, a panel of well-characterized antibodies directed against these sHsps was used in immunohistochemistry and immunoblotting. We observed extracellular expression of Hsp20, Hsp27 and HspB2 in classic SPs, and Hsp20 expression in diffuse SPs. In addition, extracellular expression of HspB2 was observed in CAA. Both Hsp27 and alphaB-crystallin were also observed in astrocytes associated with both SPs and CAA. Furthermore, none of the sHsps were observed in NFTs in AD brains. We conclude that specific sHsp species may be involved in the pathogenesis of either SPs or CAA in AD.     

Inositol levels in post mortem brain samples of Alzheimer''s patients

1. 1. Free inositol levels in occipital and parietal cortex of Alzheimer's Disease (AD) patients were reported to be significantly elevated by 10–35% compared with matched controls, studied by magnetic resonance spectroscopy (MRS) during life.

2. 2. An MRS study of post mortem samples failed to demonstrate a significant difference between AD and controls.

3. 3. The present study shows non-significant trends of 13% increase in frontal cortex and 5% and 21% decrease in occipital cortex and cerebellum respectively, in post mortem brain specimens of AD patients measured gas chromatographically (GC).

     

The spectrum of changes on 20 nerve biopsies in patients with HIV infection

Nerve and muscle biopsies were performed on 20 patients with HIV infection and peripheral neuropathy. Nine patients had distal symmetrical peripheral neuropathy (DSPN) (six ARC and three AIDS), six had inflammatory demyelinating polyneuropathy (IDP) (three ARC, one AIDS, and two otherwise asymptomatic patients), one had mononeuropathy multiplex (MM) (AIDS), 1 had mononeuropathy (ARC), one had meningoradiculitis (AIDS), and two had areflexia-associated lymphocytic meningitides (ARC), DSPN exhibited axonal degeneration in four of nine cases and was associated with segmental demyelination in five of nine cases. IDP exhibited segmental demyelination associated with axonal degeneration in four of six cases. Demyelination was more frequent in asymptomatic patients (2 of 2 cases) and in ARC (7 of 12 cases), whereas axonal degeneration was predominant in AIDS (6 of 6 cases). Mononuclear cell infiltration was seen in 1 of 2 asymptomatic patients and in 11 of 12 ARC patients but was exceptionally found in AIDS (1 of 6 cases). Involvement of the walls of small vessels, mostly venules ("subacute microvasculitis"), was found in 1 of 2 asymptomatic patients, in 8 of 12 ARC patients, and never in AIDS. The polyclonal mononuclear cell population was composed mainly of Leu 2 (T8) positive cells in seven cases of ARC. No virions were seen in electron microscopy. HIV was isolated in two cases from the CSF or the nerve biopsy.     

Rab6 is increased in Alzheimer's disease brain and correlates with endoplasmic reticulum stress

Alzheimer's disease (AD) is characterized by deposits of aggregated proteins. Accumulation of aggregation-prone proteins activates protein quality control mechanisms, such as the unfolded protein response (UPR) in the endoplasmic reticulum (ER). We previously reported upregulation of the UPR marker BiP in AD brain. In this study, we investigated the small GTPase Rab6, which is involved in retrograde Golgi-ER trafficking and may function as a post-ER quality control system. Using immunohistochemistry and semiquantitative Western blotting, the expression of Rab6 was analysed in hippocampus, entorhinal and temporal cortex of 10 AD patients and six nondemented control subjects. Rab6 is upregulated in AD temporal cortex from Braak stage 3/4, the same stage that UPR activation is found. We observe increased neuronal Rab6 immunoreactivity in all brain areas examined. Although some neurones show colocalization of immunoreactivity for Rab6 and hyperphosphorylated tau, strong Rab6 staining does not colocalize with tangles. We find a highly significant correlation between the Rab6 and BiP levels. In vitro data show that Rab6 is not upregulated as a result of UPR activation or proteasome inhibition indicating an independent regulatory mechanism. Our data suggest that ER and post-ER protein quality control mechanisms are activated early in the pathology of AD.     

病毒性脑炎患者脑血管造影的改变

目的探讨病毒性脑炎患者脑血管造影的改变。方法应用数字减影血管造影(DSA)系统对5例单纯疱疹病毒性脑炎和2例Epstein-Barr病毒性脑炎患者进行全脑血管造影检查,并与对照组(10例头痛患者)进行比较。结果病毒性脑炎患者DSA检查均异常,表现为“激惹”式血循环速度明显加快,整个脑动静脉循环时间平均6.71s,而对照组DSA检查均正常,整个脑动静脉循环时间为10.25s,两组比较差异有显著性(P<0.05)。结论病毒性脑炎的脑血管造影检查可见脑血循环速度明显加快,其对病毒性脑炎的诊断有一定价值。     

In vivo synthesis of phosphatidylcholine in rat brain via the phospholipid methylation pathway

We examined the in vivo synthesis of brain phosphatidylcholine (PC) by the methylation of phosphatidylethanolamine (PE). [3H-methyl]methionine was infused i.c.v., by indwelling cannula, and brain samples were taken 0.5-18 h thereafter and assayed for [3H]PC, as well as for its biosynthetic intermediates [3H]phosphatidylmonomethylethanolamine ([3H]PMME) and [3H]phosphatidyldimethylethanolamine ([3H]PDME), and for [3H]lysophosphatidylcholine ([3H]LPC) and S-[3H]adenosylmethionine ([3H]SAM). Most of the [3H]PC (79-94%) was present ipsilateral to the infusion site, indicating that the radioactivity in the [3H]PC was primarily of intracerebral origin, and not taken up from the blood. Moreover, only very low levels of [3H]PC were attained in brains of animals receiving [3H]methionine i.p. and these levels were symmetrically distributed. [3H]PMME and [3H]PDME turned over with apparent half-lives of 2.2 h and 2.4 h. In contrast, the accumulation of brain [3H]PC was biphasic, suggesting the existence of two pools, the more labile of which turned over rapidly (t1/2 = 5 h) and was formed for as long as [3H]PMME and [3H]PDME are present in the brain, and another, which was distinguishable only at 18 h after the [3H]methionine infusion. (The latter pool may have been synthesized from [3H]choline that was released via the hydrolysis of some of the brain [3H]PC previously formed by the methylation of PE.) Subcellular fractionation of brain tissue obtained after in vivo labelling with [3H]methionine revealed that mitochondrial PC had the highest specific radioactivity (dpm per mumol total lipid phosphorus), and myelin the least. These observations affirm that rat brain does synthesize PC in vivo by methylating PE, and the technique provides an experimental system which may be useful for examining the physiological regulation of this process.