Cerebrospinal fluid beta-2-microglobulin in multiple sclerosis and AIDS dementia complex

Abstract

Cerebrospinal fluid (CSF) and serum concentrations of beta-2-microglobulin (beta-2-m) were evaluated in 19 patients with clinically definite multiple sclerosis (MS), in 21 with AIDS dementia complex (ADC), and in 20 subjects with other neurological diseases (OND). CSF beta-2-m and CSF/serum beta-2-m ratio were significantly higher in the patients with ADC than in the MS and OND patients. The CSF and serum levels of beta-2-m in MS patients were not significantly different from those of OND patients. These findings indicate that CSF beta-2-m and CSF/serum ratio may be a ‘useful marker in the diagnosis of ADC. In MS patients the beta-2-rjn CSF determinations are of no value.     

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.     

AIDS dementia complex and Hashimoto encephalopathy in a senescent woman

AIDS dementia complex is one of the specific infectious dementias, which is rarely seen in senescent (>75 years of age) subjects. Hashimoto encephalopathy has been described as the cause of several neurological and psychiatric syndromes including dementia. The proposed pathophysiological mechanism is an autoimmune reaction to shared, thyroid gland and CNS epitopes with subsequent cerebral dysfunction. We report here the first case of a patient who fulfils both, the criteria for AIDS dementia complex and Hashimoto encephalopathy, yet being unresponsive to steroid therapy. Diagnostic and therapeutic implications are discussed.     

艾滋病痴呆综合征临床分析

目的研究中国人群艾滋病(AIDS)痴呆综合征(ADC)的特征。方法对上海交通大学附属第一人民医院和上海市传染病医院收治的诊断为ADC的6例AIDS患者进行临床分析。结果所有患者均在清醒状态下表现为近记忆减退及注意力集中困难,其中3例伴有运动障碍。6例ADC患者中2例伴有空泡性脊髓病。诊断为AIDS后,ADC的平均诊断时间为6 5个月。所有患者均死于呼吸衰竭,平均寿命为41 8岁。结论ADC是AIDS患者最常见的神经系统并发症,常发生在AIDS的进展期。ADC通常伴有空泡性脊髓病,预后极差。     

Cerebrospinal fluid analyses in HIV patients: a longitudinal study through six years

The human immunodeficiency virus (HIV) can cause neurological symptoms. It is not known how the the cerebrospinal fluid (CSF) may change during the infection. Thirty-eight neurologically asymptomatic HIV patients with CD4 lymphocyte count > 280 × 10⁶/1, were included in the prospective study. CSF was analysed once a year for cell count, oligoclonal IgG, IgG index and CSF:S albumin ratio. Cell free CSF was cultivated for HIV isolation. At inclusion, at year three and six, the CSF anti-HIV antibody synthesis was measured. HIV-DNA in CSF cells were analysed at inclusion. More than 80% of the patients had abnormal CSF. At consecutive investigations the IgG index and/or CSF:S albumin ratio were unchanged in most of the patients. These findings resemble those seen in MS, neuroborreliosis or neurolues. HIV was isolated in about half of the patients the first four times but in about one-third of them later on. At inclusion, HIV-DNA was found in CSF cells in 95% and intrathecal anti-HIV antibody synthesis in 65% of the patients. The findings did not correlate with the HIV duration, patients' age or the amount of blood CD4 cells. The results speak in favour of the early penetration of HIV in CSF but for its low neurovirulence.     

AIDS dementia complex complicated by cytomegalovirus encephalopathy

We have studied longitudinally ten patients with AIDS encephalopathy with respect to pathogenetic roles of human immunodeficiency virus (HIV) and cytomegalovirus (CMV). Three patients manifested typical AIDS dementia complex (ADC) (initially without retinitis and with slowly progressive cognitive, motor and behavioral abnormalities which were zidovudine-responsive, and relatively preserved CD4 + T cells), and seven patients presented with AIDS dementia complex complicated by CMV encephalopathy (ACE) (with CMV retinitis, peripheral neuropathy, altered sensorium, and rapidly declining clinical and immunological status). Whereas only HIV antibody was elevated in the spinal fluid of patients with ADC, both virus infections were active in the central nervous system of patients with ACE as shown by HIV p24 antigenemia and antigenrrhachia, elevated HIV and CMV antibody in the spinal fluid, disseminated CMV infection with retinitis, and basilar ventriculoencephalitis with multinucleated cytomegalic cells containing CMV and HIV proteins and CMV DNA. The recognition of ADC and ACE is important, since some patients with ACE may respond to ganciclovir or foscarnet.     

Cerebrospinal fluid catecholamine metabolites in HIV-infected patients.

Twenty-eight HIV-seropositive individuals--11 asymptomatic cases, 8 with lymphadenopathy syndrome (LAS), and 9 with AIDS--were investigated. Clinical staging of the AIDS dementia complex was done in the 9 AIDS patients. The catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in CSF were determined in all the HIV patients and in 20 healthy volunteers. The CSF MHPG levels did not differ significantly between healthy subjects and HIV-infected patients at any stage of the infection. The CSF concentrations of HVA differed between the groups only during the AIDS stage. The mean CSF HVA value in the AIDS patients was 42% lower than in the healthy subjects and significantly lower than in any other stage of HIV infection (P less than .01). Patients with signs of the AIDS dementia complex had reduced CSF HVA levels, but there was no clear relationship between HVA concentration and stage of the AIDS dementia complex.     

Cerebrospinal fluid purine metabolites after complex febrile convulsions

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and uric acid were determined in cerebrospinal fluid (CSF) of 15 children after complex febrile seizures (CFS) and in 27 after simple febrile seizures (SFS), and compared with those in a control group of 63 children. There was no statistically significant difference between the groups for any of these metabolites, suggesting that CFS and SFS neither significantly disturb the metabolism of nucleotides, nucleosides or bases nor significantly deplete neuron adenosine triphosphate levels.     

Albumin and immunoglobulin in plasma and cerebrospinal fluid, and blood-cerebrospinal fluid barrier function in patients with dementia of alzheimer type and multi-infarct dementia

Plasma and cerebrospinal fluid (CSF) from 20 patients with Alzheimer's dementia or senile dementia of Alzheimer type (AD/SDAT), 23 with multi-infarct dementia (MID) and 16 controls were assayed for their content of immunoglobulins (Ig) and albumin (Alb). The concentrations of IgG and Alb were used to analyze the blood-CSF barrier function in the respective group.

MID patients had significantly (P < 0.001) elevated plasma IgG levels compared to controls and AD/SDAT patients. CSF concentration of Alb was significantly higher in MID (P < 0.01) and AD/SDAT (P < 0.05) patients compared to the controls. Concentration of CSF IgG was significantly (P < 0.05) lower in AD/SDAT patients compared to the MID patients; no significant differences were found when CSF concentrations of IgG of demented patients were compared to controls. These findings may indicate a blood-CSF barrier dysfunction especially in cases with MID with significantly (P < 0.001) elevated values of transudation. Also these findings indicate a non-specific and/or specific binding of IgG in CNS tissue and/or vessel walls in both forms of dementia on the basis of low IgG ratios compared to proportionally higher Alb ratios.

There were no signs of local synthesis of IgG in CNS in either group of demented patients.     

Intrathecal production of HIV antibodies in suspected AIDS encephalopathy

Summary Thirty-one serum and CSF samples from 21 HIV-antibody-positive patients with neurological deficits were examined to prove or exclude intrathecal production of HIV antibodies. By dilution, sera were adjusted to the IgG concentration of the corresponding CSF samples. Both samples were then serially diluted in log₂ steps down to the detection limit and were tested in an anti-HIV ELISA. From the dilution obtained at the cut-off level, a quotient Q_HIV was derived as an indicator of intrathecal production of HIV antibodies. Six of a total of eight samples with a Q_HIV value of 2 were correlated which the clinical diagnosis of AIDS-related dementia complex (ARDC). However, a Q_HIV less than 1 did not exclude the development of ARDC, as was shown during follow-up in one case. Different methods are compared for the determination of intrathecal production of IgG and anti-HIV. A quotient Q_HIV 2 is suggested to be highly indicative of intrathecal production of anti-HIV as well as of the development of ARDC.     

Inflammatory molecules in Frontotemporal Dementia: Cerebrospinal fluid signature of progranulin mutation carriers

Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean ± SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27 ± 151.5 versus 159.7 ± 49 pg/ml; P ⩽ 0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17 ± 240.0 versus 436.61 ± 202.5 pg/ml; P = 0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18 ± 1.41 versus 35.68 ± 30.5 pg/ml; P = 0.013 and 9.34 ± 5.54 versus 19.15 ± 10.03 pg/ml; P = 0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63 ± 3.30 and 2.58 ± 20 versus 87.57 ± 70 pg/ml, respectively; P < 0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ = 0.48; P = 0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.     

Cerebrospinal fluid investigations in multi-infarct dementia and senile dementia

Thirty-eight demented patients were clinically investigated and classified into a multi-infarct dementia (MID) and senile dementia (SD) group. Total protein, albumin, immunoglobulin G, agar gel electrophoretic protein and iso-electric focusing pattern were determined in CSF and serum as well as the lactate dehydrogenase, LD-iso-enzyme pattern and uric acid. No significant differences were found regarding total protein, albumin and immunoglobulin G. The agar gel electrophoresis showed a tau-globulin increase in 18% of the SD-group against 6% of the MID group. The patterns were, however, plasma-like in 56% of the MID group against 23% of the SD group. The iso-electric focusing pattern showed an abnormal band in some SD-patients which was not found in the MID group. The uric acid and LD-enzyme concentration was equal in both CSF and serum. An index was calculated to give an approximate correction for the influence of different permeability of the blood-brain and CSF barrier. A significantly higher LD-index was found in the SD-group, suggesting a continuous cell degeneration.     

Prevalence of neuropsychological deficit in HIV infection. Incipient signs of AIDS dementia complex in patients with AIDS

The present study attempts to estimate the prevalence of Aids Dementia Complex assessed by neuropsychological testing in Norwegian patients with AIDS using a clinical control group with acute leukemia and an asymptomatic HIV-positive group as reference groups. Newly diagnosed patients with AIDS and not receiving zidovudine or other anti-viral drugs, patients with asymptomatic HIV infection, and newly diagnosed patients with acute leukemia, were studied with a battery of neuropsychological tests. Speeded tests and composite non-verbal measures discriminated significantly between groups. The results indicate higher than 50% prevalence of ADC in newly diagnosed Norwegian patients with AIDS. Our findings indicate that the AIDS population may contain two distinct groups, a subgroup with ADC and a subgroup with persistently normal neuropsychological function. The group with asymptomatic HIV infection showed normal neuropsychological performance.     

抑郁症脑脊液生长抑素的测定

目的： 进一步探讨抑郁症可能的生化病理机制。　方法： 采用非平衡放射免疫测定法（ＲＩＡ） 对符合入组标准的２６ 例抑郁症患者和２０例对照者脑脊液（ＣＳＦ） 中生长抑素（ＳＳ） 含量进行检测。　结果： 抑郁症患者ＣＳＦ中ＳＳ水平（１９．５３±９．４３） ｎｇ／Ｌ明显低于对照组（２８．５７±１６．０３） ｎｇ／Ｌ;抑郁症患者ＣＳＦ中ＳＳ水平与汉密顿抑郁量表（ＨＡＭＤ） 总分呈显著负相关（ｒ＝ － ０．４７９）。　结论： 抑郁症发病与脑ＳＳ水平低下有关。     

Locally synthesized antibodies in cerebrospinal fluid of patients with AIDS

Summary Twelve patients with AIDS were examined by enzyme-linked immunosorbent assay for antibody activity of IgG in serum and CSF. Two patients were only anti-HTLV III antibody carriers (stage I), two had lymphadenopathy syndrome (stage II) and eight had manifest AIDS (stage III). Eight of the 12 patients had 2- to 8-fold higher antibody titres in CSF than in serum, indicating that anti-HTLV III antibodies were produced in the nervous system. One of these patients with obviously locally synthesized anti-HTLV III antibodies in CSF belonged to stage I, two to stage II and five to stage III. Only four of these eight patients also showed locally synthesized IgG in CSF as measured by laser-nephelometry. In contrast, 61 controls with normal CSF (12), impaired blood-CSF barrier (12) multiple sclerosis (12) and various infections of the CNS other than HTLV III (25), the last two groups with locally synthesized IgG in CSF, all revealed negative results. It appears possible that locally synthesized anti-HTLV III antibodies in CSF are a sensitive and early indicator of an HTLV III infection of the nervous system.     

以痴呆为主要表现的麻痹性痴呆、HIV相关性痴呆和克雅病的临床特征分析

目的探讨并分析梅毒所致麻痹性痴呆(麻痹性痴呆)、HIV相关性痴呆和克雅病等中枢系统感染性疾病所致痴呆的临床特征。方法检索19例患者(麻痹性痴呆8例、HIV相关性痴呆6例、克雅病5例)临床资料,回顾分析其临床表现、实验室检查、脑电图、神经影像学及治疗转归特点。结果 3组患者临床表现均以认知损害为主,并广泛累及多系统(锥体系、锥体外系、小脑)及多组脑神经。辅助检查显示,麻痹性痴呆患者快速血浆反应素环状卡片试验和苍白密螺旋体抗体明胶颗粒凝集试验阳性(8例),脑脊液美国性病研究实验室试验阳性(4例),MRI呈现不同程度脑萎缩(6例);HIV相关性痴呆患者血清HIV抗体筛选试验及Western blotting检测阳性(6例),脑脊液平均蛋白定量明显升高(2例)、潘氏试验阳性(2例),MRI以脑内多发占位病变或大片异常密度影为特征;克雅病患者脑脊液Western blotting检测1433蛋白阳性(4例),脑电波呈弥漫性慢波(4例)伴典型三相波(1例),散发型患者MRI脑叶皮质区沟、回呈肿胀样改变(3例),变异型患者可伴丘脑"曲棍球样"改变(1例)。结论麻痹性痴呆、HIV相关性痴呆及克雅病等中枢系统感染性疾病所致痴呆临床表现复杂多样,诊断时应结合患者病史、实验室血清学和脑脊液指标,以及脑电图和神经影像学表现等综合考虑,明确诊断。     

Cerebrospinal fluid endorphins in schizophrenia

Opioid-receptor-active material, endorphins, has been measured in cerebrospinal fluid samples obtained from schizophrenics. A chromatographic procedure isolated the Fraction I endorphin which was quantitated in a receptorassay. At least two cerebrospinal fluid samples were obtained from each patient, at Day 0 with no medication and at Days 30 and 60 after medication with fluphenazine under standardized conditions. Three series of patients were included: acute schizophrenics (n = 11); re-entry schizophrenics (n = 7) who have previously been treated with neuroleptics but were readmitted to hospital usually as a consequence of stopped medication, and chronic schizophrenics (n = 9) who had been without neuroleptics for at least 2 weeks prior to Day 0. At Day 0, 6/9 acute cases, 4/6 of re-entry and 2/9 chronic cases had endorphin levels above the range of healthy volunteers. The levels in chronic cases were significantly lower than those in acute cases. Treatment with neuroleptics significantly lowered the endorphin levels in acute cases. These results confirm and extend previous observations.     

Cerebrospinal fluid levels of tau phosphorylated at threonine 181 in patients with Alzheimer’s disease and vascular dementia

In 31 patients with probable Alzheimer’s disease (AD), 19 with probable vascular dementia (VaD) and 20 with Possible AD and Possible VaD, cerebrospinal fluid (CSF) tau levels hyperphosphorylated at threonine 181 (Ptau) were measured by ELISA. Thirty-six age-matched subjects were used as controls. The severity of the cognitive decline was assessed at the time of CSF analysis and after a 12-month follow-up. The groups had comparable age, degree of cognitive impairment and disease duration; these parameters were not related to P-tau levels. P-tau discriminated between demented patients and controls, but no significant difference emerged between AD and the other groups. By contrast, higher P-tau values were found to predict, independently of the clinical diagnosis, a more rapid evolution of cognitive decline. Whether these findings are due to a lack of CSF P-tau specificity or to the low reliability of clinical and radiological criteria remains unclear. P-tau may be useful in the evaluation of disease evolution, by predicting the rate of cognitive decline.     

Cerebrospinal fluid acetylcholinesterase in patients with dementia associated with schizophrenia or chronic alcoholism

Cerebrospinal fluid (CSF) acetylcholinesterase (AChE) was determined for 11 chronic schizophrenic patients with dementia, 9 patients with dementia associated with alcoholism and 8 age-equivalent control subjects. The AChE levels in both patient groups were unrelated to the degree of cognitive decline and they were in the same range as in the control group. In schizophrenic patients no relationship was found between CSF AChE and the severity of psychotic symptoms. Our results suggest that dementia may occur in these patient groups without CSF AChE involvement.     

脑脊液生物学标志物诊断阿尔茨海默病与血管性痴呆

目的探讨脑脊液β-淀粉样蛋白（Aβ1～42）、tau蛋白和磷酸化tau蛋白诊断阿尔茨海默病与血管性痴呆的敏感性和特异性。方法采用酶联免疫吸附法检测阿尔茨海默病与血管性痴呆患者脑脊液中Aβ1～42、tau蛋白和磷酸化tau蛋白浓度的变化,根据受试者工作特征曲线观察脑脊液中这3种生物学标志物用于诊断阿尔茨海默病与血管性痴呆的敏感性和特异性;采用单因素方差分析以及受试者工作特征曲线对所获结果进行统计学分析。结果阿尔茨海默病组患者脑脊液Aβ1～42浓度低于对照组（P=0.010）,tau蛋白浓度高于对照组（P=0.001）和血管性痴呆组（P=0.030）,磷酸化tau蛋白浓度高于对照组（P=0.004）。脑脊液Aβ1～42、tau蛋白和磷酸化tau蛋白用于诊断阿尔茨海默病的敏感度为60.00%～96.70%,特异度可达70.00%～90.00%。Aβ1～42、tau蛋白和磷酸化tau蛋白联合检测可提高阿尔茨海默病与血管性痴呆鉴别诊断的敏感性和特异性,敏感度可达86.57%,特异度为90.00%。结论脑脊液Aβ1～42、tau蛋白和磷酸化tau蛋白浓度的变化,不仅对诊断阿尔茨海默病具有较高的敏感性和特异性,而且亦可作为阿尔茨海默病与血管性痴呆鉴别诊断的生物学指标。