Concentration of monoamines and their metabolites in the cerebrospinal fluid from patients with senile dementia of the Alzheimer type and vascular dementia of the Binswanger type

Summary We measured the concentrations of total (conjugated and unconjugated) monoamines (dopamine, DA; norepinephrine, NE) and monoamine metabolites (homovanillic acid, HVA; 3-methoxy-4-hydroxyphenyleneglycol, MHPG; 5-hydroxyindoleacetic acid, 5-HIAA) in the cerebrospinal fluid (CSF), using HPLC-ECD in 11 patients with Alzheimer's disease (AD) or senile dementia of the Alzheimer type (SDAT), 17 patients with vascular dementia of the Binswanger type (VDBT), and 15 controls. In AD/SDAT, there was a significant decrease in the DA concentration and a significant increase in the MHPG concentration. The average NE concentration was not altered, but significantly increased with the progression of intellectual disability. There were no significant changes in HVA and 5-HIAA concentrations. Patients with VDBT showed a significant increase in the DA concentration and a significant decrease in HVA and 5-HIAA concentrations. The DA concentrations increased significantly with the progression of dementia and ventricular enlargement. These results indicate that the noradrenergic and dopaminergic system in particular are altered in AD/SDAT, while the dopaminergic and serotonergic systems are mainly involved in VDBT.     

The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the Binswanger type, Alzheimer type dementia, and Parkinson's disease

Summary We determined the urate and xanthine concentrations in the cerebrospinal fluid (CSF) in patients with vascular dementia of the Binswanger type (VDBT), Alzheimer type dementia (ATD), and Parkinson's disease (PD). We found that the urate concentration was significantly increased in VDBT patients, but significantly decreased in ATD patients compared with controls. The ratio of the concentrations of uric acid (U_CSF) to xanthine (X_CSF) in the CSF (U_CSF/X_CSF) had a significant correlation with the ratio of the U_CSF to the urate concentration in serum (U_serum) (U_CSF/U_serum) in ATD and PD, whereas U_CSF/U_serum increased independently of U_CSF/X_CSF in VDBT. We concluded that the significant increase in the urate concentration in VDBT is mainly due to an impairment of the blood-brain barrier (BBB), and its significant reduction in ATD may reflect impaired brain metabolism.     

Indoleamine concentrations in cerebrospinal fluid from patients with Alzheimer type and Binswanger type dementias before and after administration of citalopram, a synthetic serotonin uptake inhibitor

Summary We studied changes in the concentrations of serotonin (5-HT), kynurenine, and other indoleamines in the cerebrospinal fluid of patients with Alzheimer type dementia (ATD) and those with Binswanger type vascular dementia (VDBT), and changes in these indoleamine concentrations 2 weeks after administration of citalopram, a 5-HT uptake inhibitor. The concentrations of total 5-HT (p<0.005) and kynurenine (p<0.005) were significantly decreased in ATD patients in comparison to those of the controls. After citalopram administration, there was a remarkable increase in 5-HT concentration (249%, p<0.0001) and a significant decrease in 5-HIAA concentration (22%, p<0.02). In the VDBT patients, only 5-HT showed a significant decrease (p<0.005) in comparison to the control values. It also increased significantly (214%) after citalopram administration. The 5-HT/tryptophan and kynurenine/tryptophan ratios were not correlated for the controls, but did significantly for the ATD and VDBT patients; after citalopram treatment, the increase in 5-HT/tryptophan was correlated significantly with that of kynurenine/tryptophan for ATD, but not for VDBT. These results suggest that both the serotonin and kynurenine pathways are impaired in ATD; whereas, the serotonin pathway alone is in VDBT, and that these impairments are ameliorated by the administration of citalopram.     

Cerebral perfusion patterns in vascular dementia of Binswanger type compared with senile dementia of Alzheimer type: a SPECT study

Summary Cerebral perfusion patterns in 18 cases with vascular dementia of Binswanger type (VDBT) (8 moderate and 10 severe cases) were compared with 25 cases with senile dementia of Alzheimer type (SDAT) (16 moderate and 9 severe cases) and 14 controls by single photon emission computed tomography usingN-isopropyl-p-¹²³I iodoamphetamine (IMP) as a tracer. The cerebral: cerebellar IMP uptake ratio (%) (CCR) was used as a measure of relative cerebral perfusion. The CCRs were about 85–90% in all areas in controls. Moderate VDBT patients showed a remarkable decrease of CCRs in the basal grey region (thalamus and basal ganglia) (right 79%, left 77%) and in the frontal area (right 79%, left 80%) (P<0.01). In severe VDBT patients a significant decrease of the CCR was noted in all regions (P<0.01). The decrease of mean CCRs in the hemispheres was significantly correlated with the severity of disease determined by psychometric testing. Patients with SDAT showed a significant decrease of the CCR in the parietal (right 71%, left 74%) and right temporal (78%) areas in the moderate stage (P<0.01), and further progression of dementia was associated with low perfusion areas extending to the frontal areas (78%,P<0.01). These differences in the perfusion patterns and their changes with progression of the illnesses may be reflected in characteristic clinical features.     

Recent advances in dementia research in Japan: Alzheimer-type dementia

In a previous article, recent reports by Japanese researchers on non-Alzheimer-type degenerative dementias were reviewed. In the present article, recent Japanese reports on Alzheimer-type dementia (ATD) are reviewed. Alzheimer-type dementia has received great attention and has been studied from various viewpoints in Japan as well as in Europe and the Americas. In Japan, although it was believed that vascular dementia was the most frequent dementia in the elderly, ATD has recently been shown to be the most predominant type of dementia. Such a great number of papers on ATD have been reported in Japan that mainly the clinical, neuropathological, biochemical and molecular biological research papers alone are reviewed here.     

Intrathecal synthesis of immunoglobulin G in vascular dementia

Serum and CSF from 53 vascular dementia (VD) patients and 50 controls were analysed to investigate the possibility of an intrathecal synthesis of IgG, defined as an elevated IgG index (greater than or equal to 7) and/or presence of oligoclonal IgG in cerebrospinal fluid (CSF), but not in serum. Five (9%) patients and no controls exhibited an intrathecal synthesis of IgG. The IgG index increased with the degree of dementia (p less than 0.05). It was positively related to presence/absence of hypertension (p less than 0.05) and correlated positively with diastolic blood pressure (p less than 0.05). The findings suggest that immunological factors might be involved in the pathogenesis of VD.     

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.     

Regional differences in diffusion abnormality in cerebral white matter lesions in patients with vascular dementia of the Binswanger type and Alzheimer''s disease

We investigated changes in water diffusion in the cerebral white matter of 14 patients with vascular dementia of the Binswanger type (VDBT) and ten patients with Alzheimer's disease (AD) with periventricular hyperintensity (PVH) lesions using diffusion-weighted magnetic resonance imaging (MRI) and studied the pathophysiological differences between white matter lesions found in these two conditions. Apparent diffusion coefficients (ADCs) in the anterior and posterior white matter and the genu and splenium of the corpus callosum were significantly higher in both groups of patients than in the 12 age-matched controls, and ADC values in VDBT and AD groups were almost the same. ADC ratios, defined as diffusion restricted perpendicular to the direction of nerve fibers, were also significantly higher in the patients than in the control subjects. However, there were regional differences in ADC ratios in the two conditions, with ratios in VDBT being higher in the anterior portions of the white matter but ratios in AD were higher in the posterior portions. The diffusion-weighted MRI technique may be useful in the differential diagnosis of VDBT and AD with white matter lesions.     

Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's dementia

INTRODUCTION: Cystatin C, a cysteine protease inhibitor, has been implicated in the neurodegenerative and repair processes of the nervous system, and the deposition of the same protein together with beta amyloid peptide was found as cerebral amyloid angiopathy (CAA) in different types of dementias. OBJECTIVE AND METHODS: Because of the differential diagnostic importance, serum and cerebrospinal fluid (CSF) cystatin C levels of 24 late onset Alzheimer's demented (AD) and 16 ischemic type of vascular demented (VD) probands were compared with 17 aged control (AC) persons. RESULTS: The serum and CSF cystatin levels were found in the normal range in all groups. The ischemic VD probands had the tendency to have higher cystatin C levels than the AD. No correlation has been found with the severity and duration of dementia and with the other measured parameters. CONCLUSION: These results indicate that lower than normal CSF cystatin C level is not a diagnostic marker in ischemic VD and CAA related to AD.     

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.     

血管性痴呆小鼠海马胆碱乙酰转移酶mRNA变化特征及喜得镇的影响

目的:观测喜得镇对血管性痴呆小鼠海马神经元胆碱乙酰转移酶mRNA变化的影响,以探讨胆碱乙酰转移酶mRNA变化在血管性痴呆发病中的作用及喜得镇对此变化的机制。方法:双侧颈总动脉线结.反复缺血-再灌注法制备模型,药物组用喜得镇溶液灌胃,利用跳台试验和水迷宫试验观测其行为学改变,采用原位杂交技术观测小鼠海马神经元胆碱乙酰转移酶mRNA的表达变化。结果:喜得镇组小鼠学习、记忆成绩优于模型组(P<0.01),其海马胆碱乙酰转移酶mRNA表达也明显增高(P<0.01)。结论:喜得镇改善血管性痴呆小鼠学习、记忆成绩与其恢复海马低水平的胆碱乙酰转移酶mRNA有关。     

A comparison of brain choline acetyltransferase activity in Alzheimer's disease,multi-infarct dementia,and combined dementia

Summary Brain choline acetyltransferase (ChAT) activity was determined in 43 patients with Alzheimer's disease (AD), 14 with multi-infarct dementia (MID), and 15 with combined dementia (CD) and in 53 age-matched controls. The activity of ChAT declined in the hippocampus, temporal and frontal cortex in patients with AD and CD compared to the controls. In the AD group the reduced activity of ChAT in all brain areas was associated with a greater number of cortical neurofibrillary tangles. The degree of dementia had a negative correlation with the activity of ChAT in the frontal cortex in both AD and CD patients. The activity of ChAT in the temporal cortex of CD patients was negatively associated with the cortical tangle counts. In contrast, the activity of ChAT and MID patients was not essentially different from that of the controls. Neither did the various clinical and neuropathological variables show any significant correlation with ChAT activity in MID patients. Thus, in this study the reduction in the activity of ChAT seems to be associated with Alzheimer-type pathology but not with dementia due to vascular changes.     

Theory of mind in individuals with Alzheimer-type dementia

Abstract

Background: Theory of Mind (ToM) ability allows attribution of mental states to oneself and others. Recent studies suggest that impairment of ToM may be a partial cause of social-communication impairment in adults with right hemisphere disorder, frontal lobe damage, and the frontal variant of frontotemporal dementia. Initial evidence has also been presented for a ToM impairment in individuals with Alzheimer's disease (AD), but extant investigations have inadequately controlled for other cognitive impairments.

Aims: The purpose of this study was to determine whether individuals with AD exhibit a ToM impairment that is distinguishable from cognitive and executive function deficits, and to investigate whether memory support affects their ToM performance.

Methods & Procedures: Ten participants with mild to moderate AD completed first‐order and second-order false belief tasks with and without memory support, and their performances on ToM testing were compared to those of elderly controls. All ToM testing was controlled with memory, comprehension, and general inferencing questions. AD participants completed neuropsychological testing to concurrently assess general cognitive functioning, memory, and executive functioning. Independent and paired t‐tests compared experimental and control group ToM performances. Correlations assessed relations between ToM and neurocognitive test performances.

Outcomes & Results: Results indicated that, in the absence of memory support, AD participants did not exhibit a specific ToM difficulty as compared to control participants. However, significant group differences for specific ToM impairment that appeared to be separable from comprehension, memory, and general inferencing difficulties emerged during ToM testing when memory support was provided. Correlations between ToM performance and neurocognitive test performances were not significant; however, four of the eight AD participants who exhibited specific, ToM difficulty also had difficulty with executive function testing.

Conclusions: These results indicate that individuals with mild to moderate AD may possess an underlying, mild, specific ToM impairment, which becomes apparent during supported memory testing. Such mild ToM impairment in moderate AD individuals must be further investigated, and possible contributions of executive function impairments to apparent ToM difficulty further explored before the current results can be confidently generalised to a larger AD population.     

The frequency of apolipoprotein E4 allele is not increased in patients with probable vascular dementia

We used the NINDS-AIREN criteria to diagnose vascular dementia (VD), and compared apolipoprotein E (apoE) allele frequencies and apoE concentrations in serum and cerebrospinal fluid (CSF) between patients with possible (n=19) and probable (n = 33) VD and controls (n=105). There was no difference in apoE4 frequency between patients with probable VD and controls. Serum and CSF apoE concentrations did not differ between VD patients and contols. Our results suggest that apoE plays no role in the development of VD.     

阿尔茨海默病和血管性痴呆患者脑脊液中乙酰胆碱和胆碱检测及其临床意义

目的　探讨阿尔茨海默病 (AD)和血管性痴呆 (VD)患者脑脊液 (CSF)中乙酰胆碱 (ACh)和胆碱 (Ch)含量的异同以及它们与认知障碍的关系。方法　采用简易精神状态量表 (MMSE)对 2 2例AD、2 2例VD和 2 0名对照进行认知功能评分 ,利用高效液相色谱 电化学检测方法 (HPLC ECD)进行CSF的ACh和Ch检测 ,而后进行比较和分析。结果　AD组患者CSF的ACh含量 [(10 .7± 5 .1)nmol/L]低于对照组 [(34 .5± 9.0 )nmol/L](P =0 .0 0 1) ,与MMSE评分呈正相关。VD组患者CSF的ACh含量 [(16 .8± 7.4)nmol/L]也低于对照组 (P =0 .0 0 1) ,与MMSE评分呈正相关。AD组的CSF中Ch含量与对照组相比 [分别为 (6 2 7.6± 145 .1)nmol/L和 (716 .0± 15 9.4)nmol/L],差异无显著意义 ,与MMSE不呈相关关系。VD组患者CSF的Ch含量 [(887.4± 187.4)nmol/L]高于对照组 (P =0 .0 0 2 )和AD组患者 (P =0 .0 0 1)。结论　 (1)ACh的降低与认知障碍呈正相关 ,提示ACh是与记忆有关的重要神经递质 ;(2 )VD的ACh降低提示有与AD类似的发病机制 ;(3)AD患者ACh显著降低和VD患者胆碱显著增高有助于两者之间的鉴别 ;(4 )应用胆碱酯酶抑制剂来提高脑内ACh水平 ,不仅适用于AD ,也适用于VD。     

Apolipoprotein E in patients with dementia of the Alzheimer type and vascular dementia

The phenotypes of apolioprotein E (ApoE) in the plasma of patients with dementia of the Alzheimer type (DAT) and vascular dementia (VD) were determined by the isoelectric focusing method. The ApoE mRNA level in the skin fibroblasts was also determined by the Northern blot analysis. As compared with the control subjects, the frequency of the ApoE ε4 allele was significantly higher in the DAT group as well as the VD group, but was not significantly different in the cerebrovascular disease without dementia (CVD) group. The skin fibroblast ApoE mRNA level in the DAT group and the VD group was significantly lower than that in the control group. These findings suggest that the phenotype of ApoE is associated with DAT and VD, and that the lower level of ApoE mRNA may play an important role in the development of DAT as well as VD.     

Olfactory dysfunction in dementia of Alzheimer's type and vascular dementia

Background: Olfactory function in vascular dementia has not been extensively investigated to date. We studied olfactory function in vascular dementia (VD) and dementia of Alzheimer's type (DAT). Methods: We studied olfactory functioning in 12 patients suffering from dementia of Alzheimer's type, 11 patients with vascular dementia and 30 normal subjects. For these subjects we examined a 12‐item version of the Pennsylvania smell identification test and mini‐mental state examinations. These three groups were matched for age, sex and educational level. Results: Although the dementia scores were comparable in the DAT and VD groups, the smell identifications were low in DAT patients compared with VD patients and normal control subjects. Conclusions: These results suggest that the smell identification test may be useful in differential diagnosis between DAT and VD patients     

Cognitive deficits of mild dementia:A comparison between dementia of the Alzheimer's type and vascular dementia

Abstract This study was designed to examine the profiles of cognitive deficits in 11 mildly demented patients with dementia of Alzheimer's type (DAT), five with vascular dementia with multiple subcortical lacunar infarcts (VDS), and seven with vascular dementia with extensive white matter lesions (VDW) in comparison with 23 aged individuals without dementia. Memory, attention, abstract thinking, and visuospatial function were assessed using the Japanese translation of the Wechsler Memory Scale-Revised (WMS-R) and the Japanese version of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Compared with normal aged individuals, three dementia groups were significantly impaired in the memory and abstract thinking. However, the performances on several tests on attention (i.e. Mental Control and Visual Memory Span Backward from WMS-R) and visuospatial function (i.e. Object Assembly from WAIS-R) differed significantly between the DAT and VDS groups, with VDS being the worst in terms of performance than was DAT. This study suggests that, in the mildly demented stage, the patients with DAT have few problems in the attention and visuospatial function, but those with VDS have impairments in these cognitive abilities.     

Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients

OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.