Midbrain atrophy in subcortical ischemic vascular dementia

Magnetic resonance imaging (MRI) has revealed age-related changes in midbrain volume in normal subjects. Atrophy of the midbrain in patients with progressive supranuclear palsy (PSP) has been demonstrated using conventional brain MRI, and it was recently reported that some patients with vascular dementia also have midbrain atrophy. The aim of the present study was to investigate if the patients with subcortical ischemic vascular dementia (SIVD) have atrophic changes in the midbrain. MRIs of 23 SIVD patients, 18 probable PSP patients, and 96 controls were retrospectively analyzed. Differences in the distances between midbrain structures were compared across the patient groups and controls. We measured the anteroposterior diameter (AP), and the distance between the interpeduncular fossa and the aqueduct (IF–AQ), the aqueduct and posterior margin of the superior colliculi (AQ–SC), and the peduncular prominence and the interpeduncular fossa (PP–IF) of the midbrain. The AP diameter and IF–AQ were negatively correlated with age in normal controls (r = ?0.21, p < 0.005 for AP; r = ?0.14, p < 0.0001 for IF–AQ). In SIVD patients, the AP diameter and IF–AQ were both significantly smaller than in controls (p < 0.001). Changes in the midbrain found for SIVD patients were similar to those seen in PSP patients. Our results suggest that the midbrain decreases in size with normal aging, especially around the tegmental region. This change is more pronounced in patients with SIVD and in patients with PSP. Prospective functional studies are needed to ascertain the clinical relevance of midbrain atrophy in SIVD.     

Decreased phospholipase A2 activity in cerebrospinal fluid of patients with dementia

Phospholipase A(2) (PLA(2)) is involved in important aspects of dementia, for example neurotransmission and memory processing, membrane function, choline availability, and antioxidative defense. Reduced PLA(2)-activity has been reported so far in blood samples and postmortem neuronal tissue in Alzheimer disease. For the first time, we studied PLA(2) in cerebrospinal fluid (CSF) in Alzheimer disease (AD), vascular (VD), and mixed Alzheimer/vascular dementia (MD). Intracellular PLA(2) was assessed in CSF of 16 AD, 12 VD, 15 MD patients, and 19 healthy control subjects. A fluorometric assay was applied using the PLA(2)-specific substrate NBDC6-HPC. Significantly reduced PLA(2) activity was not only found in AD, but also in VD and MD. This finding was independent of demographic co-variates and medication. PLA(2) results in CSF corroborate previous findings of impaired PLA(2) function in Alzheimer's disease and extend these to patients with VD. They are likely to reflect an involvement of PLA(2) impairment in a variety of pathomechanisms crucial in different dementia subtypes, in which disruption of cholinergic neurotransmission and disturbance of intact membrane function appear to be the key mechanisms.     

皮质下缺血性血管性痴呆的研究进展

阿尔茨海默病(AD)和脑血管病(CVD)是导致老年性痴呆的最常见原因[1].而脑血管病的范畴很大,按受累血管可分为大血管病和小血管病;按疾病性质可分为缺血性卒中和出血性卒中;按病变部位可分为皮质型和皮质下型等.不同损伤原因、部位和性质的脑血管病所导致的血管性痴呆(VaD)其认知功能障碍的差异较大,呈斑片状,不同于阿尔茨海默病的均一表现,为其诊断与治疗和研究带来一定的困难[2].     

Neurobehavioral dysfunction in patients with subcortical vascular mild cognitive impairment and subcortical vascular dementia

Amnestic mild cognitive impairment (MCI) is considered to be a prodromal stage of Alzheimer's disease. Likewise, subcortical vascular MCI (svMCI) is considered as a prodromal stage of subcortical vascular dementia (SVaD). The objective of this study was to investigate neuropsychiatric features in patients with svMCI compared to healthy controls and patients with SVaD. We evaluated 31 patients with svMCI, 42 with SVaD, and 28 healthy controls who underwent neuropsychiatric assessments using the Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI). On both the NPI and FBI, SVaD patients had the most severe neuropsychiatric symptoms, followed by svMCI patients and then healthy controls, suggesting that svMCI might be a prodromal stage of SVaD in terms of neuropsychiatric abnormalities. When we compared the differences of mean scores between negative and positive symptoms in FBI, negative symptoms tended to be more predominant than positive symptoms in both svMCI and SVaD patients, but the tendency was stronger in SVaD patients than in svMCI patients. These results suggest that vascular cognitive impairment with small vessel disease would start with both negative and positive neuropsychiatric symptoms and progress to present more severe negative symptoms. These behavioral ratings may be useful for early detection of vascular cognitive impairment associated with small vessel disease.     

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.     

Sulfatide as a biochemical marker in cerebrospinal fluid of patients with vascular dementia

The myelin-associated glycosphingolipid sulfatide in cerebrospinal fluid (CSF) was investigated in 20 patients with vascular dementia (VAD), 43 with Alzheimer's disease (AD) and 20 age-matched controls. The sulfatide concentration in the VAD group (307 +/- 118 nmol/l) was significantly (p less than 0.0001) higher than that in controls (145 +/- 86 nmol/l) and the AD group (178 +/- 79 nmol/l). Among the VAD patients, 8/20 had a significantly increased concentration of sulfatide (greater than mean + 2 S.D.), as compared with controls, while only 2/43 of the AD patients had a sulfatide concentration above this level. It is suggested that the elevated concentration of sulfatide in CSF from VAD patients reflects demyelination. Furthermore, sulfatide determinations, when combined with clinical findings, may be of diagnostic value, for discriminating between VAD and AD.     

Oligoclonal immunoglobulin bands in cerebrospinal fluid of patients with Alzheimer''s disease and vascular dementia

We examined serum and cerebrospinal fluid (CSF) of 16 patients with Alzheimer's disease (AD), 28 patients with vascular dementia (VD), their age-matched controls and multiple sclerosis (MS) patients in order to evaluate the humoral immune response within the central nervous system both quantitatively and qualitatively. Intra-blood-brain barrier (BBB) protein synthesis was calculated by CSF IgG index. The presence of oligoclonal banding (OCB) was investigated with agarose isoelectric focusing (IEF) followed by immunoblotting with antihuman IgG. No patient with AD and only 4 patients with VD had slightly elevated IgG indexes, and no statistically significant differences in the indexes were found between the two groups. No bands were found in the CSF of AD patients but 3 VD patients had OCB in both serum and CSF. One VD patient had bands in serum but no bands in CSF. No kappa or lambda free light chains were found in those demented patients with demonstrable bands in the CSF and serum. No OCB were found in control sera and CSF. For comparison, the majority of patients with MS had OCB in CSF. Thus, no consistent increase of intrathecal protein synthesis was found in patients with AD and VD. Methodological differences explain at least part of the conflicting results published earlier.     

Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease

BACKGROUND: The cause of dementia in subcortical ischemic vascular disease (SIVD) is controversial. OBJECTIVES: To determine whether cognitive impairment in SIVD 1) correlates with measures of ischemic brain injury or brain atrophy, and/or 2) is due to concomitant AD. METHODS: Volumetric MRI of the brain was performed in 1) elderly subjects with lacunes (L) and a spectrum of cognitive impairment-normal cognition (NC+L, n = 32), mild cognitive impairment (CI+L, n = 26), and dementia (D+L, n = 29); 2) a comparison group with probable AD (n = 28); and 3) a control group with normal cognition and no lacunes (NC). The authors examined the relationship between the severity of cognitive impairment and 1) volume, number, and location of lacunes; 2) volume of white matter signal hyperintensities (WMSH); and 3) measures of brain atrophy (i. e., hippocampal, cortical gray matter, and CSF volumes). RESULTS: Among the three lacune groups, severity of cognitive impairment correlated with atrophy of the hippocampus and cortical gray matter, but not with any lacune measure. Although hippocampal atrophy was the best predictor of severity of cognitive impairment, there was evidence for a second, partially independent, atrophic process associated with ventricular dilation, cortical gray matter atrophy, and increase in WMSH. Eight autopsied SIVD cases showed variable severity of ischemic and neurofibrillary degeneration in the hippocampus, but no significant AD pathology in neocortex. The probable AD group gave evidence of only one atrophic process, reflected in the severity of hippocampal atrophy. Comparison of regional neocortical gray matter volumes showed sparing of the primary motor and visual cortices in the probable AD group, but relatively uniform atrophy in the D+L group. CONCLUSIONS: Dementia in SIVD, as in AD, correlates best with hippocampal and cortical atrophy, rather than any measure of lacunes. In SIVD, unlike AD, there is evidence for partial independence between these two atrophic processes. Hippocampal atrophy may result from a mixture of ischemic and degenerative pathologies. The cause of diffuse cortical atrophy is not known, but may be partially indexed by the severity of WMSH.     

Frontal impairment in subcortical ischemic vascular dementia in comparison to Alzheimer's disease

We compared the performance of patients with Alzheimer's disease to that of patients with subcortical vascular dementia (s-IVD) in a set of tasks assessing categorization abilities, sustained and selective attention, and set-shifting and set-maintaining skills. Only the measures of naming and categorization abilities on the Test of Classification and Recall of Pictures (TCRP) proved useful in differentiating AD from s-IVD patients. s-IVD patients showed worse performance than AD on the TCRP categorization measures, while both AD and s-IVD patients were equally impaired in other tasks assessing executive functions (EF). With respect to the naming task, s-IVD patients made significantly more perseverative and unrelated errors than AD patients. Moreover, in the s-IVD group, we found a strong correlation between categorization ability and an attentional test score (Attentional Matrices), while no such correlation emerged in the AD group. These results suggest a dissociated impairment of EF in the 2 dementia groups. In our view, the lack of inhibition and the inability to manipulate complex information are responsible for a greater executive dysfunction in s-IVD patients in comparison with AD patients. The capacity to build up strategies appears more preserved in AD patients, whose impaired performance in executive tasks seems to be related to an impairment of attentional shifting and working memory.     

Differences in executive functioning between Alzheimer's disease and subcortical ischemic vascular dementia

The present study examined the performance of 114 individuals (62 males, 52 females) on a variety of tests purported to measure executive abilities. Participants were diagnosed with possible or probable Alzheimer's disease (AD), subcortical ischemic vascular dementia (SVaD), or were normal controls (NoDx). Groups were matched for age and education, and clinical groups were matched for severity of dementia. Multivariate and univariate analyses of variance were performed which indicated that the AD and SVaD patients differed from the NoDx on all measures of executive functioning. Further, the AD group made significantly more episodic memory errors than the SVaD group. On the other hand, consistent with previous research, the SVaD group performed significantly better than the AD group on recognition memory, but not on free recall measures. Present findings suggest that AD patients have more executive self-monitoring problems than SVaD patients do, but SVaD patients have more retrieval problems (executive memory search), suggesting a fractionation of executive abilities. Thus, differences between dementia groups depend on the nature of the executive function assessed.     

皮质下缺血性脑血管病认知功能障碍研究

目的应用系列神经心理学测试分析皮质下缺血性脑血管病(SIVD)患者的认知损害特征。方法入选SIVD患者53例,年龄及性别相当的健康老年人25例为正常对照组。SIVD患者按照认知损害的诊断标准分为血管性痴呆(VaD)组27例和血管性认知障碍非痴呆(VCIND)组26例。进行MMSE及血管性痴呆包括记忆力、注意力、语言、视空间结构及执行功能5个认知域在内的神经心理学测试,确定VCIND患者受损的认知域。结果①与正常对照组比较,VaD组患者各项量表测试均严重受损,具有统计学差异(P﹤0.05);②VCIND组患者MMSE、数字倒背评分下降,连线测验时间延长,差异有统计学意义(P﹤0.05);③VaD组与VCIND组相比,上述各项均受损严重,其中单词回忆、连线测验、画钟测验、数字广度测验评分差异有统计学意义(P﹤0.05)。结论①SIVD患者同时存在多个认知域损害,以执行功能、注意力损害较为突出,记忆、语言受累相对较轻;②VCIND患者表现为执行功能、注意力受损,程度均低于VaD组,晚期VaD患者全面认知功能明显下降。     

皮质下缺血性血管性疾病的MTHFR基因多态性

目的研究皮质下缺血性血管性疾病(subcortical ischemic vascualar disease,SIVD)与N5,N10-亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因C677T多态性的关系。方法应用聚合酶链反应(polymerase chain reaction,PCR)技术和限制性酶切片段长度多态性(restriction fragment length polymorphism,RFLP)分析技术检测46例SIVD患者和43名正常人的MTHFR基因C677T多态性。结果 SIVD组T/T型、C/T型基因频率分别为36.96%、34.78%,分别高于对照组(20.93%、23.26%)。SIVD组T等位基因频率明显高于对照组(分别为54.35%、32.56%,P0.01)。T/T型、C/T型患SIVD风险度较C/C型分别高3.487倍(95%CI,1.1217～9.993)和2.954倍(95%CI,1.045～8.350)。结论 MTHFR基因T等位基因可能是SIVD的遗传易感因子,而C等位基因则具有一定保护作用,MTHFR基因C677T点突变与SIVD发病密切相关。     

Nimodipine in subcortical vascular dementia trial

Vascular dementia (VaD) is a heterogeneous pathology currently regarded as the result of a variety of causes. Different types of VaD can be identified according to different criteria. This heterogeneity might be one of the causes of the controversial results observed, up to now, in clinical trials. Recently, the 10th revision of the International Classification of Diseases (ICD-10) explicitly identified subcortical VaD as a well-defined subgroup. Abnormalities of white matter are clearly detectable with computed tomography or magnetic resonance scans. The clinicoradiological association of dementia, blood hypertension, and other vascular risk factors, extensive white matter lesions, and small subcortical infarcts might be considered as a clinical univocal entity. Following the encouraging results of a preliminary pilot study, the above-mentioned criteria were followed to define a population of patients to be enrolled in a double-blind, parallel-groups, placebo-controlled clinical trial with nimodipine, which has been proposed as a drug that can improve cognitive functions in patients with VaD. The paper discusses the protocol design of this ongoing trial and its main entry criteria, with particular emphasis on the definition of the population to be enrolled. Implication for future trials in subcortical VaD are discussed further.     

Decreased cerebrospinal fluid levels of beta-phenylethylamine in patients with Rett syndrome

To clarify the mechanism of brain impairment in Rett syndrome, we measured the cerebrospinal fluid levels of beta-phenylethylamine (PEA) in 17 patients with Rett syndrome. Findings were compared with those obtained in age-matched controls and diseased controls. The cerebrospinal fluid level of PEA was significantly lower in patients with Rett syndrome than in the controls (31% of control values). The alteration in the cerebrospinal fluid level of PEA may reflect dopamine system impairment in Rett syndrome.     

Rivastigmine for subcortical vascular dementia

Rivastigmine is a second-generation cholinesterase inhibitor with selectivity for the CNS, with capacity to inhibit both acetylcholinesterase and butyrylcholinesterase. Rivastigmine is currently approved for the treatment of mild-to-moderate Alzheimer's disease. In addition to its effects on cognition and activities of daily living, rivastigmine appears to be useful in preventing and controlling behavioral and neuropsychiatric manifestations in Alzheimer's disease and dementia with Lewy bodies. This drug profile could be potentially useful in patients with subcortical vascular dementia who often present these symptoms. Small open-label studies of patients with subcortical vascular dementia showed that rivastigmine improved attention, executive function, apathy and other behavioral deficits. Rivastigmine appears to be a promising agent in vascular dementia but its effects remain to be established in double-blind, placebo-controlled clinical trials.