Is Helicobacter pylori infection a critical risk factor for vascular dementia?

Purpose: The association of Helicobacter pylori (Hp) infection and Alzheimer's disease has widely been addressed, but no relative data exist regarding vascular dementia (VD). The purpose of this study was to evaluate the relationship between Hp infection and VD. Material and method: From January 2014 to March 2015, patients at Tai'an City Central Hospital who were diagnosed with VD were included. Patients were divided into Hp positive and Hp negative group using the ¹³C-urea breath test (¹³C-UBT). Three inflammatory cytokines including interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were detected. Results: A total of 173 VD patients were included in the study. According to ¹³C-UBT, 104 patients (60.1%) were Hp positive VD patients and 69 patients (39.9%) were Hp negative patients. No differences were found between Hp positive and Hp negative patients as regard to age, gender, body mass index, education level, hypertension, diabetes mellitus and hyperlipidemia (p > 0.05). Hp positive patients demonstrated significantly lower mean mini-mental state examination and Montreal cognitive assessment scores (p < 0.05) and higher plasma levels of IL-1β, IL-6 and TNF-α than Hp negative patients (p < 0.05). Conclusions: Hp infection might contribute, at least in part, to the cognitive decline in patients with VD, and play a critical role possibly through increasing expression of IL-1β, IL-6 and TNF-α.     

Is subcortical vascular dementia a clinical entity for clinical drug trials?

Several therapeutic trials have been performed for vascular dementia, with drugs differing in type and mechanism of action. The results have been almost invariably inconclusive. Given the current notion that there are different subtypes of vascular dementia according to pathophysiological mechanisms, it is reasonable to suspect that one of the main causes of the disappointing results was that the study samples included patients not fitting with the rationale of selective treatments. Testing this hypothesis is difficult because characterization of patients in relation to different subtypes of vascular dementia is not available for most studies. However, attempts are ongoing to reclassify patients entered in some trials for post hoc subgroup analyses with some preliminary interesting results. We propose that (1) specific subtypes of vascular dementia should be the target in any single trial using a treatment with a proper rationale; and (2) subcortical vascular dementia, caused by small vessel disease leading to lacunar infarcts and subcortical white matter changes, represents a clinically and radiologically well-defined entity to be considered for future trials designed specifically for testing adequate drugs.     

Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors

Abstract

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demostrated improvement in cognition, behavior and activites of daily living.     

MRI evaluation of vascular dementia

OBJECTIVE: To explain the association between vascular dementia and the cranial MRI manifestations, and recognize the value of cranial MRI in the early diagnosis of vascular dementia and the assessment of disease conditions. DATA SOURCES: Pubmed database was searched to identify articles about the cranial MRI manifestations of patients with vascular dementia published in English from January 1992 to June 2006 by using the of "MRI, vascular dementia". Others were collected by searching the name of journals and title of articles in the Chinese full-text journal database. STUDY SELECTION: The collected articles were primarily checked, those correlated with the cranial MRI manifestations of patients with vascular dementia were selected, while the obviously irrelative ones were excluded, and the rest were retrieved manually, the full-texts were searched. DATA EXTRACTION: Totally 255 articles were collected, 41 of them were involved, and the other 214 were excluded. DATA SYNTHESIS: MRI can be taken as one of the effective methods for the early diagnosis and disease evaluation of vascular dementia. White matter lesions are the important risk factors of vascular dementia. Vascular dementia is accompanied by the atrophy of related brain sites, but further confirmation is needed to investigate whether there is significant difference. MRI can be used to quantitatively investigate the infarcted sites and sizes of patients with vascular dementia after infarction, but there is still lack of systematic investigation on the association of the infarcted sites and sizes with the cognitive function of patients with vascular dementia. CONCLUSION: Cranial MRI can detect the symptoms of vascular dementia at early period, so that corresponding measures can be adopted to prevent and treat vascular dementia in time.     

Is physical activity a potential preventive factor for vascular dementia? A systematic review

Background: Physical exercise has several beneficial effects, including reduced risk for Alzheimer's disease. Although several studies of potential risk factors for vascular dementia (VaD) exist, including physical activity, the studies have usually included few participants and there are no meta-analyses addressing this key topic.

Methods: The MEDLINE database was searched using the key words ‘physical exercise’ ‘activity’ or ‘walking’ in combination with ‘dementia’ and ‘vascular dementia’. Potentially relevant studies were assessed and summarised by two of the authors, and longitudinal studies with operationalised definition of physical activity providing risk for VaD in both groups were included in the meta-analysis using pooled estimates from a random effects model.

Results: A total of 24 longitudinal studies, including 1378 patients with VaD, were included in the review. The majority of individual studies did not report significant associations. Five studies fulfilled criteria for meta-analysis, including 10,108 non-demented control subjects and 374 individuals with VaD. The meta-analysis demonstrated a significant association between physical exercise and a reduced risk of developing VaD: OR 0.62 (95% CI 0.42–0.92).

Conclusions: We conclude that there is evidence supporting the hypothesis that physical activity is likely to prevent the development of VaD, and should be highlighted as part of secondary prevention programmes in people at risk for cerebrovascular disease.     

Alzheimer's disease versus vascular dementia -- dichotomy or interaction?

Alzheimer's dementia (AD) and vascular dementia (VD) are the two major forms of dementia in the elderly. They have been separated categorically on the basis of pathophysiological findings and clinical operationalized criteria. However, this strict separation has to be reevaluated in the light of recent data. The risk to develop a neurodegenerative dementia in old age is determined by various susceptibility genes and correlated with aging. In AD, the current understanding of pathophysiology focuses on the amyloid cascade hypothesis as the major endpoint of the complex cellular pathology. In VD, incomplete microangiopathic infarcts due to fibrohyalinosis are regarded as the major pathophysiological event. A controversial discussion exists about the coincidence or interaction of genetically determined risk factors of AD and/or VD. Further interactions between AD and VD exist with regard to perivascular mediators and those factors which impair cerebral blood flow. Based on these and other recent neuropathological and therapeutic findings the hypothesis is proposed that the two specific etiopathologies of AD and VD interact to precipitate clinical dementia in the individual and that the individual phenomenology of these dementias is modified by vascular risk factors. Neither, a categorical separation of AD and VD nor the recent idea to regard AD as a distinct form of vascular dementia, do appear convincing.     

Cholinesterase inhibitors: beyond Alzheimer’s disease

Cholinesterase inhibitors (ChEIs) are widely licensed for the symptomatic treatment of Alzheimer’s disease, but their use has also been examined in a wide variety of neurological disorders besides Alzheimer’s disease, and this article reviews these uses. The evidence currently available suggests that ChEIs may possibly have a role in the treatment of some patients with dementia with Lewy bodies and Parkinson’s disease dementia, but at this point in time there would seem to be only a limited case for recommending ChEIs in mild cognitive impairment, Down syndrome, progressive supranuclear palsy, pure vascular dementia, frontotemporal lobar degeneration, Huntington’s disease, multiple sclerosis, epilepsy, delirium, traumatic brain injury, sleep-related disorders or certain psychiatric disorders (e.g., schizophrenia and bipolar disorder). Clinical practice with respect to non-Alzheimer’s disease indications for ChEIs may vary according to jurisdiction, specifically with regards to whether national guidelines effectively limit off-licence drug use.     

Can small-vessel disease-related cerebral abnormalities be used as a surrogate marker for vascular dementia trials?

Clinical scales for measuring the effectiveness of disease-modifying therapies in patients with vascular dementia are of limited sensitivity. Moreover, they cannot serve to directly probe the potential of a drug in slowing further progression of vascular damage. Assessment of morphologic abormalities that reflect ischemia-related cerebral tissue changes and have a bearing on cognitive function could serve to address both of these aspects and, if sensitive enough, could constitute an ideal surrogate for measuring progression of the disease. For drug licensing agencies a validated surrogate has to meet several requirements: First, the surrogate must predict the future clinical course. Second, the effect of treatment on the disease must be explained by the effect of the treatment on the surrogate; the treatment needs to affect clinical outcome by working through mechanisms related to the surrogate. Third, evidence must exist that treatments of various classes affect the surrogate in the same and predictable manner. Apart from these requirements, regulatory guidelines may also allow the use of even an unvalidated surrogate if it is considered reasonably likely to predict future clinical outcome or disease activity. Various morphologic measures, particularly those using conventional or more sophisticated MRI techniques have already shown a close correlation to neuropsychologic functions. If these associations can also be confirmed in longitudinal studies and following specific treatments, morphologic markers will play a major role in future clinical trials of vascular dementia.     

Is there a role for uridine and pyrimidine nucleosides in the treatment of vascular dementia?

In the 70s, the discovery of a constant loss of acetylcholine (Ach) in the brains of people suffering from dementia led to the development, in order to improve cognitive functions, of drugs that increased Ach levels. The possibility that loss of a given neurotransmitter might be associated with the onset of a specific neurological syndrome led to suggestions that, as had already been found in Parkinson's disease, replacement therapy might drastically improve the course of the syndrome. We are now aware of the limits of this therapeutic approach. In this review, we analyse potential factors contributing to the partial failure of Ach replacement therapy, contrasting common beliefs regarding the Ach synapse with the difficulties in restoring its activity through replacement drugs. Considering the search for alternative strategies, in the second part of the review, we overview progress of research into pyrimidine compounds, now emerging as a new modulatory system acting through specific pyrimidino-receptors involved in various steps of cell signalling. Pyrimidine nucleosides might be useful in the chronic treatment of cognitive deficits resulting from vascular dementia.     

Cholinesterase inhibitors in advanced Dementia with Lewy bodies: increase or stop?

INTRODUCTION: There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB. METHOD: We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms. RESULTS: The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment. CONCLUSION: Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.     

Does perfusion CT enable differentiating Alzheimer's disease from vascular dementia and mixed dementia? A preliminary report

The purpose of the study was to evaluate the usefulness of perfusion CT (pCT) in differentiating Alzheimer's disease (AD) from vascular dementia (VaD) and mixed dementia (MixD). pCT was performed in 41 patients (mean age, 68.3 years): 24 with AD, 8 with VaD, and 9 with MixD. Regional perfusion parameters (rCBF, rCBV, and rMTT) were calculated from 31 ROIs in the grey and white matter of the frontal and temporal lobes, basal ganglia, and internal capsules bilaterally. The obtained data for the subgroups of AD, VaD, and MixD patients were compared statistically. CONCLUSIONS: On the basis of rCBF and rCBV values, pCT may be a valuable method of distinguishing between AD and VaD but it seems to be of little significance in differentiating MixD from VaD and of no usefulness in distinguishing between AD and MixD.     

Does aspirin affect outcome in vascular dementia? A retrospective case-notes analysis

BACKGROUND: Ischaemic vascular dementia shares risk factors with stroke. There is evidence that control of these risk factors may prevent or alter the course of vascular dementia. OBJECTIVE: To assess the effect of regular low-dose aspirin on outcomes for patients with vascular dementia. DESIGN: Retrospective analysis of hospital case-notes with further outcome information from telephone calls to general practitioners, social services and institutions. Comparison of outcomes for aspirin-treated and untreated patients. SETTING: One North London NHS Trust. PATIENTS: Seventy-eight patients with clinician's diagnosis of ischaemic vascular dementia, discharged from acute inpatient units between 1 January 1995 and 31 December 1997; 38 on aspirin. MAIN OUTCOME MEASURES: Survival times from dementia onset to institutionalization and death. RESULTS: Median survival time to institutionalization was 28 months and to death was 52 months. There was no overall difference between aspirin and non-aspirin groups for these outcomes. When data were stratified for social status, i.e. living alone or with carer when last at home, differences emerged for those living with carer. Aspirin was associated with a trend towards increased time to institutionalization (39 vs 22 months, p < 0.09) and a significant advantage in time to death (71 vs 27 months, p = 0.02). These effects were non-significant after statistical adjustment for confounding variables. CONCLUSIONS: The results support but do not prove a role for regular, low-dose aspirin in improving both life expectancy and survival at home for patients with vascular dementia. Compliance may be better in those living with a carer. Larger, prospective studies should be performed to confirm these findings. Cognitive and behavioural outcomes should also be studied.     

Intracranial volume in mild cognitive impairment,Alzheimer's disease and vascular dementia: evidence for brain reserve?

OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.