Trials In Vascular Dementia Research Articles

Use of Cholinesterase Inhibitors in Non-Alzheimer's Dementias.

Non-Alzheimer's dementias constitute 30% of all dementias and present with major cognitive and behavioral disturbances. Cholinesterase inhibitors improve memory by increasing brain acetylcholine levels and are approved symptomatic therapies for Alzheimer's disease (AD). They have also been investigated in other types of dementias with potential cholinergic dysfunction. There is compelling evidence for a profound cholinergic deficit in Lewy Body dementia (LBD) and Parkinson's disease dementia (PDD), even to a greater extent than AD. However, this deficit is difficult to objectivize in vascular dementia (VaD) given the increased comorbidity with AD. Furthermore, there is minimal to no evidence for cholinergic loss in frontotemporal dementia (FTD). Although cholinesterase inhibitors showed significant improvement in cognitive, behavioral, and functional measures in both LBD and PDD clinical trials, only rivastigmine is approved for PDD, due to the heterogeneity of the scales used, the duration of trials, and the limited sample sizes impacting data interpretation. Similarly, the interpretation of findings in VaD trials are limited by the lack of pre-defined inclusion criteria for 'pure VaD' and the wide heterogeneity of patients enrolled with respect to location and extent of cerebrovascular disease. In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms. In non-AD dementias, cholinesterase inhibitors were well tolerated, with increased reports of mild to moderate cholinergic side effects and a non-significant trend for increased cardio and cerebrovascular events with rivastigmine in VaD, justifying their cautious use on a case-by-case basis, especially when there is evidence for cholinergic deficit.

Assessment of free and cued recall in Alzheimer's disease and vascular and frontotemporal dementia with 24-item Grober and Buschke test.

Alzheimer's disease (AD), vascular dementia (VaD) and frontotemporal dementia (FTD) are the most common forms of dementia. It is well known that memory deficits in AD are different from those in VaD and FTD, especially with respect to cued recall. The aim of this clinical study was to compare the memory performance in 15 AD, 10 VaD and 9 FTD patients and 20 normal controls by means of a 24-item Grober-Buschke test [8]. The patients' groups were comparable in terms of severity of dementia. We considered free and total recall (free plus cued) both in immediate and delayed recall and computed an Index of Sensitivity to Cueing (ISC) [8] for immediate and delayed trials. We assessed whether cued recall predicted the subsequent free recall across our patients' groups. We found that AD patients recalled fewer items from the beginning and were less sensitive to cueing supporting the hypothesis that memory disorders in AD depend on encoding and storage deficit. In immediate recall VaD and FTD showed a similar memory performance and a stronger sensitivity to cueing than AD, suggesting that memory disorders in these patients are due to a difficulty in spontaneously implementing efficient retrieval strategies. However, we found a lower ISC in the delayed recall compared to the immediate trials in VaD than FTD due to a higher forgetting in VaD.

Huperzine A in the Treatment of Alzheimer′s Disease and Vascular Dementia: A Meta‐Analysis

The objective of our study was to perform an updated meta-analysis of placebo-controlled RCTs of Huperzine A (Hup A) on patients with Alzheimer's disease (AD) and vascular dementia (VD), in order to provide the basis and reference for clinical rational drug use. The primary outcome measures assessed were minimental state examination (MMSE) and activities of daily living scale (ADL). Eight AD trials with 733 participants and two VD trials with 92 participants that met our inclusion criteria were identified. The results showed that Hup A could significantly improve the MMSE and ADL score of AD and VD patients, and longer durations would result in better efficacy for the patients with AD. It seemed that there was significant improvement of cognitive function measured by memory quotient (MQ) in patients with AD. Most adverse effects in AD were generally of mild to moderate severity and transient. Compared to the patients with AD, Hup A may offer fewer side effects for participants with VD in this study. Therefore, Hup A is a well-tolerated drug that could significantly improve cognitive performance in patients with AD or VD, but we need to use it with caution in the clinical treatment.

Randomized, Placebo-Controlled, Clinical Trial of Donepezil in Vascular Dementia

We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference, -1.156; 95% CI, -1.98 to -0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group. Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

MRI surrogates for vascular dementia trials

There is neuropathological evidence that confluent MRI white matter lesions, lacunes and cerebral microbleeds in the elderly reflect ischemic brain damage due to microangiopathy. It has been suggested that MRI may be used to monitor treatment trials on subcortical vascular dementia. A prerequisite for the use of any small vessel disease-related brain abnormality as surrogate marker is longitudinal change allowing detection of treatment effects within a reasonable time period and correlation with cognitive decline.

Donepezil in patients with subcortical vascular cognitive impairment

Introduction: Studies of the effect of cholinesterase inhibitors in vascular dementia have been hampered by clinical heterogeneity in terms of type of vascular lesions, location of lesions, and degree of concomitant Alzheimer’s disease (AD) pathology. In a meta-analysis of eight double-blind, placebo-controlled trials in vascular dementia, including three with donepezil, one with rivastigmine, two with galantamine, and two with memantine, the extent of severe white matter lesions ranged from 18% to 64%, and the presence of cortical lesions was 12% to 46% in the cholinesterase-inhibitor groups [ 1 ]. These trials showed a consistent modest benefi t of 1 to 2 points on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog), which was derived from improvement in the treated group rather than worsening of the placebo group. However, there was no corresponding improvement in the clinical global or activity of daily living (ADL) measures, which is a requirement for regulatory approval. The mechanism by which cholinesterase inhibitors might improve cognition in vascular dementia is unknown. Cholinesterase inhibitors may act by increasing postsynaptic acetylcholine caused by disruption (infarction) of subcortical or cortical cholinergic pathways [ 2 , 3 ]. Memantine has also been shown to be effective in a pooled analysis, specifi cally in patients with vascular dementia with small vessel disease compared with placebo [ 4 ]. The similar benefi t of cholinesterase inhibitors and memantine in both AD and vascular dementia suggests that the mechanism of action could be due to the effects on AD pathology. Because so many individuals with vascular dementia also have AD pathology, it is diffi cult to determine the potential mechanism for improvement. Treatment of cerebral, autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by a mutation in the NOTCH3 gene [ 5 ], provides an opportunity to determine the extent to which treatment with cholinesterase inhibitors might affect a more pathologically homogeneous entity. Executive function and attention are the most commonly affected domains, and these impairments may occur early, prior to overt stroke. CADASIL has been shown to be a good model for sporadic cerebral small vessel disease because the pattern of cognitive impairment, particularly executive dysfunction, is similar [ 6 ] and because dementia occurs at a younger age in CADASIL, making the presence of AD pathology less likely. Disruption of ascending cholinergic pathways from the nucleus basalis of Meynert through the external capsule to the cortex without concomitant AD pathology in the nucleus basalis of Meynert or cortex has been demonstrated in CADASIL [ 7 ].

Recognizing vascular dementia

Knowledge and understanding of vascular dementia (VaD) has greatly evolved since its first descriptions in the 19th century. Yet, recognizing VaD and differentiating it from Alzheimer's disease (AD) remains a diagnostic challenge. VaD should be suspected when dementia occurs abruptly, is associated with focal neurological signs and symptoms and follows a stepwise deteriorating course. However, over half of the cases may present with a more variable course. Certain neuropsychological patterns are more consistent with VaD than AD and can lend support to its diagnosis. Advances in neuroimaging have greatly improved our ability to identify cerebral vascular pathology; however, abnormal findings should be interpreted with care, taking into account lessons learned from clinicopathological studies. We have performed clinicopathological correlations in 208 individuals to evaluate five currently used clinical criteria for VaD. We have shown that they are not interchangeable. Although they are relatively specific, most suffer from low to very low sensitivity. A clear understanding of the different performance of currently available diagnostic strategies is crucial for the correct interpretation of epidemiological studies and therapeutic trials in VaD. from International Society on Brain and Behaviour: 3rd International Congress on Brain and Behaviour Thessaloniki, Greece. 28 November – 2 December 2007

The cognitive profiles of CADASIL and sporadic small vessel disease

Interpretation of treatment trials in vascular dementia is confounded by the presence of coexistent Alzheimer disease (AD) pathology. The younger onset genetic disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) offers a model of pure vascular dementia, in which such confounding is unlikely. To validate CADASIL's use as a model it is important to show it results in a similar cognitive impairment. The same neuropsychological assessment was administered to patients with CADASIL (n = 34, 14 of whom had had stroke), sporadic small vessel disease (SVD) presenting with lacunar stroke and having confluent leukoaraiosis (n = 54), and healthy controls (n = 25). A similar pattern of neuropsychological impairment was seen in the two diseases, with prominent early executive dysfunction. Patients with CADASIL and SVD performed worse than controls on Trails switching test (CADASIL p = 0.006; SVD p < 0.001), and on verbal fluency test (CADASIL p = 0.015; SVD p = 0.004). The SVD group also performed worse on immediate (p = 0.050) and delayed (p = 0.049) memory. When only patients with CADASIL with stroke were included in analysis with SVD subjects, all of whom had had stroke, a very similar cognitive profile was seen. The only difference was on verbal fluency, where CADASIL subjects performed worse (p = 0.044). Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and small vessel disease show a similar pattern of cognitive deficits. This suggests that CADASIL provides a model of pure vascular dementia relevant for sporadic small vessel disease vascular dementia.

Subcortical vascular cognitive impairment: Similarities and differences with multiple sclerosis

Subcortical vascular cognitive impairment is caused by lacunes and widespread ischemic white matter damage which closely resembles white matter abnormalities seen in multiple sclerosis. Recent evidence suggests that the progression rate of ischemic white matter lesions on MRI is very similar to that observed in multiple sclerosis. Consequently, it has been proposed to use MRI for monitoring disease activity not only in multiple sclerosis but also in vascular dementia trials. There is first evidence from magnetization transfer imaging studies that other than in MS normal appearing white matter is not affected in cerebral small vessel disease. This contrasts the hypothesis that ischemic white matter damage extends far beyond changes visible on conventional MR. The cognitive consequences of both diseases are strikingly similar which is at least partly caused by damage to frontal–subcortical circuits. Involvement of these common functional anatomical structures and their modulatory transmitter systems has now led to common interventional approaches such as the use of cholinesterase inhibitors.

MRI and CT in the diagnosis of vascular dementia

Neuroimaging is necessary to demonstrate cerebrovascular disease (CVD) and is therefore an important examination in vascular dementia (VaD) and vascular cognitive impairment (VCI). MRI is preferred over CT because multiple planes and sequences are needed to assess various types of pathology in relevant regions. These protocols allow differentiation of VaD from other forms of dementia and sometimes identify specific underlying disorders. Different diagnostic criteria for VaD exist but the NINDS-AIREN criteria are widely used in controlled clinical trials in VaD. These criteria have relatively low sensitivity but are highly specific and include radiological requirements. The radiological criteria have poor interobserver agreement. In general, the radiological portion of the diagnostic criteria for VaD needs revision and refinement to include bone fide cases of VaD not currently accepted by imaging rules, and for the early detection of patients with VCI.

Treatment of vascular dementia: evidence from trials with non-cholinergic drugs

A considerable number of therapeutic trials have been performed in vascular dementia (VaD). The results of these trials have generally been considered as disappointing and no drug treatment has been so far approved for the treatment of VaD by regulatory agencies. The aim of the present paper is to critically review the results of randomized clinical trials performed with non-cholinergic drugs in VaD. The conclusions of the present review are that: (1) some drugs such as nicergoline, memantine, posatirelin, propentofylline, and pentoxifylline have shown some, although partly limited, benefits in VaD patients; (2) besides a lack of efficacy of the tested drugs, possible causes of the negative results of many randomized clinical trials in VaD are the enrolment of patients with heterogeneous subtypes of VaD, the small sample size, and the use of end-points and cognitive tests inadequate for the VaD setting because derived from previous experience in the field of Alzheimer disease. Preliminary analyses show that focusing therapeutic trials on specific forms of VaD such as the subcortical type may lead to results different from those obtained in a heterogeneous VaD group. This selective focus seems to be better suited for disclosing specific treatments in the field of VaD.

Controversies in vascular dementia

The main controversies in the field of vascular dementia (VaD) include the nosological classification of this disorder, the definition of dementia, the differences between the different sets of diagnostic criteria, the concept of Binswanger disease, the role of vascular lesions in Alzheimer disease, and the results of cholinesterase trials in VaD. Vascular Cognitive Disorder (VCD) is the most current nosological classification for the global diagnostic category of cognitive impairment of vascular origin, ranging from mild cognitive impairment (MCI) to vascular dementia. It includes specific disease entities such as poststroke VaD, CADASIL, Binswanger disease, and AD plus CVD. Vascular cognitive impairment (VCI) is limited to cases of vascular MCI without dementia, by analogy with the concept of amnesic MCI, currently considered the earliest clinically diagnosable stage of Alzheimer disease (AD). The main problem of VaD stems from the currently accepted definition of dementia that requires memory loss as the sine qua non for the diagnosis. This may result in over-sampling of patients with AD worsened by stroke (AD+CVD). We have proposed an operational definition of dementia in VaD based on the presence of abnormal executive control function, severe enough to interfere with social or occupational functioning. This may increase the sensitivity and specificity of the NINDS-AIREIN criteria. In donepezil trials in VaD that excluded prestroke MCI, the placebo groups were different from those in AD without CVD, and in AD+CVD trials.

Behavioral and Psychological Symptoms of Dementia: Trial Design

Behavioral and psychological symptoms in dementia (BPSD) are an important aspect of the disorder that are now receiving more attention. The design of the trials in vascular dementia needs to account for these features. The specific area of BPSD in vascular dementia, their assessment, and relationship to the design of trials are considered in this article.

Regulatory Issues in Vascular Dementia: A European Perspective

In many studies vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction; accounting for 10% to 50% of the cases, depending on the geographical area, patient population, and diagnostic criteria used. There is growing evidence that VaD does not include only multi-infarct dementia (MID) but relates to complex interactions of different etiologies (risk factors, cerebrovascular disease), structural changes in the brain, host factors and cognition. This resulted in reconceptualization of VaD to emphasize the differences from Alzheimer's disease (AD). However, the diagnostic criteria used (DSM-IV, ICD-10, NINDS-AIREN, or ADDTC) are based on the experience with AD and as such have their limitations and are not interchangeable. From a regulatory point of view, therefore, future research is needed to better define VaD in general and possible subtypes of VaD as targets for drug trials. Methodological issues in VaD trials, as opposed to AD, will be emphasized. The European Medicinal Products Evaluation Agency (EMEA) has adopted a guideline for trials of symptomatic treatments of dementia, particularly in AD. There is no explicit guideline for VaD trials; however, many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. On the other hand, VaD may be potentially preventable, underscoring the importance of primary and secondary prevention as in other cerebrovascular disorders. Large long-term trials are necessary to study the importance of different risk factors and possible intervention strategies with special reference to VaD.

Regulatory Aspects of Vascular Dementia in the United States

There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term "vascular dementia" may not be entirely appropriate to describe this population.

Value of Ginkgo biloba in treatment of Alzheimer dementia

During the last decade, there has been an explosive growth of research concerning the extract of Ginkgo biloba termed Egb 761. In experimental studies, animal studies and clinical studies Ginkgo biloba has shown a similar pharmacological potency and clinical efficacy like synthetic defined drugs in the therapy of reduced cerebral performance. Ginkgo biloba special extract Egb 761 is a standardized and highly purified extract of Ginkgo leaves. Among the active constituents are the ginkgo-flavone glycosides and the terpene-lactones (ginkgolides, bilobalide). The multifactorial principle of action of Ginkgo biloba is characterized by rheological and blood-flow-promoting properties, protective effects against ischaemia and hypoxia, effects on nerve cell energy metabolism, antioedematous and myelin-protective effects, radical-scavenger activity, effects on various cerebral transmitter and receptor systems. These action principles constitute the rationale for clinical trials in vascular dementia and primary degenerative dementia of the Alzheimer type, and in mixed forms of both. The cerebral bioavailability of Ginkgo biloba extract has been demonstrated by electroencephalography. In clinical trials of different working-groups, effects of Ginkgo biloba on the cognitive performance, global function, and activities of the daily living have been found. Metaanalysis in the indication--demential disorders--comparing Ginkgo biloba versus acetylcholinesterase inhibitors have shown a similar clinical efficacy of both therapy regimens with an additional drug safety benefit for Ginkgo. Due to the clinical efficacy the WHO accepted Ginkgo biloba as an antidementiv drug and add it in January 2000 into the recent ATC-Classification Index. In future antidementive therapy drugs with an different mode of action should be given in combination. Furthermore clinical trials with fixed combinations of acetylcholinesterase inhibitors with Ginkgo biloba extracts in moderate or severe dementia would be necessary.

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.

Neuro-radiological findings and the magnitude of cognitive benefit by memantine treatment. A subgroup analysis of two placebo-controlled clinical trials in vascular dementia

Neuro-radiological findings and the magnitude of cognitive benefit by memantine treatment. A subgroup analysis of two placebo-controlled clinical trials in vascular dementia

Dementia severity and the magnitude of cognitive benefit by memantine treatment. A subgroup analysis of two placebo-controlled clinical trials in vascular dementia

Dementia severity and the magnitude of cognitive benefit by memantine treatment. A subgroup analysis of two placebo-controlled clinical trials in vascular dementia

Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial

In Western countries, vascular dementia (VaD) is the most common form of cognitive deterioration after Alzheimer’s disease. Therapeutic trials in VaD have so far failed to yield satisfactory results. One explanation of this failure may be the etiological and clinical heterogeneity of the included patients. Patients with subcortical VaD, defined on a clinical and radiological basis, may constitute a more homogeneous group. Thus, we conducted a post-hoc subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial that evaluated the efficacy and safety of oral nimodipine administered for 6 months in 259 patients. The original patients sample was divided on the basis of head CT in those with subcortical VaD (n=92, 45 nimodipine, 47 placebo) and those with multi-infarct dementia (n=167, 83 nimodipine, 84 placebo). While in the total trial population a treatment effect could not be proved, in this subgroup analysis, the subcortical VaD patients treated with nimodipine performed better on the majority of neuropsychological tests and functional scales in comparison with patients on placebo. No trend could be evidenced in the multi-infarct dementia patients. Treatment efficacy was in particular suggested for the Zahlen-Verbindungs-Test, Fuld-Object-Memory Evaluation, Word Fluency, and for the Instrumental Activities of Daily Living scale. The results did not reach statistical significance in this small sample. Our study preliminarily indicates that nimodipine could be effective in patients with small vessel subcortical VaD and supports the rationale for a further controlled and adequately powered trial to test nimodipine in patients with subcortical VaD.