A pilot study to evaluate the effects of Cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration. A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease. Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Propentofylline improves regional cerebral glucose metabolism and neuropsychologic performance in vascular dementia. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. A 12-month, randomized, placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-R. The European Propentofylline Study Group. Cranial electrostimulation (CES) in patients with probable Alzheimer's disease.
The effects of the neurotrophic compound Cerebrolysin (Cere) on cognitive performance, evaluated with the ADAS-cog, and on qEEG activity were investigated in forty one patients with mild to moderate severe probable vascular dementia (VaD) according to NINDS-AIREN criteria, included in a placebo-controlled pilot study. Patients received i.v. infusions of Cere (10 or 30 ml) or placebo (normal saline) 5 days/week for 4 weeks. Mean score of change from baseline in the ADAS-cog and percent change from baseline in slow to fast EEG power ratio (PR) scores were the two primary endpoints. Correlations between cognition and qEEG were also evaluated for both baseline scores and for scores of change from baseline in ADAS-cog and in qEEG parameters, including EEG power ratio (PR) as an index of EEG slowing. Baseline ADAS-cog scores showed significant positive correlations with delta power, theta power and PR scores, and correlated negatively with alpha activity. These correlations indicating that an increased EEG slowing is associated with a worst cognitive performance in VaD patients. Cere treatment improved cognitive performance significantly at the 10 ml dose and reduced EEG slowing with both 10 and 30 ml dosages. A significant positive correlation between PR and ADAS-cog scores of change from baseline was observed in Cere-treated patients. According to results of this pilot study, it is concluded that Cere improves cognitive performance and reduces EEG slowing in patients with VaD, and that there is a positive relationship between changes in cognition and qEEG activity induced by Cere. The conduction of further regular clinical trials is required to confirm the potential utility of Cere in the treatment of VaD suggested by the present results. The safety and efficacy of early acetylcholinesterase inhibitors therapy in patients with cognitive impairment no dementia (CIND) after a cerebrovascular accident have not been examined. In this study, we investigated the safety and efficacy of rivastigmine in cognition, particularly executive function in patients with CIND because of cerebrovascular disease.
                This study was a 24-week, double-blind, randomized, placebo-controlled trial of ischemic stroke patients seen at a tertiary hospital who had cognitive impairment no dementia because of cerebrovascular disease. The intervention was either rivastigmine or placebo up to 9 mg/day. The primary outcome of interest was mean change from baseline in the Ten-Point Clock Drawing and Color Trails 1 and 2.
                Fifty patients were randomized into rivastigmine (n = 25) and placebo (n = 25) arms. Patients in the rivastigmine group showed statistically significant improvement (1.70 vs 0.13, P = 0.02) on the animal subtask of the verbal fluency measure compared with placebo. There was also a trend (non-significant) towards improvement in Color Trails II.
                In this pilot study, we demonstrated that rivastigmine was well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning. Cerebrolysin is a compound with neurotrophic and neuroprotective activity. It is produced by enzymatic breakdown of purified brain proteins and consists of low molecular weight peptides and amino acids. Cellular and animal models of cerebral ischaemia have shown that it is a potent neuroprotective agent. We explored the safety and preliminary outcome of Cerebrolysin treatment in patients with acute stroke.
                Randomised, placebo-controlled, parallel group trial. Patients with acute stroke were randomised within 24 h of stroke onset to IV therapy with placebo or Cerebrolysin 50 mL/day for 21 days. Both groups received concomitant treatment with ASA 250 mg/day PO and pentoxifylline 300 mg/day IV. Clinical examinations were performed on days 1, 3, 7, 21 and 90 post baseline. Outcome measures were the Canadian Neurological Scale, the Barthel Index, the Clinical Global Impressions, the Mini-Mental State Examination, and the Syndrome Short Test. Treatment emergent adverse events, lab tests, and vital signs were recorded to assess the safety of Cerebrolysin.
                146 patients were enrolled in two groups: 78 Cerebrolysin and 68 placebo. At baseline, no significant group differences were observed. Patients in the Cerebrolysin group had no significant improvement in the CNS score, the Barthel Index and the Clinical Global Impressions when compared to the placebo group. A significant improvement of cognitive function of the patients on Cerebrolysin was observed in the Syndrome Short Test when compared to the placebo group. Cerebrolysin was well tolerated and safe. Adverse events occurred with a similar frequency in both groups.
                The results demonstrate that neurotrophic treatment with Cerebrolysin is safe and well tolerated by patients with acute stroke. The findings, despite the small sample size, also indicate a potential treatment effect of Cerebrolysin in acute stroke. Larger studies, however, are needed to confirm and extend these findings. Vascular dementia is the second commonest form of dementia, and vascular factors contribute to the development of dementia in many patients with Alzheimer's disease. Galantamine amplifies the acetylcholine response by inhibiting acetylcholinesterase and modulating nicotinic receptors. It has shown broad, sustained benefits in patients with Alzheimer's disease. We investigated the effects of galantamine in patients with a diagnosis of probable vascular dementia or Alzheimer's disease combined with cerebrovascular disease.
                Eligible patients were randomly assigned galantamine 24 mg/day (n=396) or placebo (n=196) in a multicentre, double-blind, 6-month trial. Primary endpoints were cognition (Alzheimer's disease assessment scale, cognitive subscale [ADAS-cog]) and global functioning (clinician's interview-based impression of change plus caregiver input [CIBIC-plus]). Secondary endpoints included assessments of activities of daily living and behavioural symptoms. Patients were monitored for adverse events. Analyses were on the basis of observed case or last observation carried forward.
                Galantamine showed greater efficacy than placebo on ADAS-cog (galantamine change -1.7 [SE 0.4] vs placebo 1.0 [0.5]; treatment effect 2.7 points; p<0.0001) and CIBIC-plus (213 [74%] vs 95 [59%] patients remained stable or improved, p=0.0001). Activities of daily living and behavioural symptoms were also significantly improved compared with placebo (p=0.002 and p=0.016, respectively). Galantamine was well tolerated.
                Galantamine showed a therapeutic effect on all key areas of cognitive and non-cognitive abilities in this group of dementia patients. In a double-blind, placebo-controlled trial in thirty patients with mild to moderate vascular dementia (VD) according to DSM-III-R criteria, the effects of the adenosine uptake blocker propentofylline (HWA 285) on regional cerebral glucose metabolism (rCMRGl) was studied using positron emission tomography of 2-[18F]fluoro-2-deoxy-D-glucose (FDG). 25 subjects completed the 3-months study. Propentofylline significantly improved relative rCMRGl in the motor cortex, while relative rCMRGl in the placebo treated group worsened significantly. Neuropsychologically, visual information processing was improved in the propentofylline group and we observed a trend towards a slowing of the progression of cognitive deterioration in patients with VD. The results of the longitudinal analysis showed further that neuropsychological and metabolic changes are closely related. These findings justify a large-scale clinical trial to prove therapeutic efficacy. There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD.
                This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks.
                A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.
                In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo. The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD).
                VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects.
                NCT00099216.
                710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance.
                Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology. Alzheimer's disease (AD) and vascular dementia (VaD) share several features such as overactivation of microglial cells, damage induced by free radicals, glutamate and calcium overload. Propentofylline (HWA 285) has shown beneficial effects on all of these common elements, thus favouring its use in both subtypes of dementia. In a multinational, randomized, 12-month, double-blind, parallel-group study 260 out-patients with mild to moderate AD or VaD received 300 mg propentofylline (n = 129) or placebo (n = 131) three times daily 1 h before meals. The efficacy was tested at four independent rater levels (physician, psychologist, relative and patient) with assessments covering three major domains of dementia (global function, cognitive function and activities of daily living). After 12 months, the total patient population showed statistically significant treatment differences in favour of propentofylline for the global measures of dementia (Gottfries-Bråne-Steen scale, GBS, p = 0.001; Clinical Global Impressions, CGI, item I: p = 0.004, item II: p = 0.072) as well as for the cognitive measures (Syndrome Short Test, SKT, p = 0.002) and Mini-Mental State Examination (p = 0.001). The activities of daily living also showed a significant treatment difference in favour of propentofylline (p = 0.002). No significant treatment differences were found for rating scales performed by the patients. At month 12, VaD patients showed treatment differences in favour of propentofylline for the GBS total score (p = 0.006), CGI item I (p = 0.004), GGI item II (p = 0.044) and SKT (p = 0.028). Treatment differences for AD patients were all in favour of propentofylline and reached statistical significance for the SKT (p = 0.018). Propentofylline showed a good safety profile with respect to adverse events, vital signs, ECG and laboratory changes. In one study, behavioral disorders of patients with vascular dementia reacted positively to cranial electrostimulation (CES). In the present study, it was examined whether CES could improve cognition and (affective) behavior in patients with probable Alzheimer's disease (AD). Eighteen AD patients, divided into an experimental and a placebo group, were treated for 30 min per day, 5 days a week, for 6 weeks. No improvements in cognition and (affective) behavior were found after CES.
Cerebrolysin may have positive effects on cognitive function and global function in elderly patients with vascular dementia of mild to moderate severity, but there is still insufficient evidence to recommend Cerebrolysin as a routine treatment for vascular dementia due to the limited number of included trials, wide variety of treatment durations and short-term follow-up in most of the trials.