Middle Cerebral Artery Pulsatility Index is Associated with Cognitive Impairment in Lacunar Stroke.

BACKGROUND AND PURPOSE: Pulsatility index (PI) of the middle cerebral artery is postulated to reflect the vascular resistance in the artery distal of the probe, and has been reported to increase in small vessel disease, diabetes mellitus, ageing, and dementia. Lacunar infarcts are considered to be related to cognitive impairment. We therefore conducted a study to assess the association between cognitive impairment and PI in patients with a lacunar infarct. METHODS: Consecutive patients presenting with an acute lacunar syndrome who were admitted to the stroke unit were enrolled. The patients were examined with Doppler ultrasonography of the intracranial arteries, and the PI of the middle cerebral artery was recorded. Cognitive function was evaluated by mini-mental state examination (MMSE), clock drawing test, and trail making test (TMT) A and B. RESULTS: Among the 113 patients included, 85 patients had an acute lacunar infarct and 28 had one or more nonlacunar infarcts. The mean PI was 1.46 (SD = .33). PI was significantly (P < .05) associated with MMSE, TMT A and TMT B in patients with lacunar infarct, even after adjustment for multiple patient characteristics (age, sex, prestroke hypertension, smoking, previous stroke, and diabetes). CONCLUSIONS: PI was associated with the cognitive performance in patients with lacunar infarcts and a lacunar syndrome. An elevated PI may be related to impairment in several cognitive domains. These findings suggest that transcranial Doppler ultrasonography could be an adjunct tool for early diagnosis of cognitive impairment after stroke.

[Effects of Tongluo Xingnao effervescent tablets on blood rheology, iNOS, VEGF and LDH-5 in MID rats].

The study was to explore effects of Tongluo Xingnao effervescent tablets on the blood rheology, iNOS, VEGF and LDH-5 in multi-infarct dementia(MID) model rats. Establish MID model rats were induced by microthrombosis, from which 50 successful model rats were randomly divided into five groups, such as the model control group, the dihydroergotoxine mesylate tablets(hydergine) group(0.7 mg•kg⁻¹), Tongluo Xingnao effervescent tablets high-dose, medium-dose and low-dose groups(7.56, 3.78, 1.89 g•kg⁻¹). Another ten rats in the sham group were randomly selected as the parallel control group. Each group was orally administered with drugs for 90 days. The learning and memory ability was evaluated with the Morris water maze test, while the whole blood viscosity and the erythrocyte aggregation index derived from abdominal aorta were measured in different shear rates. In addition, the levels of VEGF and iNOS in the serum were determined by ELISA kits. The expression of LDH-5 in hippocampus of rats was measured with immunohistochemistry and image quantitative analysis. The result showed that Tongluo Xingnao effervescent tablets notably decreased the escape latency of MID model rats, increased times of entering into the escape platform and prolonged retention time in medium ring, meanwhile the whole blood viscosity in MID model rats was also notably reduced in four shear rates, i.e. 1, 5, 30, 200 S⁻¹, erythrocyte aggregation index, serum VEGF and iNOS, and average optical density value of LDH-5, with a statistically significant differences compared with the model control group (P<0.05). In conclusion, Tongluo Xingnao effervescent tablets could improve the ability of learning and memory of MID model rats and the blood rheology, reduce the level of iNOS, VEGF and the expression of LDH-5, and then improved the brain energy supply.

Varicella zoster virus vasculopathy: a treatable form of rapidly progressive multi-infarct dementia after 2 years' duration.

We describe an extraordinarily protracted case of varicella zoster virus (VZV) multifocal vasculopathy in a man who presented initially with ischemic optic neuropathy and then suffered 4 episodes of stroke manifesting as multi-infarct dementia over a 2-year period. Brain magnetic resonance imaging (MRI) and angiography (MRA) revealed cortical and subcortical infarctions as well as vasculitic occlusion and stenosis. The patient was treated with corticosteroids and later with cyclophosphamide. More than 2 years after the onset of neurological disease, two cerebrospinal fluid (CSF) examinations revealed the presence of anti-VZV IgG antibody with reduced serum-to-CSF ratios of anti-VZV IgG compared with ratios for total IgG and albumin, indicative of intrathecal synthesis of anti-VZV IgG. After definitive diagnosis, immunosuppressive drugs were discontinued and he was treated with intravenous acyclovir; both mental status and gait improved and no further episodes of neurological dysfunction ensued. The favorable outcome in this patient indicates that VZV vasculopathy can be treated successfully even after 26 months. VZV must be considered as a possible cause of neurological disease in any patient with idiopathic multifocal vasculopathy.

Cognitive and psychiatric effects of vitamin B12 replacement in dementia with low serum B12 levels: a nursing home study.

BACKGROUND: The aim of this study is to determine whether B12 replacement would ameliorate cognitive and psychiatric symptoms in elderly subjects with dementia and low serum B12 levels. METHODS: A test group (n = 28) of nursing home residents with low serum B12 levels (<250 pg/mL) and a matched comparison group (n = 28) with normal serum B12 levels (>300 pg/mL) were evaluated by blinded raters while the test group received intramuscular (IM) B12 replacement therapy. All subjects were assessed at baseline, 8 weeks, and 16 weeks with the Dementia Rating Scale, Brief Psychiatric Rating Scale, and Geriatric Depression Scale. RESULTS: Although B12 replacement produced significant improvement in hematologic and metabolic parameters, it yielded no significant effect on cognitive or psychiatric variables. A few subjects evidenced notable individual treatment responses; however, these were not statistically more frequent than in the normal B12 group. CONCLUSIONS: These results suggest that B12 replacement is unlikely to benefit cognitive or psychiatric symptoms in the vast majority of elderly dementia patients with low serum B12 levels.

[External validity of clinical trials for treatment of dementia with ginkgo biloba extracts]. / Die Rolle der externen Validität bei der Beurteilung klinischer Studien zur Demenzbehandlung mit Ginkgo-biloba-Extrakten.

OBJECTIVES: Ginkgo bilobaextracts have been applied in the treatment of dementia of vascular origin and Alzheimer disease for a long time. However, in the most elaborated systematic review to date, Birks and colleagues drew quite a moderate conclusion in spite of the overall positive results. The reason for such a moderate interpretation often lies in the preference of internal validity such as randomisation and blinding, sometimes at the expense of external validity (conditions of everyday practice). Because of this, we analysed the clinical trials evaluated by Birks et al. in the light of the following questions: 1) To what extent are criteria of external validity considered? 2) Does the additional evaluation of external validity lead to differences in the estimation of efficacy? 3) What are the results of our analysis in regard to the efficacy of ginkgo biloba extract? MATERIAL AND METHODS: The selection of the clinical trials was based upon those included in the review carried out by Birks et al. (2002). The criteria for evaluating external validity were developed by consulting physicians specialised in geriatrics, experts in herbal pharmaceutics and affected/ related individuals (patients and relatives). RESULTS: We analysed 34 placebo-controlled clinical trials with a total of 37 comparisons. 21 trials showed significant results in favour of the ginkgo application in more than 50% of investigated outcome parameters, eight were significant for less than 50% of the parameters, four showed a trend in favour of ginkgo, and only two studies (with 4 comparisons) found no advantage for ginkgo. One of these negative studies used daily doses far below the usual dose range [corrected] We found no evidence for publication bias. None of the studies considered all criteria of external validity. Out of the seven studies with relatively high external validity and good overall quality, five showed a significant result in more than 50% of parameters, two in < or = 50%. Severe adverse effects were not mentioned in the studies. DISCUSSION AND CONCLUSIONS: 1) In the clinical studies analysed external validity was taken into account only moderately, especially with respect to additional non-pharmaceutical interventions and selection of participants. 2) The evaluation according to external validity led to a different selection of studies that were used for estimation of the ginkgo efficacy without effects on the overall result. 3) Sufficient evidence of the efficacy of ginkgo bilobaextracts in the treatment of dementia of vascular origin and Alzheimer disease is provided in spite of methodological limitations. Further studies should focus on effectiveness, ginkgo-sensitive subgroups, more individualised therapeutic goals and corresponding outcome measurements.

Different responses to rivastigmine in subcortical vascular dementia and multi-infarct dementia.

Vascular dementia (VaD) is associated with a large amount of heterogeneity, as it groups together a broad category of patients in whom various manifestations of cognitive decline are attributed to cerebrovascular or cardiovascular disease. Thus, a study was designed to determine the effects of rivastigmine on cognitive function, global daily living performance, and behavioral disorders in VaD patients versus an active control (nimodipine), stratifying patients according to the type of VaD, subcortical vascular dementia (sVAD), and multi-infarct dementia (MID). The trial was a prospective study. This study shows that long-term treatment with rivastigmine, at dosages approved for therapeutic use in Alzheimer's disease, produces significant improvement in all behavioral symptoms in 2 forms of VaD, MID and sVaD, except delusions. It also suggests that rivastigmine may enable a reduction in concomitant neuroleptics and benzodiazepines in VaD, especially in MID. The results are discussed with an overview of the literature.

Protective effects of Nicotiflorin on reducing memory dysfunction, energy metabolism failure and oxidative stress in multi-infarct dementia model rats.

The present study aimed to determine whether Nicotiflorin, a natural flavonoid extracted from coronal of Carthamus tinctorius, has a protective effect on cerebral multi-infarct dementia in rats. The multi-infarct dementia model rats were prepared by injecting man-made micro-thrombi into the right hemisphere. The administration groups were treated once daily with 30, 60 and 120 mg/kg Nicotiflorin (i.g.) from 5 days before ischemia operation to 3 days after the operation for biochemical examination, 10 days for Morris water maze study and morphological observations and 20 days for eight-arm radial maze task. 2,3,5-triphenyltetrazolium chloride (TTC) staining showed that infarct volume of each Nicotiflorin administration group was much smaller than that of vehicle-treated multi-infarct dementia group, and hematoxylin and eosin (HE) staining showed that histopathological abnormalities of each Nicotiflorin group were also much lighter than that of vehicle-treated multi-infarct dementia group. Each Nicotiflorin group showed much better spatial memory performance in Morris water maze tests and eight-arm radial maze task compared with the vehicle-treated multi-infarct dementia group, significantly attenuated the elevation of lactic acid and malondialdehyde (MDA) contents and the decrease in lactate dehydrogenase (LDH), Na(+)K(+)ATPase, Ca(2+)Mg(2+)ATPase and superoxide dismutase (SOD) activity in the brain tissue which was composed of striatum, cortex and hippocampus of the ischemia hemisphere at day 3 after ischemia operation. These results suggest that Nicotiflorin has protective effects on reducing memory dysfunction, energy metabolism failure and oxidative stress in multi-infarct dementia model rats.

[Pharmacological treatment of vascular cognitive impairment]. / Farmakoterapia zaburzen funkcji poznawczych uwarunkowanych czynnikami naczyniowymi.

Vascular dementia is second most common cause of dementia. The paper highlights the most important trends in pharmacological treatment of vascular dementia. Result of a clinical trial of some agents appears to be promising. Pentoxifyline appears to be useful in multi-infarct vascular dementia. Nimodipine produced improvement in subcortical dementia. Some other agents like ginkgo biloba, acetylocholinesterase inhibitors, memantine and other also have shown mild benefit or at least were associated with some stabilization of dementia.

Effect of acetaminophen on behavior, well-being, and psychotropic medication use in nursing home residents with moderate-to-severe dementia.

OBJECTIVES: To evaluate the effect of regularly scheduled administration of analgesic medication on behavior, emotional well-being, and use of as-needed psychotropic medications in nursing home residents with moderate-to-severe dementia. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Nursing-home based. PARTICIPANTS: Twenty-five nursing home residents with moderate-to-severe dementia. INTERVENTION: Participants received 4 weeks of acetaminophen (3,000 mg/d) and 4 weeks of placebo. MEASUREMENTS: Behavior and emotional well-being were assessed using Dementia Care Mapping, an observational method that quantifies time spent in behaviors across 26 domains (e.g., social interaction, unattended distress) and assesses emotional state while behaviors are being observed. Agitation was measured using the Cohen-Mansfield Agitation Inventory. As-needed psychotropic medication use was aggregated from medication logs. RESULTS: Participants spent more time in social interaction, engaged with media, talking to themselves, engaged in work-like activity, and experiencing unattended distress when they received acetaminophen than they did when they received placebo. Participants also spent less time in their rooms, less time removed from the nursing home unit, and less time performing personal care activities when they received acetaminophen. There were no effects on agitation, emotional well-being, or as-needed psychotropic medication use. CONCLUSION: Untreated pain inhibits activity in nursing home residents with moderate-to-severe dementia. Pain treatment in this group may facilitate engagement with the environment.

[Delay in progression of dependency and need of care of dementia patients treated with Ginkgo special extract EGb 761]. / Verzögerung der Progression von Abhängigkeit und Pflegebedürftigkeit von Demenz-Patienten unter Behandlung mit Ginkgo-Spezialextrakt EGb 761.

In studies on the efficacy of antidementia drugs, a delay in symptom progression was often postulated based on a comparison of the change upon treatment and an assumed "natural" progression. Such comparisons were usually based on the cognitive subscore of the Alzheimer's Disease Assessment Scale (ADAS-cog), using either the drug-placebo differences after randomized treatment or the changes upon active drug treatment in open-label extension studies. Considering quality of life, competence, cost of care, and economics of therapeutic measures, a delay in the progression of dependency and need of care appears to be more relevant than a delay in cognitive abilities not directly related to activities of daily living. Therefore, for dementia patients treated with the Ginkgo special extract EGb 761, the delay in loss of capacities needed to cope with the demands of daily living was estimated, based on the Geriatric Evaluation of Relative's Rating Instrument (GERRI). The drug-placebo differences documented after 26 and 52 weeks of treatment corresponded to a delay in progression by 10 and 21 months, respectively. Regarding the subgroup with dementia of the Alzheimer type, the estimated delay was 16 and 25 months, respectively. It could thus be shown that by treatment with EGb 761 the progression of dependency and need of care can be slowed down, which may have an impact on costs for care, e.g. by delaying nursing home placement.

Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial.

In 1996, Kanowski et al. reported about the beneficial effects of ginkgo biloba special extract EGb 761 (240 mg/day) in outpatients with pre-senile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) of mild to moderate severity. The comparison of the results of this double-blind, placebo-controlled, randomized, multi-center study with other dementia studies is hampered by the fact that only the responder analysis of the per-protocol (PP) population, which was pre-specified in the protocol as confirmatory analysis, has been published in detail so far. Moreover, cognitive functioning was measured using the Syndrom-Kurztest (SKT), whereas results of other studies are based on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog). Therefore, the conventional intention-to-treat (ITT) analysis of this study is provided with an estimation of ADAS-cog scores based on measured SKT scores. After 24 weeks of treatment, the ITT analysis of the SKT and estimated ADAS-cog scores revealed a mean decrease in the total score by -2.1 (95 % CI: -2.7; -1.5) points and -2.7 (95 % CI: -3.5; -1.9) points, respectively, for the EGb 761 group, which indicates an improvement in cognitive function. On the contrary, the placebo group exhibited only a minimal change of -1.0 (95 % CI: -1.6; -0.3) and -1.3 (95 % CI: -2.0; -0.4) points, respectively. The changes from baseline differed significantly between treatment groups by 1.1 (SKT) and 1.4 (estimated ADAS-cog) points, respectively (P = 0.01). The Clinical Global Impression of Change (CGI, Item 2) favored the EGb 761 group with a mean difference of 0.4 points (P = 0.007). Changes in the rating related to activities of daily living (Nürnberger-Alters-Beobachtungs-Skala, NAB) showed a favorable trend for EGb 761R. A subgroup analysis regarding patients with DAT yielded comparable results. Using a decrease of at least 4 points on the estimated ADAS-cog scores as cutoff criterion for treatment response, 35 % of EGb 761-treated patients were considered responders versus only 19 % for the placebo group (P = 0.01). The results of this ITT analysis substantiate the outcomes previously obtained with a responder analysis of the per-protocol population and confirm that EGb 761 improves cognitive function in a clinically relevant manner in patients suffering from dementia. The therapeutic effect is in line with the outcome of another EGb 761 study conducted in the U.S.

[Vascular dementia]. / Vaskuläre Demenz.

The term vascular dementia refers to dementia syndromes which are caused by hypoxic-ischaemic brain lesions. Lesions found in vascular dementia such as complete and incomplete infarctions, selective necroses, and others are nonspecific. The characteristics and severity of the clinical syndrome are determined by the size and topography of the ischaemic lesions. Among others, age and pre-existing brain atrophy are risk factors for the development of dementia based on vascular lesions. There is a high comorbidity of Alzheimer's disease and vascular dementia. It can be presumed that ischaemic lesions and Alzheimer-like pathological changes exert additive effects in the manifestation of the clinical dementia syndrome. The diagnostic process follows three steps: 1. presence of a dementia syndrome, 2. presence of cerebrovascular disease, 3. evidence for a relationship between 1 and 2. Present diagnostic criteria, such as "International Classification of Diseases" (ICD-10), "National Institute of Neurological Disorders," "Stroke-Associated Internationale pour la Reserche et l'Enseignement en Neurosciences" (NINDS-AIREN), and "Alzheimer's Disease Diagnostic and Treatment Centers" (ADDTC) describe differing constellations and show little congruence. Estimates of the prevalence depend highly on the set of criteria used. Hence, they differ considerably.

Jian Nao Ning for treatment of memory impairment in patients with mild or moderate multi-infarct dementia.

Forty patients with multi-infarct dementia (MID) were randomly assigned to the treatment group (25 cases) treated with Jian Nao Ning (JNN) and the duxil control group (15 cases). Memory function were assessed at baseline and endpoint using memory subscales of a battery of New Psychometric Tests (Chinese version) including mini-mental state examination (MMSE), verbal memory, and non-verbal memory, etc. After treatment, the mean scores of verbal memory in the Hopkins Verbal Learning Test (P<0.05) and total memory scores of memory items (P<0.001) in JNN group increased significantly; and improvement in episodic memory function including story recall (immediate and delayed), delayed word recall, verbal learning and verbal recognition and visual recognition in the JNN group was better than that in the duxil control group, suggesting that JNN can obviously improve memory function for the patients with mild or moderate multi-infarct dementia.

[Two case reports of cerebral autosomal dominant arteriophaty with subcortical infarctions and leukoencephalopathy (CADASIL)]. / Arteriopatia cerebrale autosomica dominante con infarti sottocorticali e leucoencefalopatia (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) was first reported in European families and since 1993 it has been observed in America, Africa and Asia, suggesting that today the disease probably still remains largely underdiagnosed. CADASIL appears to be essentially a disorder of the arteries linked to single missense mutations in the Notch3 gene locus on chromosome 19; the aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of the disorder. It is characterized by recurrent stroke episodes and focal neurologic deficits progressing to pseudobulbar palsy and dementia, caused by multiple lacunar infarctions with ischemic and diffuse white matter abnormalities on neuroimaging. Migraine with aura, epileptic seizures and affective disorders are frequent additional symptoms of CADASIL. It is usually observed in the 3rd decade, but some individuals remain asymptomatic close to the age of 60. MRI displays a marked leukoencephalopathy in affected individuals as early as in the age of 20. The authors emphasize the role of a direct DNA test for gene mutation to make a differential diagnosis between CADASIL and other forms of vascular leukoencephalopathy as Alzheimer's dementia, multiple sclerosis and Binswanger's subcortical arteriopathic encephalopathy where CADASIL's arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits.

Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking.

BACKGROUND: White matter lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are underlaid by severe ultrastructural changes of the arteriolar wall. Although chronic ischemia is presumed to cause the tissue lesions, the pattern of perfusion abnormalities and hemodynamic reserve in CADASIL, particularly within the white matter, remains unknown. METHODS: We used the MRI bolus tracking method in 15 symptomatic patients with CADASIL (5 with dementia) and 10 age-matched control subjects before and 20 minutes after the intravenous injection of acetazolamide (ACZ, 17 mg/kg). Cerebral blood flow (CBF), blood volume (CBV), and mean transit time (MTT) were calculated both in the cortex and in the white matter according to the singular value decomposition technique. Perfusion parameters were obtained in regions of hyperintensities and within the normal-appearing white matter as observed on T2-weighted images. Analysis was performed with both absolute and relative (region/whole brain) values. RESULTS: A significant reduction in absolute and relative CBF and CBV was found within areas of T2 hyperintensities in white matter in the absence of significant variations of MTT. This reduction was more severe in demented than in nondemented patients. No significant change in absolute CBF and CBV values was observed in the cortex of patients with CADASIL. A decrease in relative CBF and CBV values was detected in the occipital cortex. After ACZ administration, CBF and CBV increased significantly in both the cortex and white matter of affected subjects, but the increase in absolute CBF was lower within areas of increased signal on T2-weighted images in patients than in the white matter of control subjects. CONCLUSIONS: In CADASIL, both basal perfusion and hemodynamic reserve are decreased in areas of T2 hyperintensities in the white matter. This hypoperfusion appears to be related to the clinical severity. The significant effect of ACZ on CBF and CBV suggests that cerebral perfusion might be increased using pharmacological vasodilation in CADASIL.