Efficacy and Safety of Divaza for the Correction of Oxidative Disturbances in Patients with Cerebral Atherosclerosis: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to determine if Divaza, a drug with nootropic and antioxidant effects, was safe and effective for the correction of oxidative disturbances and to stabilize cognitive impairment in patients with cerebral atherosclerosis. STUDY DESIGN: The study design consisted of a 12-week multicenter, randomized, double-blind, placebo-controlled, prospective trial in parallel groups. SETTING: The setting in which the study was conducted comprised 10 clinical centers across the Russian Federation. INTERVENTIONS: Patients were randomized into 2 groups and instructed to take either 2 tablets of the study drug or a placebo 3 times per day in conjunction with basic therapy. OUTCOMES: The primary outcome was a change in the average endogenous antioxidant potential after the completion of the study. The blood indicators of the oxidative stress (OS) were analyzed at the baseline and then after 12 weeks of therapy using iron-induced chemiluminescence analysis. The Montreal cognitive assessment test was used as a secondary outcome measure to evaluate cognitive impairment at the end of the study. RESULTS: 124 outpatients with a mean age of 60.7 ± 7.6 years were enrolled and randomly assigned to receive Divaza (n = 65) or a placebo (n = 59). An improvement of cognitive function was observed in all patients of the Divaza group at the end of the treatment; this was significantly better than the placebo group (100 [100] vs. 89.5 [89.1]%, respectively, p = 0.0272 [p = 0.0128]). The administration of Divaza restored the activity of the endogenous antioxidant system. The change in the average level of lipoprotein resistance to oxidation after 12 weeks of therapy, compared to the baseline, was significantly higher in the Divaza group (14.8 ± 14.7 [14.8 ± 14.7] seconds latent period vs. 6.4 ± 16.9 [6.9 ± 16.7] seconds in the placebo group (p = 0.007 [p = 0.0107]). CONCLUSIONS: Divaza is a safe and effective therapeutic option for attenuating OS and recovery of cognitive impairment in patients with cerebral atherosclerosis.

Brain arteriolosclerosis.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

Mid- and Late-Life Leisure-Time Physical Activity and Global Brain Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study.

BACKGROUND: Physical activity (PA) may slow the development of dementia by reducing the accumulation of amyloid. OBJECTIVE: We tested the hypothesis that higher levels of leisure-time PA in mid- or late-life were associated with lower brain amyloid burden in late-life among 326 non-demented participants from the Atherosclerosis Risk in Communities Study of brain florbetapir positron emission tomography (ARIC-PET) ancillary. METHODS: Self-reported PA was quantified using a past-year recall, interviewer-administered questionnaire in mid-life (1987-1989, aged 45-64 years) and late-life (2011-2013, aged 67-89 years). Continuous PA estimates were classified as 1) any leisure-time PA participation (yes/no); 2) meeting the 2018 United States' PA guidelines (yes/no); and 3) per 1 standard deviation (SD) higher metabolic equivalent of task (MET) minutes per week (MET·min·wk-1). A brain magnetic resonance imaging scan with Florbetapir PET was performed in late-life. Adjusted odds ratios (OR) of elevated amyloid burden, defined as a global cortical standardized uptake value ratio (>1.2), compared to no elevated amyloid burden were estimated according to PA measures. RESULTS: Among the 326 participants (mean age: 76 years, 42% male, 41% Black), 52% had elevated brain amyloid burden. Mid-life leisure-time PA did not show a statistically significant lower odds of elevated late-life amyloid burden (OR = 0.71, 95% CI: 0.43-1.18). A 1 SD (970 MET. min. wk-1) higher PA level in mid-life was also not significantly associated withelevated amyloid burden (OR = 0.89, 95% CI: 0.69-1.15). Similar estimates were observed for meeting versus not meeting PA guidelines in both mid- and late-life. CONCLUSION: Self-reported higher mid- and late-life leisure-time PA were not significantly associated with lower amyloid burden. Data show a trend of an association, which is, however, imprecise, suggesting replication in larger studies.

Poststroke Montreal Cognitive Assessment and Recurrent Stroke in Patients With Symptomatic Intracranial Atherosclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment occurs in 20%-40% of stroke patients and is a predictor of long-term morbidity and mortality. In this study, we aim to determine the association between poststroke cognitive impairment and stroke recurrence risk, in patients with anterior versus posterior circulation intracranial stenosis. METHODS: This is a post-hoc analysis of the Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. The primary predictor was poststroke cognitive function measured by Montreal Cognitive Assessment (MOCA) at 3-6 months and the primary outcome was recurrent ischemic stroke. We used univariate and multivariable cox-regression models to determine the associations between MOCA at 3-6 months and recurrent stroke. RESULTS: Of the 451 patients enrolled in SAMMPRIS, 393 patients met the inclusion criteria. The mean age of the sample (in years) was 59.5 ± 11.3, 62.6% (246 of 393) were men. Fifty patients (12.7%) had recurrent ischemic stroke during a mean follow up of 2.7 years. The 3-6 month MOCA score was performed on 351 patients. In prespecified multivariable models, there was an association between 3 and 6 month MOCA and recurrent stroke (hazard ratio [HR] per point increase .93 95% confidence interval [CI] .88-.99, P = .040). This effect was present in anterior circulation stenosis (adjusted HR per point increase .92 95% CI .85-0.99, P = .022) but not in posterior circulation artery stenosis (adjusted HR per point increase 1.00 95% .86-1.16, P = .983). CONCLUSIONS: Overall, we found weak associations and trends between MoCA at 3-6 months and stroke recurrence but more notable and stronger associations in certain subgroups. Since our study is underpowered, larger studies are needed to validate our findings and determine the mechanism(s) behind this association.

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults.

BACKGROUND: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. OBJECTIVE: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. METHODS: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. RESULTS: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-ß plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups. CONCLUSION: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

Effect of revascularization on cognitive outcomes in intracranial steno-occlusive disease: a systematic review.

OBJECTIVESteno-occlusive diseases of the cerebral vasculature have been associated with cognitive decline. The authors performed a systematic review of the existing literature on intracranial steno-occlusive disease, including intracranial atherosclerosis and moyamoya disease (MMD), to determine the extent and quality of evidence for the effect of revascularization on cognitive performance.METHODSA systematic search of PubMed/MEDLINE, the Thomson Reuters Web of Science Core Collection, and the KCI Korean Journal Database was performed to identify randomized controlled trials (RCTs) in the English-language literature and observational studies that compared cognitive outcomes before and after revascularization in patients with steno-occlusive disease of the intracranial vasculature, from which data were extracted and analyzed.RESULTSNine papers were included, consisting of 2 RCTs and 7 observational cohort studies. Results from 2 randomized trials including 142 patients with symptomatic intracranial atherosclerotic steno-occlusion found no additional benefit to revascularization when added to maximal medical therapy. The certainty in the results of these trials was limited by concerns for bias and indirectness. Results from 7 observational trials including 282 patients found some cognitive benefit for revascularization for symptomatic atherosclerotic steno-occlusion and for steno-occlusion related to MMD in children. The certainty of these conclusions was low to very low, due to both inherent limitations in observational studies for inferring causality and concerns for added risk of bias and indirectness in some studies.CONCLUSIONSThe effects of revascularization on cognitive performance in intracranial steno-occlusive disease remain uncertain due to limitations in existing studies. More well-designed randomized trials and observational studies are needed to determine if revascularization can arrest or reverse cognitive decline in these patients.

[Multicenter observational program for evaluation of the effectiveness of the recognan (citicoline) in the correction of cognitive impairment in patients with chronic cerebrovascular pathology]. / Mnogotsentrovaia nabliudatel'naia programma po otsenke éffektivnosti preparata rekognan (tsitikolin) v korrektsii kognitivnykh narushenii u patsientov s khronicheskoi tserebrovaskuliarnoi patologiei.

AIM: To study the efficacy and safety of recognan (citicoline) in the treatment of cognitive and depressive disorders in chronic cerebrovascular pathology (chronic brain ischemia) developed in patients with arterial hypertension and/or atherosclerosis. MATERIAL AND METHODS: Seven hundred and thirty-six patients with cerebrovascular pathology, cognitive impairment and mild dementia were examined. The sample included 279 (37.9%) men and 457 (62.1%) women aged from 35 to 80 years (mean age 64.5±8.7 years). The drug recognan ('Gerofarm', Russia) was administered in the dose of 1000 mg daily during 30 days. Recovery of cognitive functions was assessed with MSSE, correction of visual/spatial coordination with CDT, depression severity with MGDS. RESULTS: The improvement of cognitive function, memory and visual/spatial coordination, decrease in depression severity were observed during the treatment. CONCLUSION: Recognan reduced cognitive dysfunction and disturbances of visual/spatial coordinationas well as had a positive effect on the emotional sphere decreasing the level of depression.

Surgical Therapy.

Many prior investigations have indicated the important role of medical treatment to prevent stroke in patients with intracranial atherosclerosis, with angioplasty and stenting occasionally being performed. In a subgroup of patients with severe hemodynamic impairment, extracranial-intracranial (EC-IC) bypass surgery may be considered. Additionally, in patients with massive infarctions due to middle cerebral artery (MCA) occlusion, the use of decompressive craniectomy may lower mortality rates and improve long-term quality of life. However, the benefit of these surgical procedures in patients with intracranial atherosclerosis has long been controversial. In this chapter, we review the surgical therapies for patients with intracranial atherosclerosis. This review does not include EC-IC bypass surgery for moyamoya disease, which is discussed in another chapter.

The use of MMSE and MoCA in patients with acute ischemic stroke in clinical.

BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are brief cognitive screening tools that have been developed for the screening of patients with Mild Cognitive Impairment. METHODS: A total of 105 patients were included in this study, aged 53-89 years, with acute ischemic stroke admitted to hospital and fell into two groups: stroke patients with cognitive impairment (SCI) and controls with no cognitive impairment (n-SCI). The patient's characteristics are collected and regression analyses were performed to predict cognitive impairments. We use MMSE and MoCA assessment as prognostic indices for cognitive impairments of patient's with stroke. OBJECTIVES: Our aim was to examine the effectiveness of the MMSE and MoCA in screening cognitive impairments. MAIN RESULTS: There were significant difference among the two groups in the prevalence of diabetes mellitus (p < 0.05) and intracranial atherosclerosis (p < 0.05). A linear regression determined that the age, diabetes, intracranial atherosclerosis predicted the cognitive impairments. The ROC results for MoCA with an AUC of 0.882 and the corresponding results for MMSE show a similar AUC of 0.839. CONCLUSION: Neuropsychological performance of stroke patients was influenced by biological and demographic variables: age, diabetes and intracranial atherosclerosis. The MoCA and MMSE are both reliable assessments for the diagnosis of cognitive impairment after stroke.

[Results of intelligence investigations in civil pilots with atherosclerotic changes in cerebral vessels].

Intelligence was evaluated in 73 normal civil pilots (control) and 70 with atherosclerotic cerebral vessels including 23 men with atheromas. Intelligence was evaluated with the use of computerized EPI (Gorbov's modification). Pilots with cerebral atherosclerosis tended to slightly decrease mean IQ values in comparison with the normal; IQ values remained high enough to attest professional efficiency. Atheromas did not impact results of the numerical (IQ2) and verbal (IQ3) tests. Hemodynamically negligible stable atheromas did not disturb cognitive functions of the pilots and, therefore, they were certified for continuation of the flight career.

[Individual psychological attributes of civil pilots with atherosclerotic cerebral vessels].

Object of investigation was types of personality of civil pilots. The investigation involved healthy pilots (n = 58, controls) and pilots afflicted with cerebral atherosclerosis (n = 67) including pilots with atherosclerotic plaques (n = 23). The personality questionnaire developed by L.N. Sobchik was used. The investigation showed that signs of personality accentuation in pilots with cerebral atherosclerosis were largely manifested by distortion of individual psychological attributes. This finding may be helpful to members of the medical flight certification board in making prognosis of pilot's health and professional longevity.

Predictors of subjective cognitive difficulties in older adults with atherosclerotic vascular disease.

OBJECTIVE: The objective of this study was to describe the relationship among cognitive test performance, psychological symptoms, and subjective cognitive difficulties in older adults with atherosclerotic vascular disease. METHOD: Participants were 80 adults over the age of 55 with an unequivocal diagnosis of atherosclerotic vascular disease. Participants completed measures of neuropsychological functioning, psychological symptoms, and two measures of subjective cognitive difficulties. RESULTS: Psychological symptoms were most strongly associated with higher levels of reported cognitive difficulties. Overall neuropsychological functioning was modestly related to subjective cognitive difficulties but did not remain significant after controlling for psychological symptoms. CONCLUSIONS: In this sample of older adults with atherosclerotic vascular disease, self-reported cognitive difficulties were most strongly related to overall level of psychological distress and not to actual cognitive test scores. Therefore, psychological factors may play an important role in the phenomenon of self-perceived cognitive decline in geriatric populations.

Cognitive and functional impairment in hypertensive brain microangiopathy.

Brain microangiopathy, whose neuroimaging expression is represented by age-related white matter changes (ARWMC), is largely due to hypertension and it is, in turn, responsible for geriatric syndromes, including decline in cognitive, functional and motor/gait abilities. This review analyzes the link between hypertension and ARWMC, as well as the complex relationships between ARWMC and cognitive impairment, executive dysfunction, and movement/gait abnormalities. The available evidence supports the hypothesis that these functional consequences of ARWMC are responsible for substantial disability in the elderly. Thus, adequate treatment of hypertension may represent a feasible way to reduce the burden of disability in late life.

Clinically defined vascular depression in the general population.

BACKGROUND: Vascular depression is regarded as a subtype of depression, especially in, but not entirely restricted to, the elderly, characterized by a specific clinical presentation and an association with (cerebro)vascular risk and disease. It could have major implications for treatment if subjects at risk for such a depression could be easily identified by their clinical presentation in general practice. METHOD: We studied the symptom profile of depression in subjects with and without vascular risk factors in two large Dutch community-based studies, the Rotterdam Study and the Amsterdam Study of the Elderly (AMSTEL). RESULTS: We could not confirm the specific symptom profile in depressed subjects with vascular risk factors in either of the two cohorts. Depressed subjects with vascular risk factors showed more loss of energy and more physical disability than those without vascular risk factors. However, presumed specific symptoms of vascular depression, namely psychomotor retardation and anhedonia, were not significantly associated with any of the vascular risk indicators. Loss of energy was significantly associated with myocardial infarction and peripheral arterial disease. CONCLUSIONS: In these two large community-based studies we identified some differences between vascular and non-vascular depressed subjects but found no evidence for a specific symptom profile of vascular depression as previously defined.

Vascular risk and low serum B12 predict white matter lesions in patients with major depression.

BACKGROUND: While patients with depression have been shown to have a greater incidence of vascular risk factors and structural brain changes, any association with dietary co-factors is unclear. METHODS: Forty-seven patients with major depression (mean age = 52.8 years, SD = 12.6) and 21 healthy volunteers (mean age = 54.7 years, SD = 9.1) underwent high-resolution magnetic resonance imaging scanning. T2-weighted films were scored for deep white matter (DWM), periventricular (PV), and subcortical (SC) hyperintensities. RESULTS: There was no difference in lesion severity between patients and control subjects. After controlling for age, vitamin B12 levels were predictive of DWM lesions in patients. DWM and SC lesions were associated with histories of hypertension and diabetes. LIMITATIONS: A relatively small sample of patients were recruited from specialist services and the findings may not represent those observed in larger or community-based cohorts. CONCLUSIONS: In patients with major depression, vitamin B12 levels and histories of hypertension and/or diabetes are predictive of white matter lesions.

[Psychological health status and nursing countermeasures of cerebral arterial sclerosis patients].

OBJECTIVE: To estimate the psychological health status of attacking stage patients with cerebral arterial sclerosis(CAS). METHODS: Sixty in-patients were surveyed by filling up the questionnaire (SCL-90) and compared with the customary model in China. RESULTS: The symptomatic factor scores of somatization and depression of the patients were obviously higher than those of the customary model (P < 0.001). Their symptomatic factor scores of anxiety and obsessive-compulsive were higher than those of the customary model (P < 0.05). The symptomatic factor score of phobic anxiety was higher than that of the customary model (P < 0.01). CONCLUSION: Somatization, obsessive-compulsive, depression, anxiety and phobic anxiety are common psychological problems. Corresponding nursing countermeasures are proposed in our study.

Type-2 diabetes and cognitive function in a non-demented population.

OBJECTIVES: To study if type-2 (non-insulin-dependent) diabetes mellitus (NIDDM) is associated with cognitive dysfunction independently of clinically diagnosed dementia in an elderly population. MATERIAL AND METHODS: Cognitive function was investigated with a brief neuropsychological test battery in a non-demented elderly population consisting of 183 NIDDM (World Health Organization, 1985) patients and 732 non-diabetic subjects. RESULTS: Patients with NIDDM were impaired in the Trail-Making Test parts A and C, which may be a reflection of mildly affected frontal lobe/executive functions. Women with NIDDM performed better than non-diabetic subjects in the Mini-Mental State Examination. CONCLUSIONS: We conclude that NIDDM per se is not associated with impaired memory in the elderly, and the minor defects observed in tests of frontal lobe/executive functions are unlikely to affect daily living. In the non-demented population aged 69 78 years, NIDDM does not carry a significant risk of cognitive dysfunction, when compared to the non-diabetic subjects.