Executive function subdomains are associated with post-stroke functional outcome and permanent institutionalization.

BACKGROUND AND PURPOSE: Impairment of executive functions (EFs) is a common cognitive symptom post-stroke and affects independence in daily activities. Previous studies have often relied on brief cognitive tests not fully considering the wide spectrum of EF subdomains. A detailed assessment of EFs was used to examine which of the subdomains and tests have the strongest predictive value on post-stroke functional outcome and institutionalization in long-term follow-up. METHODS: A subsample of 62 patients from the Helsinki Stroke Aging Memory Study was evaluated with a battery of seven neuropsychological EF tests 3 months post-stroke and compared to 39 healthy control subjects. Functional impairment was evaluated with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living (IADL) scale at 3 months, and with the mRS at 15 months post-stroke. Institutionalization was reviewed from the national registers of permanent hospital admissions in up to 21-year follow-up. RESULTS: The stroke group performed more poorly than the control group in multiple EF tests. Tests of inhibition, set shifting, initiation, strategy formation and processing speed were associated with the mRS and IADL scale in stroke patients. EF subdomain scores of inhibition, set shifting and processing speed were associated with functional outcome. In addition, inhibition was associated with the risk for earlier institutionalization. CONCLUSIONS: Executive function was strongly associated with post-stroke functional impairment. In follow-up, poor inhibition was related to earlier permanent institutionalization. The results suggest the prognostic value of EF subdomains after stroke.

Post-stroke cognitive impairment is common even after successful clinical recovery.

BACKGROUND AND PURPOSE: Cognitive impairment is common after stroke, but the prevalence and long-term significance of the diverse neuropsychological deficits on functional outcome are still not well known. The frequency and prognostic value of domain-specific cognitive impairments were investigated in a large cohort of ischaemic stroke patients. METHODS: Consecutive patients (n = 409), aged 55-85 years, from the acute stroke unit of the Helsinki University Hospital, Finland, were evaluated with extensive clinical and neuropsychological assessments 3 months post-stroke. Impairments within nine cognitive domains were determined according to age-appropriate normative data from a random healthy population. Functional disability was evaluated with the modified Rankin scale (mRS) 3 and 15 months post-stroke. RESULTS: In all, 83% patients showed impairment in at least one cognitive domain, whereas 50% patients were impaired in multiple (≥3) domains. In cases with excellent clinical recovery at 3 months (mRS = 0-1, no disability), the occurrence of any cognitive impairment was 71%. Memory, visuoconstructional and executive functions were most commonly impaired. A substantially smaller proportion of patients scored below the conventional or more stringent cut-offs in the Mini-Mental State Examination (MMSE). Domain-specific cognitive impairments were associated with functional dependence at 15 months regardless of stroke severity and other confounders. CONCLUSIONS: Cognitive impairment as evaluated with a comprehensive neuropsychological assessment is prevalent in stroke survivors even with successful clinical recovery. Typically multiple domains and complex cognitive abilities are affected. MMSE is not sensitive in detecting these symptoms. Post-stroke cognitive impairment is strongly related to poor functional outcome.

Relationships between white matter hyperintensities, cerebral amyloid angiopathy and dementia in a population-based sample of the oldest old.

Previous reports suggest that brain white matter changes, a surrogate for small vessel disease, are related to cerebral amyloid angiopathy (CAA). However, this relationship has not been explored in population-based studies or in the oldest old (>85 years of age). We studied the relationships between white matter hyperintensities (WMH) determined by post-mortem magnetic resonance imaging (MRI) and neuropathologically assessed CAA in demented and nondemented subjects enrolled in the prospective community-based Finnish Vantaa 85+ Study. In this analysis, we evaluated scans and brain samples from 123 subjects (86% women) with a mean age of 90.6 years. We found CAA to be present in 63 % of the 123 subjects, whereas WMH was present in 74%, and dementia in 59 %. The presence of WMH of any severity did not relate to the presence or the degree of CAA severity, irrespective of the dementia status of the subjects. Furthermore, multivariate regression analysis showed a clear association between CAA and dementia but WMH was not related to dementia in this very old sample. We conclude that severe WMH may not be determined by CAA in this very elderly population.

Extensive white matter changes predict stroke recurrence up to 5 years after a first-ever ischemic stroke.

BACKGROUND: White matter changes (WMCs), a surrogate for small-vessel disease (SVD), have been shown to be associated with a major negative influence on cognition, mood and functioning in daily life. We aimed to investigate whether severe WMCs are a risk factor for recurrent ischemic stroke in a long-term follow-up. METHODS: 320 consecutive patients admitted to hospital with a first-ever ischemic stroke were included in the study and followed up for 12 years using extensive national registers. Patients were aged between 55 and 85 years, with a mean age of 70.8 years. WMCs were rated using MRI and stratified into two grades: absent to moderate WMCs versus severe WMCs. Univariate analysis was performed using binary logistic regression analysis, Kaplan-Meier log rank analysis and life table function. To control for factors such as age, education and cardiovascular risk factors, a multivariate Cox regression proportional hazards analysis was made with forced entry. RESULTS: At least one recurrent stroke, nonfatal or fatal, was diagnosed in 76 (23.8%) patients at 5 years and in 127 (39.7%) patients at 12 years. In univariate analysis, only advancing age was associated with WMCs. The cumulative 5-year recurrence risk was 24.5% [95% confidence interval (95% CI) 23.8-25.2] for patients with absent to moderate WMCs and 39.1% (95% CI 38.1-40.1) for patients with severe WMCs. The cumulative 12-year recurrence risk was 48.1% (95% CI 45.5-50.7) for patients with absent to moderate WMCs and 60.9% (95% CI 56.7-65.1) for patients with severe WMCs. In Cox regression proportional hazards analysis, independent predictors of recurrent stroke at 5 years were severe WMCs [hazard ratio (HR) 1.80, 95% CI 1.11-2.95], atrial fibrillation (HR 1.81, 95% CI 1.09-3.02), hypertension (HR 1.69, 95% CI 1.05-2.71) and peripheral arterial disease (HR 1.89, 95% CI 1.06-3.38). At 12 years, only increasing age remained as an independent predictor (HR 1.04, 95% CI 1.02-1.07). In receiver operating characteristic analysis, the area under the curve for severe WMCs was 0.58 (95% CI 0.51-0.65) for the prediction of stroke recurrence within 5 years. CONCLUSIONS: In our well-defined cohort of poststroke patients, the presence of severe WMCs was an indicator of stroke recurrence up to 5 years after a first-ever ischemic stroke. WMCs can be considered as an SVD marker that summarizes the effects of several classical risk factors on the small-vessel brain network and therefore can be used as a score for risk stratification of stroke recurrence. Our findings further underline the poor long-term prognosis of cerebral SVD.

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia.

BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.

Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study.

OBJECTIVE: To examine the independent contributions and combined interactions of medial temporal lobe atrophy (MTA), cortical and subcortical atrophy, and white matter lesion (WML) volume in longitudinal cognitive performance. METHODS: A total of 477 subjects with age-related WML were evaluated with brain MRI and annual neuropsychological examinations in 3-year follow-up. Baseline MRI determinants of cognitive decline were analyzed with linear mixed models controlling for multiple confounders. RESULTS: MTA and subcortical atrophy predicted significantly steeper rate of decline in global cognitive measures as well as compound scores for psychomotor speed, executive functions, and memory after adjusting for age, gender, education, lacunes/infarcts, and WML volume. Cortical atrophy independently predicted decline in psychomotor speed. WML volume remained significantly associated with cognitive decline even after controlling for the atrophy scores. Moreover, significant synergistic interactions were found between WML and atrophy measures in overall cognitive performance across time and the rate of cognitive decline. Synergistic effects were also observed between baseline lacunar infarcts and all atrophy measures on change in psychomotor speed. The main results remained robust after exclusion of subjects with clinical stroke or incident dementia, and after additional adjustments for progression of WML and lacunes. CONCLUSIONS: Brain atrophy and WML are independently related to longitudinal cognitive decline in small vessel disease. MTA, subcortical, and cortical atrophy seem to potentiate the effect of WML and lacunes on cognitive decline.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort.

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed. CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3 years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness). In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly.

Incident lacunes influence cognitive decline: the LADIS study.

BACKGROUND: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML. METHODS: Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression. RESULTS: After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016). CONCLUSION: Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.

Small-vessel disease relates to poor poststroke survival in a 12-year follow-up.

OBJECTIVE: We sought to compare ultra-long-term poststroke survival in small-vessel disease (SVD) vs non-SVD subtype of stroke. METHODS: We followed patients hospitalized with acute ischemic stroke (age 55-85) for 12 years. The diagnosis of SVD was based on the criteria of Trial of Org 10172 in Acute Stroke Treatment. A detailed medical history regarding the relevant risk factors was obtained. Stroke severity was assessed with the modified Rankin Scale (mRS) at 3 months. Influence of the SVD subtype of stroke was analyzed using Kaplan-Meier log-rank analysis with endpoint all-cause death, and Cox regression proportional hazards model was constructed for multivariate analysis. The association between SVD and causes of death (cardiac, brain-related, all other) was analyzed using Kaplan-Meier log-rank analysis. RESULTS: Of the 486 patients, stroke etiology was SVD in 63 patients (13.0%). Median survival was 4.3 years for SVD and 7.9 years for non-SVD (p ≤ 0.001). In the stepwise Cox regression analysis adjusted for relevant confounders, independent predictors of death were SVD (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.06-2.41), advanced age (HR 1.07, 95% CI 1.05-1.09), stroke severity (mRS 3-5 vs 1-2; HR 2.02, 95% CI 1.58-2.58), smoking (HR 1.44, 95% CI 1.10-1.88), and cardiac failure (HR 1.53, 95% CI 1.14-2.06). SVD was associated with cardiac cause of death (p = 0.021). CONCLUSIONS: In this well-characterized ischemic stroke cohort of patients aged 55-85 years with a 12-year follow-up, acute index stroke attributable to SVD was associated with poorer long-term survival and higher risk for cardiac death than other stroke subtypes.

Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old.

BACKGROUND: Current studies suggest an interaction between vascular mechanisms and neurodegenerative processes that leads to late-onset Alzheimer disease (AD). We tested whether AD pathology was associated with white matter hyperintensities (WMH) or cerebral infarcts in the oldest old individuals. METHODS: Brains from 132 subjects over 85 years old, who came to autopsy from the Vantaa 85+ population-based cohort, were scanned by postmortem MRI and examined for neuropathologic changes. Coronal images were analyzed to determine the degree of frontal and parietal periventricular WMH (PVWMH) and deep WMH (DWMH) and cerebral infarcts. Neuropathologic variables included Consortium to Establish a Registry for Alzheimer's Disease scores for neuritic plaques and Braak staging among subjects in 5 groups: normal aging (NA), borderline with insufficient AD pathology, AD, AD plus other pathology, and other primary degenerative diseases. RESULTS: Frontal DWMH were detected in >50% of the sample. Both frontal PVWMH and DWMH were significantly more extensive in the AD group compared to the NA group or the NA and borderline groups combined. Frontal PVWMH and DWMH were also associated with increased Braak staging (p = 0.03) and the neuritic plaque load (p = 0.01). Further analysis revealed there were a greater number of cerebral infarcts associated with frontal DWMH (p = 0.03) but not with frontal PVWMH. CONCLUSIONS: Our study showed an association between neurofibrillary pathology and frontal PVWMH and DWMH (rather than parietal), as a surrogate of small vessel disease, particularly in very old community-dwelling individuals.

White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study.

OBJECTIVE: We aimed to study if age-related white matter changes (WMC) and vascular risk factors were predictors of cognitive decline in elderly subjects with WMC living independently. METHODS: The Leukoaraiosis and Disability prospective multinational European study (LADIS) evaluates the impact of WMC on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Additionally, dementia, subtypes of dementia, and cognitive decline without dementia were classified according to usual clinical criteria. MRI was performed at entry and at the end of the study. RESULTS: A total of 639 subjects were included (74.1 +/- 5 years, 55% women, 9.6 +/- 3.8 years of schooling). At end of follow-up, 90 patients had dementia and 147 had cognitive impairment no dementia. Using Cox regression analysis, WMC severity independently predicted cognitive decline (dementia and not dementia), independently of age, education, and medial temporal atrophy (MTA). Diabetes at baseline was the only vascular risk factor that independently predicted cognitive decline during follow-up, controlling for age, education, WMC severity, and temporal atrophy. Considering subtypes of dementia, Alzheimer disease (AD) was predicted only by MTA, while vascular dementia was predicted by previous stroke, WMC severity, and MTA. CONCLUSION: WMC severity and diabetes are independent predictors of cognitive decline in an initially nondisabled elderly population. Vascular dementia is predicted by previous stroke and WMC, while AD is predicted only by MTA.

Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study.

BACKGROUND: Growing evidence suggests that cerebral white-matter changes and depressive symptoms are linked directly along the causal pathway. We investigated whether baseline severity of cerebral white-matter changes predict longer-term future depressive outcomes in a community sample of non-disabled older adults. METHOD: In the Leukoaraiosis and Disability in the Elderly (LADIS) study, a longitudinal multi-centre pan-European study, 639 older subjects underwent baseline structural magnetic resonance imaging (MRI) and clinical assessments. Baseline severity of white-matter changes was quantified volumetrically. Depressive outcomes were assessed in terms of depressive episodes and depressive symptoms, as measured by the Geriatric Depression Scale (GDS). Subjects were clinically reassessed annually for up to 3 years. Regression models were constructed to determine whether baseline severity of white-matter changes predicted future depressive outcomes, after controlling for confounding factors. RESULTS: Baseline severity of white-matter changes independently predicted depressive symptoms at both 2 (p<0.001) and 3 years (p=0.015). Similarly, white-matter changes predicted incident depression (p=0.02). Over the study period the population became significantly more disabled (p<0.001). When regression models were adjusted to account for the influence of the prospective variable transition to disability, baseline severity of white-matter changes no longer predicted depressive symptoms at 3 years (p=0.09) or incident depression (p=0.08). CONCLUSIONS: Our results support the vascular depression hypothesis and strongly implicate white-matter changes in the pathogenesis of late-life depression. Furthermore, the findings indicate that, over time, part of the relationship between white-matter changes and depression may be mediated by loss of functional activity.

Cognitive impairment predicts poststroke death in long-term follow-up.

BACKGROUND: Poststroke global cognitive decline and dementia have been related to poor long-term survival. Whether deficits in specific cognitive domains are associated with long-term survival in patients with ischaemic stroke is not known in detail. METHODS: Patients with acute stroke subjected to comprehensive neuropsychological evaluation were included in the study (n = 409) and followed up for up to 12 years. RESULTS: In Kaplan-Meier analysis, impairments in following cognitive domains predicted poor poststroke survival (estimated years): executive functions (48.2%) (5.8 vs 10.1 years, p<0.0001), memory (59.9%) (6.8 vs 9.3 years, p = 0.009), language (28.9%) (5.3 vs 8.6 years, p = 0.004) and visuospatial/constructional abilities (55.2%) (5.6 vs 10.1 years, p<0.0001). Low Mini Mental Status Examination (MMSE)

Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study.

BACKGROUND: Global age related white matter changes (ARWMC) are associated with progressive gait disturbances and falls, hypothesised to result from interruptions of cortico-subcortical circuits controlling balance, posture and locomotion. METHODS: The location of ARWMC in a large cohort of elderly non-disabled individuals with reported falls was analysed, using the cross sectional data of the Leukoaraiosis and Disability (LADIS) study. Detailed anatomical distributions of ARWMC assessed by MRI studies were analysed with respect to falls and balance performance. RESULTS: The severity of global ARWMC was significantly associated with a history of falls in the year prior to study inclusion (22.2% in the mild, 31.6% in the moderate and 37.3% in the severe ARWMC group according to the Fazekas scale; p = 0.002). Analysing the anatomical distribution of ARWMC, using the semiquantitative Scheltens scale, in multivariate analysis, periventricular (p = 0.006) and frontal deep (p = 0.033) ARWMC were independently associated with falls. Furthermore, logistic regression identified frontal deep (p = 0.003) ARWMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances. CONCLUSION: The association of frontal and periventricular ARWMC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC.

Age related white matter changes predict stroke death in long term follow-up.

OBJECTIVE: Recurrent strokes and functional decline are predicted by age related white matter changes (ARWMC). Whether they are associated with long term survival among hospital patients referred for acute stroke is not known. METHODS: A total of 396 consecutive acute stroke patients subjected to MRI were included in the study and followed-up for up to 12 years. RESULTS: 28% had mild, 18% had moderate and 54% had severe ARWMCs. In Kaplan-Meier analysis, poor survival was predicted by severe ARWMCs (p<0.0001), cardiac failure (CF, p<0.0001), atrial fibrillation (AF, p<0.0001), other arrhythmias (p = 0.003), peripheral arterial disease (PAD, p = 0.004) and poor modified Rankin score (mRS) (p<0.0001). ARWMC was related to death by all brain related causes, especially ischaemic stroke (p<0.0001). In stepwise Cox regression analysis adjusted with significant risk factors, severe ARWMCs (hazard ratio (HR) 1.34, 95% CI 1.03 to 1.73; p = 0.029), age (HR 1.07, 95% CI 1.05 to 1.09; p<0.0001), CF (HR 1.59, 95% CI 1.17 to 2.15; p = 0.003), AF (HR 1.68, 95% CI 1.24 to 2.27; p = 0.001), PAD (HR 1.59, 95% CI 1.11 to 2.26; p = 0.011), diabetes (HR 1.44, 95% CI 1.08 to 1.92; p = 0.013), smoking (HR 1.60, 95% CI 1.23 to 2.08; p<0.0001) and mRS (HR 1.65, 95% CI 1.26 to 2.14; p<0.0001) were independently associated with death from all causes. Severe ARWMCs (HR 1.80, 95% CI 1.10 to 2.96; p = 0.019), age (HR 1.05, 95% CI 1.01 to 1.09; p = 0.009), AF (HR 1.82, 95% CI 1.08 to 3.07; p = 0.026), PAD (HR 2.17, 95% CI 1.19 to 3.95; p = 0.012) and mRS (HR 2.75, 95% CI 1.67 to 4.54; p<0.0001) were specifically associated with death from brain related causes. CONCLUSIONS: In patients with acute stroke, ARWMC seems to be a significant predictor of poor long term survival and death by ischaemic stroke.

Poststroke dementia predicts poor survival in long-term follow-up: influence of prestroke cognitive decline and previous stroke.

BACKGROUND: The aim of this study was to investigate the influence of poststroke dementia on long-term survival after acute stroke and also to assess the possible influence of prestroke cognitive decline and previous stroke on this relationship. METHODS: A total of 451 consecutive patients with acute ischaemic stroke admitted to hospital were included in the study and followed up for 12 years. Dementia was diagnosed 3 months after stroke in 115 patients (25.5%). RESULTS: In Kaplan-Meier analysis, poststroke dementia predicted poor long-term survival (5.1 years vs 8.8 years in patients who did not have poststroke dementia; p<0.001). Prestroke cognitive decline had a negative influence on survival in patients with poststroke dementia (3.8 years vs 5.8 years; p<0.001); however, previous stroke did not affect survival in these patients (p = 0.676). In stepwise Cox regression proportional hazards analysis adjusted for significant covariates, poststroke dementia (hazard ratio (HR) 1.53; p = 0.003), advanced age (HR 1.07; p<0.001), severity of stroke (HR 1.91; p<0.001), smoking (HR 1.35; p = 0.035), cardiac failure (HR 1.61; p = 0.003) and atrial fibrillation (HR 1.89; p = 0.035) were all independent predictors of poor long-term survival. Poststroke dementia (HR 2.33; p<0.001), advanced age (HR 1.07; p<0.001) and poor Rankin score (HR 2.15; p = 0.001) were associated with death from brain-related causes, including infarction, haemorrhage and dementia. CONCLUSIONS: Long-term follow-up of our large well-defined poststroke cohort indicated that in patients with acute stroke, dementia is a significant predictor of poor long-term survival and death from brain-associated causes. Prestroke cognitive decline seems to have an additional negative influence on survival, but previous stroke does not seem to affect survival.

Long-term survival after ischemic stroke in postmenopausal women is affected by an interaction between smoking and genetic variation in nitric oxide synthases.

BACKGROUND: We aimed to study whether variations in vasoregulatory endothelial nitric oxide synthase (eNOS 4a/b) and tissue-injury-associated inducible nitric oxide synthase (iNOS R5/4) genes and smoking might explain gender differences in long-term survival after stroke. METHODS: A total of 486 consecutive acute stroke patients, subjected to MRI, were followed up for a mean of 7.6 years. The eNOS 4a/b (n = 300) and iNOS R5/4 (n = 310) genotypes were determined by PCR. Of these patients, 213/300 (71.0%; eNOS 4a/b) and 223/310 (71.9%; iNOS R5/4) had died. RESULTS: Despite the fact that women were older than men (72.3 vs. 69.5 years, p = 0.001) at recruitment, poor long-term survival was not sex-related, but instead predicted by age (p < 0.0001), cardiac failure (p = 0.004), smoking (p = 0.017), diabetes (p = 0.049), and variation in the eNOS gene locus (p = 0.033). Smoking and variations in both eNOS [hazard ratio (HR) = 1.53, p = 0.011] and iNOS loci (HR = 1.52, p = 0.073) were found to impact upon poor survival. We found a strong interaction between smoking, female sex, and the iNOS R5/4 genotype with the risk of death (HR = 3.23, CI = 1.51-6.90, p = 0.002). Compared with nonsmoking noncarriers, postmenopausal women who had been smokers and carried either the rare iNOS R5 allele (17.1%; HR = 4.23, CI = 1.84-9.75, p = 0.001) or the common eNOS 4b allele (71%; HR = 3.14, CI = 1.49-6.62, p = 0.003) were at a higher risk of death during the follow-up. These interactions were independent of each other, and were not found among men. CONCLUSIONS: The interaction between smoking and genetic variants of eNOS and iNOS predicts survival after stroke, especially among postmenopausal women.

White matter changes contribute to corpus callosum atrophy in the elderly: the LADIS study.

BACKGROUND AND PURPOSE: The corpus callosum (CC) is the most important structure involved in the transmission of interhemispheric information. The aim of this study was to investigate the potential correlation between regional age-related white matter changes (ARWMC) and atrophy of CC in elderly subjects. MATERIALS AND METHODS: In 578 subjects with ARWMC from the Leukoaraiosis And DISability (LADIS) study, the cross-sectional area of the CC was automatically segmented on the normalized midsagittal MR imaging section and subdivided into 5 regions. The ARWMC volumes were measured quantitatively by using a semiautomated technique and segmented into 6 brain regions. RESULTS: Significant correlation between the area of the rostrum and splenium regions of the CC and the ARWMC load in most brain regions was identified. This correlation persisted after correction for global atrophy. CONCLUSION: Increasing loads of ARWMC volume were significantly correlated with atrophy of the CC and its subregions in nondisabled elderly subjects with leukoaraiosis. However, the pattern of correlation between CC subregions and ARWMC was not specifically related to the topographic location of ARWMC. The results suggest that ARWMC may lead to a gradual loss of CC tissue.

Association of gait and balance disorders with age-related white matter changes: the LADIS study.

OBJECTIVE: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. METHODS: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. RESULTS: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 +/- 2.1 in the mild, 9.9 +/- 2.0 in the moderate, 8.9 +/- 2.6 in the severe group; p < 0.001). Walking speed correlated with the severity of ARWMC (1.24 +/- 0.28 m/second in the mild, 1.18 +/- 0.32 m/second in the moderate, and 1.09 +/- 0.31 m/second in the severe group; p < 0.001). Balance was best in individuals with mild ARWMC (single leg stance time: 18.9 +/- 10.8 seconds) compared with moderate and severe ARWMC (16.4 +/- 10.8 and 13.6 +/- 11.2 seconds) (p < 0.001). Physically inactive individuals had a higher risk of a pathologic SPPB score (moderate vs mild ARWMC: odds ratio 1.60, 95% CI 1.02 to 2.52; severe vs mild ARWMC: odds ratio 1.75, 95% CI 1.09 to 2.80). CONCLUSIONS: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

Galantamine treatment in Alzheimer's disease with cerebrovascular disease: responder analyses from a randomized, controlled trial (GAL-INT-6).

Alzheimer's disease combined with cerebrovascular disease (AD with CVD) is associated with progressive decline, with CVD impacting AD onset and severity of progression. Subjects with confirmed diagnosis of AD with CVD were treated with galantamine during a six-month, randomized, placebo-controlled trial (N = 285). Responder analyses were performed for cognitive, behavioural and functional outcome measures. Galantamine treatment resulted in significantly greater cognitive and functional improvements compared with placebo at six months, and a significantly higher percentage of treatment responders. The proportion of responders demonstrating improved or maintained cognition on the 11-item AD assessment scale-cognitive subscale (ADAS-cog/11) was 60.5% for galantamine versus 46.0% for placebo (P = 0.013). The proportion of patients responding by at least four-points on the ADAS-cog/11 was significantly greater for the galantamine group compared with placebo (33.6% versus 17.2%; P = 0.003). Seventy-five percent of galantamine-treated subjects improved or remained stable as assessed by CIBIC-plus compared with 53.6% on placebo (P = 0.0006). Significantly higher responder rates were observed with galantamine for behaviour (64.9% versus 56.6%; P = 0.024), and numerically favourable responder rates were seen with galantamine for activities of daily living. Treatment-emergent adverse events were generally related with the gastrointestinal system (nausea 20% versus 10%; vomiting 12% versus 5%; galantamine and placebo groups, respectively). Three deaths occurred during double-blind treatment: 2 of 188 subjects receiving galantamine, and 1 of 97 subjects receiving placebo. These findings are consistent with a broad range of cognitive, functional and behavioural benefits with galantamine across the spectrum of AD and AD with CVD.