Objectives To review the evidence for an association of white matter hyperintensities with risk of stroke, cognitive decline, dementia, and death.Design Systematic review and meta-analysis.Data ...sources PubMed from 1966 to 23 November 2009.Study selection Prospective longitudinal studies that used magnetic resonance imaging and assessed the impact of white matter hyperintensities on risk of incident stroke, cognitive decline, dementia, and death, and, for the meta-analysis, studies that provided risk estimates for a categorical measure of white matter hyperintensities, assessing the impact of these lesions on risk of stroke, dementia, and death.Data extraction Population studied, duration of follow-up, method used to measure white matter hyperintensities, definition of the outcome, and measure of the association of white matter hyperintensities with the outcome.Data synthesis 46 longitudinal studies evaluated the association of white matter hyperintensities with risk of stroke (n=12), cognitive decline (n=19), dementia (n=17), and death (n=10). 22 studies could be included in a meta-analysis (nine of stroke, nine of dementia, eight of death). White matter hyperintensities were associated with an increased risk of stroke (hazard ratio 3.3, 95% confidence interval 2.6 to 4.4), dementia (1.9, 1.3 to 2.8), and death (2.0, 1.6 to 2.7). An association of white matter hyperintensities with a faster decline in global cognitive performance, executive function, and processing speed was also suggested.Conclusion White matter hyperintensities predict an increased risk of stroke, dementia, and death. Therefore white matter hyperintensities indicate an increased risk of cerebrovascular events when identified as part of diagnostic investigations, and support their use as an intermediate marker in a research setting. Their discovery should prompt detailed screening for risk factors of stroke and dementia.
Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline.
A total of 1,352 participants without ...dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later.
Hypertension in midlife was associated with accelerated WMHV progression (p < 0.001) and worsening executive function (TrB-A score; p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy (p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume (p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 95%confidence interval 1.07-2.33, p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 1.02-1.88, p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 1.44-81.01, p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function.
Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.
Background and purpose
Guidelines on monogenic cerebral small‐vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of ...Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin‐A‐related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) and type IV collagen (COL4)A1/2.
Methods
We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management.
Results
We have proposed ‘red‐flag’ features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus.
Conclusions
The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.
Delaying the onset of dementia by just a few years could have a major impact on the prevalence of the disease at the population level. Vascular risk factors are modifiable and may offer an important ...opportunity for preventive approaches. Several studies have shown that diabetes, hypertension, obesity, and smoking are associated with an increased risk of cognitive decline and dementia, but other groups have not observed such a relation. Positive associations were observed mainly in studies where risk factors were assessed in midlife, suggesting that age is an important modulator in the relation between vascular risk factors and cognition. The population attributable risk of dementia is particularly high for hypertension. Associations of vascular risk factors with cognitive decline and dementia are probably mediated largely by cerebrovascular disease, including both stroke and covert vascular brain injury, which can have additive or synergistic effects with coexisting neurodegenerative lesions. To date, randomized trials have not convincingly demonstrated that treating vascular risk factors is associated with a reduction in cognitive decline or dementia risk. Of eight randomized trials testing the effect of antihypertensive agents on dementia risk, only one was positive, and another in a subgroup of individuals with recurrent stroke. In most trials, cognition and dementia were secondary outcomes, follow-up was short and treatment was initiated at an older age. No effect on cognitive decline or dementia could be demonstrated for statins and intensive glycemic control. Future areas of investigation could include differential class effects of antihypertensive drugs on cognitive outcomes and identification of high risk individuals as target population for clinical trials initiated in midlife.
Retarder la survenue de la démence de quelques années seulement aurait un impact majeur sur la prévalence de cette maladie à l’échelle de la population. Les facteurs de risque vasculaires sont modifiables et pourraient constituer une cible importante pour des stratégies de prévention. Plusieurs études ont montré que le diabète, l’hypertension, l’obésité, et le tabac étaient associés à un risque accru de déclin cognitif et démence, mais d’autres études n’ont pas pu mettre en évidence de telles associations. Des associations significatives étaient observées principalement dans des études où les facteurs de risque vasculaires étaient évalués à un âge moyen, suggérant un effet modulateur important de l’âge dans la relation entre facteurs de risque vasculaires et cognition. Le risque attribuable de démence est particulièrement élevé pour l’hypertension artérielle. L’association des facteurs de risque vasculaires avec le déclin cognitif et la démence est probablement médiée principalement par la pathologie cérébrovasculaire, incluant à la fois les accidents vasculaires cérébraux et les lésions cérébrovasculaires « silencieuses », qui peuvent avoir des effets additifs voire synergiques avec des lésions neurodégénératives coexistantes. À ce jour, les essais thérapeutiques randomisés n’ont pas démontré de façon convaincante que traiter les facteurs de risque vasculaires était associé à un ralentissement du déclin cognitif et une réduction du risque de démence. Parmi huit essais thérapeutiques randomisés testant l’effet de traitements antihypertenseurs sur le risque de démence, seul un était positif ; un autre essai était positif dans un sous-groupe d’individus avec récidive d’accident vasculaire cérébral. Dans la plupart des essais, la cognition et la démence n’étaient que des critères de jugement secondaires, le suivi était court et le traitement était initié à un âge avancé. Aucun bénéfice des statines ou d’un contrôle glycémique intensif n’a pu être démontré sur le déclin cognitif et la démence. De futurs axes de recherche pourraient inclure les effets différentiels de certaines classes d’antihypertenseurs sur la cognition ainsi que l’identification d’individus à haut risque comme population cible pour des essais thérapeutiques initiés dans des populations d’âge moyen.
Accumulating evidence links blood pressure variability (BPV) with white matter hyperintensities (WMH) and stroke. The longitudinal association between BPV with late onset depression (LOD) and ...cognitive decline remains unexplored.
Prospective cohort study of 2812 participant's age ⩾65 years (median age 72 years, 63.6% female) without dementia or stroke. Serial clinic visits assessed blood pressure, cognitive function, depression disorder, and depressive symptoms. A brain magnetic resonance imaging (MRI) substudy was performed in 1275 persons to examine possible associations with WMH.
The interaction between symptomatic LOD and systolic BPV was associated with cognitive decline on the Isaac Set Test slope -4.45; 95% confidence interval (CI) -8.92 to -0.16, p = 0.04, Benton Visual Retention Test (slope -0.89; 95% CI -1.77 to -0.01, p = 0.049), Mini Mental State Examination (slope -1.08; 95% CI -1.86 to -0.30, p = 0.007) and Finger Tapping Test (slope -7.53; 95% CI -13.71 to -1.34, p = 0.017) but not Trail Making Test-A or -B/A. The MRI substudy demonstrated that systolic BPV was associated with cognitive decline via interactions with depression and total WMH volume, but this was not dependent on either deep or periventricular WMH volumes.
The findings show that the interaction between systolic BPV with symptomatic depression and WMH increases cognitive decline in persons ⩾65 years of age. Future work could extend these findings by examining systolic BPV in relation to cognitive decline and WMH in older populations with depression.
Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable ...conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this ...association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.
We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D).
Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (β ± SE = -0.47 ± 0.18; p = 0.008), executive function (β ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.
Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.
To examine whether risk factor profile, baseline features, and outcome of cervical artery dissection (CEAD) differ according to the dissection site.
We analyzed 982 consecutive patients with CEAD ...included in the Cervical Artery Dissection and Ischemic Stroke Patients observational study (n = 619 with internal carotid artery dissection ICAD, n = 327 with vertebral artery dissection VAD, n = 36 with ICAD and VAD).
Patients with ICAD were older (p < 0.0001), more often men (p = 0.006), more frequently had a recent infection (odds ratio OR = 1.59 95% confidence interval (CI) 1.09-2.31), and tended to report less often a minor neck trauma in the previous month (OR = 0.75 0.56-1.007) compared to patients with VAD. Clinically, patients with ICAD more often presented with headache at admission (OR = 1.36 1.01-1.84) but less frequently complained of cervical pain (OR = 0.36 0.27-0.48) or had cerebral ischemia (OR = 0.32 0.21-0.49) than patients with VAD. Among patients with CEAD who sustained an ischemic stroke, the NIH Stroke Scale (NIHSS) score at admission was higher in patients with ICAD than patients with VAD (OR = 1.17 1.12-1.22). Aneurysmal dilatation was more common (OR = 1.80 1.13-2.87) and bilateral dissection less frequent (OR = 0.63 0.42-0.95) in patients with ICAD. Multiple concomitant dissections tended to cluster on the same artery type rather than involving both a vertebral and carotid artery. Patients with ICAD had a less favorable 3-month functional outcome (modified Rankin Scale score >2, OR = 3.99 2.32-6.88), but this was no longer significant after adjusting for baseline NIHSS score.
In the largest published series of patients with CEAD, we observed significant differences between VAD and ICAD in terms of risk factors, baseline features, and functional outcome.
Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major ...contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3′-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3′-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
Objective: To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeADStroke) affects outcome and major haemorrhage rates.
Methods: We used a multicentre CeADStroke ...database to compare CeADStroke patients treated with and without thrombolysis. Main outcome measures were favourable 3‐month outcome (modified Rankin Scale 0–2) and ‘major haemorrhage’ any intracranial haemorrhage (ICH) and major extracranial haemorrhage. Adjusted odds ratios OR (95% confidence intervals) were calculated on the whole database and on propensity‐matched groups.
Results: Among 616 CeADStroke patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups ORadjusted 0.95 (95% CI 0.45–2.00). The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non‐thrombolyzed‐matched CeADStroke patients OR 1.00 (0.49–2.00). Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non‐thrombolysis group, 3 (0.6%) patients had major haemorrhages asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1).
Conclusion: As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeADStroke patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies.
Click here to view the accompanying paper in this issue.Click here to view the accompanying paper in this issue.
PDF
