Long-Term Premorbid Blood Pressure and Cerebral Small Vessel Disease Burden on Imaging in Transient Ischemic Attack and Ischemic Stroke.

Background and Purpose- Studies of causes of cerebral small vessel disease (SVD) should fully adjust for blood pressure (BP), but most etiological studies use a single BP measurement or history of hypertension, which might underestimate the role of hypertension. In patients with transient ischemic attack and ischemic stroke, we therefore compared the associations of baseline and long-term premorbid BP with measures of SVD on magnetic resonance imaging brain. Methods- We studied 1009 transient ischemic attack/ischemic stroke patients who had a brain magnetic resonance imaging, in the population-based OXVASC (Oxford Vascular Study), and related baseline and 20-year premorbid BP (median: 15 readings/patient) to the total SVD score on imaging. Results- SVD score was associated with increasing mean baseline systolic BP (SBP; odds ratio of top versus bottom BP quartile: 2.28; [95% CI, 1.62-3.21]; P<0.0001) and with prior hypertension (2.53; [95% CI, 2.01-3.20]; P<0.0001), but the association was much stronger with mean premorbid SBP (6.09; [95% CI, 4.34-8.55]; P<0.0001). Mean diastolic BP at baseline was negatively associated with SVD score (0.71; [95% CI, 0.51-1.00]; P=0.050), and a positive association was only evident for diastolic BP 10 to 20 years previously (3.35; [95% CI, 2.33-4.84]; both P<0.0001). Relationships between overall mean premorbid BP and SVD burden were strongest in patients age <70 (SBP: 6.99; 4.11-11.86; diastolic BP: 3.13; 1.95-5.07; both P<0.0001) versus ≥70 years (2.37; 1.42-3.94; P=0.001; and 1.16; 0.74-1.84; P=0.52). Conclusions- Mean premorbid SBP is more strongly associated with SVD burden than baseline SBP or history of hypertension, and baseline diastolic BP yields a misleading estimate of the likely etiological importance of midlife hypertension for the subsequent development of SVD. Studies of novel potential etiological factors for SVD should aim to adjust for long-term prior BP, and trials of BP lowering with only a few years of follow-up may underestimate the overall impact on SVD.

Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review.

BACKGROUND AND PURPOSE: In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. METHODS: In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2-4, and ≥5), adjusting for age, sex, and vascular risk factors. RESULTS: Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P<0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden (Ptrend=0.87), but the 5-year risk of ICH was steeply related (Ptrend<0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden (Ptrend=0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events (Ptrend=0.007), the association with ICH was accounted for (Ptrend<0.0001) by disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke; P=0.035). CONCLUSIONS: In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter.

Effect of diagnostic criteria on prevalence of frontotemporal dementia in the elderly.

BACKGROUND: Frontotemporal dementia (FTD) is believed to be rare in the elderly, and the influence of different criteria on the prevalence of FTD is unclear. METHODS: Population-based samples of 70- to 95-year-olds (n = 2462) in Gothenburg, Sweden, underwent neuropsychiatric examinations. Behavioral variant FTD (bvFTD) was diagnosed according to the International Behavioural Variant FTD Criteria Consortium (FTDC), the Frontotemporal Lobe Degeneration Consensus criteria, and the Lund-Manchester Research Criteria. A subset (n = 1074) underwent computerized tomography (CT) of the brain. RESULTS: The prevalence of bvFTD varied between 0.2% and 0.5% at age 70 to 79 years, between 2.5% and 3.6% at age 80 to 89 years, and between 1.7% and 2.2% at age 90 to 95 years. The agreement between different criteria was low to moderate (κ = 0.20-0.42). Among those with bvFTD according to FTDC, 93.3% had frontal and/or temporal lobar atrophy on CT, compared with 12.6% of those without bvFTD (P < .001). CONCLUSIONS: The prevalence of bvFTD was higher than expected in this population. To a large extent, different criteria captured different individuals.

Validation of the Montreal cognitive assessment versus mini-mental state examination against hypertension and hypertensive arteriopathy after transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Lack of reduced cognitive impairment with blood pressure (BP) lowering in trials may reflect use of the Mini-Mental State Examination (MMSE), which is insensitive to mild cognitive impairment after cerebrovascular events compared with the Montreal Cognitive Assessment. We determined relationships between impairment on MMSE versus Montreal Cognitive Assessment (MoCA) with the major physiological determinant of vascular cognitive impairment: hypertension and hypertensive arteriopathy. METHODS: Cognitive impairment in consecutive patients 6 months after transient ischemic attack or minor stroke was defined as significant, mild, or none (MMSE<23, 23-26, ≥27; MoCA<20, 20-24, ≥25) and related to 20 premorbid systolic BP readings, home BP measurement (3 measurements, 3×daily for 1 month), and hypertensive arteriopathy (creatinine, stroke versus transient ischemic attack, leukoaraiosis) by ordinal regression. RESULTS: Of 463 patients, 45% versus 28% had at least mild cognitive impairment on the MoCA versus MMSE (P<0.001). Hypertensive arteriopathy was more strongly associated with cognitive impairment on the MoCA than MMSE (creatinine: odds ratio=3.99; 95% confidence interval, 2.06-7.73 versus 2.16, 1.08-4.33; event: 1.53, 1.06-2.19 versus 1.23, 0.81-1.85; leukoaraiosis: 2.09, 1.42-3.06 versus 1.34, 0.87-2.07). Premorbid and home BP measurement systolic BP were more strongly associated with impairment on vascular subdomains of the MoCA than MMSE (odds ratio/10 mm Hg: visuospatial 1.29 versus 1.05; attention 1.18 versus 1.07; language 1.22 versus 0.91; naming 1.07 versus 0.86). CONCLUSIONS: The stronger relationship between impairment on the MoCA with hypertensive arteriopathy, independent of age, indicates a greater sensitivity for vascular-origin cognitive impairment. Use of MoCA should improve sensitivity for cognitive impairment and treatment effects in future studies.

Population-based case-control study of white matter changes on brain imaging in transient ischemic attack and ischemic stroke.

BACKGROUND AND PURPOSE: White matter changes (WMC) are a common finding on brain imaging and are associated with an increased risk of ischemic stroke. They are most frequent in small vessel stroke; however, in the absence of comparisons with normal controls, it is uncertain whether WMC are also more frequent than expected in other stroke subtypes. Therefore, we compared WMC in pathogenic subtypes of ischemic stroke versus controls in a population-based study. METHODS: We evaluated the presence and severity of WMC on computed tomography and on magnetic resonance brain imaging using modified Blennow/Fazekas scale and age-related white matter changes scale, respectively, in a population-based study of patients with incident transient ischemic attack or ischemic stroke (Oxford Vascular Study) and in a study of local controls (Oxford Project to Investigate Memory and Ageing) without history of transient ischemic attack or ischemic stroke, with stratification by stroke pathogenesis (Trial of Org10172 in Acute Stroke Treatment classification). RESULTS: Among 1601 consecutive eligible patients with first-ever ischemic events, 1453 patients had computed tomography brain imaging, 562 had magnetic resonance imaging, and 414 patients had both. Compared with 313 controls (all with computed tomography and 131 with magnetic resonance imaging) and after adjustment for age, sex, diabetes mellitus, and hypertension, moderate/severe WMC (age-related white matter changes scale) were more frequent in patients with small vessel events (odds ratio, 3.51 [95% confidence interval, 2.13-5.76]; P<0.0001) but not in large artery (odds ratio, 1.03 [95% confidence interval, 0.64-1.67]), cardioembolic (odds ratio, 0.87 [95% confidence interval, 0.56-1.34]), or undetermined (odds ratio, 0.90 [95% confidence interval, 0.62-1.30]) subtypes. Results were consistent for ischemic stroke and transient ischemic attack, for other scales, and for magnetic resonance imaging and computed tomography separately. CONCLUSIONS: In contrast to small vessel ischemic events, WMC were not independently associated with other pathogenic subtypes, suggesting that WMC are unlikely to be an independent risk factor for nonsmall vessel events.

Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a population-based study.

BACKGROUND: Outpatient management safely and effectively prevents early recurrent stroke after transient ischaemic attack (TIA), but this approach may not be safe in patients with acute minor stroke. OBJECTIVE: To study outcomes of clinic and hospital-referred patients with TIA or minor stroke (National Institute of Health Stroke Scale score ≤3) in a prospective, population-based study (Oxford Vascular Study). RESULTS: Of 845 patients with TIA/stroke, 587 (69%) were referred directly to outpatient clinics and 258 (31%) directly to inpatient services. Of the 250 clinic-referred minor strokes (mean age 72.7 years), 237 (95%) were investigated, treated and discharged on the same day, of whom 16 (6.8%) were subsequently admitted to hospital within 30 days for recurrent stroke (n=6), sepsis (n=3), falls (n=3), bleeding (n=2), angina (n=1) and nursing care (n=1). The 150 patients (mean age 74.8 years) with minor stroke referred directly to hospital (median length-of-stay 9 days) had a similar 30-day readmission rate (9/150; 6.3%; p=0.83) after initial discharge and a similar 30-day risk of recurrent stroke (9/237 in clinic patients vs 8/150, OR=0.70, 0.27-1.80, p=0.61). Rates of prescription of secondary prevention medication after initial clinic/hospital discharge were higher in clinic-referred than in hospital-referred patients for antiplatelets/anticoagulants (p<0.05) and lipid-lowering agents (p<0.001) and were maintained at 1-year follow-up. The mean (SD) secondary care cost was £8323 (13 133) for hospital-referred minor stroke versus £743 (1794) for clinic-referred cases. CONCLUSION: Outpatient management of clinic-referred minor stroke is feasible and may be as safe as inpatient care. Rates of early hospital admission and recurrent stroke were low and uptake and maintenance of secondary prevention was high.

Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility.

BACKGROUND AND PURPOSE: Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. METHODS: Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Gosling's index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). RESULTS: In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, P<0.0001). Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: χ(2)=0.39, MCA-PI P=0.01, aortic pulse wave velocity P=0.06; age-related white matter change: χ(2)=0.38, MCA-PI P=0.015; aortic pulse wave velocity P=0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r(2)=0.68, P<0.0001), MCA-PI was independently associated with aortic pulse wave velocity (P=0.016) and aortic pulse pressure (P<0.0001) and inversely associated with aortic diastolic blood pressure (P<0.0001) and MCA transit time (P=0.001). CONCLUSIONS: MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis.

Midlife psychological distress associated with late-life brain atrophy and white matter lesions: a 32-year population study of women.

OBJECTIVE: Long-standing psychological distress increases the risk of dementia, especially Alzheimer's disease. The present study examines the relationship between midlife psychological distress and late-life brain atrophy and white matter lesions (WMLs), which are common findings on neuroimaging in elderly subjects. METHODS: A population-based sample of 1462 women, aged 38 to 60 years, was examined in 1968, with subsequent examinations in 1974, 1980, 1992, and 2000. Computed tomography (CT) of the brain was done in 379 survivors in 2000, and of those, 344 had responded to a standardized question about psychological distress in 1968, 1974, and 1980. WMLs, cortical atrophy, and central atrophy (ventricular sizes) were measured at CT scans. RESULTS: Compared with women reporting no distress, those reporting frequent or constant distress at one examination or more (in 1968, 1974, and 1980) more often had moderate-to-severe WMLs (multiadjusted odds ratio = 2.39, 95% confidence interval = 1.16-4.92) and moderate-to-severe temporal lobe atrophy (multiadjusted odds ratio = 2.51, 95% confidence interval = 1.04-6.05) on brain CT in 2000. Frequent/constant distress was also associated with central brain atrophy, that is, higher bicaudate ratio, higher cella media ratio, and larger third-ventricle width. CONCLUSIONS: Long-standing psychological distress in midlife increases risks of cerebral atrophy and WMLs on CT in late life. More studies are needed to confirm these findings and to determine potential neurobiological mechanisms of these associations.

Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study.

BACKGROUND: Age-related white matter changes (ARWMCs), frequently detected on neuroimaging, are associated with motor, cognitive, urinary, and mood disorders. The LADIS (LeukoAraiosis and DISability) Study primarily aims to assess ARWMCs as a determinant of global functional decline in the elderly population. METHODS: We enrolled 639 patients (mean age, 74.1 +/- 5.0 years; 45.1% male) referred for nondisabling complaints, who had ARWMCs detected on brain magnetic resonance imaging (MRI) of mild, moderate, or severe grade according to the Fazekas scale. At the 1-year follow-up, 619 were reassessed using the Instrumental Activities of Daily Living (IADL) scale. Of these, 506 were totally independent at baseline, and 113 were impaired in only 1 item of the IADL scale. We studied the 1-year transition to 2 or more activities limited and selective functional impairments as cofactors of functional decline. RESULTS: The rate of transition was 9%, 15%, and 26%, in the mild, moderate, and severe ARWMC group, respectively. Comparing the severe with the mild ARWMC groups and adjusting for age and for other predictors of decline, the risk was more than 2-fold higher (odds ratio; 2.38; 95% confidence interval, 1.29-4.38) in patients with 0 or 1 activity limited, and 3-fold higher (odds ratio, 3.02; 95% confidence interval, 1.34-6.78) among patients fully independent at baseline. Both motor and cognitive deterioration predominantly explained the effect of ARWMCs on global functional decline. CONCLUSION: Elderly patients who are functionally independent and who have severe ARWMCs are at considerable risk of becoming more dependent in a short period, mostly owing to motor and cognitive deterioration.

Total small vessel disease score and risk of recurrent stroke: Validation in 2 large cohorts.

OBJECTIVE: In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke. METHODS: Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered. RESULTS: In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16-1.51, p < 0.0001; c statistic 0.61, 0.56-0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11-2.13, p = 0.009; c statistic 0.65, 0.54-0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes (c statistic 0.67, 0.59-0.74, p < 0.0001 and 0.60, 0.55-0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH (c statistic 0.71, 0.60-0.81, phet = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56-0.65, phet = 0.76) on internal validation. CONCLUSIONS: The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology.

Midlife respiratory function related to white matter lesions and lacunar infarcts in late life: the Prospective Population Study of Women in Gothenburg, Sweden.

BACKGROUND AND PURPOSE: Increased evidence suggests that poor respiratory function increases risk of ischemic damage to the brain. Longitudinal studies on respiratory function and cerebral small-vessel disease are lacking. We examined midlife and late-life respiratory function in relation to small-vessel disease on computed tomography (CT) in women followed for 26 years. METHODS: White matter lesions (WMLs) and lacunar infarcts were rated on brain CT scans in 2000 in 379 women 70 to 92 years of age from a longitudinal population study in Göteborg, Sweden. Respiratory function was measured by peak expiratory flow (PEF) in 1974 and 2000 and by forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) in 1980 and 2000. RESULTS: Lower FVC and FEV1 in 1980 and 2000 were associated with presence and severity of WMLs and lacunar infarcts in 2000. Per 1-SD decrease of FVC in 1980, odds ratios (95% CIs) were 1.49 (1.11 to 2.02) for presence of WMLs and 1.95 (1.34 to 2.84) for lacunar infarcts after adjustment for potential confounders. Per 1-SD decrease of FEV1 in 1980, adjusted odds ratios were 1.46 (1.06 to 2.00) for presence of WMLs and 1.42 (1.02 to 1.97) for lacunar infarcts. PEF in 1974 and 2000 was not associated with WMLs or lacunar infarcts. CONCLUSIONS: WMLs and lacunar infarcts in elderly women were related to lower midlife respiratory function. Although our data may not establish causation between lower respiratory function and small-vessel disease, they imply the importance of good respiratory function in midlife.

Visual rating scales for age-related white matter changes (leukoaraiosis): can the heterogeneity be reduced?

BACKGROUND AND PURPOSE: It has been hypothesized that the use of different visual rating scales partly explains the discordant results of studies investigating risk factors and clinical correlates of age-related cerebral white matter changes (leukoaraiosis). We aimed to compare 6 widely used rating scales for leukoaraiosis and to calculate conversion coefficients of the score of 1 scale in the score of a second scale. METHODS: Two trained raters evaluated 80 pairs of CT and MRI scans using 2 CT and 4 MRI rating scales for white matter changes. Correlations among the scales were evaluated and regression lines were constructed with each of the CT and MRI scale scores as variables. RESULTS: A high correlation was observed in all the paired comparisons of the 6 scales (Spearman's rho ranging from 0.85 to 0.96, P<0.0001). Using regression analysis, we determined numeric parameters to transform the score of 1 scale to the corresponding score for each of the remaining scales and relative confidence intervals. The predictive values of these conversions expressed as R(2) ranged from 0.75 to 0.92. CONCLUSIONS: The present findings support the view that a good correlation exists among the considered visual rating scales for white matter changes. With the limitation that conversion parameters are calculated by applying a linear regression to partly nonlinear scales, their use allows comparison of the results of previous studies that used different scales and to pool data from past and ongoing clinical trials.

Transient isolated brainstem symptoms preceding posterior circulation stroke: a population-based study.

BACKGROUND: Transient isolated brainstem symptoms (eg, isolated vertigo, dysarthria, diplopia) are not consistently classified as transient ischaemic attacks (TIAs) and data for prognosis are limited. If some of these transient neurological attacks (TNAs) are due to vertebrobasilar ischaemia, then they should be common during the days and weeks preceding posterior circulation strokes. We aimed to assess the frequency of TNAs before vertebrobasilar ischaemic stroke. METHODS: We studied all potential ischaemic events during the 90 days preceding an ischaemic stroke in patients ascertained within a prospective, population-based incidence study in Oxfordshire, UK (Oxford Vascular Study; 2002-2010) and compared rates of TNA preceding vertebrobasilar stroke versus carotid stroke. We classified the brainstem symptoms isolated vertigo, vertigo with non-focal symptoms, isolated double vision, transient generalised weakness, and binocular visual disturbance as TNAs in the vertebrobasilar territory; atypical amaurosis fugax and limb-shaking as TNAs in the carotid territory; and isolated slurred speech, migraine variants, transient confusion, and hemisensory tingling symptoms as TNAs in uncertain territory. FINDINGS: Of the 1141 patients with ischaemic stroke, vascular territory was categorisable in 1034 (91%) cases, with 275 vertebrobasilar strokes and 759 carotid strokes. Isolated brainstem TNAs were more frequent before a vertebrobasilar stroke (45 of 275 events) than before a carotid stroke (10 of 759; OR 14·7, 95% CI 7·3-29·5, p<0·0001), particularly during the preceding 2 days (22 of 252 before a vertebrobasilar stroke vs two of 751 before a carotid stroke, OR 35·8, 8·4-153·5, p<0·0001). Of all 59 TNAs preceding (median 4 days, IQR 1-30) vertebrobasilar stroke, only five (8%) fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) criteria for TIA. The other 54 cases were isolated vertigo (n=23), non-NINDS binocular visual disturbance (n=9), vertigo with other non-focal symptoms (n=10), isolated slurred speech, hemisensory tingling, or diplopia (n=8), and non-focal events (n=4). Only 10 (22%) of the 45 patients with isolated brainstem TNAs sought medical attention before the stroke and a vascular cause was suspected by their physician in only one of these cases. INTERPRETATION: In patients with definite vertebrobasilar stroke, preceding transient isolated brainstem symptoms are common, but most symptoms do not satisfy traditional definitions of TIA. More studies of the prognosis of transient isolated brainstem symptoms are required. FUNDING: Wellcome Trust, UK Medical Research Council, Dunhill Medical Trust, Stroke Association, National Institute for Health Research (NIHR), Thames Valley Primary Care Research Partnership, and the NIHR Biomedical Research Centre, Oxford.

Population-based study of capsular warning syndrome and prognosis after early recurrent TIA.

OBJECTIVE: Many guidelines recommend emergency assessment for patients with ≥2 TIAs within 7 days, perhaps in recognition of the capsular warning syndrome. However, it is unclear whether all patients with multiple TIAs are at high early risk of stroke and whether treatable underlying pathologies are more prevalent in this group. METHODS: We studied clinical characteristics, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and risk of stroke in 1,000 consecutive patients with incident and recurrent TIAs in a prospective, population-based study (Oxford Vascular Study). RESULTS: Of 1,000 patients with TIAs, 170 had a further TIA within 7 days (105 within 24 hours). Multiple TIAs were not associated with carotid stenosis or atrial fibrillation, and much of the 10.6 (95% confidence interval [CI] 6.5-15.9) risk of stroke during the 7 days after the first TIA was due to patients with small-vessel disease (SVD) etiology (10 of 24 vs 8 of 146, odds ratio [OR] = 12.3, 95% CI 3.7-41.9, p < 0.0001), particularly those with motor weakness (i.e., capsular warning syndrome) compared with hemisensory events (9 of 15 [60%], 95% CI 35.3-84.7 vs 1 of 9 [11.1%], 95% CI 0-31.7, p = 0.03). The 7-day risk of stroke after a recurrent TIA was similar to the risk after a single TIA in patients with non-SVD TIA (8 of 146 [5.5%] vs 76 of 830 [9.2%], OR = 0.58, 95% CI 0.25-1.3, p = 0.20). Of the 9 patients with stroke after a capsular warning syndrome, all had the recurrent TIA within 24 hours after the first TIA, and the subsequent stroke occurred within 72 hours of the second TIA in 8. The ABCD2 scores of all preceding TIAs were ≥4 in all 9 patients with capsular warning syndrome before stroke. CONCLUSIONS: Capsular warning syndrome is rare (1.5% of TIA presentations) but has a poor prognosis (7-day stroke risk of 60%). Otherwise, recurrent TIA within 7 days is not associated with a greater stroke risk than that after a single TIA.

Age- and sex-specific rates of leukoaraiosis in TIA and stroke patients: population-based study.

OBJECTIVE: To determine any sex differences in age-specific prevalence or severity of leukoaraiosis, a marker of white matter ischemia, in population-based and clinic cohorts of TIA/stroke and in a systematic review of the literature. METHODS: Age-specific sex differences were calculated for both CT and MRI in the Oxford Vascular Study (OXVASC) and in an MRI-based clinic cohort. We pooled odds ratios (ORs) for leukoaraiosis in women vs men from published studies by fixed-effect meta-analysis, stratified by patient characteristics (stroke vs nonstroke) and CT vs MRI. RESULTS: Among 10 stroke studies (all CT-based), leukoaraiosis was most frequent in women (OR = 1.42, 95% confidence interval [CI] 1.27-1.57, p < 0.0001), with little heterogeneity between studies (p = 0.28). However, no such excess was seen in 10 reports of nonstroke cohorts (0.91, 0.67-1.24, p = 0.56). Moreover, excess leukoaraiosis in women on CT-imaging in OXVASC (1.38, 1.15-1.67, p = 0.001) was explained by their older age (age-adjusted OR = 1.01, 0.82-1.25, p = 0.90). Leukoaraiosis was more severe in older (≥ 75) women (CT-1.50, 1.14-1.97, p = 0.004 in OXVASC; MRI-1.70, 1.17-2.48, p = 0.006 in OXVASC and clinic cohort). However, leukoaraiosis was independently associated with early mortality (hazard ratio = 1.46, 1.23-1.73, p < 0.0001), suggesting that comparisons in older age groups will be biased by prior premature death of men with leukoaraiosis. Sex differences in severity of leukoaraiosis were not addressed in previous studies. CONCLUSIONS: Previously reported excess leukoaraiosis in women with TIA/stroke is likely to be confounded by age and apparently greater severity in older women is likely to be biased by premature death in men with leukoaraiosis.

Temporal lobe atrophy and white matter lesions are related to major depression over 5 years in the elderly.

The influence of organic brain changes on the development of depression in the elderly is uncertain. Cross-sectional studies, most often from clinical samples, report associations with brain atrophy and cerebrovascular disease, while longitudinal population studies have given mixed results. Our aim was to investigate whether cortical atrophy and white matter lesions (WMLs) on computed tomography (CT) predict occurrence of depression in the elderly. This is a prospective population-based study with 5-year follow-up. The baseline sample included 525 elderly subjects, aged 70-86 years, without dementia or major depression, with a score on the Mini-Mental State Examination above 25, and without dementia at follow-up. Cortical atrophy and WMLs were evaluated at baseline using CT. The main outcome measure was development of major or minor depression at follow-up according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, as evaluated using neuropsychiatric examinations and hospital discharge registers. Logistic regression was used to estimate risk. Over the period of 5 years, 20 individuals developed major and 63 minor depression. Presence of temporal lobe atrophy (odds ratio (OR)=2.81, 95% confidence interval (CI) 1.04-7.62) and moderate-to-severe WMLs (OR=3.21, 95% CI 1.00-10.26) independently predicted major, but not minor, depression after controlling for various confounders. Other brain changes did not predict occurrence of depression. Our findings suggest that temporal lobe atrophy and WMLs represent relatively independent and complementary pathways to major depression in the elderly. This may have implications for prevention, as both neurodegeneration and cerebrovascular disease have been related to preventable factors.

Blood pressure components and changes in relation to white matter lesions: a 32-year prospective population study.

This study aimed to examine the long-term effect of high blood pressure (systolic blood pressure, diastolic blood pressure, pulse pressure, and mean arterial pressure) on white matter lesions and to study changes in different blood pressure components in relation to white matter lesions. A representative population of women was examined in 1968 and re-examined in 1974, 1980, 1992, and 2000. The presence and severity of white matter lesions on computed tomography were rated by a visual rating scale in 1992 and 2000 in 539 women. Systolic and diastolic blood pressures were measured at all of the examinations. We found that presence and severity of white matter lesions in 1992/2000 were associated with higher diastolic blood pressure and mean arterial pressure at each examination but not with systolic blood pressure and pulse pressure. Odds ratios (95% CIs) for the presence of white matter lesions per 10-mm Hg increase in diastolic pressure were 1.4 (1.0 to 1.9) in 1968, 1.3 (1.0 to 1.8) in 1974, 1.4 (1.1 to 1.9) in 1980, and 1.3 (1.0 to 1.6) in 1992 after adjustment for confounders. The presence of white matter lesions was also associated with a 24-year increase in diastolic pressure (>10 mm Hg), systolic pressure (>40 mm Hg), pulse pressure (>24 mm Hg), and mean arterial pressure (>6 mm Hg; odds ratios [95% CIs]: 2.6 [1.3 to 5.1] for diastolic pressure; 2.0 [1.2 to 3.4] for systolic pressure; 1.8 [1.1 to 2.7] for pulse pressure; and 2.2 [1.4 to 3.4] for mean arterial pressure). Our findings suggest that lowering high diastolic blood pressure and preventing large increases in systolic and diastolic blood pressures may have a protective effect on white matter lesions.

White matter hyperintensities rather than lacunar infarcts are associated with depressive symptoms in older people: the LADIS study.

OBJECTIVE: Both white matter hyperintensities (WMH) and lacunar infarcts have been associated with the development of depression in older subjects, although the relative importance of the two and the influence of lesion location and concomitant vascular disease are unclear. This study investigates the relationship between location and burden of WMH and lacunes on depressive features in older people. METHOD: In a pan-European multicenter study of 626 older subjects, the authors examined the relationship between regional magnetic resonance imaging white matter hyperintensities, number of lacunar infarcts, depressive symptoms as assessed by the 15-item geriatric depression scale (GDS), cognitive status (Mini-Mental Status Examination), hypertension, and self-perceived health quality of life (QoL). RESULTS: The authors found depressive symptoms to be correlated with WMH rating in the frontal (N=626; Spearman's rho=0.161, p <0.001) and temporal (rho=0.14, p <0.001) but not occipitoparietal region (rho=0.07, p=0.07). Basal ganglia lacunes were only weakly correlated with GDS (rho=0.09, p=0.03), and lacunes in other regions showed no association. In a ordinal logistic regression model (controlling for QoL, Mini-Mental Status Examination, age, and with an interaction between WMH and hypertension), temporal WMH in the absence of hypertension independently predicted GDS, whereas neither history of stroke nor number of lacunar infarcts did. The authors compared left- versus right-sided WMH and found no effect of laterality on depressive symptoms. CONCLUSIONS: The results suggest that in this population of nondisabled older people, WMH have a greater influence on depressive symptoms than infarcts.

White matter hyperintensities and depression--preliminary results from the LADIS study.

BACKGROUND: White matter hyperintensities have been associated with the development of depression in older subjects, though the details of this relationship are not fully understood. METHODS: In a pan-European multicentre study of 629 older subjects, we examined the relationship between MRI white matter hyperintensities (WMH), depressive symptoms and self perceived health quality of life (QOL). WMH were rated using a three-point scale. RESULTS: We found depressive symptoms as assessed by the geriatric depression 15-item scale to be associated with WMH rating (Spearman's rho 0.11, p = 0.008) and also with the Euro-QOL health score (Spearman's rho -0.5, p < 0.001). In a ordinal logistic regression model, QOL was found to strongly predict GDS score (p < 0.001) and severe vs mild WMH were associated with increased depression (p = 0.028). The relationship between history of severe depression and WMH score was examined, but there were no differences either between those with and without a history of severe depression, or those with an early vs late onset of depression. CONCLUSIONS: The results suggest that WMH play a role in increasing depressive symptoms, even when perceived quality of life is controlled for as a possible mediating factor.