‘Post-stroke cognitive impairment’ explores in great depth the burden of post-stroke cognitive impairment, its pathological substrates and clinical characteristics, the causes of these impairments, post-stroke dementia, and the risk factors implicated. The chapter examines common definitions (vascular cognitive impairment, vascular dementia, post-stroke cognitive impairment), the DSM-5 criteria (Diagnostic and Statistical Manual of Mental Disorders-5), ICD-10 criteria (International Classification of Diseases), NINDS-AIREN criteria (National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences) for vascular dementia, and vascular mild cognitive impairment. The VASCOG (vascular cognitive disorder) criteria are also described. A pragmatic approach to investigations and various assessment scales, a description of important clinical trials, and the management of these disorders are also included.

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.

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 ( P trend =0.87), but the 5-year risk of ICH was steeply related ( P trend <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 ( P trend =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 ( P trend =0.007), the association with ICH was accounted for ( P trend <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.

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, p(het) = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56-0.65, p(het) = 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.

Introduction Homocystinuria, an autosomal recessive defect in methionine metabolism, is responsible for a multi-systemic disorder. If not treated with either pyridoxine or betaine, patients have a high risk of arterial or venous thrombotic events before the age of 30. Case report A 16 year-old woman with pyridoxine-non-responsive homocystinuria presented with a first seizure and headaches. She had bilateral papilloedema, no other deficits. MR venogram was normal, CSF opening pressure was 50 cmH20. She was treated as Idiopathic Intracranial Hypertension. Two months later she represented with behavioural changes. A new venogram showed extensive venous sinus thrombosis and right thalamic haemorrhagic infarction. Her homocysteine levels were high. She was anticoagulated. Still complaining of headaches, an MRI at one year showed new extensive diffuse white matter changes. She had been on regular betaine treatment, but, non-compliant with a low-protein diet, her methionine levels were high (>600 micromol/L). Extensive white matter changes have been reported in association with high levels of methionine, and this is the most likely diagnosis in our patient. Conclusions Only a few cases of methionine-induced cerebral white matter changes are reported in literature. Regression of the lesions and improvement of symptoms can occur after strict adherence to a low-protein diet.

Introduction ‘En coup the sabre’, a linear form of facial scleroderma, is rarely complicated by neurological symptoms. The aetiology of the underlying cerebral lesions is still obscure, but there is evidence in favour of a vasculitic process. Our case, with neurological symptoms presenting over ten years, illustrates this picture. Case report A 60 year old woman with history of facial linear scleroderma and migraine, presented to casualty with acute left sided weakness. Two months prior to this, she had been admitted for new onset of seizures. Seven years earlier she had developed acute left hemianopia and a brain scan had revealed a possible arterio-venous malformation (AVM) and gliotic changes in the right hemisphere. A new MRI showed progression of the right sided lesions. A cerebral angiogram did not confirm AVM, but showed signs of vasculitis. Identical oligoclonal bands were found in cerebrospinal fluid (CSF) and blood. ANA and ANCA were positive. She was treated with steroids and started on mycophenolate. She improved and remains stable at 2 years. Conclusions The association between linear scleroderma and neurological symptoms is well known, but its pathological nature is still debated. Vasculitis is a possible underlying process, and needs consideration and treatment in case of symptoms progression.

Introduction Neuro-Behçet’s is rare, more frequent in people from the Middle East. Vasculitis of brainstem and diencephalon and venous sinus thrombosis are typical manifestations. Case report A previously well 51-year-old white British lady was admitted for a 2 day history of blurred vision, with impaired up-gaze and convergence retraction nystagmus. The symptoms resolved rapidly. MRI demonstrated hyperintensities in the diencephalon, CSF showed 10 mononuclear cells, normal otherwise. She was re-admitted eighteen months later with sudden imbalance, headache, slurred speech and right facial weakness. She reported mouth ulcers appearing in crops continuously over the past 2 years, no genital ulcers. MRI showed T2 hyperintensities in the thalami extending into the mid-brain, pons and superior and middle cerebellar peduncles. CSF showed 54 mononucleate cells, proteins 0.67 g, and raised CSF IL-6. The symptoms resolved spontaneously. Multimodal MRI one week later showed near resolution of the lesions. After excluding neoplastic, vascular and infective causes, probable neuro- Behçet’s was diagnosed according to the International Consensus Recommendations criteria (2014). The patient remains on steroids and azathioprine, and is asymptomatic at one year. Conclusions Neuro-Behçet’s can present with relapsing brainstem symptoms. The diagnosis is challenging when not all the criteria for the systemic condition are met.

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 (kappa = 0.20-0.42). Among those with bv1,11) 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 byFTD was higher than expected in this Population. To a large extent, different criteria captured different individuals. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Background and Objectives Omitting, incorrectly prescribing, or suddenly stopping dopaminergic medications may have significant sequelae. We aimed to assess how accurately PD medications are prescribed on admission to University Hospital of Coventry and Warwickshire (UHCW). Methods The 2006 Parkinson Disease NICE guidelines were set as standard. Notes and drug charts of PD patients admitted between January and June 2013 were reviewed for possible mistakes in name, dosage, formulation and timing, for omissions and for prescription of dopamine-blocking drugs. Results Of 296 PD patients with at least one overnight stay, 67 (mean age 79.1+/−6.9 years, 67% male) were audited. 21% of patients had some incorrect prescription (name, formulation, dose, timing) on their clerking notes, and 51% had a drug chart discordant from their usual regime (mainly timing and formulation errors). 47% of the audited patients missed at least one dose of their PD medications during admission, and 8 patients (9.9%) had dopamine-blocking drugs prescribed. Conclusions Awareness of the importance of correct PD medications prescribing must increase among admitting doctors. Guidelines have been introduced in July 2013 on our Trust intranet, and they have been advertised at grand-rounds. The audit will be repeated at 12 months from their introduction.

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.

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.

Background Hypertension is a major treatable cause of incident and recurrent stroke. However, it can be missed by one–off clinic measurements. Hypertension guidelines therefore currently recommend ambulatory monitoring (ABPM) prior to treatment in primary prevention. Given high rates of under–treatment of hypertension in secondary prevention after TIA and stroke, we compared Bluetooth home BP monitoring (HBPM) and ABPM in identifying hypertension missed at initial assessment, with validation against pre–morbid BP and markers of hypertensive arteriopathy. Methods Consecutive patients recruited to the Oxford Vascular Study with TIA or minor stroke underwent HBPM (3 measurements, 3 times daily for 7 days) and ABPM at 1 month after presentation. Mean SBP was related to premorbid hypertension (defined as mean SBP>140 or mean DBP>90 based on all BP measurements during the previous 10 years in primary care or a formal diagnosis of hypertension in primary care) and markers of hypertensive arteriopathy (creatinine, aortic stiffness–pulse wave velocity–and leukoaraiosis on brain imaging). Results Among 500 eligible patients, those with premorbid hypertension (n=307) were better identified (p<0.001) by mean SBP on HBPM than by mean awake SBP on ABPM (area under ROC curve: 0.73, 95%CI 0.67–0.78 vs 0.60, 0.54–0.65). This difference was also present for identification of patients (n=205) with mean pre–morbid BP>140/90 but no formal premorbid diagnosis of hypertension (0.77, 0.69–0.85 vs 0.57, 0.46–0.69), including those who were normotensive in the stroke clinic (0.84, 0.73–0.96 vs 0.64, 0.40–0.89). HBPM SBP was also more strongly associated than ABPM with creatinine (r=0.24, p<0.001 vs r=0.14, p=0.002), aortic stiffness (r=0.21, p=0.01 vs r=0.13, p=0.13) and moderate/severe leukoaraiosis (AUC: 0.61, 0.55–0.67 vs 0.49, 0.43–0.55). Conclusions In patients with TIA or minor stroke, HBPM was more reliable than ABPM at identifying missed hypertension and hypertensive arteriopathy. Its use could significantly reduce the risk of recurrent stroke.

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. Neurology (R) 2012;79:1215-1222

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.

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.

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.

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: chi(2)=0.39, MCA-PI P=0.01, aortic pulse wave velocity P=0.06; age-related white matter change: chi(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. (Stroke. 2012; 43:2631-2636.)

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.