Sarah E. Vermeer

Silent Brain Infarcts and White Matter Lesions Increase Stroke Risk in the General Population The Rotterdam Scan Study

Background and Purpose— Silent brain infarcts and white matter lesions are associated with an increased risk of subsequent stroke in minor stroke patients. In healthy elderly people, silent brain infarcts and white matter lesions are common, but little is known about their relevance. We examined the risk of stroke associated with these lesions in the general population. Methods— The Rotterdam Scan Study is a population-based prospective cohort study among 1077 elderly people. The presence of silent brain infarcts and white matter lesions was scored on cerebral MRI scans obtained from 1995 to 1996. Participants were followed for stroke for on average 4.2 years. We estimated the risk of stroke in relation to presence of brain lesions with Cox proportional hazards regression analysis. Results— Fifty-seven participants (6%) experienced a stroke during follow-up. Participants with silent brain infarcts had a 5 times higher stroke incidence than those without. The presence of silent brain infarcts increased the risk of stroke >3-fold, independently of other stroke risk factors (adjusted hazard ratio 3.9, 95% CI 2.3 to 6.8). People in the upper tertile of the white matter lesion distribution had an increased stroke risk compared with those in the lowest tertile (adjusted hazard ratio for periventricular lesions 4.7, 95% CI 2.0 to 11.2 and for subcortical lesions 3.6, 95% CI 1.4 to 9.2). Silent brain infarcts and severe white matter lesions increased the stroke risk independently of each other. Conclusion— Elderly people with silent brain infarcts and white matter lesions are at a strongly increased risk of stroke, which could not be explained by the major stroke risk factors.

Silent brain infarcts: a systematic review

As the availability and quality of imaging techniques improve, doctors are identifying more patients with no history of transient ischaemic attack or stroke in whom imaging shows brain infarcts. Until recently, little was known about the relevance of these lesions. In this systematic review, we give an overview of the frequency, causes, and consequences of MRI-defined silent brain infarcts, which are detected in 20% of healthy elderly people and up to 50% of patients in selected series. Most infarcts are lacunes, of which hypertensive small-vessel disease is thought to be the main cause. Although silent infarcts, by definition, lack clinically overt stroke-like symptoms, they are associated with subtle deficits in physical and cognitive function that commonly go unnoticed. Moreover, the presence of silent infarcts more than doubles the risk of subsequent stroke and dementia. Future studies will have to show whether screening and treating high-risk patients can effectively reduce the risk of further infarcts, stroke, and dementia.

Incidence and Risk Factors of Silent Brain Infarcts in the Population-Based Rotterdam Scan Study

Background and Purpose— The prevalence of silent brain infarcts in healthy elderly people is high, and these lesions are associated with an increased risk of stroke. The incidence of silent brain infarcts is unknown. We investigated the incidence and cardiovascular risk factors for silent brain infarcts. Methods— The Rotterdam Scan Study is a prospective, population-based cohort study of 1077 participants 60 to 90 years of age. All participants underwent cranial MRI in 1995 to 1996, and 668 participants had a second MRI in 1999 to 2000 (response rate, 70%) with a mean interval of 3.4 years. We assessed cardiovascular risk factors by interview and physical examination at baseline. Associations between risk factors and incident silent infarcts were analyzed by multiple logistic regression. Results— Ninety-three participants (14%) had ≥1 new infarcts on the second MRI; of these, 81 had only silent and 12 had symptomatic infarcts. The incidence of silent brain infarcts strongly increased with age and was 5 times higher than that of symptomatic stroke. A prevalent silent brain infarct strongly predicted a new silent infarct on the second MRI (age- and sex-adjusted odds ratio, 2.9; 95% confidence interval, 1.7 to 5.0). Age, blood pressure, diabetes mellitus, cholesterol and homocysteine levels, intima-media thickness, carotid plaques, and smoking were associated with new silent brain infarcts in participants without prevalent infarcts. Conclusions— The incidence of silent brain infarcts on MRI in the general elderly population strongly increases with age. The cardiovascular risk factors for silent brain infarcts are similar to those for stroke.

Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI

Aim/hypothesisType 2 diabetes increases the risk not only of vascular dementia but also of Alzheimer’s disease. The question remains whether diabetes increases the risk of Alzheimer’s disease by diabetic vasculopathy or whether diabetes influences directly the development of Alzheimer neuropathology. In vivo, hippocampal and amygdalar atrophy on brain MRI are good, early markers of the degree of Alzheimer neuropathology. We investigated the association between diabetes mellitus, insulin resistance and the degree of hippocampal and amygdalar atrophy on magnetic resonance imaging (MRI) accounting for vascular pathology.MethodsData was obtained in a population-based study of elderly subjects without dementia between 60 to 90 years of age. The presence of diabetes mellitus and, in non-diabetic subjects, insulin resistance was assessed for 506 participants in whom hippocampal and amygdalar volumes on MRI were measured. We assessed the degree of vascular morbidity by rating carotid atherosclerosis, and brain white matter lesions and infarcts on MRI.ResultsSubjects with diabetes mellitus had more hippocampal and amygdalar atrophy on MRI compared to subjects without diabetes mellitus. Furthermore, increasing insulin resistance was associated with more amygdalar atrophy on MRI. The associations were not due to vascular morbidity being more pronounced in persons with diabetes mellitus.Conclusions/interpretationType 2 diabetes is associated with hippocampal and amygdalar atrophy, regardless of vascular pathology. This could suggest that Type 2 diabetes directly influences the development of Alzheimer neuropathology.

Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam scan study

Silent brain infarcts and white matter lesions are frequently seen on magnetic resonance imaging in healthy elderly people and both are associated with an increased risk of stroke and dementia. Plasma total homocysteine may be a potentially modifiable risk factor for stroke and dementia. We examined whether elevated total homocysteine levels are associated with silent brain infarcts and white matter lesions. The Rotterdam Scan Study is a population‐based study of 1,077 people aged 60 to 90 years who had cerebral magnetic resonance imaging. The cross‐sectional relation of total homocysteine with silent infarcts and white matter lesions was analyzed with adjustment for cardiovascular risk factors. The mean plasma total homocysteine level was 11.5μmol/l (standard deviation 4.1). The risk of silent brain infarcts increased with increasing total homocysteine levels (odds ratio 1.24/standard deviation increase, 95% confidence interval 1.06–1.45). The severity of periventricular white matter lesions and extent of subcortical white matter lesions were also significantly associated with total homocysteine levels, even after excluding those with silent brain infarcts. The overall risk of having either a silent brain infarct or severe white matter lesions was strongly associated with total homocysteine levels (odds ratio 1.35/standard deviation increase, 95% confidence interval 1.16–1.58). We concluded that total homocysteine levels are associated with silent brain infarcts and white matter lesions independent of each other and of other cardiovascular risk factors.

C-Reactive Protein and Cerebral Small-Vessel Disease: The Rotterdam Scan Study

Background—Inflammatory processes are involved in the development and consequences of atherosclerosis. Whether these processes are also involved in cerebral small-vessel disease is unknown. Cerebral white matter lesions and lacunar brain infarcts are caused by small-vessel disease and are commonly observed on MRI scans in elderly people. These lesions are associated with an increased risk of stroke and dementia. We assessed whether higher C-reactive protein (CRP) levels were related to white matter lesion and lacunar infarcts. Methods and Results—We based our study on 1033 participants of the population-based Rotterdam Scan Study for whom complete data on CRP levels were available and who underwent brain MRI scanning. Subjects were 60 to 90 years of age and free of dementia at baseline. Six hundred thirty-six subjects had a second MRI scan on average 3.3 years later. We used multivariate regression models to assess the associations between CRP levels and markers of small-vessel disease. Higher CRP levels were associated with presence and progression of white matter lesions, particularly with marked lesion progression (ORs for highest versus lowest quartile of CRP 3.1 [95% CI 1.3 to 7.2] and 2.5 [95% CI 1.1 to 5.6] for periventricular and subcortical white matter lesion progression, respectively). These associations persisted after adjustment for cardiovascular risk factors and carotid atherosclerosis. Persons with higher CRP levels tended to have more prevalent and incident lacunar infarcts. Conclusions—Inflammatory processes may be involved in the pathogenesis of cerebral small-vessel disease, in particular, the development of white matter lesions.

Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe

Background: Blood pressure level is associated with the risk of clinical Alzheimer disease (AD), yet the underlying mechanisms are unclear. High blood pressure levels may cause cerebral small-vessel pathology, which contributes to cognitive decline in patients with AD. Alternatively, in persons with high blood pressure, increased numbers of neurofibrillary tangles and amyloid plaques at autopsy have also been observed, suggesting direct links between blood pressure and AD. Objective: To investigate the association of blood pressure and markers of small-vessel disease (white matter lesions [WMLs] on MRI) with hippocampal and amygdalar atrophy on MRI—potential in vivo indicators of Alzheimer pathology. Methods: In 1995 to 1996, 511 nondemented elderly subjects (age 60 to 90) underwent MRI. The extent of WMLs was assessed, and volumes of the hippocampus and amygdala were measured. Blood pressure levels were assessed at the time of MRI and 5 years before the MRI. Results: Higher diastolic blood pressure 5 years before MRI predicted more hippocampal atrophy in persons untreated for hypertension (per SD increase −0.10 mL [95% CI −0.19 to −0.02, p = 0.02]). Conversely, in persons treated for hypertension, a low diastolic blood pressure was associated with more severe atrophy. Persons with more WMLs on MRI more often had severe atrophy of the hippocampus and amygdala. Conclusion: Blood pressure and indicators of small-vessel disease in the brain may be associated with atrophy of structures affected by Alzheimer pathology.

Long-term prognosis after recovery from primary intracerebral hemorrhage

Background Little is known about the long-term outcome for patients who recover from a primary intracerebral hemorrhage. The authors examined the rate of recurrence, vascular events, and death in survivors of a primary intracerebral hemorrhage and the factors related to the long-term prognosis. Methods All 243 patients admitted to one of three hospitals with a primary intracerebral hemorrhage who regained independence were interviewed about vascular events after the index hemorrhage. The authors used the Kaplan–Meier method to estimate the event-free survival and Cox proportional hazards regression analysis to identify predictors of recurrence, any vascular event, or death. Results During a mean follow-up of 5.5 years, the annual rates of recurrent primary intracerebral hemorrhage, vascular events, and vascular death were 2.1% (95% CI, 1.4 to 3.3%), 5.9% (95% CI, 4.5 to 7.7%), and 3.2% (95% CI, 2.2 to 4.5%). Age of 65 years or older was the only predictor of a recurrence (hazard ratio [HR], 2.8; 95% CI, 1.3 to 6.1) and vascular death (HR, 3.7; 95% CI, 2.0 to 7.0). In addition to age, male sex predicted the occurrence of vascular events (HR, 1.8; 95% CI, 1.1 to 3.0). Use of anticoagulation after the index bleeding tripled the risk of hemorrhagic events (HR, 3.0; 95% CI, 1.3 to 7.2). Conclusion Patients who recovered from a primary intracerebral hemorrhage had a 2.1% to 5.9% annual rate of recurrence, vascular death, or vascular events. Age of 65 years or older more than doubled the risk of recurrence, vascular event, or death. The risk of vascular events in men was increased twofold.

The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial

BACKGROUND In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Plasma amyloid beta, apolipoprotein E, lacunar infarcts, and white matter lesions.

Lacunar brain infarcts and cerebral white matter lesions are frequently observed on magnetic resonance imaging scans in elderly subjects. These lesions are also frequent in patient with cerebral amyloid angiopathy. We examined whether plasma amyloid β peptide (Aβ) levels are associated with lacunar infarcts and white matter lesions in the general population, and whether the apolipoprotein E (APOE) genotype modifies these associations. We studied 1,077 participants within the population‐based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia. Cross‐sectional associations were analyzed by regression models with adjustments for age, sex, creatinine levels, and hypertension. In APOE ε4 carriers, plasma Aβ levels were positively associated with lacunar infarcts and white matter lesions, whereas in noncarriers no associations were observed. Per standard deviation increase in Aβ1‐40 and Aβ1‐42 levels the odds ratios for lacunar infarcts were 1.72 (95% confidence interval [CI] = 1.22–2.43) and 1.93 (95% CI = 1.31–2.85), the periventricular white matter lesion grade increased by 0.32 (95% CI = 0.08–0.57) and 0.29 (95% CI = 0.00–0.57), and the subcortical white matter lesion volume increased by 0.48ml (95% CI = 0.04–0.91) and 0.24ml (95% CI = −0.27–0.75). Higher Aβ levels are associated with more lacunar infarcts and white matter lesions in elderly subjects who carry an APOE ε4 allele. Ann Neurol 2004