Cerebrovascular Risk-Factors of Prevalent and Incident Brain Infarcts in the General Population: The AGES-Reykjavik Study.

BACKGROUND: Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions. METHODS: Participants (n=2662, mean age 74.6±4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression. RESULTS: Thirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1-6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1-1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9-4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0-1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0-1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3-2.5] and IRR, 1.9 [95% CI, 1.3-2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2-2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5-4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2-1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1-2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0-2.0]). CONCLUSIONS: The risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke.

Prevalence of Multiple Sclerosis in Iceland.

BACKGROUND: In this study, we examined multiple sclerosis (MS) point prevalence in the well-defined island population of Iceland. METHODS: This study included all registered residents of Iceland with MS on the prevalence day, December 31, 2007. All included patients met at least one of the following criteria: McDonald criteria; Poser criteria for clinically definite MS, laboratory-supported definite MS, clinically probable MS; or criteria for primary progressive MS. The patients' medical records were reviewed, including all available MRI data acquired prior to the prevalence day. RESULTS: We identified 526 patients, of whom 73% (382) were women. The crude point prevalence of MS was 167.1 per 100,000 population on the prevalence day. With age adjustment made to the 2000 U.S. population, the prevalence was 166.5 per 100,000 population. The mean patient age on the prevalence day was 47 years(range 13-89) for both men and women. The mean age at diagnosis was 36 years (range 13-77): 35 years for women and 36 years for men. CONCLUSION: MS prevalence was high in Iceland compared to the prevalence mentioned in reports from most of the world, and was similar to prevalence rates in other Nordic countries.

Incidence of Brain Infarcts, Cognitive Change, and Risk of Dementia in the General Population: The AGES-Reykjavik Study (Age Gene/Environment Susceptibility-Reykjavik Study).

BACKGROUND AND PURPOSE: The differentiation of brain infarcts by region is important because their cause and clinical implications may differ. Information on the incidence of these lesions and association with cognition and dementia from longitudinal population studies is scarce. We investigated the incidence of infarcts in cortical, subcortical, cerebellar, and overall brain regions and how prevalent and incident infarcts associate with cognitive change and incident dementia. METHODS: Participants (n=2612, 41% men, mean age 74.6±4.8) underwent brain magnetic resonance imaging for the assessment of infarcts and cognitive testing at baseline and on average 5.2 years later. Incident dementia was assessed according to the international guidelines. RESULTS: Twenty-one percent of the study participants developed new infarcts. The risk of incident infarcts in men was higher than the risk in women (1.8; 95% confidence interval, 1.5-2.3). Persons with both incident and prevalent infarcts showed steeper cognitive decline and had almost double relative risk of incident dementia (1.7; 95% confidence interval, 1.3-2.2) compared with those without infarcts. Persons with new subcortical infarcts had the highest risk of incident dementia compared with those without infarcts (2.6; 95% confidence interval, 1.9-3.4). CONCLUSIONS: Men are at greater risk of developing incident brain infarcts than women. Persons with incident brain infarcts decline faster in cognition and have an increased risk of dementia compared with those free of infarcts. Incident subcortical infarcts contribute more than cortical and cerebellar infarcts to incident dementia which may indicate that infarcts of small vessel disease origin contribute more to the development of dementia than infarcts of embolic origin in larger vessels.

Diabetes, markers of brain pathology and cognitive function: the Age, Gene/Environment Susceptibility-Reykjavik Study.

OBJECTIVE: We investigated whether, and the extent to which, vascular and degenerative lesions in the brain mediate the association of diabetes with poor cognitive performance. METHODS: This cross-sectional study included 4,206 participants (age > 65 years; 57.8% women) of the Age, Gene/Environment Susceptibility-Reykjavik Study. Data were collected through interview, clinical examination, psychological testing, and laboratory tests. The composite scores on memory, information-processing speed, and executive function were derived from a cognitive test battery. Markers of cerebral macrovascular (cortical infarcts), microvascular (subcortical infarcts, cerebral microbleeds, and higher white matter lesion volume), and neurodegenerative (lower gray matter, normal white matter, and total brain tissue volumes) processes were assessed on magnetic resonance images. Mediation models were employed to test the mediating effect of brain lesions on the association of diabetes with cognitive performance controlling for potential confounders. RESULTS: There were 462 (11.0%) persons with diabetes. Diabetes was significantly associated with lower scores on processing speed and executive function, but not with memory function. Diabetes was significantly associated with all markers of brain pathology. All of these markers were significantly associated with lower scores on memory, processing speed, and executive function. Formal mediation tests suggested that markers of cerebrovascular and degenerative pathology significantly mediated the associations of diabetes with processing speed and executive function. INTERPRETATION: Diabetes is associated with poor performance on cognitive tests of information-processing speed and executive function. The association is largely mediated by markers of both neurodegeneration and cerebrovascular disease. Older people with diabetes should be monitored for cognitive problems and brain lesions.

Incidence of first stroke: a population study in Iceland.

BACKGROUND AND PURPOSE: Iceland is an island in the North Atlantic with ≈319 000 inhabitants. The study determines the incidence of first stroke in the adult population of Iceland during 12 months, which has not been previously reported in the entire Icelandic population. METHODS: The study population consisted of all residents of Iceland, aged ≥ 18 years, during the 12-month study period. Cases were identified by multiple overlapping approaches. Medical records were reviewed to verify diagnosis, to determine stroke subtype and to determine selected risk factors. RESULTS: A total of 343 individuals, aged ≥ 18 years, had a first stroke during the study period. Incidence was 144 per 100 000 person years; 81% ischemic infarction; 9% intracerebral hemorrhage; 7% subarachnoid hemorrhage; and 3% unknown. Fifty percent of the individuals were men. Mean age for ischemic infarction and intracerebral hemorrhage was 71 years for men and 73 years for women. Atrial fibrillation was previously known in 18% with first ischemic stroke or intracerebral hemorrhage and another 6% were diagnosed on routine admission ECG. Long-term ECG study (24 hours) found that 12% (18/154) of the remaining individuals had paroxysmal atrial fibrillation. CONCLUSIONS: Incidence of first stroke in Iceland is similar to other Western countries. The high number of paroxysmal atrial fibrillation found during the 24-hour ECG suggests that atrial fibrillation may be underdiagnosed in patients with stroke.

Temporal trends in the incidence of kidney stone disease.

Recent reports show an increased occurrence of kidney stone disease worldwide. To further evaluate and quantify this observation, we examined recent trends in the incidence of kidney stone disease in the adult population of Iceland over a 24-year period. Computerized databases of all major hospitals and medical imaging centers in Iceland were searched for International Classification of Diseases, radiologic and surgical procedure codes indicative of kidney stones in patients aged 18 years and older. The time trends in stone frequency of 5945 incident patients (63% men) were assessed by Poisson regression analysis. The majority of patients (90.5%) had symptomatic stone disease. The total incidence of kidney stones rose significantly from 108 per 100,000 in the first 5-year interval of the study to 138 per 100,000 in the last interval. The annual incidence of symptomatic stones did not increase significantly in either men or women. There was, however, a significant increase in the annual incidence of asymptomatic stones over time, from 7 to 24 per 100,000 for men and from 7 to 21 per 100,000 for women. The increase in the incidence of asymptomatic stones was only significant for women above 50 years of age and for men older than 40 years. Thus, we found a significant increase in the incidence of kidney stone disease resulting from increased detection of asymptomatic stones. This was largely due to a more frequent use of high-resolution imaging studies in older patients.

Mortality of multiple sclerosis in Iceland population-based mortality of MS in incidence and prevalence cohorts.

Introduction: Mortality is an important feature of the natural history of multiple sclerosis (MS). We report the mortality of all individuals with MS in Iceland, identified in a nationwide population-based study. Patients and Methods: The results are based on a prevalence cohort and an incidence cohort. The prevalence cohort consisted of all patients with MS (n = 526) living in Iceland on the 31 December 2007. The incidence cohort consisted of all residents of Iceland (n = 222) diagnosed with MS during 2002 to 2007. Mortality was determined by following both the incidence cohort (from diagnosis) and the prevalence cohort (from the prevalence day) until death or 31 December 2020. The mortality, associated with MS, was compared with that expected in the Icelandic population (standardized mortality ratio (SMR)). Results: (a) Prevalence cohort (n = 526). The mean follow up was 12.0 years (range 0.3-13.0). The SMR was 1.6 (95% confidence interval (CI) 1.3-2.0). (b) Incidence cohort (n = 222). The mean follow up was 15.4 years (range 3.7-18.5). The SMR was 1.2 (95% CI 0.6-2.2). Conclusion: During the follow-up period, there was a substantial increase in mortality among the patients with MS, compared with the general population. There was no increase in mortality among the incidence cohort, when followed for up to 18.5 years following diagnosis.

Brain tissue volumes in the general population of the elderly: the AGES-Reykjavik study.

Imaging studies have reported conflicting findings on how brain structure differs with age and sex. This may be explained by discrepancies and limitations in study population and study design. We report a study on brain tissue volumes in one of the largest cohorts of individuals studied to date of subjects with high mean age (mean ± standard deviation (SD) 76 ± 6 years). These analyses are based on magnetic resonance imaging (MRI) scans acquired at baseline on 4303 non-demented elderly, and 367 who had a second MRI, on average 2.5 ± 0.2 years later. Tissue segmentation was performed with an automatic image analysis pipeline. Total brain parenchymal (TBP) volume decreased with increasing age while there was an increase in white matter hyperintensities (WMH) in both sexes. A reduction in both normal white matter (NWM)- and gray matter (GM) volume contributed to the brain shrinkage. After adjusting for intra-cranial volume, women had larger brain volumes compared to men (3.32%, p < 0.001) for TBP volume in the cross-sectional analysis. The longitudinal analysis showed a significant age-sex interaction in TBP volume with a greater rate of annual change in men (-0.70%, 95%CI: -0.78% to -0.63%) than women (-0.55%, 95%CI: -0.61% to -0.49%). The annual change in the cross-sectional data was approximately 40% less than the annual change in the longitudinal data and did not show significant age-sex interaction. The findings indicate that the cross-sectional data underestimate the rate of change in tissue volumes with age as the longitudinal data show greater rate of change in tissue volumes with age for all tissues.

Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility--Reykjavik study.

Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid-femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility--Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69-93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta-carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta-carotid reflection coefficient (R = -0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid-femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62-1.71 per standard deviation, P<0.002). Carotid-femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (-0.127 ± 0.037 SD/SD, P<0.001), grey matter (-0.079 ± 0.038 SD/SD, P = 0.038) and white matter (-0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid-femoral pulse wave velocity (-0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (-0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (-0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (-0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (-0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.

Brain age predicts long-term recovery in post-stroke aphasia.

The association between age and language recovery in stroke remains unclear. Here, we used neuroimaging data to estimate brain age, a measure of structural integrity, and examined the extent to which brain age at stroke onset is associated with (i) cross-sectional language performance, and (ii) longitudinal recovery of language function, beyond chronological age alone. A total of 49 participants (age: 65.2 ± 12.2 years, 25 female) underwent routine clinical neuroimaging (T1) and a bedside evaluation of language performance (Bedside Evaluation Screening Test-2) at onset of left hemisphere stroke. Brain age was estimated from enantiomorphically reconstructed brain scans using a machine learning algorithm trained on a large sample of healthy adults. A subsample of 30 participants returned for follow-up language assessments at least 2 years after stroke onset. To account for variability in age at stroke, we calculated proportional brain age difference, i.e. the proportional difference between brain age and chronological age. Multiple regression models were constructed to test the effects of proportional brain age difference on language outcomes. Lesion volume and chronological age were included as covariates in all models. Accelerated brain age compared with age was associated with worse overall aphasia severity (F(1, 48) = 5.65, P = 0.022), naming (F(1, 48) = 5.13, P = 0.028), and speech repetition (F(1, 48) = 8.49, P = 0.006) at stroke onset. Follow-up assessments were carried out ≥2 years after onset; decelerated brain age relative to age was significantly associated with reduced overall aphasia severity (F(1, 26) = 5.45, P = 0.028) and marginally failed to reach statistical significance for auditory comprehension (F(1, 26) = 2.87, P = 0.103). Proportional brain age difference was not found to be associated with changes in naming (F(1, 26) = 0.23, P = 0.880) and speech repetition (F(1, 26) = 0.00, P = 0.978). Chronological age was only associated with naming performance at stroke onset (F(1, 48) = 4.18, P = 0.047). These results indicate that brain age as estimated based on routine clinical brain scans may be a strong biomarker for language function and recovery after stroke.

Impaired speech repetition and left parietal lobe damage.

Patients with left hemisphere damage and concomitant aphasia usually have difficulty repeating others' speech. Although impaired speech repetition, the primary symptom of conduction aphasia, has been associated with involvement of the left arcuate fasciculus, its specific lesion correlate remains elusive. This research examined speech repetition among 45 stroke patients who underwent aphasia testing and MRI examination. Based on lesion-behavior mapping, the primary structural damage most closely associated with impaired speech repetition was found in the posterior portion of the left arcuate fasciculus. However, perfusion-weighted MRI revealed that tissue dysfunction, in the form of either frank damage or hypoperfusion, to the left inferior parietal lobe, rather than the underlying white matter, was associated with impaired speech repetition. This latter result suggests that integrity of the left inferior parietal lobe is important for speech repetition and, as importantly, highlights the importance of examining cerebral perfusion for the purpose of lesion-behavior mapping in acute stroke.

Incidence of multiple sclerosis in Iceland, 2002-2007: a population-based study.

BACKGROUND: We conducted a study to determine the incidence of multiple sclerosis (MS) among the whole Icelandic population during a 6-year period (2002-2007). METHODS: We included all Icelandic residents diagnosed with MS during the study period. Cases were identified from records of the only neurology department in Iceland, plus the records of all practicing neurologists and all radiology departments. All patients had experienced at least two confirmed MS relapses (i.e. clinically definite MS) or had primary progressive MS as defined by the Poser criteria. RESULTS: We identified 136 individuals who met the inclusion criteria, including 102 (75%) women. The mean age at diagnosis was 36.3 years (women 35.7 years, men 38.3 years). Average annual incidence was 7.6 per 100,000 population. All but one patient (99%) had an MRI study done at diagnosis and 61% of these (83/135) fulfilled the Barkhof criteria for diagnosis of MS; one had a normal MRI. A visual evoked potential test was done in 68% (93/136) at the time of diagnosis and 44% (41/93) were abnormal. Spinal fluid was obtained from 78% (106/136), and 75% (80/106) had oligoclonal bands. CONCLUSION: A total population study is the most reliable method of determining the spectrum of clinical symptoms and the results of investigations in MS patients at diagnosis.

Coronary artery calcium, brain function and structure: the AGES-Reykjavik Study.

BACKGROUND AND PURPOSE: Several cardiovascular risk factors are associated with cognitive disorders in older persons. Little is known about the association of the burden of coronary atherosclerosis with brain structure and function. METHODS: This is a cross-sectional analysis of data from the Age, Gene, Environment Susceptibility (AGES)-Reykjavik Study cohort of men and women born 1907 to 1935. Coronary artery calcification (CAC), a marker of atherosclerotic burden, was measured with CT. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. Dementia was assessed in a multistep procedure and diagnosed according to international guidelines. Quantitative data on total intracranial and tissue volumes (total, gray matter volume, white matter volume, and white matter lesion volume), cerebral infarcts, and cerebral microbleeds were obtained with brain MRI. The association of CAC with dementia (n=165 cases) and cognitive function in nondemented subjects (n=4085), and separately with MRI outcomes, was examined in multivariate models adjusting for demographic and vascular risk factors. Analyses tested whether brain structure mediated the associations of CAC to cognitive function. RESULTS: Subjects with higher CAC were more likely to have dementia and lower cognitive scores, more likely to have lower white matter volume, gray matter volume, and total brain tissue, and to have more cerebral infarcts, cerebral microbleeds, and white matter lesions. The relations of cognitive performance and dementia to CAC were significantly attenuated when the models were adjusted for brain lesions and volumes. CONCLUSIONS: In a population-based sample, increasing atherosclerotic load assessed by CAC is associated with poorer cognitive performance and dementia, and these relations are mediated by evidence of brain pathology.

Ventricular dilation: association with gait and cognition.

OBJECTIVE: Normal pressure hydrocephalus is characterized by gait impairment, cognitive impairment, and urinary incontinence, and is associated with disproportionate ventricular dilation. Here we report the distribution of ventricular volume relative to sulcal cerebrospinal fluid (CSF) volume, and the association of increasing ventricular volume relative to sulcal CSF volume with a cluster of gait impairment, cognitive impairment, and urinary incontinence in a stroke-free cohort of elderly persons from the general population. METHODS: Data are based on 858 persons (35.4% men; age range, 66-92 years) who participated in the Age, Gene/Environment Susceptibility-Reykjavik Study. Gait was evaluated with an assessment of gait speed. Composite scores representing speed of processing, memory, and executive function were constructed from a neuropsychological battery. Bladder function was assessed with a questionnaire. Magnetic resonance brain imaging was followed by semiautomated segmentation of intracranial CSF volume. White matter hyperintensity (WMH) volume was assessed with a semiquantitative scale. For the analysis of ventricular dilation relative to the sulcal spaces, ventricular volume was divided by sulcal CSF volume (VV/SV). RESULTS: Disproportion between ventricular and sulcal CSF volume, defined as the highest quartile of the VV/SV z score, was associated with gait impairment (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3) and cognitive impairment (OR, 1.8; 95% CI, 1.1-3.0). We did not find an association between the VV/SV z score and bladder dysfunction. INTERPRETATION: The prevalence and severity of gait impairment and cognitive impairment increases with ventricular dilation in persons without stroke from the general population, independent of WMH volume.

Microvascular lesions in the brain and retina: The age, gene/environment susceptibility-Reykjavik study.

OBJECTIVE: To investigate whether the severity and location of cerebral white matter hyperintensities (WMHs) and brain infarcts are correlated with the signs of retinal microvascular abnormalities in the elderly. METHODS: The study included 4,176 men and women (mean age, 76 years) who participated in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Digital retinal images of both dilated eyes were taken and evaluated for the presence of retinal focal arteriolar signs (focal arteriolar narrowing and arteriovenous nicking) and retinopathy lesions (retinal blot hemorrhages and microaneurysms). Brain magnetic resonance imaging scans were acquired and evaluated for the presence and distribution of cerebral infarcts and WMHs. Logistic and multinomial logistic models were constructed to estimate the association of retinal microvascular signs to brain lesions. RESULTS: Controlling for demographic and major cardiovascular risk factors, we found that retinal focal arteriolar signs, but not retinopathy lesions, were significantly associated with an increasing load of subcortical and periventricular WMHs. The strongest association was found between retinal arteriolar signs and a heavier WMH load, specifically in the subcortical frontal lobe, and periventricular frontal and parietal caps. There was a tendency toward bilateral retinal focal arteriolar narrowing being more strongly associated with the heavier load of subcortical WMHs. Arteriovenous nicking was significantly associated with subcortical infarcts. INTERPRETATION: In older adults, retinal focal arteriolar signs, but not retinopathy lesions, are correlated with the load of diffuse WMHs, particularly those located in the subcortical frontal lobe, and the periventricular frontal and parietal caps of the brain.

Cerebral infarcts and cognitive performance: importance of location and number of infarcts.

BACKGROUND AND PURPOSE: Cerebral infarcts increase the risk for cognitive impairment. The relevance of location and number of infarcts with respect to cognitive function is less clear. METHODS: We studied the cross-sectional association between number and location of infarcts and cognitive performance in 4030 nondemented participants of the Age Gene/Environment Susceptibility-Reykjavik Study. Composite scores for memory, processing speed, and executive function were created from a neuropsychological battery. Subcortical, cortical, and cerebellar infarcts were identified on brain MRI. We performed linear regression analyses adjusted for demographic and vascular risk factors, depression, white matter lesions, and atrophy. RESULTS: Compared to participants with no infarcts, those with infarcts in multiple locations (n=287, 7%) had slower processing speed (beta=-0.19; P<0.001) and poorer memory (beta=-0.16; P<0.001) and executive function (beta=-0.12; P=0.003). Compared to no infarcts, the presence of either subcortical infarcts only (n=275; beta=-0.12; P=0.016) or cortical infarcts only (n=215; beta=-0.17; P=0.001) was associated with poorer memory performance. Compared to no infarcts, a combination of cortical and subcortical infarcts (n=45) was associated with slower processing speed (beta=-0.38; P<0.001) and poorer executive function (beta=-0.22; P=0.02), whereas a combination of cerebellar and subcortical infarcts (n=89) was associated with slower processing speed (beta=-0.15; P=0.04). Infarcts in all 3 locations was associated with slower processing speed (beta=-0.33; P=0.002). CONCLUSIONS: Having infarcts in >1 location is associated with poor performance in memory, processing speed, and executive function, independent of cardiovascular comorbidities, white matter lesions, and brain atrophy, suggesting that both the number and the distribution of infarcts jointly contribute to cognitive impairment.

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

White matter lesions and cognitive performance: the role of cognitively complex leisure activity.

BACKGROUND: Among persons with white matter lesions (WMLs), there is a range of cognitive function. We examine whether participation in leisure activities modifies the effect of WML load on cognitive function. METHODS: Data are from 2300 men and women (aged 66-92 years) participating in the population-based Age Gene/Environment Susceptibility-Reykjavik Study. Subcortical WML load was calculated as a weighted sum, based on size of lesions in the four lobes. Periventricular WML load was calculated as the sum of lesion scores, based on size, for the frontal caps, occipitoparietal caps and bands. The upper quartile of lesion load in either area was compared to the lower three quartiles. Composite scores of memory (MEM), speed of processing (SP), and executive function (EF) were constructed from a battery of neuropsychological tests. Frequency of participation in nine cognitively stimulating leisure activities was assessed via questionnaire; the upper quartile was compared to the lower three quartiles. Multiple regression, controlling for demographic and health factors and brain infarcts, was used to test the main effects and interaction of WMLs and leisure activity on cognitive function. RESULTS: High leisure activity was associated with higher performance in all three cognitive abilities: MEM beta = 0.20, 95% confidence interval [CI], 0.11-0.29; SP beta = 0.37, 95% CI, 0.29-0.45; and EF beta = 0.23, 95% CI, 0.15-0.29. High WML load was associated with significantly lower performance in SP (beta = -0.06, 95% CI, -0.13 to -0.01). The effect of WMLs on SP performance was modified by high leisure activity (p for interaction <.05). CONCLUSION: Participation in cognitively stimulating leisure activity may attenuate the effect of WML pathology on cognitive performance.

Co-occurrence of major depression or suicide attempt with migraine with aura and risk for unprovoked seizure.

We hypothesized and found that the co-occurrence of migraine with aura (MA) with major depression (MD) or with suicide attempt (SA) increases the risk for developing unprovoked seizure more than these conditions alone. Number of conditions showed a linear relationship to seizure risk. This may reflect a new condition cluster defined by MA, MD, SA and unprovoked seizures. Identifying the biological underpinnings this cluster may affect clinical diagnosis and treatment.

Extramedullary Cavernous Hemangioma with Intradural and Extradural Growth and Clinical Symptoms of Brown-Séquard Syndrome: Case Report and Review of the Literature.

BACKGROUND: Primary spinal tumors are rare. Symptoms depend on the size and location of the tumor. CASE DESCRIPTION: A patient presented with a rare clinical finding, Brown-Séquard syndrome. The symptoms were caused by an extramedullary tumor compressing on the thoracic spinal cord. Pathologic examination showed cavernous hemangioma with growth both intradurally and extradurally. CONCLUSIONS: This is an extremely rare finding; to our knowledge, only 1 case report has been published before in which a spinal cavernous hemangioma had intradural and extradural growth. The clinical symptoms of Brown-Séquard syndrome have not been described before in the findings of spinal cavernous hemangiomas.