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ObjectiveThe disconnectivity hypothesis postulates that partial loss of connecting white matter fibers between brain regions contributes to the development of dementia. Using diffusion MRI to quantify global and tract-specific white matter microstructural integrity, we tested this hypothesis in a longitudinal population-based study.MethodsGlobal and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) were obtained in 4,415 people without dementia (mean age 63.9 years, 55.0% women) from the prospective population-based Rotterdam Study with brain MRI between 2005 and 2011. We modeled the association of these diffusion measures with risk of dementia (follow-up until 2016) and with changes on repeated cognitive assessment after on average 5.4 years, adjusting for age, sex, education, macrostructural MRI markers, depressive symptoms, cardiovascular risk factors, and APOE genotype.ResultsDuring a median follow-up of 6.8 years, 101 participants had incident dementia, of whom 83 had clinical Alzheimer disease (AD). Lower global values of FA and higher values of MD were associated with an increased risk of dementia (adjusted hazard ratio [95% confidence interval (CI)] per SD increase for MD 1.79 [1.44–2.23] and FA 0.65 [0.52–0.80]). Similarly, lower global values of FA and higher values of MD related to more cognitive decline in people without dementia (difference in global cognition per SD increase in MD [95% CI] was −0.04 [−0.07 to −0.01]). Associations were most profound in the projection, association, and limbic system tracts.ConclusionsStructural disconnectivity is associated with an increased risk of dementia and more pronounced cognitive decline in the general population.

ObjectiveTo investigate the effect of conscious sedation (CS) on functional outcome and complication rates after intra-arterial treatment (IAT) for acute ischemic stroke (AIS) compared to the use of local anesthesia (LA) at the puncture site only.MethodsPatients undergoing IAT for AIS with CS or LA in the Erasmus University Medical Center from March 2014 to June 2016 were included for analysis. The primary outcome was the score on the ordinal modified Rankin Scale (mRS). We compared CS to LA by ordinal logistic regression with covariate adjustment using propensity scoring.ResultsIn 146 AIS patients treated with IAT, use of CS was associated with a shift towards worse mRS scores (odds ratio [OR] 0.4 [95% confidence interval (CI) 0.2–0.7]) compared to LA. Mortality after 90 days was higher in the CS group compared to the LA group (OR 2.3 [95% CI 1.0–5.2]). No differences between groups were noted with regard to procedure duration (8 minutes, β = 6.3 [95% CI −7.4 to 20.0]) or occurrence of procedure-related complications (OR 1.3 [95% CI 0.6–2.7]).ConclusionCS was associated with poor functional outcome and increased mortality rates compared to LA. Furthermore, CS did not reduce duration of intervention or interventional complications. CS during IAT for AIS is of no benefit if LA is considered safe.Classification of evidenceThis study provides Class II evidence, because of nonrandom allocation, that for patients with AIS undergoing IAT, LA rather than CS improves functional outcome.

Objective: To investigate the association of kidney function with white matter microstructural integrity. Methods: We included 2,726 participants with a mean age of 56.6 years (45% men) from the population-based Rotterdam Study. Albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR), using serum cystatin C (eGFRcys) and creatinine (eGFRcr), were measured to evaluate kidney function. Diffusion-MRI was used to assess microstructural integrity of the normal-appearing white matter. Multiple linear regression models, adjusted for macrostructural MRI markers and cardiovascular risk factors, were used to model the association of kidney function with white matter microstructure. Results: Participants had average eGFRcr of 86.1 mL/min/1.73 m 2 , average eGFRcys of 86.2 mL/min/1.73 m 2 , and median albumin-to-creatinine ratio of 3.4 mg/g. Lower eGFRcys was associated with worse global white matter microstructural integrity, reflected as lower fractional anisotropy (standardized difference per SD: −0.053, 95% confidence interval [CI]: −0.092, −0.014) and higher mean diffusivity (0.036, 95% CI: 0.001, 0.070). Similarly, higher albumin-to-creatinine ratio was associated with lower fractional anisotropy (−0.044, 95% CI: −0.078, −0.011). There was no linear association between eGFRcr and white matter integrity. Subgroup analyses showed attenuation of the associations after excluding subjects with hypertension. The associations with global diffusion tensor imaging measures did not seem to be driven by particular tracts, but rather spread across multiple tracts in various brain regions. Conclusions: Reduced kidney function is associated with worse white matter microstructural integrity. Our findings highlight the importance for clinicians to consider concomitant macro- and microstructural changes of the brain in patients with impaired kidney function.

Objective: To investigate the association between cardiac function and the risk of stroke and dementia in elderly free of clinical cardiac disease. Additionally, we investigated the relation between cardiac function and MRI markers of subclinical cerebrovascular disease. Methods: This study was conducted within the population-based Rotterdam Study. A total of 3,291 participants (60.8% female, age-range 58–98 years) free of coronary heart disease, heart failure, atrial fibrillation, stroke, and dementia underwent echocardiography in 2002–2005 to measure cardiac function. Follow-up finished in 2012. In 2005–2006, a random subset of 577 stroke-free people without dementia underwent brain MRI on which infarcts and white matter lesion volume were assessed. Results: During 21,785 person-years of follow-up, 164 people had a stroke and during 19,462 person-years of follow-up, 208 people developed dementia. Measures of better diastolic function, such as higher E/A ratio, were associated with a lower risk of stroke (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.69; 0.98) and dementia (HR 0.82; 95% CI 0.70; 0.96). Better systolic function, measured as higher fractional shortening, was only associated with a lower risk of stroke (HR 0.84; 95% CI 0.72; 0.98). Better diastolic function was related to a lower prevalence of silent infarcts on MRI, especially lacunar infarcts. Conclusions: In elderly free of clinical cardiac disease, worse diastolic function is associated with clinical stroke, dementia, and silent infarcts on MRI, whereas worse systolic function is related only to clinical stroke. These findings can form the basis for future research on the utility of cardiac function as potential intervention target for prevention of neurologic diseases.

Objective: To study the role of thyroid function in dementia, cognitive function, and subclinical vascular brain disease with MRI. Methods: Analyses were performed within the Rotterdam Study (baseline 1997), a prospective, population-based cohort. We evaluated the association of thyroid-stimulating hormone (TSH) and free thyroxine with incident dementia using Cox models adjusted for age, sex, cardiovascular risk factors, and education. Absolute risks were calculated accounting for death as a competing risk factor. Associations of thyroid function with cognitive test scores and subclinical vascular brain disease (white matter lesions, lacunes, and microbleeds) were assessed with linear or logistic regression. Additionally, we stratified by sex and restricted analyses to normal thyroid function. Results: We included 9,446 participants with a mean age of 65 years. During follow-up (mean 8.0 years), 601 participants had developed dementia. Higher TSH was associated with lower dementia risk in both the full and normal ranges of thyroid function (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.83–0.98; and HR 0.76, 95% CI 0.64–0.91, respectively). This association was independent of cardiovascular risk factors. Dementia risk was higher in individuals with higher free thyroxine (HR 1.04, 95% CI 1.01–1.07). Absolute 10-year dementia risk decreased from 15% to 10% with higher TSH in older women. Higher TSH was associated with better global cognitive scores ( p = 0.021). Thyroid function was not related to subclinical vascular brain disease as indicated by MRI. Conclusions: High and high-normal thyroid function is associated with increased dementia risk. Thyroid function is not related to vascular brain disease as assessed by MRI, suggesting a role for thyroid hormone in nonvascular pathways leading to dementia.

Objective: Cerebral microbleeds are frequently found in the general elderly population and may reflect underlying vascular disease, but their role in cognitive function is unknown. Methods: We investigated the association between cerebral microbleeds and performance in multiple cognitive domains in 3,979 persons without dementia (mean age, 60.3 years). Mini-Mental State Examination (MMSE) score and neuropsychological tests were used to assess global cognition and the following cognitive domains: memory, information processing speed, executive function, and motor speed. We used number of microbleeds as continuous variable, and additionally distinguished between persons with no microbleeds, 1 microbleed, 2–4 microbleeds, and ≥5 microbleeds. The association of microbleeds with different cognitive domains was estimated using linear regression models. Additional adjustments were made for vascular risk factors, brain atrophy, and other imaging markers of cerebral small vessel disease. We stratified analyses by location of microbleeds. Results: A higher number of microbleeds was associated with lower MMSE score and worse performance on tests of information processing speed and motor speed. When analyzed per category, presence of 5 or more microbleeds was associated with worse performance in all cognitive domains, except memory. These associations were most robust in participants with strictly lobar microbleeds, whereas after additional adjustments associations disappeared for deep or infratentorial microbleeds. Conclusions: Presence of numerous microbleeds, especially in a strictly lobar location, is associated with worse performance on tests measuring cognitive function, even after adjustments for vascular risk factors and other imaging markers of small vessel disease. These results suggest an independent role for microbleed-associated vasculopathy in cognitive impairment.

Background: Superficial siderosis is a rare radiologic diagnosis of hemosiderin deposition in subpial brain layers. In case studies, an association between superficial siderosis and cerebral amyloid angiopathy (CAA) has been described. Also, a potential role of superficial siderosis in Alzheimer disease (AD) was hypothesized. All previously reported cases of superficial siderosis were detected because of overt clinical symptoms. We studied the occurrence of superficial siderosis on brain MRI in a general population of nondemented elderly. Methods: In 1,062 persons (mean age 69.6 years) from the population-based Rotterdam Scan Study, we performed T2*-weighted MRI to assess the presence of superficial siderosis. Furthermore, the presence, number, and location of cerebral microbleeds were rated, as lobar microbleeds are thought to be indicative of CAA. Results: We found that superficial siderosis was present in 7 (0.7%) individuals, all of whom had cerebral microbleeds in lobar locations. Furthermore, in all 7 persons, microbleeds were located in close vicinity to superficial siderosis. Conclusions: Our results provide further indirect support for the presumed link between superficial siderosis and cerebral amyloid angiopathy (CAA). Whether superficial siderosis may be a marker for severity or worse prognosis of CAA needs to be further evaluated in longitudinal follow-up. Neurology (R) 2009; 73: 202-205

Demeestere et al.1 found no significant difference between the accuracy of Alberta Stroke Program Early CT Score (ASPECTS) or CT perfusion to identify ischemic stroke patients with a diffusion-weighted imaging (DWI) lesion of at least 70 mL, although CT perfusion with a core volume of 50 mL was more accurate than ASPECTS with an optimal cutoff value of less than 7.

Cerebral microbleeds are small deposits of hemosiderin, which can be imaged using MRI. In the past decade, cerebral microbleeds have become recognized as markers of cerebral microangiopathy, as they are frequently encountered in patients with hemorrhagic or ischemic stroke.1 Current thinking is that they occur either on the basis of hypertensive and arteriolosclerotic vasculopathy,2 or on the basis of cerebral amyloid angiopathy (CAA),3 an important cause of primary intracerebral hemorrhage. In stroke patients, presence of microbleeds at time of admission has been associated with an increased risk of stroke recurrence and hemorrhagic transformation after ischemic stroke.1 It has furthermore been suggested that microbleeds increase the risk of intracerebral hemorrhage following antithrombotic or thrombolytic treatment for acute ischemic stroke,1,4,5 though this issue remains controversial.6 The prognosis of microbleeds in asymptomatic stroke-free persons is unclear, yet potentially of paramount importance, as improved imaging techniques reveal that their prevalence in the general population is high: over 20% of persons aged 60 years and older have one or more microbleeds in their brain.2 We present a case of a stroke-free, neurologically asymptomatic person in whom a microbleed was incidentally identified. Two weeks later, this person had a symptomatic intracerebral hemorrhage that occurred at the site of the microbleed. ### Case report. A 58-year-old man with a history of hypertension, abdominal aortic aneurysm, …

Background: Cerebral microbleeds are focal deposits of hemosiderin that can be visualized with MRI. Little is known on their prevalence in the general population and on their etiology. It has been suggested that, in analogy to spontaneous intracranial hemorrhage, the etiology of microbleeds differs according to their location in the brain, with lobar microbleeds being caused by cerebral amyloid angiopathy and deep or infratentorial microbleeds resulting from hypertension and atherosclerosis. We investigated the prevalence of and risk factors for microbleeds in the general population aged 60 years and older. Methods: This study is based on 1,062 persons (mean age 69.6 years) from the population-based Rotterdam Scan Study. MRI was performed at 1.5 T and included a sequence optimized to increase the conspicuity of microbleeds. We assessed the relation of APOE genotype, cardiovascular risk factors, and markers of small vessel disease to the presence and location of microbleeds with multiple logistic regression. Results: Overall prevalence of cerebral microbleeds was high and increased with age from 17.8% in persons aged 60-69 years to 38.3% in those over 80 years. APOE e4 carriers had significantly more often strictly lobar microbleeds than noncarriers. In contrast, cardiovascular risk factors and presence of lacunar infarcts and white matter lesions were associated with microbleeds in a deep or infratentorial location but not in a lobar location. Conclusion: The prevalence of cerebral microbleeds is high. Our data support the hypothesis that strictly lobar microbleeds are related to cerebral amyloid angiopathy, whereas microbleeds in a deep or infratentorial location result from hypertensive or atherosclerotic microangiopathy.

Objective To identify common genetic variants associated with the presence of brain microbleeds (BMBs). Methods We performed genome-wide association studies in 11 population-based cohort studies and 3 case–control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs. Results BMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21–1.45]; p = 2.5 × 10−10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19–1.50]; p = 1.0 × 10−6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86–1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB. Conclusions Genetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

Spinal cord compression by extramedullary hemopoietic tissue is a rare complication of hemolytic anemias. This is the first report of this complication in hemolytic anemia caused by pyruvate-kinase deficiency. Indium scan, computed tomography (CT) scan, and myelography were helpful in diagnosis. Surgery and radiotherapy were followed by complete recovery during a follow-up period of 12 months.