Saloua Akoudad1, Frank J Wolters2, Anand Viswanathan3, Renée F de Bruijn2, Aad van der Lugt4, Albert Hofman5, Peter J Koudstaal6, M Arfan Ikram1, Meike W Vernooij7. 1. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands2Department of Radiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands3Department of Neurology, Erasmus MC, University Me. 2. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands3Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 3. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 4. Department of Radiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 5. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 6. Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 7. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands2Department of Radiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Abstract
IMPORTANCE: Cerebral microbleeds are hypothesized downstream markers of brain damage caused by vascular and amyloid pathologic mechanisms. To date, whether their presence is associated with cognitive deterioration in the general population remains unclear. OBJECTIVE: To determine whether microbleeds, and more specifically microbleed count and location, are associated with an increased risk for cognitive impairment and dementia in the general population. DESIGN, SETTING, AND PARTICIPANTS: The Rotterdam Study, a prospective population-based study set in the general community, assessed the presence, number, and location of microbleeds at baseline (August 2005 to December 2011) on magnetic resonance imaging studies of the brain in 4841 participants 45 years or older. Participants underwent neuropsychological testing at 2 points a mean (SD) of 5.9 (0.6) years apart and were followed up for incident dementia throughout the study period until January 1, 2013. The association of microbleeds with cognitive decline and dementia was studied using multiple linear regression, linear mixed-effects modeling, and Cox proportional hazards. EXPOSURES: Cerebral microbleed presence, location, and number. MAIN OUTCOMES AND MEASURES: Cognitive decline measured by a decrease in neuropsychological test battery scores (Mini-Mental State Examination, Letter Digit Substitution Task, Word Fluency Test, Stroop test, 15-word Verbal Learning Test, and Purdue Pegboard Test) and compound scores (eg, G factor, executive function, information processing speed, memory, motor speed) and dementia. RESULTS: In total, 3257 participants (1758 women [54.7%]; mean [SD] age, 59.6 [7.8] years) underwent baseline and follow-up cognitive testing. Microbleed prevalence was 15.3% (median [interquartile range] count, 1 [1-88]). The presence of more than 4 microbleeds was associated with cognitive decline. Lobar (with or without cerebellar) microbleeds were associated with a decline in executive functions (mean difference in z score, -0.31; 95% CI, -0.51 to -0.11; P = .003), information processing (mean difference in z score, -0.44; 95% CI, -0.65 to -0.22; P < .001), and memory function (mean difference in z score, -0.34; 95% CI, -0.64 to -0.03; P = .03), whereas microbleeds in other brain regions were associated with a decline in information processing and motor speed (mean difference in z score, -0.61; 95% CI, -1.05 to -0.17; P = .007). After a mean (SD) follow-up of 4.8 (1.4) years, 72 participants developed dementia, of whom 53 had Alzheimer dementia. The presence of microbleeds was associated with an increased risk for dementia after adjustment for age, sex, and educational level (hazard ratio, 2.02; 95% CI, 1.25-3.24), including Alzheimer dementia (hazard ratio, 2.10; 95% CI, 1.21-3.64). CONCLUSIONS AND RELEVANCE: In the general population, a high microbleed count was associated with an increased risk for cognitive deterioration and dementia. Microbleeds thus mark the presence of diffuse vascular and neurodegenerative brain damage.
IMPORTANCE: Cerebral microbleeds are hypothesized downstream markers of brain damage caused by vascular and amyloid pathologic mechanisms. To date, whether their presence is associated with cognitive deterioration in the general population remains unclear. OBJECTIVE: To determine whether microbleeds, and more specifically microbleed count and location, are associated with an increased risk for cognitive impairment and dementia in the general population. DESIGN, SETTING, AND PARTICIPANTS: The Rotterdam Study, a prospective population-based study set in the general community, assessed the presence, number, and location of microbleeds at baseline (August 2005 to December 2011) on magnetic resonance imaging studies of the brain in 4841 participants 45 years or older. Participants underwent neuropsychological testing at 2 points a mean (SD) of 5.9 (0.6) years apart and were followed up for incident dementia throughout the study period until January 1, 2013. The association of microbleeds with cognitive decline and dementia was studied using multiple linear regression, linear mixed-effects modeling, and Cox proportional hazards. EXPOSURES: Cerebral microbleed presence, location, and number. MAIN OUTCOMES AND MEASURES: Cognitive decline measured by a decrease in neuropsychological test battery scores (Mini-Mental State Examination, Letter Digit Substitution Task, Word Fluency Test, Stroop test, 15-word Verbal Learning Test, and Purdue Pegboard Test) and compound scores (eg, G factor, executive function, information processing speed, memory, motor speed) and dementia. RESULTS: In total, 3257 participants (1758 women [54.7%]; mean [SD] age, 59.6 [7.8] years) underwent baseline and follow-up cognitive testing. Microbleed prevalence was 15.3% (median [interquartile range] count, 1 [1-88]). The presence of more than 4 microbleeds was associated with cognitive decline. Lobar (with or without cerebellar) microbleeds were associated with a decline in executive functions (mean difference in z score, -0.31; 95% CI, -0.51 to -0.11; P = .003), information processing (mean difference in z score, -0.44; 95% CI, -0.65 to -0.22; P < .001), and memory function (mean difference in z score, -0.34; 95% CI, -0.64 to -0.03; P = .03), whereas microbleeds in other brain regions were associated with a decline in information processing and motor speed (mean difference in z score, -0.61; 95% CI, -1.05 to -0.17; P = .007). After a mean (SD) follow-up of 4.8 (1.4) years, 72 participants developed dementia, of whom 53 had Alzheimer dementia. The presence of microbleeds was associated with an increased risk for dementia after adjustment for age, sex, and educational level (hazard ratio, 2.02; 95% CI, 1.25-3.24), including Alzheimer dementia (hazard ratio, 2.10; 95% CI, 1.21-3.64). CONCLUSIONS AND RELEVANCE: In the general population, a high microbleed count was associated with an increased risk for cognitive deterioration and dementia. Microbleeds thus mark the presence of diffuse vascular and neurodegenerative brain damage.
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