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Objective: The 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., Methods: Global 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., Results: During 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., Conclusions: Structural disconnectivity is associated with an increased risk of dementia and more pronounced cognitive decline in the general population., (© 2020 American Academy of Neurology.)

Objective: To examine the association of diffusion-weighted image (DWI) lesions with markers of cerebrovascular disease, neurodegeneration, and cognitive functioning and to further explore the evolution of these DWI lesions and their link to risk of dementia, stroke, or TIA in the Rotterdam Study., Methods: Two thousand one hundred seventy-six participants with baseline MRI scans (assessed between January 2009 and December 2013) and data on incident clinical outcomes (until January 2016) were included. DWIs were inspected for presence of acute or subacute lesions. Markers of cerebrovascular disease, brain tissue segmentation, and microstructural integrity were collected. Cognition was assessed with a detailed neuropsychological test. Evolution of DWI lesions was evaluated on follow-up scans., Results: Thirty-three individuals (1.5%) had ≥1 DWI lesions. Persons with lacunes, white matter hyperintensities (WMHs), and reduced white matter microstructural integrity were more likely to have DWI lesions. Persons with DWI lesions performed worse on Stroop test 1. For 17 of 33 persons, follow-up scans were available to determine lesion evolution. During a mean follow-up of 4.7 years, 58.8% of DWI lesions appeared as WMHs, 17.6% developed cavitation, 5.9% changed into cortical cerebral microinfarcts, and 17.6% disappeared. People with DWI lesions at baseline were at increased risk of strokes (hazard ratio 3.72, 95% confidence interval 1.35-10.27)., Conclusion: Asymptomatic DWI lesions in community-dwelling persons are associated with markers of cerebral small vessel disease, reduced microstructural integrity, and worse cognition. Presence of DWI lesions increases the risk of further strokes. Future investigations will have to show whether screening and treating persons with DWI lesions can effectively reduce the burden of stroke., (© 2019 American Academy of Neurology.)

Objective: To investigate whether retinal microvascular damage is related to normal-appearing white matter microstructure on diffusion tensor MRI., Methods: We included 2,436 participants (age ≥45 years) from the population-based Rotterdam Study (2005-2009) who had gradable retinal images and brain MRI scans. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. White matter microstructure was assessed using diffusion tensor MRI. We used linear regression models to investigate the associations of retinal vascular calibers with markers of normal-appearing white matter microstructure, adjusting for age, sex, the fellow vascular caliber, and additionally for structural MRI markers and cardiovascular risk factors., Results: Narrower arterioles and wider venules were associated with poor white matter microstructure: adjusted difference in fractional anisotropy per SD decrease in arteriolar caliber -0.061 (95% confidence interval -0.106 to -0.016), increase in venular caliber -0.054 (-0.096 to -0.011), adjusted difference in mean diffusivity per SD decrease in arteriolar caliber 0.048 (0.007-0.088), and increase in venular caliber 0.047 (0.008-0.085). The associations for venules were more prominent in women., Conclusions: Retinal vascular calibers are related to normal-appearing white matter microstructure. This suggests that microvascular damage in the white matter is more widespread than visually detectable as white matter lesions., (© 2016 American Academy of Neurology.)

Objective: To investigate the association of cerebral white matter microstructural integrity with mortality., Methods: We included 4,294 individuals, free from stroke and dementia (mean age 63.6 years, 44% male) from the population-based Rotterdam Study (2006-2011). Diffusion-MRI was used to assess the microstructural integrity of the white matter, both globally and for specific white matter tracts. Fractional anisotropy and mean diffusivity were the measures used to quantify white matter integrity. All-cause mortality and cause-specific mortality was recorded with a median follow-up time of 5.4 and 4.6 years, respectively. Cox regression models, adjusted for age, sex, APOE ε4 allele carriership, cardiovascular risk factors, and macrostructural MRI changes, were used to estimate hazard ratios., Results: During the follow-up time, 216 participants (5.0%) died of all causes, 31 (0.7%) of cardiovascular causes, and 102 individuals (2.4%) died of noncardiovascular causes. Each SD decrease in fractional anisotropy and each SD increase in mean diffusivity was associated with a 1.37-fold (95% confidence interval: 1.20-1.57) and a 1.49-fold (95% confidence interval: 1.28-1.75) higher hazard of all-cause mortality, respectively. The associations were more prominent with cardiovascular mortality than with noncardiovascular mortality. In tract-specific analyses, we observed that association tracts were more prominently related to mortality., Conclusions: Our findings suggest that impairments in cerebral white matter, even at early stages, are not limited to adverse brain outcomes and they are related to mortality, especially from cardiovascular causes., (© 2016 American Academy of Neurology.)

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., (© 2015 American Academy of Neurology.)

Objective: To investigate whether the presence of cerebral microbleeds, which present as focal lesions on imaging, is associated with a diffuse loss of white matter microstructural integrity in the brain., Methods: In the prospective, population-based Rotterdam Scan Study, a total of 4,493 participants underwent brain MRI to determine microbleed status. With diffusion tensor imaging, global fractional anisotropy (FA) and mean diffusivity (MD) were measured in normal-appearing white matter. Multiple linear regression models, adjusted for age, sex, cardiovascular risk factors, white matter lesions, and infarcts, were applied to investigate the independent association between microbleeds and organization of brain white matter. Analyses were repeated after stratification by APOE ε4 carriership., Results: Presence of microbleeds was related to a lower mean FA and higher mean MD, in a dose-dependent manner, and was already apparent for a single microbleed (standardized FA: -0.13, 95% confidence interval -0.21 to -0.05; MD: 0.12, 95% confidence interval 0.05 to 0.19). For lobar microbleeds, alterations in diffusion tensor imaging measurements were solely driven by APOE ε4 carriers., Conclusions: Presence of microbleeds relates to poorer microstructural integrity of brain white matter, even after adjusting for cardiovascular risk and other markers of cerebral small-vessel disease. Our data suggest that microbleeds reflect diffuse brain pathology, even when only a single microbleed is present.