There is increasing recognition that much of vascular cognitive impairment and dementia (VCID) is attributable to cerebral small vessel disease (SVD), which typically manifests as white matter hyperintensities (WMH) on T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). WMH are highly prevalent in older adults, including asymptomatic individuals, and are also linked to clinical progression in mild cognitive impairment (MCI) and Alzheimer?s disease (AD). Yet, the mechanisms by which WMH cause cognitive deficits remain incompletely understood. White matter lesions such as lacunar infarcts classically cause disconnection syndromes by interrupting communication between the brain regions that they connect. Connectivity effects of WMH in SVD are more challenging to study because they are more diffuse than lacunar infarcts and often occur in regions of crossing white matter fiber tracts. We recently implemented a ?virtual lesion connectome? approach to characterize the evolution of widespread partial disconnection caused by WMH using FLAIR-based WML data from older subjects as regions of avoidance for fiber tracking on high quality diffusion tensor imaging (DTI) data acquired in healthy subjects. For this project, we will apply the virtual lesion approach to MRI and cognitive performance data from the Alzheimer?s Disease Neuroimaging Initiative (ADNI) to test the hypothesis that the spatial distribution and extent of WM tract disconnection due to WMH is associated with corresponding cognitive performance deficits. We will also examine the effects of amyloid status on the relationship between structural connectivity and cognition. The results of this project will provide the computational infrastructure to calculate robust individual virtual lesion connectomes, advance knowledge on the mechanisms by which WMH cause cognitive deficits, provide mechanistically-specific biomarkers for cognitive decline in VCID, and help dissociate the direct effects of WMH on cognition in patients with mixed pathologies.
Nearly every older adult eventually develops MRI visible brain lesions in white matter, which is composed of fibers tracts connecting different gray matter lesions. This project will combine advanced image analysis methods with publicly shared data from the Alzheimer's Disease Neuroimaging Initiative and the Human Connectome Project to determine whether cognitive changes in aging and dementia can be explained by partial disconnection of fiber tracts.
