Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy

Abstract

Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.

Ischemic brain injury in cerebral amyloid angiopathy

“…80 Furthermore, impairments in wholebrain white matter connectivity in CAA patients correlated with SVD burden on MRI (i.e., WMH, microbleeds, and total brain volume) and with cortical amyloid load as quantified with PiB positron emission tomography imaging. 80 These findings suggest that CAA-related vasculopathy can indeed be captured with DTI.…”

“…76,77 Diffusion tensor imaging parameters have also found to be altered in patients with probable CAA (Figure 2). [78][79][80] A recent study showed that diffusion abnormalities in CAA resemble the distribution of CAA pathology: between-group differences in FA were observed in white-matter tracts projecting onto the posterior cortex (i.e., the occipital, posterior temporal, and parietal lobes), whereas tracts projecting onto subcortical regions were relatively spared ( Figure 2A). 80 Furthermore, impairments in wholebrain white matter connectivity in CAA patients correlated with SVD burden on MRI (i.e., WMH, microbleeds, and total brain volume) and with cortical amyloid load as quantified with PiB positron emission tomography imaging.…”

“…Patients with advanced CAA showed a reduced change in mean blood flow velocity 88 and reduced amplitude and delayed time to peak of the BOLD (blood oxygen level-dependent) response 89,90 compared with controls. Furthermore, the lower flow velocity response and (a) DTI-based brain network analysis 80 shows local differences in connectivity strength between patients with CAA (n ¼ 38) compared with age-matched controls (n ¼ 29). Whole brain fiber tractography results were registered to a gray-matter atlas.…”

“…The global mean diffusion coefficient of the white matter in the ICH-free hemisphere was associated with a 2.5-fold increased risk of pre-ICH cognitive impairment, independent of WMH, microbleeds, and cerebral atrophy. 127 The other study 80 combined DTI with fiber tractography to examine alterations in whole-brain connectivity using graph theory, also referred to as DTI-based network analysis. 128 The DTI-based network analysis is a promising technique to study the structural basis of cognitive functions that rely on the interaction between widely distributed brain regions, such as executive functioning and information processing speed-cognitive functions that are preferentially affected in patients with SVD.…”

Aberrant White Matter Networks Mediate Cognitive Impairment in Patients with Silent Lacunar Infarcts in Basal Ganglia Territory

“…2 Significant link has been observed between silent lacunar infarcts in both cortical and subcortical regions and the risk of subsequent stroke and dementia. 1 In recent findings, disrupted white matter has been suggested to mediate the relationship between multiple small vessel diseases including cerebral microbleeds in early Alzheimer's disease (AD), 3 lacunar infarcts, 4 cerebral amyloid angiopathy, 5 and cognitive dysfunction. However, it remains unclear whether disrupted white matter (WM) contributes to the neural mechanism by which silent subcortical lacunar infarcts lead to cognitive impairment.…”