Relationship between β-amyloid and structural network topology in decedents without dementia

Abstract

ObjectiveTo investigate the association between β-amyloid (Aβ) load and postmortem structural network topology in decedents without dementia.MethodsFourteen decedents (mean age at death 72.6 ± 7.2 years) without known clinical diagnosis of neurodegenerative disease and meeting pathology criteria only for no or low Alzheimer disease (AD) pathologic change were selected from the Normal Aging Brain Collection Amsterdam database. In situ brain MRI included 3D T1-weighted images for anatomical registration and diffusion tensor imaging for probabilistic tractography with subsequent structural network construction. Network topologic measures of centrality (degree), integration (global efficiency), and segregation (clustering and local efficiency) were calculated. Tissue sections from 12 cortical regions were sampled and immunostained for Aβ and hyperphosphorylated tau (p-tau), and histopathologic burden was determined. Linear mixed effect models were used to assess the relationship between Aβ and p-tau load and network topologic measures.ResultsAβ was present in 79% of cases and predominantly consisted of diffuse plaques; p-tau was sparsely present. Linear mixed effect models showed independent negative associations between Aβ load and global efficiency (β = −0.83 × 10−3, p = 0.014), degree (β = −0.47, p = 0.034), and clustering (β = −0.55 × 10−2, p = 0.043). A positive association was present between Aβ load and local efficiency (β = 3.16 × 10−3, p = 0.035). Regionally, these results were significant in the posterior cingulate cortex (PCC) for degree (β = −2.22, p < 0.001) and local efficiency (β = 1.01 × 10−2, p = 0.014) and precuneus for clustering (β = −0.91 × 10−2, p = 0.017). There was no relationship between p-tau and network topology.ConclusionThis study in deceased adults with AD-related pathologic change provides evidence for a relationship among early Aβ accumulation, predominantly of the diffuse type, and structural network topology, specifically of the PCC and precuneus.

Cellular Substrates of Functional Network Integration and Memory in Temporal Lobe Epilepsy

“…This would bridge the gap between focal TLE pathology and its widespread cross-scale effects on the brain, ultimately pertaining to cognitive impairment. Such studies are of particular interest, since our current finding of cross-scale preservation of integrative propensity in a non-pathological brain region may not necessarily be specific to TLE: Previous work in macaques and postmortem donors also report on such correlations ( Scholtens et al 2014 ; Kiljan et al 2019 ; Jonkman et al 2020 ), raising the question whether cross-scale integration is a basic organizational principle conserved across species to begin with. By also involving focal pathological cellular properties (and their large-scale network counterparts), disease-specific processes may be disentangled from such fundamental principles, ultimately leading to a more comprehensive framework on the development of cognitive complaints in TLE.…”

“…In animals, more integrative structural network regions are comprised of bigger neurons with more axons ( Scholtens et al 2014 ). Moreover, cross-scale relations between structural brain properties covary with disease characteristics in postmortem studies of multiple sclerosis ( Kiljan et al 2019 ) and Alzheimer’s disease ( Jonkman et al 2020 ). However, the cellular substrates of functional network integration as an important correlate of cognitive impairment have been impossible to investigate in vivo.…”

Cellular substrates of functional network integration and memory in temporal lobe epilepsy

“…This would bridge the gap between focal TLE pathology and its widespread cross-scale effects on the brain, ultimately pertaining to cognitive impairment. Such studies are of particular interest, since our current finding of cross-scale preservation of integrative propensity in a non-pathological brain region may not necessarily be specific to TLE: previous work in macaques and postmortem donors also report on such correlations (Scholtens et al 2014;Kiljan et al 2019;Jonkman et al 2020), raising the question whether cross-scale integration is a basic organizational principle conserved across species to begin with. By also involving focal pathological cellular properties (and their large-scale network counterparts), disease-specific processes may be disentangled from such fundamental principles.…”

Structural (dys)connectivity associates with cholinergic cell density of the nucleus basalis of Meynert in Alzheimer’s disease

“…To minimize the impact of age-related white matter abnormalities (e.g., vascular change) on automated segmentations, the 3D T1 images were lesion-filled 27 , as previously described 28 . Subsequently, normalized brain volumes of the whole brain, white matter and gray matter were estimated from 3D T1 images using SIENAX 29 , FMRIB Software Library (FSL) tools version 5.0.9 (https://fsl.fmrib.ox.ac.uk/fsl/).…”

“…To minimize the impact of age-related white matter abnormalities (e.g., vascular change) on automated segmentations, the 3D T1 images were lesion-filled 27 , as previously described 28 .…”