Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Abstract

Normal aging and Alzheimer's Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD.Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD. The brain becomes progressively disorganized with age, and brain alterations accelerated in Alzheimer's disease may occur gradually over the lifespan. Although hemispheric asymmetry aids efficient network organization, efforts to identify structural markers of age-related decline have largely overlooked cortical asymmetry. Here we show the hemisphere that is thicker when younger, thins faster. This leads to progressive system-wide loss of regional thickness asymmetry across life. In multiple aging cohorts, asymmetry-loss showed high reproducibility topologically across cortex and similar timing-of-change in aging. Asymmetry-change was further accelerated in AD. Our findings uncover a new principle of brain aging -thicker homotopic cortex thins faster -and suggest we may have unveiled a structural marker for a widely-hypothesized decline in hemispheric specialization in aging and AD.

Repeatability of Peripapillary OCT Angiography in Neurodegenerative Disease

“…While asymmetric findings on brain imaging or symptomology have been observed in neurodegenerative conditions such as AD and PD and unilateral central pathology may correspond with unilateral signs and symptoms, it is unclear how common asymmetric progression may manifest at the population level, or what the etiology and clinical significance of these phenomena are specific to the eye. [33][34][35] It is possible that the eye may be less overtly affected by asymmetric progression of disease centrally or that our sample size was insufficient to capture many such patients with asymmetric disease; larger studies may consider performing a sub-analysis on patients who demonstrate more asymmetric retinal findings in the contexts of repeatability but also in the primary pathophysiology of disease. By convention, subjects with only one eye included (if both eyes are eligible) tended to have the right eye imaged (we routinely image the right eye first, followed by the left eye); however, our findings of symmetry between eyes indicates that this is unlikely to have introduced appreciable bias in our results.…”

Exploratory factor analysis with structured residuals for brain network data

“…For instance, typical language ability is associated with an asymmetry in focal brain regions Exploratory factor analysis with structure for brain network data (e.g., Bishop, 2013;Gauger, Lombardino, & Leonard, 1997), whereas structural differences in the right hemisphere may be more strongly associated with face perception mechanisms (Frässle et al, 2016). Developmentally, there is evidence that the degree of asymmetry changes across the lifespan (e.g., Plessen, Hugdahl, Bansal, Hao, & Peterson, 2014;Roe et al, 2020). Within a SEM context, recent work shows that model fit of a hypothesized covariance structure may differ substantially between the right and left hemispheres despite focusing on the same brain regions (Meyer, Garzón, Lövdén, & Hildebrandt, 2019).…”

Tracing the development and lifespan change of population-level structural asymmetry in the cerebral cortex

“…However, structural asymmetry is also a ubiquitous aspect of brain organization 8,9 . For instance, cortical thickness (CT) and surface area (SA) are known to exhibit distinct asymmetry patterns 8,10 , but these have been reported inconsistently 8,9,[11][12][13][14][15][16][17][18][19][20][21] . Yet disrupted cortical asymmetry is a confirmed feature of neurodevelopmental disorders 22 , aging 11 , and Alzheimer's disease 11,23,24 .…”

“…For instance, cortical thickness (CT) and surface area (SA) are known to exhibit distinct asymmetry patterns 8,10 , but these have been reported inconsistently 8,9,[11][12][13][14][15][16][17][18][19][20][21] . Yet disrupted cortical asymmetry is a confirmed feature of neurodevelopmental disorders 22 , aging 11 , and Alzheimer's disease 11,23,24 . Hence, achieving consensus on cortical asymmetries and understanding the genetic-developmental and lifespan influences that shape and alter them is necessary to discover precise biomarkers for disease.…”