Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions

Abstract

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most whole-brain neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell-types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell-types extensively predicts tissue damage in eleven neurodegenerative disorders, including early- and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, frontotemporal dementia, and tauopathies. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell-types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, on spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorders pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration. Major cell-types distinctively associate with spatial vulnerability to tissue loss in eleven neurodegenerative disorders.

Gray matter volume alterations in de novo Parkinson's disease: A mediational role in the interplay between sleep quality and anxiety

“…VBM is recognized for its unbiased, whole‐brain analytical capabilities, which are particularly advantageous for the characterization of neurodegenerative diseases 28,29 . The technique's sensitivity to subtle and diffuse structural alterations is pivotal in delineating the neurodegenerative trajectory of such conditions 30 .…”