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Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration
| Content Provider | Oxford Academic |
|---|---|
| Author | Fernández-Cabello, Sara Kronbichler, Martin Van Dijk, Koene R A Goodman, James A Spreng, R Nathan Schmitz, Taylor W |
| Copyright Year | 2020 |
| Abstract | Alzheimer's disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer's degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer's disease pathogenesis. |
| Related Links | https://academic.oup.com/brain/article-pdf/143/3/993/32963686/awaa012.pdf |
| Ending Page | 1009 |
| Starting Page | 993 |
| File Format | |
| ISSN | 00068950 |
| e-ISSN | 14602156 |
| DOI | 10.1093/brain/awaa012 |
| Journal | Brain |
| Issue Number | 3 |
| Volume Number | 143 |
| Language | English |
| Publisher | Oxford Academic |
| Publisher Date | 2020-03-01 |
| Access Restriction | Open |
| Subject Keyword | Clinical Medicine Medicine and Health Neurology Neuroscience Science and Mathematics Amyloid Alzheimer's Disease Biological Markers Entorhinal Cortex Basal Forebrain Tissue Degeneration Nerve Degeneration Brain Magnetic Resonance Imaging Gray Matter Basal Nucleus of Meynert Clinical Diagnosis Cholinergic Agents Nbm Nucleus Basalis of Meynert |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neurology (clinical) |
