Abstract
Stereotypical isocortical tau protein pathology along the Braak-Stages has been described as an instigator of neurodegeneration in Alzheimer's Disease (AD). Less is known about tau pathology in motor regions, although higher-order motor deficits such as praxis dysfunction are part of the clinical description. Here, we examined how tau pathology in cytoarchitectonically mapped regions of the primary and higher-order motor network in comparison to primary visual and sensory regions varies across the clinical spectrum of AD. We analyzed tau PET scans from the ADNI-cohort in patients with mild cognitive impairment (MCI; N = 84) and dementia of the Alzheimer's Disease type (DAD; N = 25). Additionally, an amyloid-negative sample of healthy older individuals (HC; N = 26) were included. Standard-uptake ratio values (SUVR) were extracted in native space from the left and the right hemispheres. A repeated measurement analysis of variance was conducted to assess the effect of diagnostic disease category on tau pathology in the individual motor regions, controlling for age. We observed that tau pathology varies as a function of diagnostic category in predominantly higher motor regions (i.e., supplementary motor area, superior parietal lobe, angular gyrus and dorsal premotor cortex) compared to primary visual, sensory and motor regions. Indeed, tau in higher-order motor regions was significantly associated with decline in cognitive function. Together, these results expand our knowledge on the in vivo pattern of tau pathology in AD and suggest that higher motor regions are not spared from tau aggregation in the course of disease, potentially contributing to the symptomatic appearance of the disease.
Significance Statement The presented data show relevant tau pathology in higher-order motor regions of patients with mild cognitive impairment (MCI) and dementia of the Alzheimer's Disease type (DAD), in a set of regions often neglected in the previous literature. Tau accumulation in higher-order motor regions was associated with clinical disease severity and increased cognitive dysfunction. These findings suggest that the concerted vulnerability of motor regions to tau pathology may contribute to motor/ praxis dysfunction observed in Alzheimer's Disease.
Footnotes
No competing interest declared.
A.D., G.N.B., E.J., M.C.H. and P.H.W. are funded by the Deutsche Forschungsgemeinschaft - Project-ID 431549029 - SFB 1451. G.N.B. received funding from Alzheimer Forschung Initiative e.V., Germany (AFI K1707). In addition, this study was supported by the German Research Foundation (DFG, DR 445/9-1). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
↵* Data used in preparation of this article were obtained from the Alzheimer's disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). Thus, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data, but did not participate in this analysis or the writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf/.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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