White matter damage due to vascular, tau, and TDP-43 pathologies and its relevance to cognition

Sheelakumari Raghavan, Scott A. Przybelski, Robert I. Reid, Timothy G. Lesnick, Vijay K. Ramanan, Hugo Botha, Billie J. Matchett, Melissa E. Murray, R. Ross Reichard, David S. Knopman, Jonathan Graff-Radford, David T. Jones, Val J. Lowe, Michelle M. Mielke, Mary M. Machulda, Ronald C. Petersen, Kejal Kantarci, Jennifer L. Whitwell, Keith A. Josephs, Clifford R. JackPrashanthi Vemuri

Research output: Contribution to journalArticlepeer-review


Multi-compartment modelling of white matter microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on white matter health through neurite density index and free water measures. We hypothesized that cerebrovascular disease, Alzheimer’s disease, and TDP-43 proteinopathy would be associated with distinct NODDI readouts of white matter damage which would be informative for identifying the substrate for cognitive impairment. We identified two independent cohorts with multi-shell diffusion MRI, amyloid and tau PET, and cognitive assessments: specifically, a population-based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota, population and a clinical research-based cohort of 61 amyloid positive Alzheimer’s dementia participants. We observed an increase in free water and decrease in neurite density using NODDI measures in the genu of the corpus callosum associated with vascular risk factors, which we refer to as the vascular white matter component. Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal white matter where we measured parahippocampal cingulum and inferior temporal white matter bundles. Worsening temporal white matter neurite density was associated with (antemortem confirmed) FDG TDP-43 signature. Post-mortem neuropathologic data on a small subset of this sample lend support to our findings. In the community-dwelling cohort where vascular disease was more prevalent, the NODDI vascular white matter component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory). In the AD dementia cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non-trivial contribution of the temporal white matter component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition. White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether cerebrovascular disease versus neurodegenerative disease caused by tau deposition or TDP-43 pathology) for cognitive impairment in older adults. Graphical abstract: [Figure not available: see fulltext.].

Original languageEnglish (US)
Article number16
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Dec 2022


  • Cerebrovascular disease
  • Diffusion tensor imaging
  • Neurite dispersion density imaging
  • TAR DNA binding protein of 43 kDa
  • Tau positron emission tomography

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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