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. 2024 Feb:134:135-145.
doi: 10.1016/j.neurobiolaging.2023.12.001. Epub 2023 Dec 10.

Neurite-based white matter alterations in MAPT mutation carriers: A multi-shell diffusion MRI study in the ALLFTD consortium

Nick Corriveau-Lecavalier  1 , Nirubol Tosakulwong  2 , Timothy G Lesnick  2 , Angela J Fought  2 , Robert I Reid  3 , Christopher G Schwarz  3 , Matthew L Senjem  3 , Clifford R Jack Jr  3 , David T Jones  4 , Prashanthi Vemuri  3 , Rosa Rademakers  5 , Eliana Marisa Ramos  6 , Daniel H Geschwind  7 , David S Knopman  8 , Hugo Botha  8 , Rodolfo Savica  8 , Jonathan Graff-Radford  8 , Vijay K Ramanan  8 , Julie A Fields  9 , Neill Graff-Radford  10 , Zbigniew Wszolek  10 , Leah K Forsberg  8 , Ronald C Petersen  8 , Hilary W Heuer  11 , Adam L Boxer  11 , Howard J Rosen  11 , Bradley F Boeve  8 , Kejal Kantarci  12 ; ALLFTD consortium
Affiliations

Neurite-based white matter alterations in MAPT mutation carriers: A multi-shell diffusion MRI study in the ALLFTD consortium

Nick Corriveau-Lecavalier et al. Neurobiol Aging. 2024 Feb.

Abstract

We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor imaging (DTI) (fractional anisotropy; FA, mean diffusivity; MD) and neurite orientation dispersion and density imaging (NODDI) (neurite density index; NDI, orientation and dispersion index; ODI). Linear mixed-effects models accounting for age and family relatedness revealed alterations across DTI and NODDI metrics in all mutation carriers and in symptomatic carriers, with the most significant differences involving fronto-temporal WM tracts. Asymptomatic carriers showed higher entorhinal MD and lower cingulum FA and patterns of higher ODI mostly involving temporal areas and long association and projections fibers. Regression models between estimated time to or time from disease and DTI and NODDI metrics in key regions (amygdala, cingulum, entorhinal, inferior temporal, uncinate fasciculus) in all carriers showed increasing abnormalities with estimated time to or time from disease onset, with FA and NDI showing the strongest relationships. Neurite-based metrics, particularly ODI, appear to be particularly sensitive to early WM involvement in asymptomatic carriers.

Keywords: Diffusion magnetic resonance imaging; Diffusion tensor imaging; Frontotemporal dementia; Microtubule-associated protein tau; Neurite orientation dispersion and density imaging.

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Conflict of interest statement

Declaration of Competing Interest CRJ receives no personal compensation from any commercial entity. He receives research support from National Institute of Health (NIH), the GHR Foundation, and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. RCP consults for Roche, Inc., Merck, Inc., Biogen, Inc., Genentech, Inc., Eisai, Inc., and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role. BB receives honoraria for SAB activities for the Tau Consortium, and has received research grant support but no personal compensation for clinical trials from Alector, Biogen, Transposon, Cognition Therapeutics, GE Healthcare. VKR receives research funding from the NIH and the Mangurian Foundation for Lewy Body disease research, has provided educational content for Medscape, is co-PI for a clinical trial supported by the Alzheimer’s Association, and is a site clinician for clinical trials supported by Eisai, the Alzheimer's Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. EMR has no disclosure and receives funding from the NIH. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157–206) and Vigil Neuroscience, Inc. (VGL101–01.002, VGL101–01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. KK consults Biogen, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly and receives funding from NIH and Alzheimer’s Drug Discovery Foundation.

Figures

Figure 1.
Figure 1.
Region of interest analyses. Green areas are statistically significant at an uncorrected threshold of P<0.05, while red areas are statistically significant after applying a false discovery rate correction for multiple comparisons at a threshold of q<0.05. Of note, these differences reflect lower FA values and higher MD values in MAPT carriers compared to controls. FA = Fractional anisotropy; MD = Mean diffusivity. MRIcroGL (http://www.mccauslandcenter.sc.edu/mricrogl/) was used to display the results.
Figure 2.
Figure 2.
Region of interest analyses. Green areas are statistically significant at an uncorrected threshold of P<0.05, while red areas are statistically significant after applying a false discovery rate correction for multiple comparisons at a threshold of q<0.05. Of note, these differences reflect lower tNDI values and higher ODI values in MAPT carriers compared to controls. tNDI = tissue-weighted Neurite Density Index; ODI = Orientation Dispersion Index. MRIcroGL (http://www.mccauslandcenter.sc.edu/mricrogl/) was used to display the results.
Figure 3.
Figure 3.
Regression models between actual/estimated time to symptom onset and FA and MD. Only models excluding the influential observation are displayed. FA = Fractional anisotropy; MD = Mean diffusivity; IQR = Interquartile range.
Figure 4.
Figure 4.
Regression models between actual/estimated time to symptom onset and NODDI DTI metrics. tNDI = tissue-weighted Neurite Density Index; ODI = Orientation Dispersion Index; IQR = Interquartile Range.
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