Voxel-based morphometry method
VBM was performed using Statistical Parametric Mapping 12 (SPM12) software, implemented in Matlab 8.3. T1 images for subject A.IV.1 and controls were reoriented and segmented into gray and white matter tissue probability maps in native and Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra(DARTEL) imported space.1 DARTEL space maps were used as inputs to create a study-specific template with the DARTEL toolbox, and native space grey matter maps were normalized to this template using subject specific deformation fields.2 An 8 mm FWHM Gaussian kernel was applied for smoothing, and images were modulated to preserve overall tissue amounts.Voxelwise contrasts were performed to illustrate regions of likely grey matter atrophy in the patient relative to controls, using the normalized, smoothed, and modulated grey matter probability maps as inputs.
Neuropathology methods
Subject A.IV.1’s mother’s brain wasevaluatedat both Mayo Clinic Rochester and Mayo Clinic Jacksonville according to the CERAD protocol.3 Immunohistochemical staining was performed using antibodies to tau (CP13, 1:1000 mouse monoclonal, gift from Dr. Peter Davies), Aβ (6F/3D; 1:10; NovocastraVectorLabs, Burlingame, CA), α-synuclein (LB509; 1:200 dilution; Zymed, San Francisco, CA), and TDP-43 (MC20854, 1:2500 rabbit polyclonal, from Leonard Petrucelli, Mayo Clinic). The Bielschowsky silver stain was used to assess Braak staging5 and CERAD score3, with the Aβ immunostain used to assess Thal amyloid phase as previously described6. The recommended ‘ABC’ AD neuropathology scale was assessed using the National Institute of Aging and Alzheimer’s Association criteria7. FTLD neuropathology, TDP-43 subtype, and hippocampal sclerosis were assessed as previously described.8, 9 All pathological assessments were performed blinded to [18F]AV-1451PET results.
Subject B.II.1’s brain was hemisected along the corpus callosum. The right cerebral and cerebellar hemispheres and the entire brainstem were fixed in 10% neutral buffered formalin. The neuropathological assessment was performed at the UCSF Neurodegenerative Disease Brain Bank. Tissue blocks coveringdementia-related right hemisphere regions of interestwere dissected and basic and immunohistochemicalstains were applied following standarddiagnostic procedures.3Immunohistochemistry was performedusing antibodies to: TDP43 (anti-rabbit, 1:2000, ProteintechGroup, Chicago, IL, USA), phosphorylatedtau (CP13 antibody), 3R and4R tau (anti-mouse,1:500, Millipore, Billericia, MA, USA), beta-amyloid(anti-mouse, 1:250, Millipore, Billerica, MA, USA),alpha synuclein (anti-mouse, 1:1000, Millipore, Billerica,MA, USA).
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8.Murray ME, Cannon A, Graff-Radford NR, et al. Differential clinicopathologic and genetic features of late-onset amnestic dementias. Acta Neuropathol 2014;128:411-421.
9.Mackenzie IR, Neumann M, Baborie A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011;122:111-113.