Sylvia Mihailescu ¹ Quinn Hlava ² Philip A. Cook ³ Maria Luisa Mandelli ⁴ Suzee E. Lee ⁴ Bradley F. Boeve ⁵ Bradford C. Dickerson ⁶ Maria Luisa Gorno-Tempini ⁴ Emily Rogalski ^7,8 Murray Grossman ² James Gee ³ Corey T. McMillan ² Christopher A. Olm ^2*

• ¹ School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States
• ² Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
• ³ Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
• ⁴ Memory and Aging Center, Medical Center, University of California, San Francisco, San Francisco, California, United States
• ⁵ Department of Neurology and Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, United States
• ⁶ Department of Neurology, Massachusetts General Hospital, Boston, United States
• ⁷ Department of Neurology, University of Chicago, Chicago, United States
• ⁸ Healthy Aging and Alzheimer's Care Center, University of Chicago, Chicago, United States

Introduction: Frontotemporal lobar degeneration (FTLD) is associated with FTLD due to tau (FTLD-tau) or TDP (FTLD-TDP) inclusions found at autopsy. Arterial Spin Labeling (ASL) MRI is often acquired in the same session as a structural T1-weighted image (T1w), enabling detection of regional changes in cerebral blood flow (CBF). We hypothesize that ASL-T1w registration with more degrees of freedom using boundary-based registration (BBR) will better align ASL and T1w images and show increased sensitivity to regional hypoperfusion differences compared to manual registration in patient participants. We hypothesize that hypoperfusion will be associated with a clinical measure of disease severity, the FTLD-modified clinical dementia rating scale sum-of-boxes (FTLD-CDR). Materials and Methods: Patients with sporadic likely FTLD-tau (sFTLD-tau; N=21), with sporadic likely FTLD-TDP (sFTLD-TDP; N=14), and controls (N=50) were recruited from the Connectomic Imaging in Familial and Sporadic Frontotemporal Degeneration project (FTDHCP). Pearson’s Correlation Coefficients (CC) were calculated on cortical vertex-wise CBF between each participant for each of 3 registration methods: 1) manual registration, 2) BBR initialized with manual registration (manual+BBR), 3) and BBR initialized using FLIRT (FLIRT+BBR). Mean CBF was calculated in the same regions of interest (ROIs) for each registration method after image alignment. Paired t-tests of CC values for each registration method were performed to compare alignment. Mean CBF in each ROI was compared between groups using t-tests. Differences were considered significant at p<0.05 (Bonferroni-corrected). We performed linear regression to relate FTLD-CDR to mean CBF in patients with sFTLD-tau and sFTLD-TDP, separately (p<0.05, uncorrected). Results: All registration methods demonstrated significant hypoperfusion in frontal and temporal regions in each patient group relative to controls. All registration methods detected hypoperfusion in the left insular cortex, middle temporal gyrus, and temporal pole in sFTLD-TDP relative to sFTLD-tau. FTLD-CDR had an inverse association with CBF in right temporal and orbitofrontal ROIs in sFTLD-TDP. Manual+BBR performed similarly to FLIRT+BBR. Discussion: ASL is sensitive to distinct regions of hypoperfusion in patient participants relative to controls, and in patients with sFTLD-TDP relative to sFTLD-tau, and decreasing perfusion is associated with increasing disease severity, at least in sFTLD-TDP. BBR can register ASL-T1w images adequately for controls and patients.