Hyperorality in Frontotemporal Dementia: How Psychiatric and Neural Correlates Change Across the Disease Course

Objectives Hyperorality is one of the core features of behavioral variant frontotemporal dementia (bvFTD), however, the cognitive, psychiatric, and neuroanatomic correlates of hyperorality across disease stages remain unclear. This study works to fill this knowledge gap by exploring these associations in the early and advanced stages of bvFTD. Methods Participants with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium (ALLFTD). The primary analyses used baseline data to compare cognitive and psychiatric symptoms in those with and without hyperorality stratified by disease severity. Linear multivariable regressions adjusting for age and total intracranial volume were used to examine baseline associations between regional gray matter volumes and hyperorality status. Five anatomic regions of interest were pre-selected for analysis based on previously identified neuroanatomic correlates of hyperorality in bvFTD. Results Hyperorality was present in 50% of early-stage bvFTD participants (n = 136) and was associated with higher rates of ritualistic/compulsive behavior. Hyperorality was present in 63% of advanced-stage participants (n = 208) and was associated higher rates of apathy, and ritualistic/compulsive behavior. Regional gray matter volumes were similar in those with and without hyperorality in early-stage participants. In the advanced-stage participants, hyperorality was associated with lower gray matter volumes in the right dorsal and ventral striatum. Conclusions Hyperorality emerges early in bvFTD and is accompanied by deficits in social cognition and complex-ritualistic behavior prior to clinically significant gray matter volume loss. These findings suggest that early identification and treatment of hyperorality could improve neuropsychiatric trajectories in bvFTD. ### Competing Interest Statement Preliminary analysis from this work was presented as an abstract at the ACTS Conference in Washington, DC on April 18 2023. CM is funded my KL2TR003099. AP is funded by NIA/NIH (K23AG059891). JR is funded by NIA/NIH K23AG059888, AlzOut, Shenandoah fund and Jon and Gale Love Alzheimer's fund and is a site PI for clinical trials sponsored by Eli-Lilly and Eisai and a consultant and speaker for Roon Health, Inc. 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. Herringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, The Albertson Parkinson's Research Foundation, and the PPND Family 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 the diagnosis and management of CSF1R-related adult-onset leukoencephaloparthy with axonal steroids 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 the neurodegenerative medical research for Eli Lilli & Company. VK is partially supported by the NIH/NIA and NIH/NINDS (RO1AG064093, RO1NS108452). ### Funding Statement CM is funded by KL2TR003099. AP is funded by NIA/NINDS (K23AG059891 and U01NS102035). JR is funded by NIA/NIH K23AG059888, AlzOut, Shenadoah fund and Jon and Gale Love Alzheimer's fund. 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, The Albertson Parkinson's Research Foundation, the PPND Family Foundation. IL's research is supported by the National Institutes of Health grants 2RO1AG038791-O6A, U01NS100610, R25NS098999, U19 AG063911-1 and 1R21NS114764-01A1, the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Lundbeck, EIP-Pharma, Biohaven Pharamceuticals, Novartis, and United Biopharma SRL, UCB. VK is partially supported by the NIH/NIA and NIH/NINDS (RO1AG064093, RO1NS108452). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Johns Hopkins School of Medicine Institutional Review Board approved this study under IRB00227492 on January 8th 2020. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in this study are from the ALLFTD consortium. Data requests can be submitted at: https://mayojointresearch.sjc1.qualtrics.com/jfe/form/SV_8eTGP626bMRIbyK