Association of Physical Activity With Neurofilament Light Chain Trajectories in Autosomal Dominant Frontotemporal Lobar Degeneration Variant Carriers
Authors: Casaletto Kaitlin B. , Kornack John , Paolillo Emily W. , Rojas Julio C. , VandeBunte Anna , Staffaroni Adam S. , Lee Shannon , Heuer Hilary , Forsberg Leah , Ramos Eliana M. , Miller Bruce L. , Kramer Joel H. , Yaffe Kristine , Petrucelli Leonard , Boxer Adam , Boeve Brad , Gendron Tania F. , Rosen Howard ,   ALLFTD Consortium, Apostolova Liana , Appleby Brian , Barmada Sami , Boeve Bradley , Bordelon Yvette , Botha Hugo , Boxer Adam L. , Bozoki Andrea , Brushaber Danielle , Clark David , Coppola Giovanni , Darby Ryan , Dickerson Bradford C. , Dickson Dennis , Domoto-Reilly Kimiko , Faber Kelley , Fagan Anne , Fields Julie A. , Foroud Tatiana , Forsberg Leah , Geschwind Daniel , Ghoshal Nupur , Goldman Jill , Galasko Douglas R. , Gavrilova Ralitza , Gendron Tania F. , Graff-Radford Jonathon , Graff-Radford Neill , Grant Ian M. , Grossman Murray , Hall Matthew GH , Huang Eric , Heuer Hilary W. , Hsiung Ging-Yuek , Huey Edward D. , Irwin David , Kantarci Kejal , Kauer Daniel , Kerwin Diana , Knopman David , Kornak John , Kramer Joel , Kremers Walter , Lapid Maria , Lario Lago Argentina , Lee Suzee , Leger Gabriel , Ljubenkov Peter , Litvan Irene , Lucente Diana , Mackenzie Ian R. , Masdeux Joseph C. , McGinnis Scott , Mendez Mario , Mester Carly , Miller Bruce L. , Onyike Chiadi , Pascual Maria Belen , Petrucelli Leonard , Pressman Peter , Rademakers Rosa , Ramanan Vijay , Ramos Eliana Marisa , Rao Meghana , Rascovsky Katya , Rankin Katherine P. , Ritter Aaron , Rojas Julio C. , Rosen Howard J. , Savica Rodolfo , Seeley William W. , Syrjanen Jeremy , Staffaroni Adam M. , Tartaglia Maria Carmela , Taylor Jack C. , VandeVrede Lawren , Weintraub Sandra , Wong Bonnie 
Published: November 2022

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.