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Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.
Vandebergh, Marijne; Ramos, Eliana Marisa; Corriveau-Lecavalier, Nick; Ramanan, Vijay K; Kornak, John; Mester, Carly; Kolander, Tyler; Brushaber, Danielle; Staffaroni, Adam M; Geschwind, Daniel; Wolf, Amy; Kantarci, Kejal; Gendron, Tania F; Petrucelli, Leonard; Van den Broeck, Marleen; Wynants, Sarah; Baker, Matthew C; Borrego-Écija, Sergi; Appleby, Brian; Barmada, Sami; Bozoki, Andrea; Clark, David; Darby, R Ryan; Dickerson, Bradford C; Domoto-Reilly, Kimiko; Fields, Julie A; Galasko, Douglas R; Ghoshal, Nupur; Graff-Radford, Neill; Grant, Ian M; Honig, Lawrence S; Hsiung, Ging-Yuek Robin; Huey, Edward D; Irwin, David; Knopman, David S; Kwan, Justin Y; Léger, Gabriel C; Litvan, Irene; Masdeu, Joseph C; Mendez, Mario F; Onyike, Chiadi; Pascual, Belen; Pressman, Peter; Ritter, Aaron; Roberson, Erik D; Snyder, Allison; Sullivan, Anna Campbell; Tartaglia, M Carmela; Wint, Dylan; Heuer, Hilary W.
Afiliación
  • Vandebergh M; VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • Ramos EM; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • Corriveau-Lecavalier N; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Ramanan VK; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • Kornak J; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
  • Mester C; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • Kolander T; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
  • Brushaber D; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • Staffaroni AM; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • Geschwind D; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • Wolf A; Department of Neurology, Memory and Aging Center, University of California, San Francisco Weill Institute for Neurosciences, San Francisco, CA, USA.
  • Kantarci K; Institute for Precision Health, Departments of Neurology, Psychiatry and Human Genetics at David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Gendron TF; Department of Neurology, Memory and Aging Center, University of California, San Francisco Weill Institute for Neurosciences, San Francisco, CA, USA.
  • Petrucelli L; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • Van den Broeck M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Wynants S; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Baker MC; VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • Borrego-Écija S; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • Appleby B; VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • Barmada S; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • Bozoki A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Clark D; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona, Barcelona, Spain.
  • Darby RR; Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
  • Dickerson BC; Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
  • Domoto-Reilly K; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
  • Fields JA; Department of Neurology, Indiana University, Indianapolis, IN, USA.
  • Galasko DR; Department of Neurology, Vanderbilt University, Nashville, TN, USA.
  • Ghoshal N; Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
  • Graff-Radford N; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Grant IM; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
  • Honig LS; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
  • Hsiung GR; Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
  • Huey ED; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Irwin D; Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
  • Knopman DS; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Columbia University, New York, NY, USA.
  • Kwan JY; Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
  • Léger GC; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
  • Litvan I; Department of Neurology and Penn Frontotemporal Degeneration Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Masdeu JC; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
  • Mendez MF; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Onyike C; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
  • Pascual B; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
  • Pressman P; Department of Neurology, Houston Methodist, Houston, TX, USA.
  • Ritter A; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Roberson ED; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
  • Snyder A; Department of Neurology, Houston Methodist, Houston, TX, USA.
  • Sullivan AC; Department of Neurology, University of Colorado, Aurora, CO, USA.
  • Tartaglia MC; Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, 89106, USA.
  • Wint D; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Heuer HW; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
medRxiv ; 2024 Apr 05.
Article en En | MEDLINE | ID: mdl-38633784
ABSTRACT
Background and

Objectives:

TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients.

Methods:

Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted.

Results:

The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model.

Discussion:

We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.
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Texto completo: 1 Base de datos: MEDLINE Idioma: En Revista: MedRxiv Año: 2024 Tipo del documento: Article País de afiliación: Bélgica
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Idioma: En Revista: MedRxiv Año: 2024 Tipo del documento: Article País de afiliación: Bélgica