Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences

  1. Isis So
  2. Arabella Bouzigues
  3. Lucy L. Russell
  4. Phoebe H. Foster
  5. Eve Ferry-Bolder
  6. John C. van Swieten
  7. Lize C. Jiskoot
  8. Harro Seelaar
  9. Raquel Sanchez-Valle
  10. Robert Laforce
  11. Caroline Graff
  12. Daniela Galimberti
  13. Rik Vandenberghe
  14. Alexandre de Mendonça
  15. Pietro Tiraboschi
  16. Isabel Santana
  17. Alexander Gerhard
  18. Johannes Levin
  19. Sandro Sorbi
  20. Markus Otto
  21. Florence Pasquier
  22. Simon Ducharme
  23. Chris R. Butler
  24. Isabelle Le Ber
  25. Maria Carmela Tartaglia
  26. Mario Masellis
  27. James B. Rowe
  28. Matthis Synofzik
  29. Fermin Moreno
  30. Barbara Borroni
  31. Tyler Kolander
  32. Carly Mester
  33. Danielle Brushaber
  34. Kejal Kantarci
  35. Hilary W. Heuer
  36. Leah K. Forsberg
  37. Jonathan D. Rohrer
  38. Bradley F. Boeve
  39. Adam L. Boxer
  40. Howard J. Rosen
  41. Elizabeth C. Finger
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Abstract

Background and Objectives

Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD), including associations between FTD-causing mutations and neurodevelopmental disorders, and differences in young adult mutation carriers compared to familial non-mutation carriers in total intracranial volume (TIV) and cognition. We aimed to investigate TIV and educational attainment differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of the FTD-causing genetic mutations.

Methods

This cross-sectional cohort study was facilitated through the FTD Prevention Initiative (FPI). Participants, aged 18 to 86 years, were pathogenic mutation carriers ofGRN,MAPT, orC9orf72, or familial non-carriers. ANCOVAs were computed per gene to compare outcome means for the main effect of group by carrier status, while controlling for birth decade, sex, and visit site (to account for unique scanners and educational systems). Pearson’s correlations were used to examine associations between TIV and education.

Results

Nine-hundred two mutation carriers (mean±SD; age=50.0±13.2 years, sex=55% female,n(GRN)=298, n(MAPT)=187,n(C9orf72)=417) were compared to 532 familial non-carriers (age=48.0±12.9 years, sex=58% female,n(GRN)=201, n(MAPT)=114),n(C9orf72)=217). Consistent with prior findings in young adults,GRNcarriers showed larger TIV compared to familial non-carriers (95% confidence interval [CI]=1431994-1457123,p=0.049,η2p=0.008). Larger TIV correlated with higher years of education inGRNcarriers (95% CI=0.01-0.24,r(295)=0.12,p=0.03) andGRNnon-carriers (95% CI=0.08-0.34, r(198)=0.21,p=0.002).MAPTcarriers demonstrated smaller TIV than non-carriers (95% CI=1417819-1450628,p=0.039,η2p=0.02). Models withC9orf72and education as outcome variables did not reveal significant differences.

Discussion

In support of the neurodevelopmental hypothesis of FTD,GRNandMAPTmutations are linked to likely structural neurodevelopmental changes in TIV, some of which correlate to years of education. These findings motivate further research to identify mechanisms by which FTD mutations influence neurodevelopment and ascertain their suitability as targets for interventions.

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