White Matter Hyperintensities Precede other Biomarkers inGRNFrontotemporal Dementia

  1. Mahdie Soltaninejad
  2. Mahsa Dadar
  3. D. Louis Collins
  4. Reza Rajabli
  5. Vikram Venkatraghavan
  6. Arabella Bouzigues
  7. Lucy L. Russell
  8. Phoebe H. Foster
  9. Eve Ferry-Bolder
  10. John C. van Swieten
  11. Lize C. Jiskoot
  12. Harro Seelaar
  13. Raquel Sanchez-Valle
  14. Robert Laforce
  15. Caroline Graff
  16. Daniela Galimberti
  17. Rik Vandenberghe
  18. Alexandre de Mendonça
  19. Pietro Tiraboschi
  20. Isabel Santana
  21. Alexander Gerhard
  22. Johannes Levin
  23. Benedetta Nacmias
  24. Markus Otto
  25. Maxime Bertoux
  26. Thibaud Lebouvier
  27. Chris R. Butler
  28. Isabelle Le Ber
  29. Elizabeth Finger
  30. Maria Carmela Tartaglia
  31. Mario Masellis
  32. James B. Rowe
  33. Matthis Synofzik
  34. Fermin Moreno
  35. Barbara Borroni
  36. Jonathan D. Rohrer
  37. Yasser Iturria Medina
  38. Simon Ducharme
  39. GENFI
0 evaluations Published on
Read the full article Related papers
This article on Sciety

Abstract

INTRODUCTION

Increased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear.

METHODS

Using a large dataset (n=763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stages. Cortical and subcortical volumes were parcellated, and serum neurofilament light chain (NfL) levels were measured. Biomarker progression was assessed with discriminative event-based and regression modeling.

RESULTS

SymptomaticGRNcarriers showed elevated WMHs, primarily in the frontal lobe, while no significant increase was observed inC9orf72orMAPTcarriers. WMH abnormalities preceded NfL elevation, ventricular enlargement, and cortical atrophy. Longitudinally, baseline WMHs predicted subcortical changes, while subcortical volumes did not predict WMH changes, suggesting WMHs may precede neurodegeneration.

DISCUSSION

WMHs are elevated in a subset ofGRN-related FTD. When present, they appear early and should be considered in disease progression models.

Highlights

  • Elevated WMH volumes in symptomaticGRNcarriers, but not in other mutations.

  • WMH accumulation is mostly observed in the frontal lobe.

  • WMH abnormalities appear early inGRN-FTD, before NfL, atrophy, and ventriculomegaly.

  • Longitudinally, WMH volumes can predict subcortical changes, but not vice versa.

  • WMHs are key early markers inGRN-FTD and should be included in progression models.

RESEARCH IN CONTEXT

Systematic review

We systematically reviewed the literature on white matter hyperintensities (WMHs) in frontotemporal dementia (FTD) using PubMed. While a few small studies reported increased WMHs inGRNmutation carriers, their sample sizes were limited, and they did not assess the timing of WMHs within disease progression or their temporal relationship to other biomarkers.

Interpretation

We identified a sequence of key biomarkers inGRN-related FTD and demonstrated that WMHs are among the earliest biomarkers, preceding cortical and subcortical atrophy as well as blood biomarkers. This aligns with neuropathological evidence of early white matter involvement in FTLD-GRN. Additionally, using a larger dataset, we validated previous reports of elevated WMHs inGRNcarriers, confirming their reliability.

Future directions

Future studies should integrate WMHs into FTD progression models to enhance early diagnosis. Understanding why only a subset ofGRNcarriers exhibit high WMH volumes remains a key research priority.

Related articles

Related articles are currently not available for this article.