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

Isis So^{1

2}, Arabella Bouzigues³, Lucy L Russell³, Phoebe H Foster³, Eve Ferry-Bolder³, John C van Swieten⁴, Lize C Jiskoot⁴, Harro Seelaar⁴, Raquel Sanchez-Valle⁵, Robert Laforce Jr⁶, Caroline Graff⁷, Daniela Galimberti^{8

9}, Rik Vandenberghe¹⁰, Alexandre de Mendonça¹¹, Pietro Tiraboschi¹², Isabel Santana¹³, Alexander Gerhard¹⁴, Johannes Levin¹⁵, Sandro Sorbi¹⁶, Markus Otto¹⁷, Florence Pasquier¹⁸, Simon Ducharme¹⁹, Chris R Butler²⁰, Isabelle Le Ber²¹, Maria Carmela Tartaglia²², Mario Masellis²³, James B Rowe²⁴, Matthis Synofzik²⁵, Fermin Moreno²⁶, Barbara Borroni²⁷, Tyler Kolander²⁸, Carly Mester²⁹, Danielle Brushaber²⁹, Kejal Kantarci³⁰, Hilary W Heuer³¹, Leah K Forsberg²⁸, Jonathan D Rohrer³, Bradley F Boeve²⁸, Adam L Boxer³¹, Howard J Rosen³¹, Elizabeth C Finger^{1

2

32}; Frontotemporal Dementia Prevention Initiative (FPI) Investigators

Affiliations

¹ Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
² Lawson Health Research Institute, Parkwood Institute, London, ON, Canada.
³ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁴ Department of Neurology and Alzheimer Centre, Erasmus MC University Medical Centre, Rotterdam, the Netherlands.
⁵ Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.
⁶ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Québec City, QC, Canada.
⁷ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Bioclinicum, Karolinska Institutet, Stockholm, Sweden.
⁸ Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
⁹ University of Milan, Milan, Italy.
¹⁰ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
¹¹ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
¹² Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹³ University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
¹⁴ Division of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
¹⁵ Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.
¹⁶ Department of Neuropharmacology, University of Florence, Florence, Italy.
¹⁷ Department of Neurology, University of Ulm, Ulm, Germany.
¹⁸ University of Lille, Lille, France.
¹⁹ Douglas Mental Health University Health Centre, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
²⁰ Global Brain Health, Department of Brain Sciences, Imperial College London, London, UK.
²¹ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
²² Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, University of Toronto, Toronto, ON, Canada.
²³ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust and Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
²⁵ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
²⁶ Cognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.
²⁷ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
²⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
³⁰ Department of Radiology, Division of Neuroradiology, Mayo Clinic, Rochester, MN, USA.
³¹ Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
³² Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.

PMID: 41259271
DOI: 10.1177/13872877251393414

Free article

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

Isis So et al. J Alzheimers Dis. 2025.

Free article

. 2025 Nov 19:13872877251393414.

doi: 10.1177/13872877251393414. Online ahead of print.

Authors

Affiliations

¹ Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
² Lawson Health Research Institute, Parkwood Institute, London, ON, Canada.
³ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁴ Department of Neurology and Alzheimer Centre, Erasmus MC University Medical Centre, Rotterdam, the Netherlands.
⁵ Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.
⁶ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Québec City, QC, Canada.
⁷ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Bioclinicum, Karolinska Institutet, Stockholm, Sweden.
⁸ Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
⁹ University of Milan, Milan, Italy.
¹⁰ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
¹¹ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
¹² Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹³ University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
¹⁴ Division of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
¹⁵ Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.
¹⁶ Department of Neuropharmacology, University of Florence, Florence, Italy.
¹⁷ Department of Neurology, University of Ulm, Ulm, Germany.
¹⁸ University of Lille, Lille, France.
¹⁹ Douglas Mental Health University Health Centre, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
²⁰ Global Brain Health, Department of Brain Sciences, Imperial College London, London, UK.
²¹ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
²² Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, University of Toronto, Toronto, ON, Canada.
²³ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust and Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
²⁵ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
²⁶ Cognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.
²⁷ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
²⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
³⁰ Department of Radiology, Division of Neuroradiology, Mayo Clinic, Rochester, MN, USA.
³¹ Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
³² Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.

PMID: 41259271
DOI: 10.1177/13872877251393414

Abstract

BackgroundConverging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD).ObjectiveWe investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations.MethodsThis cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN, MAPT, or C9orf72, and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education.ResultsMutation carriers (mean ± SD age = 50.0 ± 13.2 years, sex = 55% female, n(GRN) = 298, n(MAPT) = 187, n(C9orf72) = 417) were compared to 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, GRN carriers showed larger TIV, on average by 20531 mm³, compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η²p = 0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI [0.01, 0.24], r(295) = 0.12, p = 0.03) and GRN non-carriers (95% CI [0.08, 0.34], r(198) = 0.21, p = 0.002). MAPT carriers demonstrated smaller TIV than non-carriers, on average by 29896 mm³ (95% CI [-58248, -1545], p = 0.039, η²p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences.ConclusionsIn support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.

Keywords: Alzheimer’s disease; development; familial dementia; frontotemporal dementia; magnetic resonance imaging.

PubMed Disclaimer

LinkOut - more resources

Full Text Sources
- Atypon
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources

Miscellaneous