Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations

Article type: Research Article

Authors: Luis, Elkin^{a; b} | Ortiz, Alexandra^a | Eudave, Luis^a | Ortega-Cubero, Sara^{c; d} | Borroni, Barbara^h | van der Zee, Julie^{f; g} | Gazzina, Stefano^h | Caroppo, Paola^{i; j} | Rubino, Elisa^e | D’Agata, Federico^e | Le Ber, Isabelle^j | Santana, Isabel^k | Cunha, Gil^l | Almeida, Maria R.^m | Boutoleau-Bretonnière, Claireⁿ | Hannequin, Didier^{o; p; q; r} | Wallon, David^{p; q} | Rainero, Innocenzo^s | Galimberti, Daniela^t | Van Broeckhoven, Christine^{f; g} | Pastor, Maria A.^{a; b; d; u} | Pastor, Pau^{c; d; v; *}

Affiliations: [a] Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain | [b] School of Education and Psychology, University of Navarra, Pamplona, Spain | [c] Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain | [d] CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain | [e] Università degli Studi di Torino, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, Turin, Italy | [f] Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium | [g] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium | [h] Centre for Aging Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy | [i] Besta Neurological Institut, Milan, Italy | [j] Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Universités, Université Pierre et Marie, Hôpital Pitié-Salpêtrière, Paris, France | [k] Neurology Department, Centro Hospitalar e Universitério de Coimbra, Coimbra, Portugal and Faculty of Medicine, Coimbra University, Coimbra, Portugal | [l] Neurorradiology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal | [m] Neurogenetics Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal | [n] Claire Boutoleau-Bretonnière: Department of Neurology, CMRR, Nantes University Hospital, Nantes, France | [o] Department of Genetics, Rouen University Hospital, Rouen, France | [p] Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France | [q] CNR-MAJ, Rouen University Hospital, Rouen, France | [r] Department of Neurology, Rouen University Hospital, Rouen, France | [s] Department of Neuroscience “Rita Levi Montalcini”, University of Torino, Turin, Italy | [t] Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy | [u] Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain | [v] Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain

Correspondence: [*] Correspondence to: Pau Pastor, MD, PhD, Department of Neurology, Hospital Universitari Mutua de Terrasa, Terrassa, Barcelona, Spain, Plaza Dr. Robert, 5, 08221-Terrasa, Spain. Tel.: +34 937365050; Fax: +34 937365059; E-mail: pastorpau@gmail.com.

Abstract: Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget’s disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

Keywords: Dementia, frontotemporal dementia, SQSTM1 protein, voxel-based morphometry

DOI: 10.3233/JAD-160006

Journal: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 303-313, 2016