TY - JOUR
T1 - Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants with Genetic Frontotemporal Dementia
AU - Schönecker, Sonja
AU - Martinez-Murcia, Francisco J.
AU - Denecke, Jannis
AU - Franzmeier, Nicolai
AU - Danek, Adrian
AU - Wagemann, Olivia
AU - Prix, Catharina
AU - Wlasich, Elisabeth
AU - Vöglein, Jonathan
AU - Loosli, Sandra V.
AU - Brauer, Anna
AU - Górriz Sáez, Juan Manuel
AU - Bouzigues, Arabella
AU - Russell, Lucy L.
AU - Foster, Phoebe H.
AU - Ferry-Bolder, Eve
AU - Van Swieten, John C.
AU - Jiskoot, Lize C.
AU - Seelaar, Harro
AU - Sanchez-Valle, Raquel
AU - Laforce, Robert
AU - Graff, Caroline
AU - Galimberti, Daniela
AU - Vandenberghe, Rik
AU - De Mendonça, Alexandre
AU - Tiraboschi, Pietro
AU - Santana, Isabel
AU - Gerhard, Alexander
AU - Sorbi, Sandro
AU - Otto, Markus
AU - Pasquier, Florence
AU - Ducharme, Simon
AU - Butler, Christopher
AU - Le Ber, Isabelle
AU - Finger, Elizabeth
AU - Tartaglia, Maria Carmela
AU - Masellis, Mario
AU - Rowe, James B.
AU - Synofzik, Matthis
AU - Moreno, Fermin
AU - Borroni, Barbara
AU - Rohrer, Jonathan D.
AU - Priller, Josef
AU - Höglinger, Günter U.
AU - Levin, Johannes
N1 - Publisher Copyright:
© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2024/9/16
Y1 - 2024/9/16
N2 - Background and ObjectivesBehavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.MethodsWe analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms.ResultsA total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness.DiscussionWe identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.
AB - Background and ObjectivesBehavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.MethodsWe analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms.ResultsA total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness.DiscussionWe identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.
UR - http://www.scopus.com/inward/record.url?scp=85206097671&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000209569
DO - 10.1212/WNL.0000000000209569
M3 - Article
AN - SCOPUS:85206097671
SN - 0028-3878
VL - 103
JO - Neurology
JF - Neurology
IS - 8
M1 - e209569
ER -