Differential early subcortical involvement in genetic FTD within the GENFI cohort

Bocchetta, Martina; Todd, Emily; Peakman, Georgia; Cash, David M.; Convery, Rhian S.; Russell, Lucy L.; Thomas, David L.; Iglesias, Juan Eugenio; Swieten, John C. van; Jiskoot, Lize C.; Seelaar, Harro; Borroni, Barbara; Galimberti, Daniela; Sánchez‐Valle, Raquel; Laforce, Robert; Moreno, Fermín; Synofzik, Matthis; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Vandenberghe, Rik; Finger, Elizabeth; Tagliavini, Fabrizio; Mendonça, Alexandre de; Santana, Isabel; Butler, Chris; Ducharme, Simon; Gerhard, Alexander; Danek, Adrian; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Ber, Isabelle Le; Pasquier, Florence; Rohrer, Jonathan D.; Initiative, GENetic Frontotemporal dementia

doi:10.1016/j.nicl.2021.102646

Cited by 34 publications

(66 citation statements)

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“…When we assessed patients defined on the specific underlying mutation, a greater damage of the inferior parietal cortices (namely, the angular gyrus) and the thalami was shared by C9-MND, C9-FTD, and GRN mutation carriers, compared with sporadic cases. The greater involvement of the inferior parietal regions is consistent with previous reports in C9orf72 24 , 36 - 38 and GRN mutation carriers, 11 , 33 even from the presymptomatic stages. 37 , 38 Patients with GRN showed a left-sided prevalence of parietal cortical damage, consistent with the relatively large proportion (3/8) of PPA presentations in our cohort and the known asymmetrical atrophy of this group, 11 , 33 although the overall average pattern of GM atrophy was relatively symmetrical.…”

Section: Discussionsupporting

confidence: 92%

“…The greater involvement of the inferior parietal regions is consistent with previous reports in C9orf72 24 , 36 - 38 and GRN mutation carriers, 11 , 33 even from the presymptomatic stages. 37 , 38 Patients with GRN showed a left-sided prevalence of parietal cortical damage, consistent with the relatively large proportion (3/8) of PPA presentations in our cohort and the known asymmetrical atrophy of this group, 11 , 33 although the overall average pattern of GM atrophy was relatively symmetrical. Of note, characteristic posterior thalamic and cerebellar atrophy was found in C9orf72 mutation carriers with either FTD or MND presentations, in contrast with the involvement of anterior thalamic regions in GRN mutation carriers.…”

Section: Discussionsupporting

confidence: 92%

“…When looking at single genetic alterations, we identified gMND and, particularly, C9-MND as driving these results, which are consistent with recent studies indicating the involvement of the cognitive/affective regions of the posterior cerebellum (particularly, lobule VII and crus regions, involved in the modulation of emotions and social behaviors) as indicative of the presence of a C9orf72 mutation, 7 possibly as a consequence of the close structural and functional connections with the thalami through cerebello-thalamo-cortical networks. 42 , 45 Similar alterations have been demonstrated in presymptomatic C9orf72 mutation carriers, 37 , 38 , 46 correlating with cognitive inhibition deficits. 46 Although the role in cognition and the topologic organization of the cerebellar cortex has started being elucidated only in recent years, 45 this is an exciting area of developing research for biomarkers of disease pathology in the FTLD spectrum (including MND) that might be combined with other more established measures of cortical damage.…”

Section: Discussionsupporting

confidence: 66%

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Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum

et al. 2021

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Objective.To assess cortical, subcortical and cerebellar grey matter (GM) atrophy using magnetic resonance imaging (MRI) in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.Methods.Sixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.Results.Compared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas sporadic MND (sMND) patients showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, gFTLD patients showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, gFTLD patients showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, gFTLD patients showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of gFTLD patients with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.Conclusions.Measures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless the clinical presentation within the FTLD spectrum.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 66%

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Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum

et al. 2021

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“…MAPT LV included a very limited atrophy of the cerebellum but a larger atrophy of the amygdala compared to the other two genetic groups. These findings are in line with previous studies showing thalamic and cerebellar symmetrical and widespread patterns of atrophy in C9orf72 expansion carriers 57,58 , while amygdalar atrophy seemed to be more related to MAPT carriers (in line with its predominant antero-medial temporal atrophy 18,56 .…”

Section: Discussionsupporting

confidence: 92%

“…Our PLS analyses demonstrated overlapping association between brain and behaviour, but with specificity corresponding to each genetic group. While all brain maps included the thalamus, globus pallidus and striatum, C9orf72 demonstrated a unique atrophy of a large area of the cerebellum including lobules Crus I, Crus II, VIIIB and IX, which is in agreement with a recent study showing preferential cerebellar involvement in C9orf72 carriers 56 . GRN cerebellum map demonstrated more restricted atrophy of the cerebellar lobules Crus I and Crus II.…”

Section: Discussionsupporting

confidence: 90%

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Bussy

Levy

Cupo

et al. 2021

Preprint

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Recent studies have suggested that cerebellar and subcortical structures are impacted early in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the C9orf72 group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity for each genetic group. The biggest differences were in the extent of the cerebellar involvement (larger extent in C9orf72 group) and more prominent amygdalar contribution in the MAPT group. Finally, our findings demonstrated that C9orf72 and MAPT brain scores were related to estimated years before the age of symptom onset (EYO) in a second order relationship highlighting a steeper brain score decline 20 years before expected symptom onset, while GRN brain scores were related to age and not EYO. Overall, these results demonstrated the important role of the subcortical structures and especially of the cerebellum in genetic FTD symptom expression.

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Anatomical MRI staging of frontotemporal dementia variants

Planche

Mansencal

Manjón

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONThe three clinical variants of frontotemporal dementia (behavioral variant [bvFTD], semantic dementia, and progressive non‐fluent aphasia [PNFA]) are likely to develop over decades, from the preclinical stage to death.METHODSTo describe the long‐term chronological anatomical progression of FTD variants, we built lifespan brain charts of normal aging and FTD variants by combining 8022 quality‐controlled MRIs from multiple large‐scale data‐bases, including 107 bvFTD, 44 semantic dementia, and 38 PNFA.RESULTSWe report in this manuscript the anatomical MRI staging schemes of the three FTD variants by describing the sequential divergence of volumetric trajectories between normal aging and FTD variants. Subcortical atrophy precedes focal cortical atrophy in specific behavioral and/or language networks, with a “radiological” prodromal phase lasting 8–10 years (time elapsed between the first structural alteration and canonical cortical atrophy).DISCUSSIONAmygdalar and striatal atrophy can be candidate biomarkers for future preclinical/prodromal FTD variants definitions.Highlights We describe the chronological MRI staging of the most affected structures in the three frontotemporal dementia (FTD) syndromic variants. In behavioral variant of FTD (bvFTD): bilateral amygdalar, striatal, and insular atrophy precedes fronto‐temporal atrophy. In semantic dementia: bilateral amygdalar atrophy precedes left temporal and hippocampal atrophy. In progressive non‐fluent aphasia (PNFA): left striatal, insular, and thalamic atrophy precedes opercular atrophy.

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Differential early subcortical involvement in genetic FTD within the GENFI cohort

Cited by 34 publications

References 48 publications

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Anatomical MRI staging of frontotemporal dementia variants

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