Longitudinal changes in resting state networks in early presymptomatic carriers of C9orf72 expansions

Shoukry, Rachel Smallwood; Waugh, Rebecca E.; Bartlett, Dan; Raitcheva, Denitza; Floeter, Mary Kay

doi:10.1016/j.nicl.2020.102354

Cited by 11 publications

(9 citation statements)

References 47 publications

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“…These trends in structural and functional alterations reinforce the hypothesis that the structural alteration of the pulvinar in C9orf carriers could be linked to the neurodevelopmental profile [46], which might lead a functional adaptation over time, even if reduced in some occipital–parietal regions, as we reported. This hypothesis is corroborated by the longitudinal observation of presymptomatic C9orf72 carriers in which the decrease of thalamic functional connectivity (MNI coordinates of thalamic seeds fall within the anterior seed of pulvinar) was stable over time [47]. It has been suggested that maintaining the topography of functional networks facilitates cognitive resilience in the face of ongoing structural changes in presymptomatic patients [16, 48, 49].…”

Section: Discussionmentioning

confidence: 86%

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers

Nigri,

Stanziano,

Fedeli

et al. 2024

Euro J of Neurology

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Background and purposeThalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia–amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high‐order thalamic nucleus and timekeeper for large‐scale cortical networks, has been hypothesized to be involved in C9orf72‐related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region.MethodsWe studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild‐type ALS (ALSC9−) and ALS mimic (ALSmimic) patients using structural and resting‐state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed‐to‐voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation.ResultsPulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9− (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9− showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital–temporal–parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9− patients showed reduced pulvinar–occipital connectivity for anterior and inferior pulvinar seeds.ConclusionsPulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar–cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild‐type patients.

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Section: Discussionmentioning

confidence: 86%

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers

Nigri,

Stanziano,

Fedeli

et al. 2024

Euro J of Neurology

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“…Gray matter findings are complemented by WM analyses that consistently capture anterior thalamic radiation changes in both ALS and ALS–FTD phenotypes (Bede et al., 2013 ; Floeter et al., 2016 ; Mahoney et al., 2012 ). Functional studies invariably detect reduced connectivity in thalamus‐seeded circuits (Shoukry et al., 2020 ) and the salience network (Lee et al., 2014 ). 18 FDG‐PET studies are consistent in identifying bilateral thalamic hypometabolism (Cistaro et al., 2014 ; Diehl‐Schmid et al., 2019 ; Soleimani‐Meigooni et al., 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype‐specific signatures, clinical correlates, and practical relevance

et al. 2023

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Background Frontotemporal dementia (FTD) phenotypes are classically associated with distinctive cortical atrophy patterns and regional hypometabolism. However, the spectrum of cognitive and behavioral manifestations in FTD arises from multisynaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit, the anterior cingulate circuit, and the orbitofrontal circuit. Methods In this paper, we have reviewed evidence for thalamic pathology in FTD based on radiological and postmortem studies. Original research papers were systematically reviewed for preferential involvement of specific thalamic regions, for phenotype‐associated thalamic disease burden patterns, characteristic longitudinal changes, and genotype‐associated thalamic signatures. Moreover, evidence for presymptomatic thalamic pathology was also reviewed. Identified papers were systematically scrutinized for imaging methods, cohort sizes, clinical profiles, clinicoradiological associations, and main anatomical findings. The findings of individual research papers were amalgamated for consensus observations and their study designs further evaluated for stereotyped shortcomings. Based on the limitations of existing studies and conflicting reports in low‐incidence FTD variants, we sought to outline future research directions and pressing research priorities. Results FTD is associated with focal thalamic degeneration. Phenotype‐specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei mediating behavioral and language functions are preferentially involved. Given the compelling evidence for considerable thalamic disease burden early in the course of most FTD subtypes, we also reflect on the practical relevance, diagnostic role, prognostic significance, and monitoring potential of thalamic metrics in FTD. Conclusions Cardinal manifestations of FTD phenotypes are likely to stem from thalamocortical circuitry dysfunction and are not exclusively driven by focal cortical changes.

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“…Memory is usually not early impaired in bvFTD and therefore has been less studied. Nevertheless, one study reported a positive correlation between memory performance and RSFC between the right anterior insula and the right precuneus in symptomatic C9orf72 mutation carriers (a mix of bvFTD and ALS) (Shoukry et al., 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…A number of studies have found associations between FC and specific FTD‐related mutations (Lee et al., 2017 ; Shoukry et al., 2020 ; Tsvetanov et al., 2021 ; Whitwell et al., 2011 ), but there are also studies that failed to detect gene‐related changes in FC (Bouts et al., 2018 ; Pievani, Paternicò, et al., 2014 ). The influence of specific FTD‐related genes in FC is complex enough to warrant a separate review.…”

Section: Resultsmentioning

confidence: 99%

Functional connectivity in behavioral variant frontotemporal dementia

et al. 2022

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Introduction: Functional connectivity (FC)-which reflects relationships between neural activity in different brain regions-has been used to explore the functional architecture of the brain in neurodegenerative disorders. Although an increasing number of studies have explored FC changes in behavioral variant frontotemporal dementia (bvFTD), there is no focused, in-depth review about FC in bvFTD. Methods: Comprehensive literature search and narrative review to summarize the current field of FC in bvFTD. Results: (1) Decreased FC within the salience network (SN) is the most consistent finding in bvFTD; (2) FC changes extend beyond the SN and affect the interplay between networks; (3) results within the Default Mode Network are mixed; (4) the brain as a network is less interconnected and less efficient in bvFTD; (5) symptoms, functional impairment, and cognition are associated with FC; and (6) the functional architecture resembles patterns of neuropathological spread. Conclusions: FC has potential as a biomarker, and future studies are expected to advance the field with multicentric initiatives, longitudinal designs, and methodological advances.

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Longitudinal changes in resting state networks in early presymptomatic carriers of C9orf72 expansions

Cited by 11 publications

References 47 publications

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers

Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype‐specific signatures, clinical correlates, and practical relevance

Functional connectivity in behavioral variant frontotemporal dementia

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