Longitudinal changes in network homogeneity in presymptomatic C9orf72 mutation carriers

Waugh, Rebecca E.; Danielian, Laura E.; Shoukry, Rachel F Smallwood; Floeter, Mary Kay

doi:10.1016/j.neurobiolaging.2020.11.014

Cited by 5 publications

(20 citation statements)

References 61 publications

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“…Salience network and thalamic-seeded network alterations are identifiable early, and are somewhat reminiscent of what observed in C9orf72-associated bvFTD [58,60]. The profile of connectivity changes extends over time, spreading towards the areas mostly affected in the symptomatic phase, which could herald impending neurodegeneration [59,61].…”

Section: Biomarkers To Define the Preclinical Disease Trajectorymentioning

confidence: 72%

“…Similarly, few studies have investigated the potential of fMRI to detect functionally compensated network dysregulations in asymptomatic carriers [58,59]. Salience network and thalamic-seeded network alterations are identifiable early, and are somewhat reminiscent of what observed in C9orf72-associated bvFTD [58,60].…”

Section: Biomarkers To Define the Preclinical Disease Trajectorymentioning

confidence: 99%

“…Early salience and thalamicseeded network dysregulation [58,59] Cerebral blood flow (ASL) Decreased from 12.5 years before onset [104] Gyrification index Congenitally reduced in C9orf72 carriers [109] Cervical spinal cord WM volume and FA Altered metrics mostly in carriers >40 years [73] FDG PET uptake Hypometabolism consistent with structural changes [36] UCB-J PET uptake Reduced synaptic density in preclinical phase [102] Neuropsychological Verbal fluencies Reduced scores since young age [91] Episodic memory Preclinical changes reflecting executive dysfunction [92] Social cognition Deficits in late presymptomatic phase [93] Cognitive inhibition Deficits mostly in >40 years [94] Semantic knowledge Deficits in late presymptomatic phase [98] Gestural praxis Impaired before 40 years [35] Neurophysiological Cortical excitability Increase in ALS patients [74]…”

Section: Functional Connectivitymentioning

confidence: 99%

See 2 more Smart Citations

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

Ber

2022

Revue Neurologique

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Section: Biomarkers To Define the Preclinical Disease Trajectorymentioning

confidence: 72%

Section: Biomarkers To Define the Preclinical Disease Trajectorymentioning

confidence: 99%

Section: Functional Connectivitymentioning

confidence: 99%

See 1 more Smart Citation

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

Ber

2022

Revue Neurologique

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“…In pre-symptomatic carriers of the mutation, disruption of the salience network and of thalamic networks was detected, while other studies pointed out the presence of early alteration in visual related regions [68,69]. Globally, alterations in brain networks are considered to be an early event in the history of the disease, further supporting the hypothesis of a neurodevelopmental origin of at least a part of the C9orf72-related syndrome.…”

Section: Functional Connectivitymentioning

confidence: 81%

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Querin

Biferi

2022

JND

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The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.

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“…This trend of progressive changes in older subgroups was shown in a study that described widespread changes in pre-symptomatic cohorts aged > 40 years compared with those aged < 40 years (Bertrand et al, 2018 ). The rate of cortical thinning has been calculated as either faster (Blanc et al, 2020 ) or no different (Waugh et al, 2021 ) compared to controls. Patterns of atrophy have been evaluated (Olney et al, 2020 ) to predict phenoconversion (Staffaroni et al, 2020 ).…”

Section: C9orf72mentioning

confidence: 99%

Pre-symptomatic radiological changes in frontotemporal dementia: propagation characteristics, predictive value and implications for clinical trials

McKenna

Lope

Tan

et al. 2022

Brain Imaging and Behavior

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Computational imaging and quantitative biomarkers offer invaluable insights in the pre-symptomatic phase of neurodegenerative conditions several years before clinical manifestation. In recent years, there has been a focused effort to characterize pre-symptomatic cerebral changes in familial frontotemporal dementias using computational imaging. Accordingly, a systematic literature review was conducted of original articles investigating pre-symptomatic imaging changes in frontotemporal dementia focusing on study design, imaging modalities, data interpretation, control cohorts and key findings. The review is limited to the most common genotypes: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) genotypes. Sixty-eight studies were identified with a median sample size of 15 (3–141) per genotype. Only a minority of studies were longitudinal (28%; 19/68) with a median follow-up of 2 (1–8) years. MRI (97%; 66/68) was the most common imaging modality, and primarily grey matter analyses were conducted (75%; 19/68). Some studies used multimodal analyses 44% (30/68). Genotype-associated imaging signatures are presented, innovative study designs are highlighted, common methodological shortcomings are discussed and lessons for future studies are outlined. Emerging academic observations have potential clinical implications for expediting the diagnosis, tracking disease progression and optimising the timing of pharmaceutical trials.

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Longitudinal changes in network homogeneity in presymptomatic C9orf72 mutation carriers

Cited by 5 publications

References 61 publications

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Pre-symptomatic radiological changes in frontotemporal dementia: propagation characteristics, predictive value and implications for clinical trials

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