Focal thalamus pathology in frontotemporal dementia: Phenotype-associated thalamic profiles

McKenna, Mary C.; Shing, Stacey Li Hi; Murad, Aizuri; Lope, Jasmin; Hardiman, Orla; Hutchinson, Siobhan; Bede, Peter

doi:10.1016/j.jns.2022.120221

Cited by 16 publications

(25 citation statements)

References 84 publications

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“…Our neuroimaging analyses confirmed previous findings of global thalamic atrophy in C9orf72 HRE carriers ( Sha et al, 2012 ; Bocchetta et al, 2018 , 2020 ) and also identified atrophy of many individual thalamic nuclei, including those previously associated with HRE expansion ( Lee et al, 2014 , 2017 ; Yokoyama et al, 2014 ; Vatsavayai et al, 2016 ; Bocchetta et al, 2020 ). Of note, these findings are remarkably consistent despite significant differences in analytic technique; our analyses used parametric multiple regression models in keeping with prior work from our center ( Sha et al, 2012 ), whereas other groups have used both parametric ( Bocchetta et al, 2018 , 2020 ) and nonparametric models ( Schönecker et al, 2018 ) and hybrid frameworks ( McKenna et al, 2022 ). Beyond this, by controlling for total thalamic volume we identified the R MDl nucleus as disproportionately atrophied in HRE carriers independent of global thalamic atrophy.…”

Section: Discussionsupporting

confidence: 74%

Radiogenomics ofC9orf72Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment

Bonham

Geier²,

Sirkis³

et al. 2022

J. Neurosci.

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Hexanucleotide repeat expansion (HRE) withinC9orf72is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, includingC9orf72HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheralC9orf72expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects ofC9orf72HRE and clinical diagnosis (n= 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheralC9orf72expression, TE activation, thalamic atrophy, and clinical severity (n= 114 individuals, male and female). We confirmed global thalamic atrophy and reducedC9orf72expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed thatC9orf72expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 elementL1HS.L1HSlevels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated thatC9orf72levels relate to clinical severity, and identified marked derepression of TEs, includingL1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENTPathogenic repeat expansion inC9orf72is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction ofC9orf72in blood and found broad dysregulation of transposable elements—genetic elements typically repressed in the human genome—in symptomaticC9orf72expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD.C9orf72expression was also associated with clinical severity, suggesting that peripheralC9orf72levels capture disease-relevant information.

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Section: Discussionsupporting

confidence: 74%

Radiogenomics ofC9orf72Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment

Bonham

Geier²,

Sirkis³

et al. 2022

J. Neurosci.

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“…Subcortical (Popuri et al, 2018 ; Walhout et al, 2015 ; Bocchetta et al, 2021 ; Bertrand et al, 2018 ; Lee et al, 2016 ; Papma et al, 2017 ) degeneration has been recently further characterised by reports of preferential degenerative change in specific subcortical sub-regions. Focal thalamic changes (Rohrer et al, 2015 ; Popuri et al, 2018 ; Panman et al, 2019 ; Bocchetta et al, 2021 ; Bertrand et al, 2018 ; Lee et al, 2016 ; Olney et al, 2020 ; Cash et al, 2018 ; Papma et al, 2017 ; Cury et al, 2019 ; McKenna et al, 2022 ) have been described in the anterior (Cury et al, 2019 ; McKenna et al, 2022 ), laterodorsal (Bocchetta et al, 2021 ), lateral geniculate nuclei (Bocchetta et al, 2021 ) as well as in pulvinar regions (Bocchetta et al, 2021 ). Preferential caudate (Popuri et al, 2018 ; Walhout et al, 2015 ; Russell et al, 2020 ), putamen (Walhout et al, 2015 ; Bocchetta et al, 2021 ; Russell et al, 2020 ), amygdala (Bocchetta et al, 2021 ; Russell et al, 2020 ; Chipika et al, 2020 ) and hypothalamus (Bocchetta et al, 2021 ) pathology has also been described.…”

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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“…Frontotemporal dementia (FTD) is a group of neurodegenerative diseases affecting the frontal and temporal lobes as well as subcortical structures such as the thalamus (Devenney et al., 2015 ; McKenna et al., 2022 ; WHO, 2019 ). FTD is the clinical syndrome, while frontotemporal lobar degeneration (FTLD) refers to neuropathological changes (Cairns et al., 2007 ).…”

Section: Introductionmentioning

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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Focal thalamus pathology in frontotemporal dementia: Phenotype-associated thalamic profiles

Cited by 16 publications

References 84 publications

Radiogenomics ofC9orf72Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment

Radiogenomics ofC9orf72Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment

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

Functional connectivity in behavioral variant frontotemporal dementia

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