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

Spinelli, Edoardo Gioele; Ghirelli, Alma; Basaia, Silvia; Cividini, Camilla; Riva, Nilo; Canu, Elisa; Castelnovo, Veronica; Domi, Teuta; Magnani, Giuseppe; Caso, Francesca; Caroppo, Paola; Prioni, Sara; Rossi, Giacomina; Tremolizzo, Lucio; Appollonio, Ildebrando; Silani, Vincenzo; Carrera, Paola; Filippi, Massimo

doi:10.1212/wnl.0000000000012702

Cited by 21 publications

(35 citation statements)

References 48 publications

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“…In addition, this region is connected to the frontal cortex to regulate motor and premotor functions [53,54]. In contrast with previous studies [43,51,52], we did not find any significant changes in cerebellar subregions in the ALS group. It may be that parcellating the cerebellum into smaller subregions reduces our capacity to detect significant differences in this group.…”

Section: Discussioncontrasting

confidence: 99%

“…Considering next the impact of genetic status on thalamic volumes, we found that C9orf72 expansion carriers exhibited more extensive thalamic atrophy, with more extreme negative w-scores relative to the sporadic groups. This was in line with another study looking at the extent of atrophy across the disease spectrum [43]. In our study, in particular, the pulvinar showed lower values in carriers compared to non-carriers in all clinical syndromes, confirming the specific involvement of this region in C9orf72-related neurodegenerative diseases [39,41,45].…”

Section: Discussionsupporting

confidence: 92%

“…Independent of genotype, our correlation analyses revealed significant associations between the thalamic midline and MD subregions and overall cognitive function, resonating with perspectives that propose a fundamental role for the thalamus in flexible forms of cognition [59]. Our correlation analyses further revealed striking associations between the MD and level of behavioural changes exclusively in the C9orf72 bvFTD group, similarly to what was reported for the whole thalamus by Spinelli and colleagues [43]. These results, together with the selective MD abnormality in bvFTD and ALS-FTD but not pure ALS, suggest that MD dysfunction could be central to the severity of behavioural and cognitive changes in FTD [41] and a potential imaging marker for disease progression.…”

Section: Discussionsupporting

confidence: 89%

“…These regions are connected to the thalamic areas that we have now found to be affected in ALS [41]. The areas particularly abnormal in bvFTD and ALS-FTD are instead connected to the limbic areas, including subcortical structures and prefrontal regions, as previously reported [34,43].…”

Section: Discussionsupporting

confidence: 74%

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Thalamic and Cerebellar Regional Involvement across the ALS–FTD Spectrum and the Effect of C9orf72

et al. 2022

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic–cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS–FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS–FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS–FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS–FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS–FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS–FTD predominantly in the superior–posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS–FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 74%

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Thalamic and Cerebellar Regional Involvement across the ALS–FTD Spectrum and the Effect of C9orf72

et al. 2022

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“…Blood-oxygen-level-dependent (BOLD) signals measured by rs-fMRI are widely used for non-invasive mapping of brain function between neural activity and its accompanying hemodynamics. Recent studies have shown that the spreading of misfolded tau follows a disease-specific region-dependent pattern in the brain not only in the anatomically connected regions but also in the functionally connected regions in patients with AD ( Franzmeier et al, 2020 ; Vogel et al, 2021 ) and with FTD ( Kim et al, 2020 ; Spinelli et al, 2021 ; Young et al, 2021 ). The default mode network (DMN) is a set of network nodes consisting of the medial prefrontal cortex, the posterior cingulate/precuneus, inferior parietal lobe, lateral temporal cortex, and hippocampal formation ( Buckner and DiNicola, 2019 ).…”

Section: Functional Imagingmentioning

confidence: 99%

Magnetic Resonance Imaging in Tauopathy Animal Models

2022

Front. Aging Neurosci.

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The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer’s disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models.

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

Cited by 21 publications

References 48 publications

Thalamic and Cerebellar Regional Involvement across the ALS–FTD Spectrum and the Effect of C9orf72

Thalamic and Cerebellar Regional Involvement across the ALS–FTD Spectrum and the Effect of C9orf72

Magnetic Resonance Imaging in Tauopathy Animal Models

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

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