Basal ganglia involvement in amyotrophic lateral sclerosis

Bede, Peter; Elamin, Marwa; Byrne, Susan; McLaughlin, Russell L.; Kenna, Kevin P.; Vajda, Alice; Pender, Niall; Bradley, Daniel G.; Hardiman, Orla

doi:10.1212/01.wnl.0000437313.80913.2c

Cited by 154 publications

(171 citation statements)

References 38 publications

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“…Several prior neuroimaging studies have suggested that the regions observed in the current neuroimaging study are selectively reduced in C9orf72 expansion relative to sporadic forms of disease, [9][10][11][12][13][14]28 including hippocampus, 10 frontal cortex, 12,13,28 and thalamus, 13,14,29 among other cortical and subcortical regions. One study evaluated longitudinal neuroimaging in a small cohort (n 5 6) of patients with C9orf72 expansion and observed that bilateral thalamus and left globus pallidus decline significantly more than controls, while hippocampus decline did not differ from controls.…”

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confidence: 54%

“…Neuroimaging comparisons of C9orf72 expansion relative to C9orf72-negative patients provide preliminary evidence for regional selectivity of gray matter (GM) disease associated with C9orf72 expansion. [9][10][11][12][13][14] In vivo demonstration of effects related to C9orf72 hypermethylation would provide an important method for monitoring response during a disease-modifying treatment trial.…”

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confidence: 99%

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C9orf72 promoter hypermethylation is neuroprotective

et al. 2015

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Objective: To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective.Methods: Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n 5 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing. Regional neuronal loss was measured in an independent autopsy series (n 5 35) of C9orf72 repeat expansion patients.Results: GM analysis revealed that hippocampus, frontal cortex, and thalamus are associated with hypermethylation and thus appear to be relatively protected from mutant C9orf72. Neuropathologic analysis demonstrated an association between reduced neuronal loss and hypermethylation in hippocampus and frontal cortex. Longitudinal neuroimaging revealed that hypermethylation is associated with reduced longitudinal decline in GM regions protected by hypermethylation and longitudinal neuropsychological assessment demonstrated that longitudinal decline in verbal recall is protected by hypermethylation.Conclusions: These cross-sectional and longitudinal neuroimaging studies, along with neuropathologic validation studies, provide converging evidence for neuroprotective properties of C9orf72 promoter hypermethylation. These findings converge with prior postmortem studies suggesting that C9orf72 promoter hypermethylation may be a neuroprotective target for drug discovery. The C9orf72 hexanucleotide repeat expansion 1,2 is associated with inclusions of TAR DNA binding protein of 43 kDa (TDP-43) as the primary pathologic substrate of neurodegeneration 3 and accounts for the largest proportion of inherited forms of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).4 From a translational perspective, it is critical to improve our understanding of the C9orf72 expansion because expanded individuals have a known source of underlying pathology during life and may be good candidates for clinical trials of disease-modifying therapeutic agents. 5A candidate mechanism for therapeutic agents relates to recent molecular and neuropathologic studies suggesting that C9orf72 promoter hypermethylation can contribute to transcriptional silencing of mutant C9orf72. Hypermethylation is equally observed in ALS and FTD 6,7 and at autopsy it has been associated with reduced pathologic inclusions.8 While postmortem studies suggest that C9orf72 promoter hypermethylation may be neuroprotective, in vivo longitudinal investigations of the potential neuroprotective properties of C9orf72 promoter

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confidence: 54%

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confidence: 99%

C9orf72 promoter hypermethylation is neuroprotective

et al. 2015

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“…To detect subtle regional volume changes of DGM, we performed a shape analysis of DGM (thalamus, putamen, caudate nucleus, nucleus accumbens, and hippocampus), previously reported to be altered in ALS (Agosta et al, 2009;Bede et al, 2013;Chang et al, 2005;Thivard et al, 2007). The shape of the above-mentioned DGM (except the hippocampus, the subfields of which were studied) was analyzed using the FSLs FIRST module version 5.0.0 (Patenaude et al, 2011).…”

Section: Data Processingmentioning

confidence: 99%

“…In addition, studies using positron emission tomographyecomputed tomography (PET-CT), single-photon emission computed tomography (SPECT), magnetic resonance spectroscopy, and diffusion tensor imaging have also shown involvement of deep gray matter (DGM; thalamus, caudatus, putamen, pallidum, hippocampus, amygdala, accumbens), but morphometric changes have been reported sporadically (Sach et al, 2004;Turner et al, 2004;Verstraete et al, 2014). Currently, there is only 1 cross-sectional study that has reported a more detailed morphometric analysis of the DGM in ALS (Bede et al, 2013). This cross-sectional study in 39 ALS patients showed reduced volumes of the left caudate, left hippocampus, and right accumbens in ALS, underscoring the relevance of the subcortical structures in the disease process.…”

Section: Introductionmentioning

confidence: 99%

“…Longitudinal neuroimaging studies may be an important tool to assess cerebral neurodegeneration in detail in a noninvasive way. For example, hippocampal atrophy has been reported in ALS but also in other neurological and psychiatric diseases (Bede et al, 2013;Thompson et al, 2004). Longitudinal analyses, in combination with a more detailed analysis of the hippocampus (hippocampal subfield segmentations), might shed more light on when the hippocampus becomes involved and which subfields in particular may be affected.…”

Section: Introductionmentioning

confidence: 99%

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Subcortical structures in amyotrophic lateral sclerosis

Westeneng

Verstraete

Walhout

et al. 2015

Neurobiology of Aging

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Combining structural and metabolic markers in a quantitative MRI study of motor neuron diseases

Canna

Trojsi

Nardo

et al. 2021

Ann Clin Transl Neurol

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Objective To assess the performance of a combination of three quantitative MRI markers (iron deposition, basal neuronal metabolism, and regional atrophy) for differential diagnosis between amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Methods In total, 33 ALS, 12 PLS, and 28 healthy control (HC) subjects underwent a 3T MRI study including single‐ and multi‐echo sequences for gray matter (GM) volumetry and quantitative susceptibility mapping (QSM) and a pseudo‐continuous arterial spin labeling (ASL) sequence for cerebral blood flow (CBF) measurement. Mean values of QSM, CBF, and GM volumes were extracted in the motor cortex, basal ganglia, thalamus, amygdala, and hippocampus. A generalized linear model was applied to the three measures to binary discriminate between groups. The diagnostic performances were evaluated via receiver operating characteristic analyses. Results A significant discrimination was obtained: between ALS and HCs in the left and right motor cortex, where QSM increases were respectively associated with disability scores and disease duration; between PLS and ALS in the left motor cortex, where PLS patients resulted significantly more atrophic; between ALS and HC in the right motor cortex, where GM volumes were associated with upper motor neuron scores. Significant discrimination between ALS and HC was achieved in subcortical structures only combining all three parameters. Interpretation While increased QSM values in the motor cortex of ALS patients is a consolidated finding, combining QSM, CBF, and GM volumetry shows higher diagnostic potential for differentiating ALS patients from HC subjects and, in the motor cortex, between ALS and PLS.

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Basal ganglia involvement in amyotrophic lateral sclerosis

Cited by 154 publications

References 38 publications

C9orf72 promoter hypermethylation is neuroprotective

C9orf72 promoter hypermethylation is neuroprotective

Subcortical structures in amyotrophic lateral sclerosis

Combining structural and metabolic markers in a quantitative MRI study of motor neuron diseases

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