Publications by authors named "Peter Bede"

106 Publications

Infratentorial pathology in frontotemporal dementia: cerebellar grey and white matter alterations in FTD phenotypes.

J Neurol 2021 May 13. Epub 2021 May 13.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Peter Bede, Room 5.43, Pearse Street, Dublin 2, Ireland.

The contribution of cerebellar pathology to cognitive and behavioural manifestations is increasingly recognised, but the cerebellar profiles of FTD phenotypes are relatively poorly characterised. A prospective, single-centre imaging study has been undertaken with a high-resolution structural and diffusion tensor protocol to systematically evaluate cerebellar grey and white matter alterations in behavioural-variant FTD(bvFTD), non-fluent variant primary progressive aphasia(nfvPPA), semantic-variant primary progressive aphasia(svPPA), C9orf72-positive ALS-FTD(C9 + ALSFTD) and C9orf72-negative ALS-FTD(C9-ALSFTD). Cerebellar cortical thickness and complementary morphometric analyses were carried out to appraise atrophy patterns controlling for demographic variables. White matter integrity was assessed in a study-specific white matter skeleton, evaluating three diffusivity metrics: fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Significant cortical thickness reductions were identified in: lobule VII and crus I in bvFTD; lobule VI VII, crus I and II in nfvPPA; and lobule VII, crus I and II in svPPA; lobule IV, VI, VII and Crus I and II in C9 + ALSFTD. Morphometry revealed volume reductions in lobule V in all groups; in addition to lobule VIII in C9 + ALSFTD; lobule VI, VIII and vermis in C9-ALSFTD; lobule V, VII and vermis in bvFTD; and lobule V, VI, VIII and vermis in nfvPPA. Widespread white matter alterations were demonstrated by significant fractional anisotropy, axial diffusivity and radial diffusivity changes in each FTD phenotype that were more focal in those with C9 + ALSFTD and svPPA. Our findings indicate that FTD subtypes are associated with phenotype-specific cerebellar signatures with the selective involvement of specific lobules instead of global cerebellar atrophy.
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http://dx.doi.org/10.1007/s00415-021-10575-wDOI Listing
May 2021

Cognitive network hyperactivation and motor cortex decline correlate with ALS prognosis.

Neurobiol Aging 2021 Mar 10;104:57-70. Epub 2021 Mar 10.

Academic Unit of Neurology, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland.

We aimed to quantitatively characterize progressive brain network disruption in Amyotrophic Lateral Sclerosis (ALS) during cognition using the mismatch negativity (MMN), an electrophysiological index of attention switching. We measured the MMN using 128-channel EEG longitudinally (2-5 timepoints) in 60 ALS patients and cross-sectionally in 62 healthy controls. Using dipole fitting and linearly constrained minimum variance beamforming we investigated cortical source activity changes over time. In ALS, the inferior frontal gyri (IFG) show significantly lower baseline activity compared to controls. The right IFG and both superior temporal gyri (STG) become progressively hyperactive longitudinally. By contrast, the left motor and dorsolateral prefrontal cortices are initially hyperactive, declining progressively. Baseline motor hyperactivity correlates with cognitive disinhibition, and lower baseline IFG activities correlate with motor decline rate, while left dorsolateral prefrontal activity predicted cognitive and behavioural impairment. Shorter survival correlates with reduced baseline IFG and STG activity and later STG hyperactivation. Source-resolved EEG facilitates quantitative characterization of symptom-associated and symptom-preceding motor and cognitive-behavioral cortical network decline in ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.002DOI Listing
March 2021

Increased cerebral integrity metrics in poliomyelitis survivors: putative adaptation to longstanding lower motor neuron degeneration.

J Neurol Sci 2021 May 21;424:117361. Epub 2021 Feb 21.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address:

Background: Post-polio syndrome (PPS) has been traditionally considered a slowly progressive condition that affects poliomyelitis survivors decades after their initial infection. Cerebral changes in poliomyelitis survivors are poorly characterised and the few existing studies are strikingly conflicting.

Objective: The overarching aim of this study is the comprehensive characterisation of cerebral grey and white matter alterations in poliomyelitis survivors with reference to healthy- and disease-controls using quantitative imaging metrics.

Methods: Thirty-six poliomyelitis survivors, 88 patients with ALS and 117 healthy individuals were recruited in a prospective, single-centre neuroimaging study using uniform MRI acquisition parameters. All participants underwent standardised clinical assessments, T1-weighted structural and diffusion tensor imaging. Whole-brain and region-of-interest morphometric analyses were undertaken to evaluate patterns of grey matter changes. Tract-based spatial statistics were performed to evaluate diffusivity alterations in a study-specific whiter matter skeleton.

Results: In contrast to healthy controls, poliomyelitis survivors exhibited increased grey matter partial volumes in the brainstem, cerebellum and occipital lobe, accompanied by increased FA in the corticospinal tracts, cerebellum, bilateral mesial temporal lobes and inferior frontal tracts. Polio survivors exhibited increased integrity metrics in the same anatomical regions where ALS patients showed degenerative changes.

Conclusions: Our findings indicate considerable cortical and white matter reorganisation in poliomyelitis survivors which may be interpreted as compensatory, adaptive change in response to severe lower motor neuron injury in infancy.
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http://dx.doi.org/10.1016/j.jns.2021.117361DOI Listing
May 2021

Neuropsychological Assessment Should Always be Considered in Myotonic Dystrophy Type 2.

Cogn Behav Neurol 2021 03 3;34(1):1-10. Epub 2021 Mar 3.

First Department of Neurology, Medical School, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Myotonic dystrophies (DMs) are hereditary, multisystem, slowly progressive myopathies. One of the systems they affect is the CNS. In contrast to the well-established cognitive profile of myotonic dystrophy type 1 (DM1), only a few studies have investigated cognitive dysfunction in individuals with myotonic dystrophy type 2 (DM2), and their findings have been inconsistent. To identify the most commonly affected cognitive domains in individuals with DM2, we performed a formal comprehensive review of published DM2 studies. Using the terms "myotonic dystrophy type 2" AND "cognitive deficits," "cognitive," "cognition," "neuropsychological," "neurocognitive," and "neurobehavioral" in all fields, we conducted an advanced search on PubMed. We read and evaluated all of the available original research articles (13) and one case study, 14 in total, and included them in our review. Most of the research studies of DM2 reported primary cognitive deficits in executive functions (dysexecutive syndrome), memory (short-term nonverbal, verbal episodic memory), visuospatial/constructive-motor functions, and attention and processing speed; language was rarely reported to be affected. Based on the few neuroimaging and/or multimodal DM2 studies we could find, the cognitive profile of DM2 is associated with brain abnormalities in several secondary and high-order cortical and subcortical regions and associative white matter tracts. The limited sample size of individuals with DM2 was the most prominent limitation of these studies. The multifaceted profile of cognitive deficits found in individuals with DM2 highlights the need for routine neuropsychological assessment at both baseline and follow-up, which could unveil these individuals' cognitive strengths and deficits.
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http://dx.doi.org/10.1097/WNN.0000000000000263DOI Listing
March 2021

Extra-motor manifestations in post-polio syndrome (PPS): fatigue, cognitive symptoms and radiological features.

Neurol Sci 2021 Feb 26. Epub 2021 Feb 26.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Room 5.43, Pearse Street, Dublin 2, Ireland.

Background: There is a paucity of cerebral neuroimaging studies in post-polio syndrome (PPS), despite the severity of neurological and neuropsychological sequelae associated with the condition. Fatigue, poor concentration, limited exercise tolerance, paraesthesia and progressive weakness are frequently reported, but the radiological underpinnings of these symptoms are poorly characterised.

Objective: The aim of this study is to evaluate cortical and subcortical alterations in a cohort of adult polio survivors to explore the anatomical substrate of extra-motor manifestations.

Methods: Thirty-six patients with post-polio syndrome, a disease-control group with amyotrophic lateral sclerosis patients and a cohort of healthy individuals were included in a prospective neuroimaging study with a standardised clinical and radiological protocol. Validated clinical instruments were utilised to assess mood, cognitive and behavioural domains and specific aspects of fatigue. Cortical thickness analyses, subcortical volumetry, brainstem segmentation and region-of-interest (ROI) white matter analyses were undertaken to assess regional grey and white matter alterations.

Results: A high proportion of PPS patients exhibited apathy, verbal fluency deficits and reported self-perceived fatigue. On ROI analyses, cortical atrophy was limited to the cingulate gyrus, and the temporal pole and subcortical atrophy were only detected in the left nucleus accumbens. No FA reductions were noted to indicate white matter degeneration in any of the lobes.

Conclusions: Despite the high incidence of extra-motor manifestations in PPS, only limited cortical, subcortical and white matter degeneration was identified. Our findings suggest that non-structural causes, such as polypharmacy and poor sleep, may contribute to the complex symptomatology of post-polio syndrome.
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http://dx.doi.org/10.1007/s10072-021-05130-4DOI Listing
February 2021

Neuroimaging in primary lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11;21(sup1):18-27

Computational Neuroimaging Group, Trinity College Dublin, Dublin, Ireland.

Increased interest in the underlying pathogenesis of primary lateral sclerosis (PLS) and its relationship to amyotrophic lateral sclerosis (ALS) has corresponded to a growing number of CNS imaging studies, especially in the past decade. Both its rarity and uncertainty of definite diagnosis prior to 4 years from symptom onset have resulted in PLS being less studied than ALS. In this review, we highlight most relevant papers applying magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) to analyzing CNS changes in PLS, often in relation to ALS. In patients with PLS, mostly brain, but also spinal cord has been evaluated since significant neurodegeneration is essentially restricted to upper motor neuron (UMN) structures and related pathways. Abnormalities of cortex and subcortical white matter tracts have been identified by structural and functional MRI and MRS studies, while metabolic and cell-specific changes in PLS brain have been revealed using various PET radiotracers. Future neuroimaging studies will continue to explore the interface between the PLS-ALS continuum, identify more changes unique to PLS, apply novel MRI and MRS sequences showing greater structural and neurochemical detail, as well as expand the repertoire of PET radiotracers that reveal various cellular pathologies. Neuroimaging has the potential to play an important role in the evaluation of novel therapies for patients with PLS.
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http://dx.doi.org/10.1080/21678421.2020.1837176DOI Listing
November 2020

Cognitive reserve in amyotrophic lateral sclerosis (ALS): a population-based longitudinal study.

J Neurol Neurosurg Psychiatry 2021 May 9;92(5):460-465. Epub 2021 Feb 9.

Department of Psychology, Beaumont Hospital, Dublin 9, Ireland.

Background: Amyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort.

Methods: Longitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out.

Results: CR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out.

Conclusions: These findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.
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http://dx.doi.org/10.1136/jnnp-2020-324992DOI Listing
May 2021

Extra-motor cerebral changes and manifestations in primary lateral sclerosis.

Brain Imaging Behav 2021 Jan 7. Epub 2021 Jan 7.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.

Primary lateral sclerosis (PLS) is classically considered a 'pure' upper motor neuron disorder. Motor cortex atrophy and pyramidal tract degeneration are thought to be pathognomonic of PLS, but extra-motor cerebral changes are poorly characterized. In a prospective neuroimaging study, forty PLS patients were systematically evaluated with a standardised imaging, genetic and clinical protocol. Patients were screened for ALS and HSP associated mutations, as well as C9orf72 hexanucleotide repeats. Clinical assessment included composite reflex scores, spasticity scales, functional rating scales, and screening for cognitive and behavioural deficits. The neuroimaging protocol evaluated cortical atrophy patterns, subcortical grey matter changes and white matter alterations in whole-brain and region-of-interest analyses. PLS patients tested negative for known ALS- and HSP-associated mutations and C9orf72 repeat expansions. Voxel-wise analyses revealed anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal and bilateral mesial temporal grey matter changes and white matter alterations in the fornix, brainstem, temporal lobes, and cerebellum. Significant thalamus, caudate, hippocampus, putamen and accumbens nucleus volume reductions were also identified. Extra-motor clinical manifestations were dominated by verbal fluency deficits, language deficits, apathy and pseudobulbar affect. Our clinical and radiological evaluation confirms considerable extra-motor changes in a population-based cohort of PLS patients. Our data suggest that PLS should no longer be considered a neurodegenerative disorder selectively affecting the pyramidal system. PLS is associated with widespread extra-motor changes and manifestations which should be carefully considered in the multidisciplinary management of this low-incidence condition.
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http://dx.doi.org/10.1007/s11682-020-00421-4DOI Listing
January 2021

Cortical progression patterns in individual ALS patients across multiple timepoints: a mosaic-based approach for clinical use.

J Neurol 2021 May 5;268(5):1913-1926. Epub 2021 Jan 5.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.

Introduction: The majority of imaging studies in ALS infer group-level imaging signatures from group comparisons, as opposed to estimating disease burden in individual patients. In a condition with considerable clinical heterogeneity, the characterisation of individual patterns of pathology is hugely relevant. In this study, we evaluate a strategy to track progressive cortical involvement in single patients by using subject-specific reference cohorts.

Methods: We have interrogated a multi-timepoint longitudinal dataset of 61 ALS patients to demonstrate the utility of estimating cortical disease burden and the expansion of cerebral atrophy over time. We contrast our strategy to the gold-standard approach to gauge the advantages and drawbacks of our method. We modelled the evolution of cortical integrity in a conditional growth model, in which we accounted for age, gender, disability, symptom duration, education and handedness. We hypothesised that the variance associated with demographic variables will be successfully eliminated in our approach.

Results: In our model, the only covariate which modulated the expansion of atrophy was motor disability as measured by the ALSFRS-r (t(153) = - 2.533, p = 0.0123). Using the standard approach, age also significantly influenced progression of CT change (t(153) = - 2.151, p = 0.033) demonstrating the validity and potential clinical utility of our approach.

Conclusion: Our strategy of estimating the extent of cortical atrophy in individual patients with ALS successfully corrects for demographic factors and captures relevant cortical changes associated with clinical disability. Our approach provides a framework to interpret single T1-weighted images in ALS and offers an opportunity to track cortical propagation patterns both at individual subject level and at cohort level.
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http://dx.doi.org/10.1007/s00415-020-10368-7DOI Listing
May 2021

The imaging signature of C9orf72 hexanucleotide repeat expansions: implications for clinical trials and therapy development.

Brain Imaging Behav 2021 Jan 5. Epub 2021 Jan 5.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in young mutation carriers, considerable inconsistencies exist in the literature. Accordingly, a systematic review of C9orf72-imaging studies has been performed to identify consensus findings, stereotyped shortcomings, and unique contributions to outline future directions. A formal literature review was conducted according to the STROBE guidelines. All identified papers were individually reviewed for sample size, choice of controls, study design, imaging modalities, statistical models, clinical profiling, and identified genotype-associated pathological patterns. A total of 74 imaging papers were systematically reviewed. ALS patients with GGGGCC repeat expansions exhibit relatively limited motor cortex involvement and widespread extra-motor pathology. C9orf72 positive FTD patients often show preferential posterior involvement. Reports of thalamic involvement are relatively consistent across the various phenotypes. Asymptomatic hexanucleotide repeat carriers often exhibit structural and functional changes decades prior to symptom onset. Common shortcomings included sample size limitations, lack of disease-controls, limited clinical profiling, lack of genetic testing in healthy controls, and absence of post mortem validation. There is a striking paucity of longitudinal studies and existing presymptomatic studies have not evaluated the predictive value of radiological changes with regard to age of onset and phenoconversion. With the advent of antisense oligonucleotide therapies, the meticulous characterisation of C9orf72-associated changes has gained practical relevance. Neuroimaging offers non-invasive biomarkers for future clinical trials, presymptomatic ascertainment, diagnostic and prognostic applications.
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http://dx.doi.org/10.1007/s11682-020-00429-wDOI Listing
January 2021

Development of new outcome measures for adult SMA type III and IV: a multimodal longitudinal study.

J Neurol 2021 May 2;268(5):1792-1802. Epub 2021 Jan 2.

Laboratoire D'Imagerie Biomédicale, Sorbonne Université, CNRS, INSERM, Paris, France.

Objective: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials.

Methods: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables.

Results: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials.

Conclusions: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.
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http://dx.doi.org/10.1007/s00415-020-10332-5DOI Listing
May 2021

Degenerative and regenerative processes in amyotrophic lateral sclerosis: motor reserve, adaptation and putative compensatory changes.

Neural Regen Res 2021 Jun;16(6):1208-1209

First Department of Neurology, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.4103/1673-5374.300440DOI Listing
June 2021

The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?

J Neurol 2020 Oct 31. Epub 2020 Oct 31.

Computational Neuroimaging Group (CNG), Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin, Ireland.

Presymptomatic studies in ALS have consistently captured considerable disease burden long before symptom manifestation and contributed important academic insights. With the emergence of genotype-specific therapies, however, there is a pressing need to address practical objectives such as the estimation of age of symptom onset, phenotypic prediction, informing the optimal timing of pharmacological intervention, and identifying a core panel of biomarkers which may detect response to therapy. Existing presymptomatic studies in ALS have adopted striking different study designs, relied on a variety of control groups, used divergent imaging and electrophysiology methods, and focused on different genotypes and demographic groups. We have performed a systematic review of existing presymptomatic studies in ALS to identify common themes, stereotyped shortcomings, and key learning points for future studies. Existing presymptomatic studies in ALS often suffer from sample size limitations, lack of disease controls and rarely follow their cohort until symptom manifestation. As the characterisation of presymptomatic processes in ALS serves a multitude of academic and clinical purposes, the careful review of existing studies offers important lessons for future initiatives.
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http://dx.doi.org/10.1007/s00415-020-10289-5DOI Listing
October 2020

Imaging and clinical data indicate considerable disease burden in 'probable' PLS: Patients with UMN symptoms for 2-4 years.

Data Brief 2020 Oct 1;32:106247. Epub 2020 Sep 1.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland.

Primary lateral sclerosis (PLS) is an adult-onset upper motor neuron disease manifesting in progressive spasticity and gradually resulting in considerably motor disability. In the absence of early disease-specific diagnostic indicators, the majority of patients with PLS face a circuitous diagnostic journey. Until the recent publication of consensus diagnostic criteria, 4-year symptom duration was required to establish the diagnosis. The new diagnostic criteria introduced the category of 'probable PLS' for patients with a symptom duration of 2-4 years. "Evolving diagnostic criteria in primary lateral sclerosis: The clinical and radiological basis of "probable PLS" [1]. This dataset provides radiological metrics in a cohort of 'probable PLS' patients, 'definite PLS' patients and age-matched healthy controls. Region-of-interest radiological data include diffusivity metrics in the corticospinal tracts and corpus callosum as well as mean cortical thickness values in the pre- and para-central gyri in each hemisphere. Our data indicate considerable grey matter and relatively limited white matter involvement in 'probable PLS' which supports the rationale for this diagnostic category as a clinically useful entity. The introduction of this diagnostic category will likely facilitate the timely recruitment of PLS patients into research studies and pharmacological trials before widespread neurodegenerative change ensues.
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http://dx.doi.org/10.1016/j.dib.2020.106247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481824PMC
October 2020

MRI data confirm the selective involvement of thalamic and amygdalar nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis.

Data Brief 2020 Oct 1;32:106246. Epub 2020 Sep 1.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland.

A standardised imaging protocol was implemented to evaluate disease burden in specific thalamic and amygdalar nuclei in 133 carefully phenotyped and genotyped motor neuron disease patients. "Switchboard malfunction in motor neuron diseases: selective pathology of thalamic nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis" [1] "Amygdala pathology in amyotrophic lateral sclerosis and primary lateral sclerosis" [2] Raw volumetric data, group comparisons, effect sizes and percentage change are presented. Both ALS and PLS patients exhibited focal thalamus atrophy in ventral lateral and ventral anterior regions revealing extrapyramidal motor degeneration. Reduced accessory basal nucleus and cortical nucleus volumes were noted in the amygdala of negative ALS patients compared to healthy controls. ALS patients carrying the GGGGCC hexanucleotide repeats in exhibited preferential pathology in the mediodorsal-paratenial-reuniens thalamic nuclei and in the lateral nucleus and cortico-amygdaloid transition area of the amygdala. Considerable thalamic atrophy was observed in the sensory nuclei and lateral geniculate region of PLS patients. Our data demonstrate genotype-specific patterns of thalamus and amygdala involvement in ALS and a distinct disease-burden pattern in PLS. The dataset may be utilised for validation purposes, meta-analyses and the interpretation of thalamic and amygdalar profiles from other ALS genotypes.
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http://dx.doi.org/10.1016/j.dib.2020.106246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481815PMC
October 2020

Neural Correlates of Motor Imagery of Gait in Amyotrophic Lateral Sclerosis.

J Magn Reson Imaging 2021 01 7;53(1):223-233. Epub 2020 Sep 7.

Department of Neurology, Pitié-Salpêtrière University Hospital, Paris, France.

Background: Gait impairment is poorly characterized in amyotrophic lateral sclerosis (ALS), despite increasing evidence of extrapyramidal and cerebellar dysfunction. Gait impairment adds to the considerable motor disability of ALS patients and requires targeted multidisciplinary interventions.

Purpose: To assess gait imagery-specific networks and functional adaptation in ALS.

Study Type: Prospective.

Population: Seventeen ALS patients with lower motor neuron predominant (LMNp) disability, 14 patients with upper motor neurons predominant (UMNp) disease, and 14 healthy controls were included.

Field Strength/sequences: 3T / gradient echo echo planar (GE-EPI).

Assessment: Subjects performed a dual motor imagery task: normal and precision gait. The Movement Imagery Questionnaire - Revised Second Version (MIQ-rs) was used to appraise movement imagery in each participant. Study group-specific activation patterns were evaluated during motor imagery of gait. Additional generalized psychophysiological interaction analyses were carried out using the supplementary motor area, caudate, cerebellum, and superior parietal lobule as seed regions.

Statistical Tests: Repeated-measures analysis of variance (ANOVA) was used to compare time imagery and MIQ-rs scores between groups. Size effects were also reported as partial eta squared (η2). One-way ANOVA was performed to explore differences in terms of connexions during motor imagery tasks.

Results: A significant increase in imagery time in UMNp patients compared to controls (P < 0.05) and LMNp (P < 0.05) during imagined gait was demonstrated. UMNp patients exhibited altered supplementary motor area, precentral gyrus, superior parietal lobule, and dorsolateral prefrontal cortex activation and increased orbitofrontal (pFDR  < 0.05), posterior parietal (pFDR < 0.05) caudate (pFDR < 0.05), and cerebellar (pFDR < 0.05) signal during imagined locomotion. Increased effective connectivity of the striato-cerebellar and parieto-cerebellar circuits was also demonstrated. Additional activation was detected in the insula and cingulate cortex.

Data Conclusion: Enhanced striato- and parieto-cerebellar networks in UMNp ALS patients are likely to represent a compensatory response to impaired postural control.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 5.
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http://dx.doi.org/10.1002/jmri.27335DOI Listing
January 2021

Manifold learning for amyotrophic lateral sclerosis functional loss assessment : Development and validation of a prognosis model.

J Neurol 2021 Mar 4;268(3):825-850. Epub 2020 Sep 4.

Laboratoire d'Imagerie Biomédicale, Sorbonne Université, Paris, France.

Amyotrophic lateral sclerosis (ALS) is an inexorably progressive neurodegenerative condition with no effective disease-modifying therapy at present. Given the striking clinical heterogeneity of the condition, the development and validation of reliable prognostic models is a recognised research priority. We present a prognostic model for functional decline in ALS where outcome uncertainty is taken into account. Patient data were reduced and projected onto a 2D space using Uniform Manifold Approximation and Projection (UMAP), a novel non-linear dimension reduction technique. Information from 3756 patients was included. Development data were sourced from past clinical trials. Real-world population data were used as validation data. Predictors included age, gender, region of onset, symptom duration, weight at baseline, functional impairment, and estimated rate of functional loss. UMAP projection of patients showed an informative 2D data distribution. As limited data availability precluded complex model designs, the projection was divided into three zones defined by a functional impairment range probability. Zone membership allowed individual patient prediction. Patients belonging to the first zone had a probability of [Formula: see text] (± [Formula: see text]) to have an ALSFRS score over 20 at 1-year follow-up. Patients within the second zone had a probability of [Formula: see text] (± [Formula: see text]) to have an ALSFRS score between 10 and 30 at 1 year follow-up. Finally, patients within the third zone had a probability of [Formula: see text] (± [Formula: see text]) to have an ALSFRS score lower than 20 at 1 year follow-up. This approach requires a limited set of features, is easily updated, improves with additional patient data, and accounts for results uncertainty. This method could therefore be used in a clinical setting for patient stratification and outcome projection.
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http://dx.doi.org/10.1007/s00415-020-10181-2DOI Listing
March 2021

Consideration of -associated ALS-FTD as a neurodevel-opmental disorder: insights from neuroimaging.

J Neurol Neurosurg Psychiatry 2020 11 27;91(11):1138. Epub 2020 Aug 27.

Computational Neuroimaging Group, Trinity College Dublin, Dublin, Ireland.

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http://dx.doi.org/10.1136/jnnp-2020-324416DOI Listing
November 2020

Development and validation of a 1-year survival prognosis estimation model for Amyotrophic Lateral Sclerosis using manifold learning algorithm UMAP.

Sci Rep 2020 08 7;10(1):13378. Epub 2020 Aug 7.

Laboratoire d'Imagerie Biomédicale, Sorbonne Université, Paris, 75005, France.

Amyotrophic Lateral Sclerosis (ALS) is an inexorably progressive neurodegenerative condition with no effective disease modifying therapies. The development and validation of reliable prognostic models is a recognised research priority. We present a prognostic model for survival in ALS where result uncertainty is taken into account. Patient data were reduced and projected onto a 2D space using Uniform Manifold Approximation and Projection (UMAP), a novel non-linear dimension reduction technique. Information from 5,220 patients was included as development data originating from past clinical trials, and real-world population data as validation data. Predictors included age, gender, region of onset, symptom duration, weight at baseline, functional impairment, and estimated rate of functional loss. UMAP projection of patients shows an informative 2D data distribution. As limited data availability precluded complex model designs, the projection was divided into three zones with relevant survival rates. These rates were defined using confidence bounds: high, intermediate, and low 1-year survival rates at respectively [Formula: see text] ([Formula: see text]), [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]). Predicted 1-year survival was estimated using zone membership. This approach requires a limited set of features, is easily updated, improves with additional patient data, and accounts for results uncertainty.
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http://dx.doi.org/10.1038/s41598-020-70125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414917PMC
August 2020

Evolving diagnostic criteria in primary lateral sclerosis: The clinical and radiological basis of "probable PLS".

J Neurol Sci 2020 Oct 24;417:117052. Epub 2020 Jul 24.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address:

Introduction: Primary lateral sclerosis is a rare neurodegenerative disorder of the upper motor neurons. Diagnostic criteria have changed considerably over the years, and the recent consensus criteria introduced 'probable PLS' for patients with a symptom duration of 2-4 years. The objective of this study is the systematic evaluation of clinical and neuroimaging characteristics in early PLS by studying a group of 'probable PLS patients' in comparison to a cohort of established PLS patients.

Methods: In a prospective neuroimaging study, thirty-nine patients were stratified by the new consensus criteria into 'probable' (symptom duration 2-4 years) or 'definite' PLS (symptom duration >4 years). Patients were evaluated with a standardised battery of clinical instruments (ALSFRS-r, Penn upper motor neuron score, the modified Ashworth spasticity scale), whole genome sequencing, and underwent structural and diffusion MRI. The imaging profile of the two PLS cohorts were contrasted to a dataset of 100 healthy controls. All 'probable PLS' patients subsequently fulfilled criteria for 'definite' PLS on longitudinal follow-up and none transitioned to develop ALS.

Results: PLS patients tested negative for known ALS- or HSP-associated mutations on whole genome sequencing. Despite their shorter symptom duration, 'probable PLS' patients already exhibited considerable functional disability, upper motor neuron disease burden and the majority of them required walking aids for safe ambulation. Their ALSFRS-r, UMN and modified Ashworth score means were 83%, 98% and 85% of the 'definite' group respectively. Motor cortex thickness was significantly reduced in both PLS groups in comparison to controls, but cortical changes were less widespread in 'probable' PLS on morphometric analyses. Corticospinal tract and corpus callosum metrics were relatively well preserved in the 'probable' group in contrast to the widespread white matter degeneration observed in the 'definite' group.

Conclusions: Our clinical and radiological analyses support the recent introduction of the 'probable' PLS category, as this cohort already exhibits considerable disability and cerebral changes consistent with established PLS. Before the publication of the new consensus criteria, these patients would have not been diagnosed with PLS on the basis of their symptom duration despite their significant functional impairment and motor cortex atrophy. The introduction of this new category will facilitate earlier recruitment into clinical trials, and shorten the protracted diagnostic uncertainty the majority of PLS patients face.
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http://dx.doi.org/10.1016/j.jns.2020.117052DOI Listing
October 2020

Amygdala pathology in amyotrophic lateral sclerosis and primary lateral sclerosis.

J Neurol Sci 2020 Oct 18;417:117039. Epub 2020 Jul 18.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland. Electronic address:

Temporal lobe studies in motor neuron disease overwhelmingly focus on white matter alterations and cortical grey matter atrophy. Reports on amygdala involvement are conflicting and the amygdala is typically evaluated as single structure despite consisting of several functionally and cytologically distinct nuclei. A prospective, single-centre, neuroimaging study was undertaken to comprehensively characterise amygdala pathology in 100 genetically-stratified ALS patients, 33 patients with PLS and 117 healthy controls. The amygdala was segmented into groups of nuclei using a Bayesian parcellation algorithm based on a probabilistic atlas and shape deformations were additionally assessed by vertex analyses. The accessory basal nucleus (p = .021) and the cortical nucleus (p = .022) showed significant volume reductions in C9orf72 negative ALS patients compared to controls. The lateral nucleus (p = .043) and the cortico-amygdaloid transition (p = .024) were preferentially affected in C9orf72 hexanucleotide carriers. A trend of total volume reduction was identified in C9orf72 positive ALS patients (p = .055) which was also captured in inferior-medial shape deformations on vertex analyses. Our findings highlight that the amygdala is affected in ALS and our study demonstrates the selective involvement of specific nuclei as opposed to global atrophy. The genotype-specific patterns of amygdala involvement identified by this study are consistent with the growing literature of extra-motor clinical features. Mesial temporal lobe pathology in ALS is not limited to hippocampal pathology but, as a key hub of the limbic system, the amygdala is also affected in ALS.
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http://dx.doi.org/10.1016/j.jns.2020.117039DOI Listing
October 2020

Cerebro-cerebellar white matter connectivity in bipolar disorder and associated polarity subphenotypes.

Prog Neuropsychopharmacol Biol Psychiatry 2021 01 22;104:110034. Epub 2020 Jul 22.

2nd Department of Psychiatry, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Background: The cerebellum has a crucial role in mood regulation. While cerebellar grey matter (GM) alterations have been previously reported in bipolar disorder (BD), cerebro-cerebellar white matter (WM) connectivity alterations and cerebellar GM profiles have not been characterised in the context of predominant polarity (PP) and onset polarity (OP) subphenotypes of BD patients which is the aim of the present study.

Methods: Forty-two euthymic BD patients stratified for PP and OP and 42 healthy controls (HC) were included in this quantitative neuroimaging study to evaluate cerebellar GM patterns and cerebro-cerebellar WM connections. Diffusion tensor tractography was used to characterise afferent and efferent cerebro-cerebellar tract integrity. False discovery rate corrections were applied in post-hoc comparisons.

Results: BD patients exhibited higher fractional anisotropy (FA) in fronto-ponto-cerebellar tracts bilaterally compared to HC. Subphenotype-specific FA profiles were identified within the BD cohort. Regarding PP subgroups, we found FA changes in a) left contralateral fronto-ponto-cerebellar tract (depressive-PP > HC) and b) contralateral/ipsilateral fronto-ponto-cerebellar tracts bilaterally (manic-PP > HC). Regarding OP subgroups, we observed FA changes in a) left/right contralateral fronto-ponto-cerebellar tracts (depressive-OP > HC) and b) all fronto-ponto-cerebellar, most parieto-ponto-cerebellar and right contralateral occipito-ponto-cerebellar tracts (manic-OP>HC). In general, greater and more widespread cerebro-cerebellar changes were observed in manic-OP patients than in depressive-OP patients compared to HC. Manic-OP showed higher FA compared to depressive-OP patients in several afferent WM tracts. No GM differences were identified between BD and HC and across BD subgroups.

Conclusions: Our findings highlight fronto-ponto-cerebellar connectivity alterations in euthymic BD. Polarity-related subphenotypes have distinctive cerebro-cerebellar WM signatures with potential clinical and pathobiological implications.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110034DOI Listing
January 2021

"Switchboard" malfunction in motor neuron diseases: Selective pathology of thalamic nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis.

Neuroimage Clin 2020 30;27:102300. Epub 2020 May 30.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address:

The thalamus is a key cerebral hub relaying a multitude of corticoefferent and corticoafferent connections and mediating distinct extrapyramidal, sensory, cognitive and behavioural functions. While the thalamus consists of dozens of anatomically well-defined nuclei with distinctive physiological roles, existing imaging studies in motor neuron diseases typically evaluate the thalamus as a single structure. Based on the unique cortical signatures observed in ALS and PLS, we hypothesised that similarly focal thalamic involvement may be observed if the nuclei are individually evaluated. A prospective imaging study was undertaken with 100 patients with ALS, 33 patients with PLS and 117 healthy controls to characterise the integrity of thalamic nuclei. ALS patients were further stratified for the presence of GGGGCC hexanucleotide repeat expansions in C9orf72. The thalamus was segmented into individual nuclei to examine their volumetric profile. Additionally, thalamic shape deformations were evaluated by vertex analyses and focal density alterations were examined by region-of-interest morphometry. Our data indicate that C9orf72 negative ALS patients and PLS patients exhibit ventral lateral and ventral anterior involvement, consistent with the 'motor' thalamus. Degeneration of the sensory nuclei was also detected in C9orf72 negative ALS and PLS. Both ALS groups and the PLS cohort showed focal changes in the mediodorsal-paratenial-reuniens nuclei, which mediate memory and executive functions. PLS patients exhibited distinctive thalamic changes with marked pulvinar and lateral geniculate atrophy compared to both controls and C9orf72 negative ALS. The considerable ventral lateral and ventral anterior pathology detected in both ALS and PLS support the emerging literature of extrapyramidal dysfunction in MND. The involvement of sensory nuclei is consistent with sporadic reports of sensory impairment in MND. The unique thalamic signature of PLS is in line with the distinctive clinical features of the phenotype. Our data confirm phenotype-specific patterns of thalamus involvement in motor neuron diseases with the preferential involvement of nuclei mediating motor and cognitive functions. Given the selective involvement of thalamic nuclei in ALS and PLS, future biomarker and natural history studies in MND should evaluate individual thalamic regions instead overall thalamic changes.
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http://dx.doi.org/10.1016/j.nicl.2020.102300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303672PMC
March 2021

Commissural fiber degeneration in motor neuron diseases.

Amyotroph Lateral Scler Frontotemporal Degener 2020 08 14;21(5-6):321-323. Epub 2020 Apr 14.

Computational Neuroimaging Group (CNG), Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.

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http://dx.doi.org/10.1080/21678421.2020.1752253DOI Listing
August 2020

The French national protocol for Kennedy's disease (SBMA): consensus diagnostic and management recommendations.

Orphanet J Rare Dis 2020 04 10;15(1):90. Epub 2020 Apr 10.

Pôle Neurosciences - Service de Neurologie, Centre de Référence SLA et les maladies du neurone moteur, Hôpital Pasteur2, CHU de Nice Université Côte d'Azur, Nice, France.

Background: Kennedy's disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations.

Results: The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy.

Conclusion: The French national Kennedy's disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines.
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http://dx.doi.org/10.1186/s13023-020-01366-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149864PMC
April 2020

Progressive brainstem pathology in motor neuron diseases: Imaging data from amyotrophic lateral sclerosis and primary lateral sclerosis.

Data Brief 2020 Apr 3;29:105229. Epub 2020 Feb 3.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.

A standardised, single-centre, longitudinal imaging protocol was used to evaluate longitudinal brainstem alterations in 100 patients with amyotrophic lateral sclerosis (ALS) with reference to 33 patients with primary lateral sclerosis (PLS), 30 patients with frontotemporal dementia (FTD) and 100 healthy controls. "Brainstem pathology in amyotrophic lateral sclerosis and primary lateral sclerosis: A longitudinal neuroimaging study" [1] ALS patients were scanned twice; 4 months apart. T1-weighted imaging data were acquired on a 3 T Philips Achieva MRI system, using a 3D Inversion Recovery prepared Spoiled Gradient Recalled echo (IR-SPGR) sequence. Raw MRI data underwent meticulous quality control before pre-processing. A Bayesian segmentation algorithm was utilised to parcellate the brainstem into the medulla oblongata, pons and mesencephalon before estimating the volume of each segment. Vertex-based shape analyses were carried out to characterise anatomical patterns of atrophy. Brainstem volume loss in ALS was dominated by medulla oblongata atrophy, but significant pontine pathology was also detected. Brainstem volume reductions were more significant in PLS than in ALS after correcting for demographic variables and total intracranial volume. Shape analyses revealed bilateral 'flattening' of the medullary pyramids in ALS compared to healthy controls. Our data demonstrate that computational neuroimaging readily detects brainstem pathology in vivo in both amyotrophic lateral sclerosis and primary lateral sclerosis.
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http://dx.doi.org/10.1016/j.dib.2020.105229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016370PMC
April 2020

Connectome-Based Propagation Model in Amyotrophic Lateral Sclerosis.

Ann Neurol 2020 05 11;87(5):725-738. Epub 2020 Mar 11.

Dutch Connectome Lab, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Free University Amsterdam, Amsterdam, the Netherlands.

Objective: Clinical trials in amyotrophic lateral sclerosis (ALS) continue to rely on survival or functional scales as endpoints, despite the emergence of quantitative biomarkers. Neuroimaging-based biomarkers in ALS have been shown to detect ALS-associated pathology in vivo, although anatomical patterns of disease spread are poorly characterized. The objective of this study is to simulate disease propagation using network analyses of cerebral magnetic resonance imaging (MRI) data to predict disease progression.

Methods: Using brain networks of ALS patients (n = 208) and matched controls across longitudinal time points, network-based statistics unraveled progressive network degeneration originating from the motor cortex and expanding in a spatiotemporal manner. We applied a computational model to the MRI scan of patients to simulate this progressive network degeneration. Simulated aggregation levels at the group and individual level were validated with empirical impairment observed at later time points of white matter and clinical decline using both internal and external datasets.

Results: We observe that computer-simulated aggregation levels mimic true disease patterns in ALS patients. Simulated patterns of involvement across cortical areas show significant overlap with the patterns of empirically impaired brain regions on later scans, at both group and individual levels. These findings are validated using an external longitudinal dataset of 30 patients.

Interpretation: Our results are in accordance with established pathological staging systems and may have implications for patient stratification in future clinical trials. Our results demonstrate the utility of computational models in ALS to predict disease progression and underscore their potential as a prognostic biomarker. ANN NEUROL 2020;87:725-738.
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http://dx.doi.org/10.1002/ana.25706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186838PMC
May 2020

Thalamic, hippocampal and basal ganglia pathology in primary lateral sclerosis and amyotrophic lateral sclerosis: Evidence from quantitative imaging data.

Data Brief 2020 Apr 10;29:105115. Epub 2020 Jan 10.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.

Primary lateral sclerosis and amyotrophic lateral sclerosis are primarily associated with motor cortex and corticospinal tract pathology. A standardised, prospective, single-centre neuroimaging protocol was used to characterise thalamic, hippocampal and basal ganglia involvement in 33 patients with primary lateral sclerosis (PLS), 100 patients with amyotrophic lateral sclerosis (ALS), and 117 healthy controls. "Widespread subcortical grey matter degeneration in primary lateral sclerosis: a multimodal imaging study with genetic profiling" [1] Imaging data were acquired on a 3 T MRI system using a 3D Inversion Recovery prepared Spoiled Gradient Recalled echo sequence. Model based segmentation was used to estimate the volumes of the thalamus, hippocampus, amygdala, caudate, pallidum, putamen and accumbens nucleus in each hemisphere. The hippocampus was further parcellated into cytologically-defined subfields. Total intracranial volume (TIV) was estimated for each participant to aid the interpretation of subcortical volume alterations. Group comparisons were corrected for age, gender, TIV, education and symptom duration. Considerable thalamic, hippocampal and accumbens nucleus atrophy was detected in PLS compared to healthy controls and selective dentate, molecular layer, CA1, CA3, and CA4 hippocampal pathology was also identified. In ALS, additional volume reductions were noted in the amygdala, left caudate and the hippocampal-amygdala transition area of the hippocampus. Our imaging data provide evidence of extensive and phenotype-specific patterns of subcortical degeneration in PLS.
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http://dx.doi.org/10.1016/j.dib.2020.105115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005372PMC
April 2020