The role of genetically predicted serum iron levels on neurodegenerative and cardiovascular traits.

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson's disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide.

Comparison of machine learning methods for genomic prediction of selected Arabidopsis thaliana traits.

We present a comparison of machine learning methods for the prediction of four quantitative traits in Arabidopsis thaliana. High prediction accuracies were achieved on individuals grown under standardized laboratory conditions from the 1001 Arabidopsis Genomes Project. An existing body of evidence suggests that linear models may be impeded by their inability to make use of non-additive effects to explain phenotypic variation at the population level. The results presented here use a nested cross-validation approach to confirm that some machine learning methods have the ability to statistically outperform linear prediction models, with the optimal model dependent on availability of training data and genetic architecture of the trait in question. Linear models were competitive in their performance as per previous work, though the neural network class of predictors was observed to be the most accurate and robust for traits with high heritability. The extent to which non-linear models exploit interaction effects will require further investigation of the causal pathways that lay behind their predictions. Future work utilizing more traits and larger sample sizes, combined with an improved understanding of their respective genetic architectures, may lead to improvements in prediction accuracy.

Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS. METHODS: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures. RESULTS: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule (padj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura (padj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients (padj = 0.003, t(249) = 3.04 and padj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (padj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (padj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection (padj = 0.025, t(199) = -2.26), and progressive flocculonodular lobule degeneration (padj = 0.017, t(249) = -2.24). C9POS patients showed progressive ventral dentate atrophy (padj = 0.007, t(249) = -2.75). The CSTs (padj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (padj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection (padj = 0.001, t(190) = 6.93). DISCUSSION: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.

Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data. RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation. INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

Supra- and infra-tentorial degeneration patterns in primary lateral sclerosis: a multimodal longitudinal neuroradiology study.

BACKGROUND: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease. METHODS: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS. RESULTS: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured. CONCLUSIONS: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect.

Language deficits in primary lateral sclerosis: cortical atrophy, white matter degeneration and functional disconnection between cerebral regions.

BACKGROUND: Primary lateral sclerosis (PLS) is traditionally regarded as a pure upper motor neuron disorder, but recent cases series have highlighted cognitive deficits in executive and language domains. METHODS: A single-centre, prospective neuroimaging study was conducted with comprehensive clinical and genetic profiling. The structural and functional integrity of language-associated brain regions and networks were systematically evaluated in 40 patients with PLS in comparison to 111 healthy controls. The structural integrity of the arcuate fascicle, frontal aslant tract, inferior occipito-frontal fascicle, inferior longitudinal fascicle, superior longitudinal fascicle and uncinate fascicle was evaluated. Functional connectivity between the supplementary motor region and the inferior frontal gyrus and connectivity between Wernicke's and Broca's areas was also assessed. RESULTS: Cortical thickness reductions were observed in both Wernicke's and Broca's areas. Fractional anisotropy reduction was noted in the aslant tract and increased radical diffusivity (RD) identified in the aslant tract, arcuate fascicle and superior longitudinal fascicle in the left hemisphere. Functional connectivity was reduced along the aslant track, i.e. between the supplementary motor region and the inferior frontal gyrus, but unaffected between Wernicke's and Broca's areas. Cortical thickness alterations, structural and functional connectivity changes were also noted in the right hemisphere. CONCLUSIONS: Disease-burden in PLS is not confined to motor regions, but there is also a marked involvement of language-associated tracts, networks and cortical regions. Given the considerably longer survival in PLS compared to ALS, the impact of language impairment on the management of PLS needs to be carefully considered.

C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.

Background and Objectives: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion. Methods: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing. Results: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds. Discussion: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.

The involvement of language-associated networks, tracts, and cortical regions in frontotemporal dementia and amyotrophic lateral sclerosis: Structural and functional alterations.

BACKGROUND: Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality-of-life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS-FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied. METHODS: A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language-associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS-FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72-negative ALS-FTD, C9orf72-positive ALS-FTD, behavioral-variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed. RESULTS: Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language-associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS-FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72-negative ALS-FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72-positive ALS-FTD patients do not. CONCLUSIONS: Language-associated tracts and networks are not only affected in language-variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype.

Radiological correlates of pseudobulbar affect: Corticobulbar and cerebellar components in primary lateral sclerosis.

INTRODUCTION: Pseudobulbar affect (PBA) is a distressing symptom of a multitude of neurological conditions affecting patients with a rage of neuroinflammatory, neurovascular and neurodegenerative conditions. It manifests in disproportionate emotional responses to minimal or no contextual stimulus. It has considerable quality of life implications and treatment can be challenging. METHODS: A prospective multimodal neuroimaging study was conducted to explore the neuroanatomical underpinnings of PBA in patients with primary lateral sclerosis (PLS). All participants underwent whole genome sequencing and screening for C9orf72 hexanucleotide repeat expansions, a comprehensive neurological assessment, neuropsychological screening (ECAS, HADS, FrSBe) and PBA was evaluated by the emotional lability questionnaire. Structural, diffusivity and functional MRI data were systematically evaluated in whole-brain (WB) data-driven and region of interest (ROI) hypothesis-driven analyses. In ROI analyses, functional and structural corticobulbar connectivity and cerebello-medullary connectivity alterations were evaluated separately. RESULTS: Our data-driven whole-brain analyses revealed associations between PBA and white matter degeneration in descending corticobulbar as well as in commissural tracts. In our hypothesis-driven analyses, PBA was associated with increased right corticobulbar tract RD (p = 0.006) and decreased FA (p = 0.026). The left-hemispheric corticobulbar tract, as well as functional connectivity, showed similar tendencies. While uncorrected p-maps revealed both voxelwise and ROI trends for associations between PBA and cerebellar measures, these did not reach significance to unequivocally support the "cerebellar hypothesis". CONCLUSIONS: Our data confirm associations between cortex-brainstem disconnection and the clinical severity of PBA. While our findings may be disease-specific, they are consistent with the classical cortico-medullary model of pseudobulbar affect.

Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Brainstem-cortex disconnection in amyotrophic lateral sclerosis: bulbar impairment, genotype associations, asymptomatic changes and biomarker opportunities.

BACKGROUND: Bulbar dysfunction is a cardinal feature of ALS with important quality of life and management implications. The objective of this study is the longitudinal evaluation of a large panel imaging metrics pertaining to bulbar dysfunction, encompassing cortical measures, structural and functional cortico-medullary connectivity indices and brainstem metrics. METHODS: A standardised, multimodal imaging protocol was implemented with clinical and genetic profiling to systematically appraise the biomarker potential of specific metrics. A total of 198 patients with ALS and 108 healthy controls were included. RESULTS: Longitudinal analyses revealed progressive structural and functional disconnection between the motor cortex and the brainstem over time. Cortical thickness reduction was an early feature on cross-sectional analyses with limited further progression on longitudinal follow-up. Receiver operating characteristic analyses of the panel of MR metrics confirmed the discriminatory potential of bulbar imaging measures between patients and controls and area-under-the-curve values increased significantly on longitudinal follow-up. C9orf72 carriers exhibited lower brainstem volumes, lower cortico-medullary structural connectivity and faster cortical thinning. Sporadic patients without bulbar symptoms, already exhibit significant brainstem and cortico-medullary connectivity alterations. DISCUSSION: Our results indicate that ALS is associated with multi-level integrity change from cortex to brainstem. The demonstration of significant corticobulbar alterations in patients without bulbar symptoms confirms considerable presymptomatic disease burden in sporadic ALS. The systematic assessment of radiological measures in a single-centre academic study helps to appraise the diagnostic and monitoring utility of specific measures for future clinical and clinical trial applications.

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival.

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Not a benign motor neuron disease: longitudinal imaging captures relentless motor connectome disintegration in primary lateral sclerosis.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a progressive upper motor neuron disorder associated with considerable clinical disability. Symptoms are typically exclusively linked to primary motor cortex degeneration and the contribution of pre-motor, supplementary motor, cortico-medullary and inter-hemispheric connectivity alterations are less well characterized. METHODS: In a single-centre, prospective, longitudinal neuroimaging study 41 patients with PLS were investigated. Patients underwent standardized neuroimaging, genetic profiling with whole exome sequencing, and comprehensive clinical assessments including upper motor neuron scores, tapping rates, mirror movements, spasticity assessment, cognitive screening and evaluation for pseudobulbar affect. Longitudinal neuroimaging data from 108 healthy controls were used for image interpretation. A standardized imaging protocol was implemented including 3D T1-weighted structural, diffusion tensor imaging and resting-state functional magnetic resonance imaging. Following somatotopic segmentation, cortical thickness analyses, probabilistic tractography, blood oxygenation level dependent signal analyses and brainstem volumetry were conducted to evaluate cortical, brainstem, cortico-medullary and inter-hemispheric connectivity alterations both cross-sectionally and longitudinally. RESULTS: Our data confirm progressive primary motor cortex degeneration, considerable supplementary motor and pre-motor area involvement, progressive brainstem atrophy, cortico-medullary and inter-hemispheric disconnection, and close associations between clinical upper motor neuron scores and somatotopic connectivity indices in PLS. DISCUSSION: Primary lateral sclerosis is associated with relentlessly progressive motor connectome degeneration. Clinical disability in PLS is likely to stem from a combination of intra- and inter-hemispheric connectivity decline and primary, pre- and supplementary motor cortex degeneration. Simple 'bedside' clinical tools, such as tapping rates, are excellent proxies of the integrity of the relevant fibres of the contralateral corticospinal tract.

Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.

EFSUMB Clinical Practice Guidelines for Point-of-Care Ultrasound: Part One (Common Heart and Pulmonary Applications) SHORT VERSION.

OBJECTIVE: To evaluate the evidence and produce a summary and recommendations for the most common heart and lung point-of-care ultrasound (PoCUS). METHODS: We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendations were produced, including assigning levels of evidence (LoE) and grading of recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement of the summary and recommendation for each question (using a 5-point Likert scale), which was approved in the case of a level of agreement of greater than 75 %. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses. FINDINGS AND RECOMMENDATIONS: One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1), the remaining 9 questions achieved broad agreement with an assigned LoE of 4 and a weak GRADE recommendation (question 2), three achieved an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8) and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10). CONCLUSION: These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings.

EFSUMB Clinical Practice Guidelines for Point-of-Care Ultrasound: Part One (Common Heart and Pulmonary Applications) LONG VERSION.

AIMS: To evaluate the evidence and produce a summary and recommendations for the most common heart and lung applications of point-of-care ultrasound (PoCUS). METHODS: We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendation were produced, including assignment of levels of evidence (LoE) and grading of the recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement regarding the summary and recommendation for each question (using a 5-point Likert scale), which was approved if a level of agreement of greater than 75 % was reached. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses. FINDINGS AND RECOMMENDATIONS: One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1). The remaining 9 questions achieved broad agreement with one assigned an LoE of 4 and weak GRADE recommendation (question 2), three achieving an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8), and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10). CONCLUSION: These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings.

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration.

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.

Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis.

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.