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Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis. ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:24 issue:5-6 ispartof: location:England status: Published online

Background The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes. Methods Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients. Results One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P Conclusions Maximum resection was especially beneficial in the subgroups aged

Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

BACKGROUND: FMRI resting state networks (RSNs) are used to characterize brain disorders. They also show extensive heterogeneity across patients. Identifying systematic differences between RSNs in patients, i.e. discovering neurofunctional subtypes, may further increase our understanding of disease heterogeneity. Currently, no methodology is available to estimate neurofunctional subtypes and their associated RSNs simultaneously. NEW METHOD: We present an unsupervised learning method for fMRI data, called Clusterwise Independent Component Analysis (C-ICA). This enables the clustering of patients into neurofunctional subtypes based on differences in shared ICA-derived RSNs. The parameters are estimated simultaneously, which leads to an improved estimation of subtypes and their associated RSNs. RESULTS: In five simulation studies, the C-ICA model is successfully validated using both artificially and realistically simulated data (N = 30-40). The successful performance of the C-ICA model is also illustrated on an empirical data set consisting of Alzheimer's disease patients and elderly control subjects (N = 250). C-ICA is able to uncover a meaningful clustering that partially matches (balanced accuracy = .72) the diagnostic labels and identifies differences in RSNs between the Alzheimer and control cluster. COMPARISON WITH OTHER METHODS: Both in the simulation study and the empirical application, C-ICA yields better results compared to competing clustering methods (i.e., a two step clustering procedure based on single subject ICA's and a Group ICA plus dual regression variant thereof) that do not simultaneously estimate a clustering and associated RSNs. Indeed, the overall mean adjusted Rand Index, a measure for cluster recovery, equals 0.65 for C-ICA and ranges from 0.27 to 0.46 for competing methods. CONCLUSIONS: The successful performance of C-ICA indicates that it is a promising method to extract neurofunctional subtypes from multi-subject resting state-fMRI data. This method can be applied on fMRI scans of patient groups to study (neurofunctional) subtypes, which may eventually further increase understanding of disease heterogeneity. ispartof: JOURNAL OF NEUROSCIENCE METHODS vol:382 ispartof: location:Netherlands status: published

Funder: CIBERNED, Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative, Funder: Italian Ministry of Health, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Mady Browaaeys Fund, Funder: Miriam Marks Brain Research UK, Funder: Bluefield Project, OBJECTIVE: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). METHODS: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). RESULTS: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). CONCLUSIONS: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

AIM: To create a shortened, more user-friendly Second Edition of the Dyskinesia Impairment Scale (DIS-II) to assess dystonia and choreoathetosis, and evaluate its construct validity and reliability. METHOD: Scale development included an online expert meeting (n = 21) and iterative discussions within the research group (n = 6). A Rasch measurement model analysis on DIS scores from individuals with dyskinetic cerebral palsy or inherited/idiopathic dystonia (n = 123, 74 males, mean age 14 years, SD 5 years) was performed to evaluate the construct validity and reliability of the DIS-II. RESULTS: The DIS-II evaluates dystonia and choreoathetosis in action and rest in 11 body regions, with action items scored from 0 to 3 and rest items 0 to 2. The number of videos to record are reduced from 26 to 14 and the items to score are reduced from 144 to 88. Rating scale functioning, goodness-of-fit evaluation, principal component analysis, and targeting met the predefined quality criteria of the study and construct validity was therefore considered good. Furthermore, person reliability indicated that the DIS-II can separate individuals into eight distinct ability levels. INTERPRETATION: The DIS-II provides valid and reliable measures for dystonia and choreoathetosis, and reduces the administration and scoring time compared with the DIS. The DIS-II logit scores (interval level data) enhance comparison over time and between individuals in clinical practice and research. WHAT THIS PAPER ADDS: Compared with the Dyskinesia Impairment Scale (DIS), the shortened edition (DIS-II) requires half of the number of videos to be scored. The DIS-II has a simplified rating scale, requiring scoring of 88 instead of 144 items. The DIS-II has shown excellent reliability and good construct validity. The interval properties of the DIS-II are superior to the ordinal level outcome measures of the DIS. ispartof: DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY vol:65 issue:5 pages:683-690 ispartof: location:England status: published

Dysphagia, which refers to difficult and/or disordered swallowing, is a common problem associated with various neurological diseases such as stroke, motor neuron diseases and neurodegenerative diseases. Traditionally, dysphagia treatments are either compensatory, which includes modifications of bolus texture or feeding posture, or rehabilitative, which includes behavioral exercises and sensory stimulation. Despite being widely adopted in clinical practice, recent views have challenged the clinical efficacy of these treatments due to the low level of evidence supported by mainly non-controlled studies. As such, with advancements in technology and scientific research methods, recent times have seen a surge in the development of novel dysphagia treatments and an increasing number of robust randomized controlled clinical trials. In this review, we will review the clinical evidence of several newly introduced treatments for dysphagia in the last two decades, including rehabilitative exercises, biofeedback, pharmacological treatments, neuromodulation treatments and soft robotics. Despite the recent improvements in the quality of evidence for the efficacy of dysphagia treatments, several critical issues, including heterogeneity in treatment regimens, long-term treatment effects, underlying mechanisms of some neuromodulation treatments, and the effects of these techniques in non-stroke dysphagia, remain to be addressed in future clinical trials. ispartof: NEUROPSYCHIATRIC DISEASE AND TREATMENT vol:18 pages:2251-2263 ispartof: location:New Zealand status: published

Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration. ispartof: BRAIN vol:145 issue:12 pages:4349-4367 ispartof: location:England status: published

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Neural processing of the speech envelope is of crucial importance for speech perception and comprehension. This envelope processing is often investigated by measuring neural synchronization to sinusoidal amplitude-modulated stimuli at different modulation frequencies. However, it has been argued that these stimuli lack ecological validity. Pulsatile amplitude-modulated stimuli, on the other hand, are suggested to be more ecologically valid and efficient, and have increased potential to uncover the neural mechanisms behind some developmental disorders such a dyslexia. Nonetheless, pulsatile stimuli have not yet been investigated in pre-reading and beginning reading children, which is a crucial age for developmental reading research. We performed a longitudinal study to examine the potential of pulsatile stimuli in this age range. Fifty-two typically reading children were tested at three time points from the middle of their last year of kindergarten (5 years old) to the end of first grade (7 years old). Using electroencephalography, we measured neural synchronization to syllable rate and phoneme rate sinusoidal and pulsatile amplitude-modulated stimuli. Our results revealed that the pulsatile stimuli significantly enhance neural synchronization at syllable rate, compared to the sinusoidal stimuli. Additionally, the pulsatile stimuli at syllable rate elicited a different hemispheric specialization, more closely resembling natural speech envelope tracking. We postulate that using the pulsatile stimuli greatly increases EEG data acquisition efficiency compared to the common sinusoidal amplitude-modulated stimuli in research in younger children and in developmental reading research. ispartof: NEUROIMAGE vol:277 ispartof: location:United States status: accepted

The link between the gut and the brain in Parkinson's disease (PD) pathogenesis is currently a subject of intense research. Indeed, gastrointestinal dysfunction is known as an early symptom in PD and inflammatory bowel disease (IBD) has recently been recognised as a risk factor for PD. The leucine-rich repeat kinase 2 (LRRK2) is a PD- and IBD-related protein with highest expression in immune cells. In this study, we provide evidence for a central role of LRRK2 in gut inflammation and PD. The presence of the gain-of-function G2019S mutation significantly increases the disease phenotype and inflammatory response in a mouse model of experimental colitis based on chronic dextran sulphate sodium (DSS) administration. Bone marrow transplantation of wild-type cells into G2019S knock-in mice fully rescued this exacerbated response, proving the key role of mutant LRRK2 in immune cells in this experimental colitis model. Furthermore, partial pharmacological inhibition of LRRK2 kinase activity also reduced the colitis phenotype and inflammation. Moreover, chronic experimental colitis also induced neuroinflammation and infiltration of peripheral immune cells into the brain of G2019S knock-in mice. Finally, combination of experimental colitis with overexpression of α-synuclein in the substantia nigra aggravated motor deficits and dopaminergic neurodegeneration in G2019S knock-in mice. Taken together, our results link LRRK2 with the immune response in colitis and provide evidence that gut inflammation can impact brain homeostasis and contribute to neurodegeneration in PD. ispartof: ACTA NEUROPATHOLOGICA vol:146 issue:2 ispartof: location:Germany status: Published online

Obesity and sarcopenia are associated with cognitive impairments at older age. Current research suggests that blood biomarkers may mediate this body-brain crosstalk, altering neurometabolism and brain structure eventually resulting in cognitive performance changes. Seventy-four older adults (60-85 years old) underwent bio-impedance body composition analysis, handgrip strength measurements, 8-Foot Up-and-Go (8UG) test, Montreal Cognitive Assessment (MoCA), blood analysis of interleukin-6 (IL-6), kynurenine, and insulin-like growth factor-1 (IGF-1), as well as brain magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-1-MRS), estimating neurodegeneration and neuroinflammation. Normal fat% or overweight was associated with larger total gray matter volume compared to underweight or obesity in older adults and obesity was associated with higher N-acetylaspartate/Creatine levels in the sensorimotor and dorsolateral prefrontal cortex. Muscle strength, not muscle mass/physical performance, corresponded to lower kynurenine and higher N-acetylaspartate/Creatine levels in the dorsal posterior cingulate and dorsolateral prefrontal cortex. The inflammatory and neurotrophic blood biomarkers did not significantly mediate these body-brain associations. This study used a multimodal approach to comprehensively assess the proposed mechanism of body-brain crosstalk. (c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license

Neuronal swelling is a pathological feature of stroke which contributes to the formation of cytotoxic edema. Under hypoxic condition, aberrant accumulation of sodium and chloride ions inside neurons increases osmotic pressure, leading to cell volume increase. Sodium entry pathway in neurons has been studied extensively. Here, we determine whether SLC26A11 is the major chloride entry pathway under hypoxia and could be the target for protection against ischemic stroke. In this study, electrophysiological properties of chloride current in primary cultured neurons were characterized using low chloride solution, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid, and SLC26A11-specific siRNA under physiological conditions or ATP-depleted conditions. In vivo effect of SLC26A11 was evaluated on a rat stroke reperfusion model. We found that SLC26A11 mRNA in primary cultured neurons was upregulated as early as 6 h after oxygen glucose deprivation, and later, the protein level was elevated accordingly. Blockade of SLC26A11 activity could reduce chloride entry and attenuate hypoxia-induced neuronal swelling. In the animal stroke model, SLC26A11 upregulation was mainly located in surviving neurons close to the infarct core. SLC26A11 inhibition ameliorates infarct formation and improves functional recovery. These findings demonstrate that SLC26A11 is a major pathway for chloride entry in stroke, contributing to neuronal swelling. Inhibition of SLC26A11 could be a novel therapeutic strategy for stroke. ispartof: MOLECULAR NEUROBIOLOGY ispartof: location:United States status: Published online

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

Functional constipation; Functional dyspepsia; Functional gastrointestinal disorders Estreñimiento funcional; Dispepsia funcional; Trastornos gastrointestinales funcionales Restrenyiment funcional; Dispèpsia funcional; Trastorns gastrointestinals funcionals Objective Many studies have been published on disorders of the gut–brain interaction (DGBI) in Asia and Western Europe, but no previous study has directly assessed the difference between the two regions. The aim was to compare the prevalence of DGBI in Asia and Western Europe. Methods We used data collected in a population-based Internet survey, the Rome Foundation Global Epidemiology Study, from countries in Western Europe (Belgium, France, Germany, Netherlands, Italy, Spain, Sweden, and the United Kingdom) and Asia (China, Japan, South Korea, and Singapore). We assessed DGBI diagnoses (Rome IV Adult Diagnostic Questionnaire), anxiety/depression (Patient Health Questionnaire-4, PHQ-4), non-GI somatic symptoms (PHQ-12), and access to and personal costs of doctor visits. Results The study included 9487 subjects in Asia and 16,314 in Western Europe. Overall, 38.0% had at least one DGBI; younger age, female sex, and higher scores on PHQ4 and PHQ12 were all associated with DGBI. The prevalence of having at least one DGBI was higher in Western Europe than in Asia (39.1% vs 36.1%, OR 1.14 [95% CI 1.08–1.20]). This difference was also observed for DGBI by anatomical regions, most prominently esophageal DGBI (OR 1.67 [1.48–1.88]). After adjustment, the difference in DGBI prevalence diminished and psychological (PHQ-4) and non-GI somatic symptoms (PHQ-12) had the greatest effect on the odds ratio estimates. Conclusion The prevalence of DGBI is generally higher in Western Europe compared to Asia. A considerable portion of the observed difference in prevalence rates seems to be explained by more severe psychological and non-GI somatic symptoms in Western Europe.

Long-term outcomes are difficult to predict after paediatric traumatic brain injury. The presence or absence of focal brain injuries often do not explain cognitive, emotional and behavioural disabilities that are common and disabling. In adults, traumatic brain injury produces progressive brain atrophy that can be accurately measured and is associated with cognitive decline. However, the effect of paediatric traumatic brain injury on brain volumes is more challenging to measure because of its interaction with normal brain development. Here we report a robust approach to the individualized estimation of brain volume following paediatric traumatic brain injury and investigate its relationship to clinical outcomes. We first used a large healthy control dataset (n > 1200, age 8–22) to describe the healthy development of white and grey matter regions through adolescence. Individual estimates of grey and white matter regional volume were then generated for a group of moderate/severe traumatic brain injury patients injured in childhood (n = 39, mean age 13.53 ± 1.76, median time since injury = 14 months, range 4–168 months) by comparing brain volumes in patients to age-matched controls. Patients were individually classified as having low or normal brain volume. Neuropsychological and neuropsychiatric outcomes were assessed using standardized testing and parent/carer assessments. Relative to head size, grey matter regions decreased in volume during normal adolescence development whereas white matter tracts increased in volume. Traumatic brain injury disrupted healthy brain development, producing reductions in both grey and white matter brain volumes after correcting for age. Of the 39 patients investigated, 11 (28%) had at least one white matter tract with reduced volume and seven (18%) at least one area of grey matter with reduced volume. Those classified as having low brain volume had slower processing speed compared to healthy controls, emotional impairments, higher levels of apathy, increased anger and learning difficulties. In contrast, the presence of focal brain injury and microbleeds were not associated with an increased risk of these clinical impairments. In summary, we show how brain volume abnormalities after paediatric traumatic brain injury can be robustly calculated from individual T1 MRI using a large normative dataset that allows the effects of healthy brain development to be controlled for. Using this approach, we show that volumetric abnormalities are common after moderate/severe traumatic brain injury in both grey and white matter regions, and are associated with higher levels of cognitive, emotional and behavioural abnormalities that are common after paediatric traumatic brain injury.

BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD. ispartof: ALZHEIMERS & DEMENTIA vol:19 issue:3 pages:807-820 ispartof: location:United States status: published

We describe a scalp-recorded measure of tonotopic selectivity, the "cortical onset response" (COR) and compare the results between humans and cats. The COR results, in turn, were compared with psychophysical masked-detection thresholds obtained using similar stimuli and obtained from both species. The COR consisted of averaged responses elicited by 50-ms tone-burst probes presented at 1-s intervals against a continuous noise masker. The noise masker had a bandwidth of 1 or 1/8th octave, geometrically centred on 4000 Hz for humans and on 8000 Hz for cats. The probe frequency was either - 0.5, - 0.25, 0, 0.25 or 0.5 octaves re the masker centre frequency. The COR was larger for probe frequencies more distant from the centre frequency of the masker, and this effect was greater for the 1/8th-octave than for the 1-octave masker. This pattern broadly reflected the masked excitation patterns obtained psychophysically with similar stimuli in both species. However, the positive signal-to-noise ratio used to obtain reliable COR measures meant that some aspects of the data differed from those obtained psychophysically, in a way that could be partly explained by the upward spread of the probe's excitation pattern. Our psychophysical measurements also showed that the auditory filter width obtained at 8000 Hz using notched-noise maskers was slightly wider in cat than previous measures from humans. We argue that although conclusions from COR measures differ in some ways from conclusions based on psychophysics, the COR measures provide an objective, noninvasive, valid measure of tonotopic selectivity that does not require training and that may be applied to acoustic and cochlear-implant experiments in humans and laboratory animals. ispartof: JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY vol:23 issue:4 pages:513-534 ispartof: location:United States status: published

Purpose The focus of SPINE20 is to develop evidence-based policy recommendations for the G20 countries to work with governments to reduce the burden of spine disease, and disability. Methods On September 17–18, 2021, SPINE20 held its annual meeting in Rome, Italy. Prior to the meeting, the SPINE20 created six proposed recommendations. These recommendations were uploaded to the SPINE20 website 10 days before the meeting and opened to the public for comments. The recommendations were discussed at the meeting allowing the participants to object and provide comments. Results In total, 27 societies endorsed the following recommendations. SPINE20 calls upon the G20 countries: (1) to expand telehealth for the access to spine care, especially in light of the current situation with COVID-19. (2) To adopt value-based interprofessional spine care as an approach to improve patient outcomes and reduce disability. (3) To facilitate access and invest in the development of a competent rehabilitation workforce to reduce the burden of disability related to spine disorders. (4) To adopt a strategy to promote daily physical activity and exercises among the elderly population to maintain an active and independent life with a healthy spine, particularly after COVID-19 pandemic. (5) To engage in capacity building with emerging countries and underserved communities for the benefit of spine patients. (6) To promote strategies to transfer evidence-based advances into patient benefit through effective implementation processes. Conclusions SPINE20’s initiatives will make governments and decision makers aware of efforts to reduce needless suffering from disabling spine pain through education that can be instituted across the globe.

Muscular dystrophies (MD) are a class of rare genetic diseases resulting in progressive muscle weakness affecting specific muscle groups, depending on the type of disease. Disease progression is characterized by the gradual replacement of muscle tissue by fat, which can be assessed with fat-sensitive magnetic resonance imaging (MRI) and objectively evaluated by quantifying the fat fraction percentage (FF%) per muscle. Volumetric quantification of fat replacement over the full 3D extent of each muscle is more precise and potentially more sensitive than 2D quantification in few selected slices only, but it requires an accurate 3D segmentation of each muscle individually, which is time consuming when this has to be performed manually for a large number of muscles. A reliable, largely automated approach for 3D muscle segmentation is thus needed to facilitate the adoption of fat fraction quantification as a measure of MD disease progression in clinical routine practice, but this is challenging due to the variable appearance of the images and the ambiguity in the discrimination of the contours of adjacent muscles, especially when the normal image contrast is affected and diminished by the fat replacement. To deal with these challenges, we used deep learning to train AI-models to segment the muscles in the proximal leg from knee to hip in Dixon MRI images of healthy subjects as well as patients with MD. We demonstrate state-of-the-art segmentation results of all 18 muscles individually in terms of overlap (Dice score, DSC) with the manual ground truth delineation for images of cases with low fat infiltration (mean overall FF%: 11.3%; mean DSC: 95.3% per image, 84.4-97.3% per muscle) as well as with medium and high fat infiltration (mean overall FF%: 44.3%; mean DSC: 89.0% per image, 70.8-94.5% per muscle). In addition, we demonstrate that the segmentation performance is largely invariant to the field of view of the MRI scan, is generalizable to patients with different types of MD and that the manual delineation effort to create the training set can be drastically reduced without significant loss of segmentation quality by delineating only a subset of the slices. ispartof: FRONTIERS IN NEUROLOGY vol:14 ispartof: location:Switzerland status: published

The multifaceted nature of neuroinflammation is highlighted by its ability to both aggravate and promote neuronal health. While in mammals retinal ganglion cells (RGCs) are unable to regenerate following injury, acute inflammation can induce axonal regrowth. However, the nature of the cells, cellular states and signalling pathways that drive this inflammation-induced regeneration have remained elusive. Here, we investigated the functional significance of macrophages during RGC de- and regeneration, by characterizing the inflammatory cascade evoked by optic nerve crush (ONC) injury, with or without local inflammatory stimulation in the vitreous. By combining single-cell RNA sequencing and fate mapping approaches, we elucidated the response of retinal microglia and recruited monocyte-derived macrophages (MDMs) to RGC injury. Importantly, inflammatory stimulation recruited large numbers of MDMs to the retina, which exhibited long-term engraftment and promoted axonal regrowth. Ligand-receptor analysis highlighted a subset of recruited macrophages that exhibited expression of pro-regenerative secreted factors, which were able to promote axon regrowth via paracrine signalling. Our work reveals how inflammation may promote CNS regeneration by modulating innate immune responses, providing a rationale for macrophage-centred strategies for driving neuronal repair following injury and disease. ispartof: ACTA NEUROPATHOLOGICA COMMUNICATIONS vol:11 issue:1 ispartof: location:England status: published

BACKGROUND: The gait modification strategies Trunk Lean and Medial Thrust have been shown to reduce the external knee adduction moment (EKAM) in patients with knee osteoarthritis which could contribute to reduced progression of the disease. Which strategy is most optimal differs between individuals, but the underlying mechanism that causes this remains unknown. RESEARCH QUESTION: Which gait parameters determine the optimal gait modification strategy for individual patients with knee osteoarthritis? METHODS: Forty-seven participants with symptomatic medial knee osteoarthritis underwent 3-dimensional motion analysis during comfortable gait and with two gait modification strategies: Medial Thrust and Trunk Lean. Kinematic and kinetic variables were calculated. Participants were then categorized into one of the two subgroups, based on the modification strategy that reduced the EKAM the most for them. Multiple logistic regression analysis with backward elimination was used to investigate the predictive nature of dynamic parameters obtained during comfortable walking on the optimal modification gait strategy. RESULTS: For 68.1 % of the participants, Trunk Lean was the optimal strategy in reducing the EKAM. Baseline characteristics, kinematics and kinetics did not differ significantly between subgroups during comfortable walking. Changes to frontal trunk and tibia angles correlated significantly with EKAM reduction during the Trunk Lean and Medial Thrust strategies, respectively. Regression analysis showed that MT is likely optimal when the frontal tibia angle range of motion and peak knee flexion angle in early stance during comfortable walking are high (R2Nagelkerke = 0.12). SIGNIFICANCE: Our regression model based solely on kinematic parameters from comfortable walking contained characteristics of the frontal tibia angle and knee flexion angle. As the model explains only 12.3 % of variance, clinical application does not seem feasible. Direct assessment of kinetics seems to be the most optimal strategy for selecting the most optimal gait modification strategy for individual patients with knee osteoarthritis. ispartof: GAIT & POSTURE vol:102 pages:1-9 ispartof: location:England status: published

Enteric glial cells (EGCs), the major components of the enteric nervous system (ENS), are implicated in the maintenance of gut homeostasis, thereby leading to severe pathological conditions when impaired. However, due to technical difficulties associated with EGCs isolation and cell culture maintenance that results in a lack of valuable in vitro models, their roles in physiological and pathological contexts have been poorly investigated so far. To this aim, we developed for the first time, a human immortalized EGC line (referred as ClK clone) through a validated lentiviral transgene protocol. As a result, ClK phenotypic glial features were confirmed by morphological and molecular evaluations, also providing the consensus karyotype and finely mapping the chromosomal rearrangements as well as HLA-related genotypes. Lastly, we investigated the ATP- and acetylcholine, serotonin and glutamate neurotransmitters mediated intracellular Ca2+ signaling activation and the response of EGCs markers (GFAP, SOX10, S100β, PLP1, and CCL2) upon inflammatory stimuli, further confirming the glial nature of the analyzed cells. Overall, this contribution provided a novel potential in vitro tool to finely characterize the EGCs behavior under physiological and pathological conditions in humans.

BackgroundOne of the experimental neuromodulation techniques being researched for the treatment of Alzheimer's disease (AD) is deep brain stimulation (DBS). To evaluate the effectiveness of DBS in AD, we performed a systematic review and meta-analysis of the available evidence.MethodsFrom the inception through December 2021, the following databases were searched: Medline via PubMed, Scopus, Embase, Cochrane Library, and Web of Science. The search phrases used were “Alzheimer's disease,” “AD,” “deep brain stimulation,” and “DBS.” The information from the included articles was gathered using a standardized data-collecting form. In the included papers, the Cochrane Collaboration methodology was used to evaluate the risk of bias. A fixed-effects model was used to conduct the meta-analysis.ResultsOnly five distinct publications and 6 different comparisons (one study consisted of two phases) were included out of the initial 524 papers that were recruited. DBS had no impact on the cognitive ability in patients with AD [0.116 SMD, 95% confidence interval (CI), −0.236 to 0.469, p = 0.518]. The studies' overall heterogeneity was not significant (κ2 = 6.23, T2 = 0.053, df = 5, I2 = 19.76%, p = 0.284). According to subgroup analysis, the fornix-DBS did not improve cognitive function in patients with AD (0.145 SMD, 95%CI, −0.246 to 0.537, p = 0.467). Unfavorable neurological and non-neurological outcomes were also reported.ConclusionThe inconsistencies and heterogeneity of the included publications in various target and age groups of a small number of AD patients were brought to light by this meta-analysis. To determine if DBS is useful in the treatment of AD, further studies with larger sample sizes and randomized, double-blinded, sham-controlled designs are required.

BackgroundStepping accuracy, speed, and stability are lower in older compared to young adults. Lower stepping performance in older adults may be due to larger accuracy-speed-stability trade-offs because of reduced ability to simultaneously fulfill these task-level goals. Our goal was to evaluate whether trade-offs are larger in older compared to young adults in a targeted stepping task. Since sensorimotor function declines with age, our secondary goal was to evaluate whether poorer sensorimotor function was associated with larger trade-offs.Methods25 young (median 22 years old) and 25 older (median 70 years old) adults stepped into projected targets in conditions with various levels of accuracy, speed, and stability requirements. We determined trade-offs as the change in performance, i.e. foot placement error, step duration, and mediolateral center of pressure path length, between each of these conditions and a control condition. To assess age-related differences in the magnitude of trade-offs, we compared the change in performance between age groups. Associations between trade-offs and measures of sensorimotor function were tested using correlations.ResultsWe found an accuracy-speed and an accuracy-stability trade-off in both young and older adults, but trade-offs were not different between young and older adults. Inter-subject differences in sensorimotor function could not explain inter-subject differences in trade-offs.ConclusionAge-related differences in the ability to combine task-level goals do not explain why older adults stepped less accurate and less stable than young adults. However, lower stability combined with an age-independent accuracy-stability trade-off could explain lower accuracy in older adults.

Optical mapping is a widely used tool to record and visualize the electrophysiological properties in a variety of myocardial preparations such as Langendorff-perfused isolated hearts, coronary-perfused wedge preparations, and cell culture monolayers. Motion artifact originating from the mechanical contraction of the myocardium creates a significant challenge to performing optical mapping of contracting hearts. Hence, to minimize the motion artifact, cardiac optical mapping studies are mostly performed on non-contracting hearts, where the mechanical contraction is removed using pharmacological excitation–contraction uncouplers. However, such experimental preparations eliminate the possibility of electromechanical interaction, and effects such as mechano-electric feedback cannot be studied. Recent developments in computer vision algorithms and ratiometric techniques have opened the possibility of performing optical mapping studies on isolated contracting hearts. In this review, we discuss the existing techniques and challenges of optical mapping of contracting hearts.

This study aimed to investigate the influence of stroke lesions in pre-defined highly interconnected (rich club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance.We analyzed MRI data recorded at index stroke and ∼3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke (AIS) enrolled in the multisite MRI-GENIE study. Structural stroke lesions were spatially normalized and parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS>2) was modeled in a Bayesian logistic regression framework that relied on both lesion location, as well as the covariates: age, sex, total DWI lesion volume and comorbidities. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. Via model comparisons, we first tested whether the rich club region model was superior to a baseline model considering clinical covariates and lesion volume only. In spatial specificity analyses, we randomized the split into “rich club” and “non-rich club” regions and compared the effect of the actual rich club regions to the distribution of effects from 1,000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club region effects.A total of 822 patients (age: 64.7 (standard deviation: 15.0), 39% women, 27.7% with mRS>2) were analyzed. The rich club model substantially outperformed the baseline model (weights of model comparison: rich club model: 0.96; baseline: 0.04). Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations (15/1,000 random constellations with higher mean posterior values). Among the these 15 random constellations with higher means, the most frequently selected regions were the inferior temporal gyrus (posterior division, 8/15), the putamen (8/15), the cingulate gyrus (7/15) and the superior parietal lobule (6/15). Rich club regions were substantially more important in explaining long-term outcome in women than in men (mean of the difference distribution:-0.107, 90%-HDPI:-0.193 to -0.0124).Lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific, i.e., the majority of random combinations of six regions had comparably smaller effects on long-term outcome. Effects were substantially more pronounced in women.

Background Long-term sequelae of COVID-19 can result in reduced functionality of the central nervous system and substandard quality of life. Gaining insight into the recovery trajectory of admitted COVID-19 patients on their cognitive performance and global structural brain connectivity may allow a better understanding of the diseases' relevance. Objectives To assess whole-brain structural connectivity in former non-intensive-care unit (ICU)- and ICU-admitted COVID-19 survivors over 2 months following hospital discharge and correlate structural connectivity measures to cognitive performance. Methods Participants underwent Magnetic Resonance Imaging brain scans and a cognitive test battery after hospital discharge to evaluate structural connectivity and cognitive performance. Multilevel models were constructed for each graph measure and cognitive test, assessing the groups' influence, time since discharge, and interactions. Linear regression models estimated whether the graph measurements affected cognitive measures and whether they differed between ICU and non-ICU patients. Results Six former ICU and six non-ICU patients completed the study. Across the various graph measures, the characteristic path length decreased over time (β = 0.97, p = 0.006). We detected no group-level effects (β = 1.07, p = 0.442) nor interaction effects (β = 1.02, p = 0.220). Cognitive performance improved for both non-ICU and ICU COVID-19 survivors on four out of seven cognitive tests 2 months later (p Conclusion Adverse effects of COVID-19 on brain functioning and structure abate over time. These results should be supported by future research including larger sample sizes, matched control groups of healthy non-infected individuals, and more extended follow-up periods.

Background Several neurologic complications have been reported in close temporal association with both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and following vaccination against SARS-CoV-2. Specifically, several cases of Guillain-Barré syndrome (GBS) have been reported in temporal relationship with COVID-19 vaccination, with two small case series describing a specific phenotype with bifacial weakness and paresthesia in the limbs. Methods We retrospectively collected patients who developed a new-onset neuromuscular disorder in the first 6 weeks after receiving a COVID-19 vaccine (either first or second dose). The patients were collected from one tertiary care centre and one secondary care centre from February to July 2021. Results We report eight patients who developed phenotypically diverse neuromuscular disorders in the weeks following COVID-19 vaccination, with a presumed immune-mediated etiology. In our case series, we report three patients with classical GBS, one patient with bifacial weakness with paresthesia variant of GBS, two patients with subacute-onset chronic inflammatory demyelinating polyneuropathy (CIDP), one patient with brachial plexopathy and one patient with subacute axonal sensorimotor polyneuropathy. Conclusions New-onset neuromuscular disorders with onset in the weeks after COVID-19 vaccination can include diverse phenotypes. A causal relationship between these disorders and the vaccine cannot be proven at present, and further epidemiological studies are needed to further investigate this association.

Biomedical research can generally be categorized into 1 of 3 aims: describing the occurrence of disease; identifying persons with or at increased risk of disease including diagnostic and prognostic studies; and explaining the occurrence of disease including etiologic and efficacy studies. ispartof: WORLD NEUROSURGERY vol:161 pages:240-244 ispartof: location:United States status: published

Severe spinal cord injury in adults leads to irreversible paralysis below the lesion. However, adult rodents that received a complete thoracic lesion just after birth demonstrate proficient hindlimb locomotion without input from the brain. How the spinal cord achieves such striking plasticity remains unknown. In this study, we found that adult spinal cord injury prompts neurotransmitter switching of spatially defined excitatory interneurons to an inhibitory phenotype, promoting inhibition at synapses contacting motor neurons. In contrast, neonatal spinal cord injury maintains the excitatory phenotype of glutamatergic interneurons and causes synaptic sprouting to facilitate excitation. Furthermore, genetic manipulation to mimic the inhibitory phenotype observed in excitatory interneurons after adult spinal cord injury abrogates autonomous locomotor functionality in neonatally injured mice. In comparison, attenuating this inhibitory phenotype improves locomotor capacity after adult injury. Together, these data demonstrate that neurotransmitter phenotype of defined excitatory interneurons steers locomotor recovery after spinal cord injury. ispartof: Nature Neuroscience vol:25 issue:5 pages:617-629 ispartof: location:United States status: published

The entactogen 3,4-Methylenedioxymethamphetamine (MDMA) is increasingly being recognized for its therapeutic potential but is also widespread in nightlife settings where it may co-occur with crime. Since previous research detected impaired verbal memory during acute MDMA intoxication, understanding the drug's ramifications in an applied legal context becomes crucial. We conducted a double-blind, placebo-controlled trial to examine acute and delayed effects of MDMA (75 mg) on false memory in 60 healthy volunteers with a history of MDMA use, using three well-established false memory methods: a basic, associative word list (Deese/Roediger-McDermott (DRM)) paradigm and two applied misinformation tasks using a virtual reality crime. Memory was tested immediately (encoding and retrieval under drug influence) and 1 week later (retrieval when sober). Small MDMA-induced impairments of true memory in the word list task were detected at both time points. MDMA increased false memory for related but non-critical lures during the immediate test, and decreased false memory for critical lures after a delay. Episodic memory assessed in the misinformation tasks was not consistently affected. Findings indicate a complex memory profile but no heightened vulnerability to external suggestion in response to MDMA intoxication. Recommendations for future applied legal psychological research include adding measures of recall on top of recognition, using study designs that separate the different memory phases, and potentially testing higher doses. Further research on false memories and suggestibility using imagination procedures can also be relevant for the clinical context. ispartof: EUROPEAN NEUROPSYCHOPHARMACOLOGY vol:57 pages:59-68 ispartof: location:Netherlands status: published

INTRODUCTION: Radiofrequency (RF) treatment of the genicular nerves is a promising treatment for chronic osteoarthritic and persistent postsurgical knee pain (PPSP), refractory to conventional medical management. METHODS: The RECORGEN study is a retrospective single-center cohort study of patients treated with ultrasound-guided conventional RF of the genicular nerves for chronic knee pain in Hospital Oost-Limburg, Genk from September 2017 to June 2020. Subgroup analysis based on etiology of pain (PPSP and degenerative knee pain) was performed in addition to the total study population analysis. Outcome parameters were global perceived effect (GPE), Numeric Rating Scale for pain, consumption of strong opioids, and safety of the treatment at 6 weeks and cross-sectionally at a variable time point. Treatment success was defined as GPE≥50%. RESULTS: Sixty-eight cases were screened of which 59 (46 diagnosed with PPSP and 13 with degenerative knee pain) were included in the study. Treatment success at 6 weeks was achieved in 19 of 59 interventions (32.2%) and was similar in both groups. Seventeen responders were evaluated at follow-up. 45.1% (8/17) continued to have a positive effect at the second time point. The mean duration of effect of the RF treatment was 8.3 months. Safety analysis at 6 weeks and at the second time point showed a good safety profile of the treatment. CONCLUSION: Conventional RF of the genicular nerves was clinically successful in more than 30% of the study population refractory to conventional medical management. Overall, the treatment was well tolerated. The mean duration of effect was 8.3 months. ispartof: PAIN PRACTICE vol:22 issue:3 pages:340-348 ispartof: location:United States status: published

We investigated the impact of hearing loss on the neural processing of speech. Using a forward modelling approach, we compared the neural responses to continuous speech of 14 adults with sensorineural hearing loss with those of age-matched normal-hearing peers. Compared with their normal-hearing peers, hearing-impaired listeners had increased neural tracking and delayed neural responses to continuous speech in quiet. The latency also increased with the degree of hearing loss. As speech understanding decreased, neural tracking decreased in both populations; however, a significantly different trend was observed for the latency of the neural responses. For normal-hearing listeners, the latency increased with increasing background noise level. However, for hearing-impaired listeners, this increase was not observed. Our results support the idea that the neural response latency indicates the efficiency of neural speech processing: More or different brain regions are involved in processing speech, which causes longer communication pathways in the brain. These longer communication pathways hamper the information integration among these brain regions, reflected in longer processing times. Altogether, this suggests decreased neural speech processing efficiency in HI listeners as more time and more or different brain regions are required to process speech. Our results suggest that this reduction in neural speech processing efficiency occurs gradually as hearing deteriorates. From our results, it is apparent that sound amplification does not solve hearing loss. Even when listening to speech in silence at a comfortable loudness, hearing-impaired listeners process speech less efficiently. ispartof: EUROPEAN JOURNAL OF NEUROSCIENCE vol:55 issue:6 pages:1671-1690 ispartof: location:France status: published

PURPOSE: Obstructive sleep apnea (OSA) is a prevalent and multifaceted disease. To date, the presence and severity of objectively identified comorbidities and their association with specific OSA phenotypes, CPAP adherence, and survival remain to be elucidated. The aim of this study is to cluster patients with OSA based on 10 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical and polysomnographic characteristics, CPAP adherence, and survival. STUDY DESIGN AND METHODS: Seven hundred ten consecutive patients starting CPAP for moderate-to-severe OSA were included. Comorbidities were based on generally accepted cutoffs identified in the peer-reviewed literature. Self-organizing maps were used to order patients based on presence and severity of their comorbidities and to generate clusters. RESULTS: The majority of patients were men (80%). They were generally middle-aged (52 years) and obese (BMI: 31.5 kg/m2). Mean apnea-hypopnea index (AHI) was 41 ± 20 per h of sleep. More than 94% of the patients had one or more comorbidities with arterial hypertension, dyslipidemia, and obesity being the most prevalent. Nine comorbidity clusters were identified. The clinical relevance of these comorbidity clusters was highlighted by the difference in symptoms, PSG parameters, and cardiovascular risk. Also, differences in CPAP adherence, improvements in ESS, and long-term survival were present between the clusters. CONCLUSION: Comorbidity prevalence in patients with OSA is high, and different comorbidity clusters, demonstrating differences in cardiovascular risk, CPAP adherence, and survival, can be identified. These results further substantiate the need for a comprehensive assessment of patients with OSA beyond the AHI. ispartof: SLEEP AND BREATHING vol:26 issue:1 pages:195-204 ispartof: location:Germany status: published

Funder: Fondation Brain Canada; Id: http://dx.doi.org/10.13039/100009408, Funder: Fonds de Recherche du Québec ‐ Santé; Id: http://dx.doi.org/10.13039/501100000156, Funder: Health Canada; Id: http://dx.doi.org/10.13039/501100000008, Funder: Brain Canada Foundation; Id: http://dx.doi.org/10.13039/100009408, Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.

There are over 7 million people worldwide suffering from Parkinson's disease, and this number will double in the next decade. Causative mutations and risk variants in >20 genes that predominantly act at synapses have been linked to Parkinson's disease. Synaptic defects precede neuronal death. However, we are only now beginning to understand which molecular mechanisms contribute to this synaptic dysfunction. In this review, we discuss recent data demonstrating that Parkinson proteins act centrally to various protein quality control pathways at the synapse, and we argue that disturbed synaptic proteostasis is an early driver of neurodegeneration in Parkinson's disease. ispartof: CURRENT OPINION IN NEUROBIOLOGY vol:72 pages:72-79 ispartof: location:England status: published

The queen mandibular pheromone (QMP) identified from the honeybee is responsible for maintaining reproductive division of labour in the colony, and affects multiple behaviours. Interestingly, QMP inhibits reproduction not only in honeybee workers, but also in distantly related insect species such as fruit flies and bumblebees. This study examines whether QMP also affects worker reproduction in the common wasp Vespula vulgaris. Wasp workers were exposed to one of the following treatments: QMP, wasp queen pheromone (the hydrocarbon heptacosane n-C27), or acetone (solvent-only control). After dissecting the workers, no evidence that QMP inhibits development in V. vulgaris could be found. However, this study could confirm the inhibitory effect of the hydrocarbon heptacosane on ovary activation. The reason why non-social species such as the fruit fly and social species such as bumblebees and ants respond to the QMP, while the social wasp V. vulgaris does not, is unclear. The investigation of whether olfaction is key to sensing QMP in other insect species, and the detailed study of odorant receptors in other social insects, may provide insights into the mechanisms of response to this pheromone. ispartof: JOURNAL OF COMPARATIVE PHYSIOLOGY A-NEUROETHOLOGY SENSORY NEURAL AND BEHAVIORAL PHYSIOLOGY vol:208 issue:2 pages:297-302 ispartof: location:Germany status: published

Introduction: As their name suggests, ‘psychedelic’ (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). Methods: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific ‘global psychedelic survey’ study. Results: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach’s α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. Conclusion: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight – as measured by the PIS – was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Funder: Alzheimer's Research UK, Funder: Alzheimer's Society, Funder: Brain Research UK, Funder: the Wolfson Foundation, Funder: NIHR UCL/H Biomedical Research Centre, Funder: Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, Funder: UK Dementia Research Institute, Funder: UK Medical Research Council, Funder: Bluefield project, Funder: the Association for Frontotemporal Dementias Research Grant 2009, BACKGROUND: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. METHODS: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR�� plus NACC-FTLD ��� 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR�� plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR�� plus NACC-FTLD ��� 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR�� plus NACC-FTLD = 0.5 to ��� 1 (and therefore how long a trial would need to be). RESULTS: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR�� plus NACC-FTLD 0.5 to ��� 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR�� plus NACC FTLD 0.5 to ��� 1 without treatment over that time period. DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE e4-related sporadic AD and APOE e4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD. The amyloid hypothesis has been the dominant model for the pathogenesis of Alzheimer disease for several decades. In this Perspective, Giovanni Frisoni and colleagues examine evidence for and against this hypothesis before outlining an alternative model, the probabilistic model of Alzheimer disease.

A growing number of studies has investigated temporal processing deficits in dyslexia. These studies largely focus on neural synchronization to speech. However, the importance of rise times for neural synchronization is often overlooked. Furthermore, targeted interventions, phonics-based and auditory, are being developed, but little is known about their impact. The current study investigated the impact of a 12-week tablet-based intervention. Children at risk for dyslexia received phonics-based training, either with (n = 31) or without (n = 31) auditory training, or engaged in active control training (n = 29). Additionally, neural synchronization and processing of rise times was longitudinally investigated in children with dyslexia (n = 26) and typical readers (n = 52) from pre-reading (5 years) to beginning reading age (7 years). The three time points in the longitudinal study correspond to intervention pre-test, post-test and consolidation, approximately 1 year after completing the intervention. At each time point neural synchronization was measured to sinusoidal stimuli and pulsatile stimuli with shortened rise times at syllable (4 Hz) and phoneme rates (20 Hz). Our results revealed no impact on neural synchronization at syllable and phoneme rate of the phonics-based and auditory training. However, we did reveal atypical hemispheric specialization at both syllable and phoneme rates in children with dyslexia. This was detected even before the onset of reading acquisition, pointing towards a possible causal rather than consequential mechanism in dyslexia. This study contributes to our understanding of the temporal processing deficits underlying the development of dyslexia, but also shows that the development of targeted interventions is still a work in progress. ispartof: EUROPEAN JOURNAL OF NEUROSCIENCE vol:57 issue:3 pages:547-567 ispartof: location:France status: published

Peer reviewed: True, Acknowledgements: We thank the research participants and their families for their contribution to the study. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510., Funder: Bluefield Project, Funder: National Institute for Health Research Cambridge Biomedical Research Centre, BACKGROUND: Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. METHODS: 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. RESULTS: Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. CONCLUSIONS: Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

BACKGROUND: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. METHODS: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. RESULTS: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. DISCUSSION: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. HIGHLIGHTS: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. ispartof: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS vol:9 issue:1 ispartof: location:United States status: published

© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license., 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., This study was funded by the Thierry Latran Foundation and the Dutch ALS foundation. Project MinE Belgium was supported by a grant from IWT (n° 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. M.A.v.E. is additionally supported by the Rudolf Magnus Brain Center Talent Fellowship. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS,” “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund.” Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD). A.A.-C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. R.L.M is also supported by the Thierry Latran Foundation (ALSIBD) and the ALS Association (2284). The Swedish Brain Foundation (grants nr. 2012-0262, 2012-0305, 2013-0279, 2016-0303), the Swedish Science Council (grants nr 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305), the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation, the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen (223-2808-12, 223-1881-13, 2.1.12-1605-14), Västerbotten County Council, Swedish Brain Power, King Gustaf V:s and Queen Victoria's Freemason's Foundation.

BACKGROUND: Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. OBJECTIVE: Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. METHODS: Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models. RESULTS: This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p