The Performance Effect of Scheduled Carbohydrate and Caffeine Intake during Simulated Team Sport Match-Play

The aim of the current investigation was to identify the effects of scheduled carbohydrate (CHO) and caffeine (CAF) supplementation on simulated team sport match-play performance. Ten male hurling players completed three hurling match-play simulation protocols (HSP) performed 7 days apart in a double-blind, randomized design. Supplementation included CHO, CHO + CAF, and placebo (PLA). In a randomized order, participants ingested either a 6% CHO solution, a PLA solution of similar taste, or a combined intake of 6% CHO solution + 200 mg CAF capsule. At specific time points (Pre-0 min; half time (HT)-30 min; full time (FT)-60 min), participants completed a repeated sprint protocol (RAST; 12 7 20 m). Physiological [% maximal oxygen uptake (%VO2max), % mean oxygen uptake (%VO2mean), % maximal heart rate (%HRmax), % mean heart rate (%HRmean), respiratory exchange ratio (RER), and blood lactate (BLa)] and performance [(best sprint time (RSAbest), mean sprint time (RSAmean), and rate of perceived exertion (RPE)] variables were monitored throughout each simulation. Non-significant differences were observed between supplement trials (CHO, CHO + CAF, and PLA) for BLa (\u3b72 = 0.001, small), %VO2max (\u3b72 = 0.001, small), %VO2mean (\u3b72 = 0.004, small), %HRmax (\u3b72 = 0.007, small), %HRmean (\u3b72 = 0.018, small), RER (\u3b72 = 0.007, small), RPE (\u3b72 = 0.007, small), and RSAbest (\u3b72 = 0.050, small). RSAmean performance significantly improved in CHO + CAF trials compared to PLA, with sprint times significantly improved from Pre to FT also (\u3b72 = 0.135, medium). A significant difference was observed in BLa between time points (Pre, HT, and FT) (\u3b72 = 0.884, large) in % HRmax (\u3b72 = 0.202, medium), %HRmean (\u3b72 = 0.477, large), and RER (\u3b72 = 0.554, large) across halves and in RPE across time points (\u3b72 = 0.670, large). Our data provide novel data regarding the effects of CHO and CAF supplementation on team sport performance, with co-ingestion of CHO + CAF reducing the decrement in repeated sprint performance compared to PLA

The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity - evidence from a longitudinal study.

BACKGROUND: This study aimed to i) examine the frequency of C9orf72 expansions in a cohort of patients with the behavioural variant frontotemporal dementia (bvFTD) phenocopy syndrome, ii) observe outcomes in a group of phenocopy syndrome with very long term follow-up and iii) compare progression in a cohort of patients with the phenocopy syndrome to a cohort of patients with probable bvFTD. METHODS: Blood was obtained from 16 phenocopy cases. All met criteria for possible bvFTD and were labeled as phenocopy cases if they showed no functional decline, normal cognitive performance on the Addenbrooke's Cognitive Examination-Revised (ACE-R) and a lack of atrophy on brain imaging, over at least 3 years of follow-up. In addition, we obtained very long term follow-up data in 6 cases. A mixed model analysis approach determined the pattern of change in cognition and behaviour over time in phenocopy cases compared to 27 probable bvFTD cases. RESULTS: All 16 patients were screened for the C9orf72 expansion that was present in only one (6.25%). Of the 6 cases available for very long-term follow-up (13 - 21 years) none showed progression to frank dementia. Moreover, there was a decrease in the caregiver ratings of behavioural symptoms over time. Phenocopy cases showed significantly slower rates of progression compared to probable bvFTD patients (p < 0.006). CONCLUSION: The vast majority of patients with the bvFTD phenocopy syndrome remain stable over many years. An occasional patient can harbor the C9orf72 expansion. The aetiology of the remaining cases remains unknown but it appears very unlikely to reflect a neurodegenerative syndrome due to lack of clinical progression or atrophy on imaging

Neuronal network disintegration: common pathways linking neurodegenerative diseases

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration

Tackling clinical heterogeneity across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia spectrum using a transdiagnostic approach

The disease syndromes of amyotrophic lateral sclerosis and frontotemporal dementia display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant frontotemporal dementia (n = 58) and amyotrophic lateral sclerosis-frontotemporal dementia (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus, and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-amyotrophic lateral sclerosis patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the amyotrophic lateral sclerosis-frontotemporal dementia and behavioural variant frontotemporal dementia groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in amyotrophic lateral sclerosis-frontotemporal dementia relative to pure-amyotrophic lateral sclerosis. In contrast, pure-amyotrophic lateral sclerosis displayed significantly greater parietal atrophy. Both behavioural variant frontotemporal dementia and amyotrophic lateral sclerosis-frontotemporal dementia were characterised by volume decrease in the frontal lobes relative to pure-amyotrophic lateral sclerosis. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in amyotrophic lateral sclerosis-frontotemporal dementia compared to pure-amyotrophic lateral sclerosis, and greater left motor cortex and insula atrophy relative to behavioural variant frontotemporal dementia. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum, with key structures including the motor cortex and insula, Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum

The pro-apoptotic K-Ras 4A proto-oncoprotein does not affect tumorigenesis in the ApcMin/+ mouse small intestine.

BACKGROUND: Alterations in gene splicing occur in human sporadic colorectal cancer (CRC) and may contribute to tumour progression. The K-ras proto-oncogene encodes two splice variants, K-ras 4A and 4B, and K-ras activating mutations which jointly affect both isoforms are prevalent in CRC. Past studies have established that splicing of both the K-ras oncogene and proto-oncogene is altered in CRC in favour of K-ras 4B. The present study addressed whether the K-Ras 4A proto-oncoprotein can suppress tumour development in the absence of its oncogenic allele, utilising the ApcMin/+ (Min) mouse that spontaneously develops intestinal tumours that do not harbour K-ras activating mutations, and the K-rastmDelta4A/tmDelta4A mouse that can express the K-ras 4B splice variant only. By this means tumorigenesis in the small intestine was compared between ApcMin/+, K-ras+/+ and ApcMin/+, K-rastmDelta4A/tmDelta4A mice that can, and cannot, express the K-ras 4A proto-oncoprotein respectively. METHODS: The relative levels of expression of the K-ras splice variants in normal small intestine and small intestinal tumours were quantified by real-time RT-qPCR analysis. Inbred (C57BL/6) ApcMin/+, K-ras+/+ and ApcMin/+, K-rastmDelta4A/tmDelta4A mice were generated and the genotypes confirmed by PCR analysis. Survival of stocks was compared by the Mantel-Haenszel test, and tumour number and area compared by Student's t-test in outwardly healthy mice at approximately 106 and 152 days of age. DNA sequencing of codons 12, 13 and 61 was performed to confirm the intestinal tumours did not harbour a K-ras activating mutation. RESULTS: The K-ras 4A transcript accounted for about 50% of K-ras expressed in the small intestine of both wild-type and Min mice. Tumours in the small intestine of Min mice showed increased levels of K-ras 4B transcript expression, but no appreciable change in K-ras 4A transcript levels. No K-ras activating mutations were detected in 27 intestinal tumours derived from Min and compound mutant Min mice. K-Ras 4A deficiency did not affect mouse survival, or tumour number, size or histopathology. CONCLUSION: The K-Ras 4A proto-oncoprotein does not exhibit tumour suppressor activity in the small intestine, even though the K-ras 4A/4B ratio is reduced in adenomas lacking K-ras activating mutations.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

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

Data Availability Statement: Data will be available on request from the authors until 2030.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/brainsci12030336/s1, Table S1: Spearman’s correlations between w-scores and behavioural and cognitive total scores across the clinical and genetic groups. Table S2: Spearman’s correlations between w-scores and behavioural and cognitive subscores across the clinical and genetic groups.Copyright © 2022 by the authors. . Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic–cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS–FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS–FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS–FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS–FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS–FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS–FTD predominantly in the superior–posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS–FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.This work was supported in part by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (GNT1037746 to O.P., M.C.K. and J.R.H.) and the Australian Research Council Centre of Excellence in Cognition and Its Disorders Memory Program (#CE110001021 to O.P. and J.R.H.) and other grants/sources (NHMRC project grant GNT1003139 to O.P.), and Royal Australasian College of Physicians, MND Research Institute of Australia. We are grateful to the research participants involved with the ForeFront research studies. R.M.A. is an NHMRC Early Career Fellow (#1120770). O.P. was an NHMRC Senior Research Fellow (GNT1103258). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). M.B.’s work was also supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. M.I. is supported by an Australian Research Council Future Fellowship (FT160100096). J.D.R. has received funding from an MRC Clinician Scientist fellowship (MR/M008525/1) as well as from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. M.C.K. receives funding from the NHMRC Partnership Project (APP1153439) and Practitioner Fellowship (APP1156093) schemes

Distinct hypothalamic involvement in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum

Background Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored. Methods Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls). Results Graded variation in hypothalamic involvement but relative sparing of the inferior tuberal region was evident across all patient groups. Bilateral anterior inferior, anterior superior, and posterior hypothalamic subregions were selectively implicated in memory, fluency and processing speed impairments in addition to apathy and abnormal eating habits, taking into account disease duration, age, sex, total intracranial volume, and acquisition parameters (all p ≤ .001). Conclusions These findings revealed that subdivisions of the hypothalamus are differentially affected in the ALS-FTD spectrum and contribute to canonical cognitive and behavioural disturbances beyond eating abnormalities. The anterior superior and superior tuberal subregions containing the paraventricular nucleus (housing oxytocin-producing neurons) displayed the greatest volume loss in bvFTD and ALS-FTD, and ALS, respectively. Importantly, the inferior tuberal subregion housing the arcuate nucleus (containing different groups of neuroendocrine neurons) was selectively preserved across the ALS-FTD spectrum, supporting pathophysiological findings of discrete neuropeptide expression abnormalities that may underlie the pathogenesis of autonomic and metabolic abnormalities and potentially certain cognitive and behavioural symptom manifestations, representing avenues for more refined symptomatic treatment targets.National Health and Medical Research Council of Australia program (#1037746 and #1132524) and dementia team (#1095127) grants and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Program (#CE110001021). Dr E.M. Devenney is supported by a MNDRIA post-doctoral fellowship. Dr S. Tu is supported by a NHMRC post-doctoral fellowship (APP1121859). Dr R.M. Ahmed is supported by a NHMRC post-doctoral fellowship. Prof G.M. Halliday is a NHMRC Leadership Fellow (#1176607). Prof M.C. Kiernan received funding support from NHMRC Partnership Grant (#1153439) and Practitioner Fellowship (#115609). Prof O. Piguet is supported by a NHMRC Leadership Fellowship (GNT2008020). Dr M. Bocchetta is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). Dr M. Bocchetta’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Dr M. Bocchetta acknowledges the support of NVIDIA Corporation with the donation of the Titan V GPU used for part of the analyses in this research. Prof J. D Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH)