Search

Background: Fluid resuscitation is a widely used intervention that is mandated in the management of sepsis. While its use can be life-saving, its overuse is associated with harm. Despite this, the best means of assessing a need for fluid resuscitation in an acute medical setting is unclear., Objective: To assess studies of diagnostic tests that identify the need for fluid resuscitation in adults with sepsis, as defined by the presence of fluid responsiveness., Design: Protocol registration was performed in advance (PROSPERO:CRD42017048651). Research database searches were performed alongside additional searches to identify grey literature. Diagnostic test accuracy studies that assessed any fluid assessment tool were identified independently by two authors, before data extraction and quality assessments were performed., Participants: Adults with sepsis, without intensive care organ support, who would be appropriate for admission to an acute medical unit., Key Results: Of the 26,841 articles that were screened, 14 studies were identified for inclusion, involving a combined total of 594 patients. Five categories of index test were identified: inferior vena cava collapsibility index (IVCCI), haemodynamic change with passive leg raise, haemodynamic change with respiration, haemodynamic change with intravenous fluid administration, and static assessment tools. Due to the high level of clinical heterogeneity affecting all aspects of study design, quantitative analysis was not feasible. There was a lack of consensus on reference tests to determine fluid responsiveness., Conclusion: While fluid resuscitation is considered a key part of the management of sepsis, evidence to support fluid assessment in awake adults is lacking. This review has highlighted a number of research recommendations that should be addressed as a matter of urgency if patient harm is to be avoided.

Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Parkinson's disease (PD) is one of the progressive neurological diseases which affect around 10 million population worldwide. The clinical manifestation of motor symptoms in PD patients appears later when most dopaminergic neurons have degenerated. Thus, for better management of PD, the development of accurate biomarkers for the early prognosis of PD is imperative. The present work will discuss the potential biomarkers from various attributes covering biochemical, microRNA, and neuroimaging aspects (α-synuclein, DJ-1, UCH-L1, β-glucocerebrosidase, BDNF, etc.) for diagnosis, recent development in PD management, and major limitations with current and conventional anti-Parkinson therapy. This manuscript summarizes potential biomarkers and therapeutic targets, based on available preclinical and clinical evidence, for better management of PD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline. Various quality control pathways, such as mitochondrial unfolded protein response (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy), respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria. This work provides a concise review of mechanisms by which disease-linked aberrant proteins affect mitochondrial function and an overview of mitochondrial quality control pathways that counteract mitochondrial proteotoxicity. We focus on mitochondrial quality control mechanisms relying on the Ub-mediated protein degradation, such as mitochondria-specific autophagy and the mitochondrial arm of the Ub proteasome system (UPS). We highlight the importance of a widening perspective of how these pathways protect mitochondria from proteotoxic stress to better understand mitochondrial proteotoxicity in overlapping pathophysiological pathways. Implications of these mechanisms in disease development are also briefly summarized., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The neural correlates of action language processing are still debated within embodied cognition research and little is known about the flexible involvement of modality-specific pre-motor system and multimodal high-level temporo-parietal regions as a function of explicit and implicit tasks. A systematic review and the Activation likelihood estimation (ALE) meta-analyses on functional neuroimaging studies were performed to identify neural correlates of action language processing activated during explicit and implicit tasks. The contrast ALE meta-analysis revealed activation of modality-specific premotor area and inferior frontal areas during explicit action language tasks while a greater activation of posterior temporo-occipital areas emerged for implicit tasks. The conjunction analysis revealed overlap in the temporo-parietal multimodal high-level regions for both types of tasks. Functional specialization of the middle temporal gyrus was found where the more posterior-occipital part resulted activated during implicit action language tasks whereas the antero-lateral part was involved in explicit tasks. Our findings were discussed within a conceptual flexibility perspective about the involvement of both the modality-specific and multimodal brain system during action language processing depending on different types of tasks., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Genistein (GE) or 4',5,7-trihydroxyflavone, a plant derived isoflavone, is a biologically active compound having several beneficial properties. Studies showed that GE possesses anti-neoplastic, anti-tumor, anti-helminthic, anti-oxidant, and anti-inflammatory activities. Herein, we investigated the neuroprotective effects of GE in a mouse model of hypoxia-induced amnesia. Mice were exposed to hypoxic conditions (10% O2) in a designated hypoxia chamber and co-treated with GE (10, 20, or 30 mg/kg) for 4 weeks. Following this, behavioral tests were performed to evaluate memory performance. We assessed microglial activation in the hippocampus, amygdala, and pre-frontal cortex (PFC) regions by evaluating the Iba-1 and GFAP transcript levels, and MIP-1β, Cox-2, and IL6 protein levels. Apoptosis was assessed by evaluating Bax, BAD, and Bcl-2 mRNA levels, and caspase-3 activity. To uncover the underlying molecular mechanism, we evaluated the levels of Nrf2, HO-1, and NQO1 in different brain regions of mice from all groups. Results showed that hypoxia-exposed mice have reduced performance in the behavioral tests and GE treatment enhanced the memory performance in hypoxia-exposed mice. Moreover, hypoxia-exposed mice showed increased expression of microglial activation markers and enhanced apoptosis in the hippocampus, amygdala, and PFC. GE treatment suppressed microglial activation and prevented apoptosis in the brain of hypoxia-exposed mice. Furthermore, hypoxia-exposure reduced the expression of Nrf2, NQO1, and HO-1 while GE treatment ameliorated this decrease in different regions of hypoxia-exposed mice brain. In conclusion, GE prevents cognitive dysfunction by suppressing microglial activation and inhibiting apoptosis in the hypoxia-exposed mice brain., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Imaging studies of FTD typically present group-level statistics between large cohorts of genetically, molecularly or clinically stratified patients. Group-level statistics are indispensable to appraise unifying radiological traits and describe genotype-associated signatures in academic studies. However, in a clinical setting, the primary objective is the meaningful interpretation of imaging data from individual patients to assist diagnostic classification, inform prognosis, and enable the assessment of progressive changes compared to baseline scans. In an attempt to address the pragmatic demands of clinical imaging, a prospective computational neuroimaging study was undertaken in a cohort of patients across the spectrum of FTD phenotypes. Cortical changes were evaluated in a dual pipeline, using standard cortical thickness analyses and an individualised, z-score based approach to characterise subject-level disease burden. Phenotype-specific patterns of cortical atrophy were readily detected with both methodological approaches. Consistent with their clinical profiles, patients with bvFTD exhibited orbitofrontal, cingulate and dorsolateral prefrontal atrophy. Patients with ALS-FTD displayed precentral gyrus involvement, nfvPPA patients showed widespread cortical degeneration including insular and opercular regions and patients with svPPA exhibited relatively focal anterior temporal lobe atrophy. Cortical atrophy patterns were reliably detected in single individuals, and these maps were consistent with the clinical categorisation. Our preliminary data indicate that standard T1-weighted structural data from single patients may be utilised to generate maps of cortical atrophy. While the computational interpretation of single scans is challenging, it offers unrivalled insights compared to visual inspection. The quantitative evaluation of individual MRI data may aid diagnostic classification, clinical decision making, and assessing longitudinal changes., (© 2021. The Author(s).)

Objective: To assess the needs of patients with amyotrophic lateral sclerosis (ALS) and their families when being communicated the diagnosis., Methods: We held a nationwide webinar in September 2020, titled "ALS Café", and distributed a self-report questionnaire to participants., Patients: This cross-sectional study included 56 respondents (patients, n = 32; family members, n = 24)., Results: Of the 56 respondents, 47 (84%) reported being anxious when they were communicated their diagnosis. The average time allocated for communicating the diagnosis was 36.3 ± 25.6 min, and 30% of respondents believed that insufficient time was allocated. Nearly half of the respondents were communicated their diagnosis by one physician, and 57% of the respondents received their diagnosis in one session. Approximately 80% of respondents received information about ventilators when they were being communicated their diagnosis, but most patients did not want to receive this information at that time. The anxious group tended to answer that the time to communicate the diagnosis was short. Meanwhile, all respondents in the mildly anxious group were provided with one or more information about the supportive contents along with the diagnosis. Moreover, in Japan, many patients with ALS and their families desire the legalization of euthanasia, which might affect decision-making., Conclusions: This study shows that a longer amount of time spent communicating the diagnosis and provision of descriptions needed by patients and their families are important. This can help clinicians understand what the patient requires while being communicated their diagnosis., (© 2021. Belgian Neurological Society.)

The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p < .05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures., (© 2020. The Author(s).)

Cognitive impairment is now recognized in a subset of patients with amyotrophic lateral sclerosis (ALS). The objective of the study was to identify group differences and neuroanatomical correlates of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in participants ALS. Fifty-three ALS patients and 43 healthy controls recruited as a part of our multicentre study (CALSNIC) were administered the ECAS and underwent an MRI scan. Voxel-based morphometry and tract based spatial statistics (TBSS) was performed to identify structural changes and associations with impaired ECAS scores. Lower performance in the ECAS verbal fluency and executive domains were noted in ALS patients as compared to controls (p < 0.01). Extensive white matter degeneration was noted in the corticospinal tract in all ALS patients, while ALS patients with impaired verbal fluency or executive domains (ALS-exi, n = 22), displayed additional degeneration in the corpus callosum, cingulum and superior longitudinal fasciculus as compared to controls (p < 0.05, TFCE corrected). Mild grey matter changes and associations with ECAS verbal fluency or executive performance were noted at lenient statistical thresholds (p < 0.001, uncorrected). Executive impairment was detected using the ECAS in our multicentre sample of Canadian ALS patients. White matter degeneration in motor regions was revealed in ALS patients with extensive spread to frontal regions in the ALS-exi sub-group. Mild associations between ECAS verbal fluency, executive function scores and MRI metrics suggest that reduced performance may be associated with widespread structural integrity., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroprotective peptides are promising candidate molecules for the treatment of Alzheimer's disease (AD). Oral application of KED (Lys-Glu-Asp) improved memory and attention in elderly individuals with functional CNS disorders. Peptide KED also restores synaptic plasticity in in vitro model of AD. This review is focused on the analysis of the influence of KED peptide on the expression of genes and synthesis of proteins regulating apoptosis, aging, neurogenesis, and involved in AD pathogenesis. Analysis of published reports and our experimental findings suggests that KED regulates the expression of genes of cell aging and apoptosis (р16, р21), genes (NES, GAP43) and proteins (nestin, GAP43) of the neuronal differentiation, and genes involved in AD pathogenesis (SUMO, APOE, and IGF1). The study the effectiveness of neuroprotective peptide KED in animal models of AD seems to be very important.

Stress granules (SGs) are dynamic ribonucleoprotein granules induced by environmental stresses. They play an important role in the stress response by integrating mRNA stability, translation, and signaling pathways. Recent work has connected SG dysfunction to neurodegenerative diseases. In these diseases, SG dynamics are impaired because of mutations in SG proteins or protein quality control factors. Impaired SG dynamics and delayed SG dissolution have also been observed for SGs that accumulate misfolding-prone defective ribosomal products (DRiPs). DRiP accumulation inside SGs is controlled by a surveillance system referred to as granulostasis and encompasses the molecular chaperones VCP and the HSPB8-BAG3-HSP70 complex. BAG3 is a member of the BAG family of proteins, which includes five additional members. One of these proteins, BAG6, is functionally related to BAG3 and able to assist degradation of DRiPs. However, whether BAG6 is involved in granulostasis is unknown. We report that BAG6 is not recruited into SGs induced by different types of stress, nor does it affect SG dynamics. BAG6 also does not replace BAG3's function in SG granulostasis. We show that BAG3 and BAG6 target different subsets of DRiPs, and BAG3 binding to DRiPs is mediated by HSPB8 and HSP70. Our data support the idea that SGs are sensitive to BAG3-HSP70-bound DRiPs but not to BAG6-bound DRiPs. Additionally, only BAG3 is strongly upregulated in the stress recovery phase, when SGs dissolve. These data exclude a role for BAG6 in granulostasis and point to a more specialized function in the clearance of a specific subset of DRiPs.

In 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of evidence favors gain of toxicity as the main pathogenic mechanism for C9orf72 repeat expansions. Alterations in several downstream cellular functions, such as nucleocytoplasmic transport and autophagy, are implicated. Exciting progress has also been made in therapy development targeting this mutation, such as by antisense oligonucleotide therapies targeting sense transcripts and small molecules targeting nucleocytoplasmic transport, and these are now in phase 1 clinical trials.