Tau, Glial Fibrillary Acidic Protein, and Neurofilament Light Chain as Brain Protein Biomarkers in Cerebrospinal Fluid and Blood for Diagnosis of Neurobiological Diseases.

Neurological damage is the pathological substrate of permanent disability in various neurodegenerative disorders. Early detection of this damage, including its identification and quantification, is critical to preventing the disease's progression in the brain. Tau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), as brain protein biomarkers, have the potential to improve diagnostic accuracy, disease monitoring, prognostic assessment, and treatment efficacy. These biomarkers are released into the cerebrospinal fluid (CSF) and blood proportionally to the degree of neuron and astrocyte damage in different neurological disorders, including stroke, traumatic brain injury, multiple sclerosis, neurodegenerative dementia, and Parkinson's disease. Here, we review how Tau, GFAP, and NfL biomarkers are detected in CSF and blood as crucial diagnostic tools, as well as the levels of these biomarkers used for differentiating a range of neurological diseases and monitoring disease progression. We also discuss a biosensor approach that allows for the real-time detection of multiple biomarkers in various neurodegenerative diseases. This combined detection system of brain protein biomarkers holds significant promise for developing more specific and accurate clinical tools that can identify the type and stage of human neurological diseases with greater precision.

Gain-of-function variants in CLCN7 cause hypopigmentation and lysosomal storage disease.

Together with its ß-subunit OSTM1, ClC-7 performs 2Cl-/H+ exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies, including osteopetrosis, lysosomal storage, and pigmentation defects. CLCN7 variants can cause recessive or dominant disease. Different variants entail different sets of symptoms. Loss of ClC-7 causes osteopetrosis and mostly neuronal lysosomal storage. A recently reported de novo CLCN7 mutation (p.Tyr715Cys) causes widespread severe lysosome pathology and hypopigmentation ('HOD syndrome'), but no osteopetrosis. We now describe two additional HOD individuals with the previously described p.Tyr715Cys and a novel p.Lys285Thr mutation, respectively. Both mutations decreased ClC-7 inhibition by PI(3,5)P2 and affected residues lining its binding pocket, and shifted voltage-dependent gating to less positive potentials, an effect partially conferred to WT subunits in WT/mutant heteromers. This shift predicts augmented pH gradient-driven Cl- uptake into vesicles. Overexpressing either mutant induced large lysosome-related vacuoles. This effect depended on Cl-/H+-exchange, as shown using mutants carrying uncoupling mutations. Fibroblasts from the p.Y715C patient also displayed giant vacuoles. This was not observed with p.K285T fibroblasts probably due to some ClC-7K285T-retained PI(3,5)P2 sensitivity. The gain of function caused by the shifted voltage-dependence of either mutant likely is the main cause of their pathogenicity. Their loss of PI(3,5)P2 inhibition will further increase currents, but may not be a general feature of HOD. Overactivity of ClC-7 induces pathologically enlarged vacuoles in many tissues, which is distinct from lysosomal storage observed with the loss of ClC-7 function. Osteopetrosis results from a loss of ClC-7, but osteoclasts remain resilient to increased ClC-7 activity.

Stem cell-derived extracellular vesicles in the therapeutic intervention of Alzheimer's Disease, Parkinson's Disease, and stroke.

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.

Varicella-Zoster Virus-Induced Neurologic Disease After COVID-19 Vaccination: A Multicenter Observational Cohort Study.

Background: Early reports described an increased risk of herpes zoster following receipt of mRNA-based COVID-19 vaccines. The objective was to assess whether COVID-19 vaccine is associated with varicella-zoster virus-induced neurologic disease (VZV-ND). Methods: This multicenter retrospective case-control study with a test-negative design was conducted at 12 hospitals in Israel. We included all patients admitted with VZV-ND between January 2020 and December 2021 and matched controls with a negative polymerase chain reaction result for VZV in cerebrospinal fluid. Results: We identified 188 patients meeting the case definition of VZV-ND who were admitted during the study period. Cases were matched with 376 controls. There was no significant variation in the incidence of VZV-ND between 1 year preceding and 1 year following the deployment of BNT162b2 in Israel. Analysis of persons who had received at least 1 dose of COVID-19 vaccine (n = 259) showed similar proportions of VZV-ND and non-VZV-ND in 4 intervals (30, 42, 50, 60 days) following the last vaccine dose. The median time from the last vaccine dose to hospitalization with a neurologic syndrome was 53 days (IQR, 25-128) and 82 days (IQR, 36-132) for VZV-ND and non-VZV-ND, respectively, not reaching statistical significance (P = .056). The rate of VZV-ND in vaccinated patients was no different from the rate in the unvaccinated group (30.9% vs 35.4%, P = .2). Conclusions: We did not find an association between COVID-19 vaccine and VZV-ND. Since COVID-19 vaccine is now recommended yearly, every fall and winter, establishing the safety of the vaccine is of great importance.

JCPyV infection of primary choroid plexus epithelial cells reduces expression of critical junctional proteins and increases expression of barrier disrupting inflammatory cytokines.

The human polyomavirus, JCPyV, establishes a lifelong persistent infection in the peripheral organs of a majority of the human population worldwide. Patients who are immunocompromised due to underlying infections, cancer, or to immunomodulatory treatments for autoimmune disease are at risk for developing progressive multifocal leukoencephalopathy (PML) when the virus invades the CNS and infects macroglial cells in the brain parenchyma. It is not yet known how the virus enters the CNS to cause disease. The blood-choroid plexus barrier is a potential site of virus invasion as the cells that make up this barrier are known to be infected with virus both in vivo and in vitro. To understand the effects of virus infection on these cells we challenged primary human choroid plexus epithelial cells with JCPyV and profiled changes in host gene expression. We found that viral infection induced the expression of proinflammatory chemokines and downregulated junctional proteins essential for maintaining blood-CSF and blood-brain barrier function. These data contribute to our understanding of how JCPyV infection of the choroid plexus can modulate the host cell response to neuroinvasive pathogens. IMPORTANCE: The human polyomavirus, JCPyV, causes a rapidly progressing demyelinating disease in the CNS of patients whose immune systems are compromised. JCPyV infection has been demonstrated in the choroid plexus both in vivo and in vitro and this highly vascularized organ may be important in viral invasion of brain parenchyma. Our data show that infection of primary choroid plexus epithelial cells results in increased expression of pro-inflammatory chemokines and downregulation of critical junctional proteins that maintain the blood-CSF barrier. These data have direct implications for mechanisms used by JCPyV to invade the CNS and cause neurological disease.

Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.

INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas. METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected. RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease. CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.

Elevated fecal calprotectin is associated with gut microbial dysbiosis, altered serum markers and clinical outcomes in older individuals.

Fecal calprotectin is an established marker of gut inflammation in inflammatory bowel disease (IBD). Elevated levels of fecal calprotectin as well as gut microbial dysbiosis have also been observed in other clinical conditions. However, systemic and multi-omics alterations linked to elevated fecal calprotectin in older individuals remain unclear. This study comprehensively investigated the relationship between fecal calprotectin levels, gut microbiome composition, serum inflammation and targeted metabolomics markers, and relevant lifestyle and medical data in a large sample of older individuals (n = 735; mean age ± SD: 68.7 ± 6.3) from the TREND cohort study. Low (0-50 µg/g; n = 602), moderate (> 50-100 µg/g; n = 64) and high (> 100 µg/g; n = 62) fecal calprotectin groups were stratified. Several pro-inflammatory gut microbial genera were significantly increased and short-chain fatty acid producing genera were decreased in high vs. low calprotectin groups. In serum, IL-17C, CCL19 and the toxic metabolite indoxyl sulfate were increased in high vs. low fecal calprotectin groups. These changes were partially mediated by the gut microbiota. Moreover, the high fecal calprotectin group showed increased BMI and a higher disease prevalence of heart attack and obesity. Our findings contribute to the understanding of fecal calprotectin as a marker of gut dysbiosis and its broader systemic and clinical implications in older individuals.

Perceptions of digital technology use for monitoring health in people living with neurological disorders.

BACKGROUND: Digital technology offers individuals the opportunity to monitor their symptoms. Information gathered from apps, devices, and web platforms may be used to direct clinical care and to support research. AIM: Using this survey, we aim to explore the views of people attending the Anne Rowling Regenerative Neurology Clinic (ARRNC) and their relatives/caregivers regarding the use of digital health technologies to monitor health. METHOD: People attending the ARRNC were invited to complete a structured 18-item questionnaire evaluating their experience and attitudes to using technology for monitoring health. People with neurodegenerative disease (pwND) and their caregivers completed a mix of closed and open-ended questions. RESULTS: 249 people responded, 51 relatives/caregivers and 198 pwND. 67.1% (n= 167) of respondents do not use technology for monitoring their health, but 98.2% (n = 164) of these are interested in their future use. 29.7% (n = 74) respondents currently use a smartphone for health monitoring, 20.9% (n = 52) use a wearable device, and 13.3% (n = 33) use a tablet. 79.3% (n = 65) of users use their technology for monitoring physical activity, 37.8% (n = 31) use it for assisting with self-management, and 41.5% (n = 34) use it for tracking sleep. Factors which would encourage use of technology are ease of access to devices and ability to monitor health. Respondents reported data security concerns and difficulty using technology as potential barriers. CONCLUSION: People attending a neurology clinic, and their relatives/caregivers, support the use of digital technologies as an adjunct to routine care. There is a need for coordinated digital strategies for development and delivery of validated measures.

Association between exposure to particulate matter and incidence of Parkinson's disease: A nationwide cohort study in Taiwan.

Objective: Emerging evidence suggests that air pollution exposure may increase the risk of Parkinson's disease (PD). We aimed to investigate the association between exposure to fine particulate matter (PM2.5) and the risk of incident PD nationwide. Methods: We utilized data from the Taiwan National Health Insurance Research Database, which was spatiotemporally linked with air quality data from the Taiwan Environmental Protection Administration website. The study population consisted of participants who were followed from the index date (January 1st, 2005) until the occurrence of PD or the end of the study period (December 31st, 2017). Participants who had a prior diagnosis of PD before the index date were excluded. To evaluate the association between exposure to PM2.5 and incident PD, we employed a Cox regression to estimate the hazard ratio with a 95% confidence interval (CI). Results: A total of 454,583 participants were included, with a mean (SD) age of 63.1 (9.9) years and a male proportion of 50%. Over a mean follow-up period of 11.1 (3.6) years, 4% of the participants (n = 18,862) developed PD. We observed a significant positive association between PM2.5 exposure and the risk of PD, with a hazard ratio of 1.22 (95% CI, 1.20-1.23) per interquartile range increase in exposure (10.17 µg/m3) when adjusting for both SO2 and NO2. Conclusion: We provide further evidence of an association between PM2.5 exposure and risk of PD. These findings underscore the urgent need for public health policies aimed at reducing ambient air pollution and its potential impact on PD.

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice.

Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic Mcoln1 -/- mice at a dose of 1e12 vg per mouse resulted in MCOLN1 expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of MCOLN1 transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.

Therapeutic potential of berries in age-related neurological disorders.

Aging significantly impacts several age-related neurological problems, such as stroke, brain tumors, oxidative stress, neurodegenerative diseases (Alzheimer's, Parkinson's, and dementia), neuroinflammation, and neurotoxicity. Current treatments for these conditions often come with side effects like hallucinations, dyskinesia, nausea, diarrhea, and gastrointestinal distress. Given the widespread availability and cultural acceptance of natural remedies, research is exploring the potential effectiveness of plants in common medicines. The ancient medical system used many botanical drugs and medicinal plants to treat a wide range of diseases, including age-related neurological problems. According to current clinical investigations, berries improve motor and cognitive functions and protect against age-related neurodegenerative diseases. Additionally, berries may influence signaling pathways critical to neurotransmission, cell survival, inflammation regulation, and neuroplasticity. The abundance of phytochemicals in berries is believed to contribute to these potentially neuroprotective effects. This review aimed to explore the potential benefits of berries as a source of natural neuroprotective agents for age-related neurological disorders.

U-shaped convolutional transformer GAN with multi-resolution consistency loss for restoring brain functional time-series and dementia diagnosis.

Introduction: The blood oxygen level-dependent (BOLD) signal derived from functional neuroimaging is commonly used in brain network analysis and dementia diagnosis. Missing the BOLD signal may lead to bad performance and misinterpretation of findings when analyzing neurological disease. Few studies have focused on the restoration of brain functional time-series data. Methods: In this paper, a novel U-shaped convolutional transformer GAN (UCT-GAN) model is proposed to restore the missing brain functional time-series data. The proposed model leverages the power of generative adversarial networks (GANs) while incorporating a U-shaped architecture to effectively capture hierarchical features in the restoration process. Besides, the multi-level temporal-correlated attention and the convolutional sampling in the transformer-based generator are devised to capture the global and local temporal features for the missing time series and associate their long-range relationship with the other brain regions. Furthermore, by introducing multi-resolution consistency loss, the proposed model can promote the learning of diverse temporal patterns and maintain consistency across different temporal resolutions, thus effectively restoring complex brain functional dynamics. Results: We theoretically tested our model on the public Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and our experiments demonstrate that the proposed model outperforms existing methods in terms of both quantitative metrics and qualitative assessments. The model's ability to preserve the underlying topological structure of the brain functional networks during restoration is a particularly notable achievement. Conclusion: Overall, the proposed model offers a promising solution for restoring brain functional time-series and contributes to the advancement of neuroscience research by providing enhanced tools for disease analysis and interpretation.

Mnemonics for the use and interpretation of amplitude-integrated electroencephalography in newborn infants. / Mnemotecnias para la aplicación e interpretación del electroencefalograma de amplitud integrada en recién nacidos.

An electroencephalography (EEG) has always been considered a specialized field, whose use and interpretation requires training. For this reason, access to these monitoring studies has been restricted to neurologists and neurophysiologists. Newborn infants admitted to the neonatal intensive care unit (NICU) require neurophysiological monitoring to establish their diagnosis and prognosis, so a simple and accessible tool is required for NICU staff. Such features have been covered by amplitude-integrated electroencephalography (aEEG), which, through simple visual patterns of brain activity, allows to approach neurological conditions. The objective of this study is to help with the management of mnemonics that facilitate the identification of normal and pathological visual patterns in an aEEG. Although simple in appearance, this nomenclature is intended to create an easy-to-understand idea of basic concepts for the use and interpretation of neurophysiological monitoring with aEEG.

La electroencefalografía (EEG) siempre ha sido considerada una materia especializada, que amerita de entrenamiento para su aplicación e interpretación; esto ha provocado que el acceso a estos estudios quedara confinado a neurólogos y neurofisiólogos. El recién nacido ingresado en la unidad de cuidados intensivos neonatales (UCIN) amerita de monitorización neurológica para establecer diagnóstico y pronóstico, por lo que se necesita una herramienta sencilla y accesible para el personal de la UCIN. Estas características han sido cubiertas por el electroencefalograma de amplitud integrada (aEEG) que, a través de patrones visuales simples de la actividad cerebral, permite el abordaje de la condición neurológica. El objetivo de este ensayo se orienta al manejo de mnemotecnias que faciliten la identificación de patrones visuales normales y patológicos en el aEEG. La nomenclatura empleada, aunque puede parecer simple, pretende crear una idea fácilmente asimilable de los conceptos básicos para la aplicación e interpretación de la neuromonitorización con aEEG.

New Insights into the Role of Mild Hypoxia in Regulating Neural Stem Cell Characteristics.

The proliferation of neural stem cells (NSCs) is precisely regulated by extracellular environmental factors. In situ hypoxia, one of the key factors involved in the regulation of NSC characteristics, has attracted increasing amounts of attention. Numerous studies have demonstrated that hypoxia can significantly promote the formation of neurospheres and the proliferation of NSCs in vitro and that intermittent hypoxia can promote the proliferation of endogenous NSCs in vivo. In this article, the effects of different concentrations of oxygen on NSC proliferation and differentiation both in vivo and in vitro are reviewed, and the potential applications of hypoxia-preconditioned NSCs, as well as research progress and challenges in the treatment of central nervous system diseases, are further summarized. Here, the critical role of oxygen in the neurogenesis of NSCs is emphasized, and insights into the use of hypoxia to regulate NSC characteristics are provided.

A Review of the CACNA Gene Family: Its Role in Neurological Disorders.

Calcium channels are specialized ion channels exhibiting selective permeability to calcium ions. Calcium channels, comprising voltage-dependent and ligand-gated types, are pivotal in neuronal function, with their dysregulation is implicated in various neurological disorders. This review delves into the significance of the CACNA genes, including CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1G, and CACNA1H, in the pathogenesis of conditions such as migraine, epilepsy, cerebellar ataxia, dystonia, and cerebellar atrophy. Specifically, variants in CACNA1A have been linked to familial hemiplegic migraine and epileptic seizures, underscoring its importance in neurological disease etiology. Furthermore, different genetic variants of CACNA1B have been associated with migraine susceptibility, further highlighting the role of CACNA genes in migraine pathology. The complex relationship between CACNA gene variants and neurological phenotypes, including focal seizures and ataxia, presents a variety of clinical manifestations of impaired calcium channel function. The aim of this article was to explore the role of CACNA genes in various neurological disorders, elucidating their significance in conditions such as migraine, epilepsy, and cerebellar ataxias. Further exploration of CACNA gene variants and their interactions with molecular factors, such as microRNAs, holds promise for advancing our understanding of genetic neurological disorders.

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles.

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the 'good' or 'bad' aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis-localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell-specific genetic tools are critically important to tease out the potential roles of cell type-dependent Serpina3n in CNS diseases/injuries.

Neuroimage analysis using artificial intelligence approaches: a systematic review.

In the contemporary era, artificial intelligence (AI) has undergone a transformative evolution, exerting a profound influence on neuroimaging data analysis. This development has significantly elevated our comprehension of intricate brain functions. This study investigates the ramifications of employing AI techniques on neuroimaging data, with a specific objective to improve diagnostic capabilities and contribute to the overall progress of the field. A systematic search was conducted in prominent scientific databases, including PubMed, IEEE Xplore, and Scopus, meticulously curating 456 relevant articles on AI-driven neuroimaging analysis spanning from 2013 to 2023. To maintain rigor and credibility, stringent inclusion criteria, quality assessments, and precise data extraction protocols were consistently enforced throughout this review. Following a rigorous selection process, 104 studies were selected for review, focusing on diverse neuroimaging modalities with an emphasis on mental and neurological disorders. Among these, 19.2% addressed mental illness, and 80.7% focused on neurological disorders. It is found that the prevailing clinical tasks are disease classification (58.7%) and lesion segmentation (28.9%), whereas image reconstruction constituted 7.3%, and image regression and prediction tasks represented 9.6%. AI-driven neuroimaging analysis holds tremendous potential, transforming both research and clinical applications. Machine learning and deep learning algorithms outperform traditional methods, reshaping the field significantly.

Study protocol: exercise training for treating major depressive disorder in multiple sclerosis.

BACKGROUND: Major depressive disorder (MDD) is prevalent, yet sub-optimally treated among persons with multiple sclerosis (MS). We propose that exercise training may be a promising approach for treating depression in persons with MS who have MDD. Our primary hypothesis predicts a reduction in depression severity immediately after an exercise training intervention compared with minimal change in an attention control condition, and the reduction will be maintained during a follow-up period. METHODS: This study involves a parallel-group, assessor-blinded RCT that examines the effect of a 4-month home-based exercise training intervention on depression severity in a sample of persons with MS who have MDD based on the MINI International Neuropsychiatric Interview. The primary outcomes of depression severity are the Patient Health Questionnaire-9 and Hamilton Depression Rating Scale. Participants (N = 146) will be recruited from within 200 miles of the University of Illinois at Chicago and randomized (1:1) into either a home-based exercise training condition or control condition with concealed allocation. The exercise training and social-contact, attention control (i.e., stretching) conditions will be delivered remotely over a 4-month period and supported through eight, 1:1 Zoom-based behavioral coaching sessions guided by social-cognitive theory and conducted by persons who are uninvolved in screening, recruitment, random assignment, and outcome assessment. We will collect outcome data at 0, 4 and 8 months using treatment-blinded assessors, and data analyses will involve intent-to-treat principles. DISCUSSION: If successful, the proposed study will provide the first Class I evidence supporting a home-based exercise training program for treating MDD in persons with MS. This is critical as exercise training would likely have positive secondary effects on symptoms, cognition, and quality of life, and provide a powerful, behavioral approach for managing the many negative outcomes of MDD in MS. The program in the proposed research is accessible and scalable for broad treatment of depression in MS, and provides the potential for integration in the clinical management of MS. TRIAL REGISTRATION: The trial was registered on September 10, 2021 at clinicaltrials.gov with the identifier NCT05051618. The registration occurred before we initiated recruitment on June 2, 2023.

Neurotoxicities induced by micro/nanoplastics: A review focusing on the risks of neurological diseases.

Pollution of micro/nano-plastics (MPs/NPs) is ubiquitously prevalent in the environment, leading to an unavoidable exposure of the human body. Despite the protection of the blood-brain barrier, MPs/NPs can be transferred and accumulated in the brain, which subsequently exert negative effects on the brain. Nevertheless, the potential neurodevelopmental and/or neurodegenerative risks of MPs/NPs remain largely unexplored. In this review, we provide a systematic overview of recent studies related to the neurotoxicity of MPs/NPs. It covers the environmental hazards and human exposure pathways, translocation and distribution into the brain, the neurotoxic effects, and the possible mechanisms of environmental MPs/NPs. MPs/NPs are widely found in different environment matrices, including air, water, soil, and human food. Ambient MPs/NPs can enter the human body by ingestion, inhalation and dermal contact, then be transferred into the brain via the blood circulation and nerve pathways. When MPs/NPs are present in the brain, they can initiate a series of molecular or cellular reactions that may harm the blood-brain barrier, cause oxidative stress, trigger inflammatory responses, affect acetylcholinesterase activity, lead to mitochondrial dysfunction, and impair autophagy. This can result in abnormal protein folding, loss of neurons, disruptions in neurotransmitters, and unusual behaviours, ultimately contributing to the initiation and progression of neurodegenerative changes and neurodevelopmental abnormalities. Key challenges and further research directions are also proposed in this review as more studies are needed to focus on the potential neurotoxicity of MPs/NPs under realistic conditions.