Development and validation of neurological health score using machine learning algorithms

Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.

Adropin, a peptide hormone has role in various various physiological processes, including metabolic regulation and cardiovascular health. This systematic review aimed to synthesize findings from observational studies on the involvement of adropin in neurological disorders and cognitive performance. An extensive literature search was conducted across PubMed, Scopus, Web of Science, Embase, CORE, and Google Scholar using terms such as "adropin," "Neurological Disorders," "cognitive function," "Alzheimer's disease," "Parkinson's disease," "cognition," and "brain function." Studies published from 2020 to 2024 were selected and reviewed. The search and selection process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Out of 127 screened articles, 5 met the inclusion criteria for this review. The combined research findings suggest a consistent link between decreased adropin levels and a range of neurological disorders and cognitive impairments. In particular, reduced adropin levels were seen in individuals with dementia, cognitive impairment, bipolar disorder, Parkinson's disease, and multiple sclerosis. These findings highlight adropin's potential role in modulating neurological health and cognitive function. This systematic review underscores the importance of adropin in neurological health and its potential as a therapeutic agent. Based on the observed connections, adropin might serve as a new focus for treating neurological disorders, prompting the need for more research and trials.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease for which no cure or viable treatment has been identified. ALS, like most noncommunicable diseases, is not a nationally notifiable disease in the United States. The prevalence of ALS in the United States during 2010-2011 was estimated to be 3.9 cases per 100,000 persons in the general population. Updated prevalence estimates are needed to help monitor disease status, better understand etiology, and identify risk factors for ALS. 2012-2013. The National ALS Registry, established in 2009, collects data on ALS patients in the United States to better describe the incidence and prevalence of ALS, examine risk factors such as environmental and occupational exposures, and characterize the demographics of those living with ALS. To identify prevalent cases of ALS, data are compiled from four national administrative databases (maintained by the Centers for Medicare and Medicaid Services, the Veterans Health Administration, and the Veterans Benefits Administration). To identify cases not included in these databases and to better understand risk-factors associated with ALS and disease progression, the Registry also includes data that are collected from patients who voluntarily enroll and complete online surveys. During 2012 and 2013, the Registry identified 14,713 and 15,908 persons, respectively, who met the surveillance case definition of ALS. The estimated ALS prevalence rate was 4.7 cases per 100,000 U.S. population for 2012 and 5.0 per 100,000 for 2013. Due to revisions to the algorithm and use of death data from the National Death Index, an updated prevalence estimate has been calculated retrospectively for October 19, 2010-December 31, 2011. This updated estimate showed a prevalence rate of 4.3 per 100,000 population and a total of 13,282 cases. Since the inception of the Registry, the pattern of characteristics (e.g., age, sex, and race/ethnicity) among persons with ALS have remained unchanged. Overall, ALS was more common among whites, males, and persons aged 60-69 years. The age groups with the lowest number of ALS cases were persons aged 18-39 years and those aged ≥80 years. Males had a higher prevalence rate of ALS than females overall and across all data sources. These findings remained consistent during October 2010-December 2013. The Registry is the only available data source that can be used to estimate the national prevalence for ALS in the United States. Use of both administrative national databases and self-report from patients enables a comprehensive approach to estimate ALS prevalence. The overall increase in the prevalence rate from 4.3 per 100,000 persons (revised) during 2010-2011 to 4.7 and 5.0 per 100,000 persons, respectively, during 2012-2013 likely is not an actual increase in the number of ALS cases. Rather, this increase might be attributed to improved case ascertainment due to the refinement of the algorithm used to identify definite ALS cases, along with an increased public awareness of the Registry. Registry estimates of ALS prevalence are consistent with findings from long-established ALS registries in Europe and from smaller-scale epidemiologic studies previously conducted in the United States. Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to help facilitate research. The combined approach of using national administrative databases and a self-enrollment web portal to collect data is novel and potentially could be used for other non-notifiable diseases such as Parkinson's disease or multiple sclerosis. Increased public awareness of the Registry might lead to more ALS cases being identified from the secure web portal (https://www.cdc.gov/als), which can ascertain cases apart from the national administrative databases. For example, in 2014, the ALS Ice Bucket Challenge, a social media-centered campaign, received extensive public visibility and created increased awareness of ALS. The Agency for Toxic Substances and Disease Registry (ATSDR) works closely with ALS advocacy and support groups, researchers, health care professionals, and others to promote the National ALS Registry and to identify all cases of ALS in the United States. In addition to estimating the prevalence of ALS, the Registry is being used to collect specimens from patient enrollees through a new biorepository, connect patient enrollees with new clinical trials and epidemiologic studies, and fund studies to help learn more about the etiology of ALS. Additional information about the National ALS Registry is available at http://www.cdc.gov/als or by calling toll-free at 1-877-442-9719.

Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.

Vitamin D status has been proposed as relevant to many neurological disorders. Data suggest that vitamin D may be important for the development of the nervous system, and it also plays a role in neuroimmunology and neuroprotection. Lower levels of circulating 25-hydroxyvitamin D have been linked with increased risk of multiple sclerosis (MS) and Alzheimer's disease (AD). While people with amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and stroke have lower vitamin D levels than those without the diseases, it is unclear if this is because hypovitaminosis D contributes to disease risk or is a consequence of immobility and other factors caused by the disease. Lower levels of vitamin D have been associated with worse prognosis in MS, PD, ALS, and stroke, while no longitudinal studies have been performed to evaluate such an association in AD. Small pilot trials have been performed to evaluate vitamin D supplementation for some of these diseases, but there have been no phase III studies to support vitamin D supplementation in these patient populations; further, ideal levels of 25-hydroxyvitamin D are not known. Thus, while some expert panels or individuals have suggested routine testing and supplementation for patients with these neurological conditions, it is our opinion that there are currently insufficient data to support high-dose vitamin D supplementation to specifically treat or prevent these conditions.

Dear editors, Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. It affects motor neurons in the brain and spinal cord resulting in bulbar palsy and respiratory failure. It also causes weakness of limbs. The disease usually progresses to fatal outcome within 2–4 years. Neural stem cell research for diagnosis and treatment of neurodegenerative disorders is highly promising. But more data are required to prove their efficacy. There is evidence regarding stem cell application in traumatic brain injury and other neurological disorders (Mouhieddine et al., 2014). Neurotrophic factors (NTFs) have been reported to increase the survival of motor neurons in ALS (Petrou et al., 2016). A culture-based method has been developed to promote the secretion of NTFs by mesenchymal stem cells (MSCs) (Petrou et al., 2016). NTFs have been shown to protect neurons in an animal model of neurodegenerative diseases (Chen et al., 2015). One phase I/II pilot trial (identifier {type:clinical-trial,attrs:{text:NCT00781872,term_id:NCT00781872}}NCT00781872) used intrathecal combined intravenous injections of bone marrow-derived MSCs in 34 patients with multiple sclerosis and ALS. Long-term (6–25 months) follow up observations did not show any severe adverse outcomes. MSCs transplantation was found to be a clinically feasible and relatively safe procedure (Karussis et al., 2010). Recently, in open-label proof-of-concept studies (Petrou et al., 2016), all patients enrolled between June 2011 and October 2014 were followed up from 3 months prior to transplantation to 6 months after transplantation. In six patients with early-stage ALS, MSC-secreting NTF (MSC-NTF) cells were intramuscularly administered in the phase I/II of the trial. Another six patients with more advanced diseases received intrathecal administration of MSC-NTF cells. In a phase IIa study, 14 patients who had early-stage ALS received a combined intramuscular and intrathecal transplantation of autologous MSC-NTF cells. The primary endpoints of the studies were tolerability and safety of this treatment. The secondary endpoint was the impact of such intervention on various clinical parameters, including the ALS Functional Rating Scale-Revised score and the respiratory function. In the phase I/II trial, the treatment was well tolerated by all included 12 patients over the study follow up period. A similar effect was shown in 14 patients in the phase IIa trial. The rate of deterioration in lung function and the ALS Functional Rating Scale-Revised score in the intrathecal (or intrathecal + intramuscular) group was found to be reduced (P < 0.04) in comparison with the pre-treatment phase. The result suggests the safety of intrathecal and intramuscular transplantation of MSC-NTF cells in patients with ALS (identifier {type:clinical-trial,attrs:{text:NCT01051882,term_id:NCT01051882}}NCT01051882 and {type:clinical-trial,attrs:{text:NCT01777646,term_id:NCT01777646}}NCT01777646) (Petrou et al., 2016). Bone marrow-derived MSCs have many advantages. For example, MSCs can be obtained safely from adult bone marrow; they can be cultured in vitro. Autologous MSCs can be administered safely without immunosuppressive therapy. Adult MSCs were shown to be associated with a low risk for induction of treatment-related malignant neoplasms (Karussis et al., 2010). We can focus on some other studies regarding the safety profile of stem cell transplant in the treatment of ALS. Animal studies have shown no clinically significant alteration of cytokine levels (involved in cell-mediated and humoral immunity) after MSC-NTF cell transplantation. Repeated injections of human MSC-NTF cells are found to be well tolerated in the studied animals (mice) (Gothelf et al., 2014). Pre-clinical and clinical trials have suggested that MSCs are safe and feasible as a therapeutic option. They are not immunogenic and have immunosuppressive features (Thomsen et al., 2014). Genetic stability and opportunity for cryopreservation for future use of MSCs are still in the research stage. Cryopreservation can preserve the biological behavior of MSCs including differentiation potential, growth capacity, and surface marker. Therefore, cryopreserved MSCs can be used safely in future (Wang et al., 2012). A meta-analysis of randomized controlled trials did not reveal any adverse effects of MSC transplants like infusion toxicity, any disorder of organ systems, infection, malignant transformation or fatal outcome (Dulamea, 2015). Another open-label phase I clinical trial showed the safety profile of two repeated intrathecal injections of autologous MSCs in ALS patients (Oh et al., 2015). Safety and Efficiency of Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSC) in Patients with Alzheimer's Disease (SEMAD) [identifier {type:clinical-trial,attrs:{text:NCT01547689,term_id:NCT01547689}}NCT01547689] is an ongoing study, and hopefully, it will provide more definite results (https://clinicaltrials.gov/ct2/show/{type:clinical-trial,attrs:{text:NCT01547689,term_id:NCT01547689}}NCT01547689, last accessed on 27/03/2016). Before conclusion, we want to raise another issue about some biological markers of the efficacy of such therapy. The levels of vascular endothelial growth factor, angiogenin, and transforming growth factor-β were reported to be significantly higher in responders than in nonresponders after autologous MSC therapy in patients with ALS. The disease outcomes were evaluated by their scores on the revised ALS Functional Rating Scale (ALSFRS-R) (Kim et al., 2014). So this new treatment modality is hoped to be successful in ALS patients. More study results will enlighten us about it.

Pseudobulbar affect (PBA) is characterized by involuntary and uncontrollable laughing and/or crying episodes, occurring secondary to neurological disease or injury. The impact of PBA on social and occupational function, health status, quality of life (QOL), and quality of relationships (QOR) is not well studied. This US survey conducted by Harris Interactive compared health status and daily function of patients with and without PBA. Eligible respondents were Harris Panel Online registrants previously diagnosed with stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, traumatic brain injury, or amyotrophic lateral sclerosis, or primary, nonpaid caregivers for such patients who were too debilitated to participate. PBA was identified by a Center for Neurologic Study lability scale score of 13 or greater. Measures included the 36-item short form health survey (SF-36), the work productivity and impairment (WPAI) questionnaire, visual analog scales (VAS) for impact of PBA symptoms on QOL and QOR, and customized questions related to burden and impact of involuntary laughing/crying episodes on patients' lives. Survey responses were weighted to adjust for the relative proportion of the primary neurological conditions in the overall population and between group differences in patient age and gender. PBA and non-PBA group responses were compared using two-tailed t tests adjusted for severity of the primary neurological conditions. The 1,052 respondents included 399 PBA group participants and 653 controls. The PBA group showed significantly worse scores versus non-PBA controls on component and summary SF-36 scores (P<0.05 for all), VAS scores (P<0.05 for both), and WPAI scores (P<0.05). Among PBA group respondents, PBA contributed a great deal to or was the main cause of patients becoming housebound for 24% and being moved to supervised living placement for 9% of respondents. PBA is associated with considerable burden incremental to that of the underlying neurological conditions, affecting QOL, QOR, health status, and social and occupational functioning.

Neurological disorders have been linked to suicide, but the risk across a broad spectrum of neurological disorders remains to be assessed. To examine whether people with neurological disorders die by suicide more often than other people and to assess for temporal associations. Nationwide, retrospective cohort study on all persons 15 years or older living in Denmark, from 1980 through 2016 (N = 7 300 395). Medical contact for head injury, stroke, epilepsy, polyneuropathy, diseases of myoneural junction, Parkinson disease, multiple sclerosis, central nervous system infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington disease, dementia, intellectual disability, and other brain diseases from 1977 through 2016 (n = 1 248 252). Death by suicide during 1980-2016. Adjusted incidence rate ratio (IRRs) were estimated using Poisson regressions, adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and self-harm. Of the more than 7.3 million individuals observed over 161 935 233 person-years (49.1% males), 35 483 died by suicide (median duration of follow-up, 23.6 years; interquartile range, 10.0-37.0 years; mean age, 51.9 years; SD, 17.9 years). Of those, 77.4% were males, and 14.7% (n = 5141) were diagnosed with a neurological disorder, equivalent to a suicide rate of 44.0 per 100 000 person-years compared with 20.1 per 100 000 person-years among individuals not diagnosed with a neurological disorder. People diagnosed with a neurological disorder had an adjusted IRR of 1.8 (95% CI, 1.7-1.8) compared with those not diagnosed. The excess adjusted IRRs were 4.9 (95% CI, 3.5-6.9) for amyotrophic lateral sclerosis, 4.9 (95% CI, 3.1-7.7) for Huntington disease, 2.2 (95% CI, 1.9-2.6) for multiple sclerosis, 1.7 (95% CI, 1.6-1.7) for head injury, 1.3 (95% CI, 1.2-1.3) for stroke, and 1.7 (95% CI, 1.6-1.8) for epilepsy. The association varied according to time since diagnosis with an adjusted IRR for 1 to 3 months of 3.1 (95% CI, 2.7-3.6) and for 10 or more years, 1.5 (95% CI, 1.4 to 1.6, P < .001). Compared with those who were not diagnosed with a neurological disorder, those with dementia had a lower overall adjusted IRR of 0.8 (95% CI, 0.7-0.9), which was elevated during the first month after diagnosis to 3.0 (95% CI, 1.9-4.6; P < .001). The absolute risk of suicide for people with Huntington disease was 1.6% (95% CI, 1.0%-2.5%). In Denmark from 1980 through 2016, there was a significantly higher rate of suicide among those with a diagnosed neurological disorder than persons not diagnosed with a neurological disorder. However, the absolute risk difference was small.

The neurological complications of AIDS (neuroAIDS) during the infection of human immunodeficiency virus (HIV) are symptomized by non-specific, multifaceted neurological conditions and therefore, defining a specific diagnosis/treatment mechanism(s) for this neuro-complexity at the molecular level remains elusive. Using an in silico based integrated gene network analysis we discovered that HIV infection shares convergent gene networks with each of twelve neurological disorders selected in this study. Importantly, a common gene network was identified among HIV infection, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and age macular degeneration. An mRNA microarray analysis in HIV-infected monocytes showed significant changes in the expression of several genes of this in silico derived common pathway which suggests the possible physiological relevance of this gene-circuit in driving neuroAIDS condition. Further, this unique gene network was compared with another in silico derived novel, convergent gene network which is shared by seven major neurological disorders (Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, Age Macular Degeneration, Amyotrophic Lateral Sclerosis, Vascular Dementia, and Restless Leg Syndrome). These networks differed in their gene circuits; however, in large, they involved innate immunity signaling pathways, which suggests commonalities in the immunological basis of different neuropathogenesis. The common gene circuits reported here can provide a prospective platform to understand how gene-circuits belonging to other neuro-disorders may be convoluted during real-time neuroAIDS condition and it may elucidate the underlying–and so far unknown–genetic overlap between HIV infection and neuroAIDS risk. Also, it may lead to a new paradigm in understanding disease progression, identifying biomarkers, and developing therapies.

Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not. We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants. Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older. The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.

Health-related quality-of-life measures have been increasingly used in research into neurological disorders in recent years. The aim of this paper is to provide an objective appraisal of the evidence in regard to disease-specific quality-of-life measures used in research on health interventions for three degenerative neurological disorders: multiple sclerosis, motor neurone disease/amyotrophic lateral sclerosis and Parkinson's disease. A comprehensive search strategy was developed to include nine relevant electronic databases. Only studies pertaining to patient-based outcome measurements in multiple sclerosis, motor neurone disease and Parkinson's disease were included. We identified 76 eligible studies. As studies consisted of descriptive and cross-sectional survey study designs, results were reported qualitatively rather than in the form of a meta-analysis. Four disease-specific measures were found for Parkinson's disease, 11 for multiple sclerosis and one for motor neurone disease. We conclude that health-related quality-of-life measures are useful in assessing the impact of treatments and interventions for neurological disorders. However, further research is needed on the development of instruments using psychometric methods and on the validation, utilization and responsiveness of instruments to change.

Aaron Gitler: yeast, proteins, and pioneering brain research

Chronic neurological disorders generate disabilities affecting multiple aspects of life, including sexuality. To describe the presence of sexual dysfunction and comorbidities in a population with chronic neurological disorders. To analyze the relationship between disability and sexual dysfunction. A cross-sectional case-control study was carried out. Patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease (PD), and stroke of at least one year since the onset of symptoms were included, and compared with controls with no neurological disease, matched by age and sex. We included 71 participants: 29 controls, with a mean age of 49.4 years, and 42 patients with a mean age of 53.8 years. Sexual dysfunction was present in 22.5% of the controls and 77.5% of the patients. A statistically significant relationship between sexual dysfunction and disability was found in the logistic regression analysis (OR = 20.38, 95%CI: 2.5 -165.86). Disability proved to be the main variable related to the presence of sexual dysfunction. Patients with ALS had the worst rates of sexual dysfunction. Patients with MS were similar to the control group. As for the PD group, no patient had normal sexuality. Finally, in stroke patients, the presence of comorbidities and their treatment may have negatively influenced sexuality. These findings showed that patients with chronic neurological diseases have sexual dysfunction and underscore the need for neurologists to know and address this problem.

Previous observational studies focused on the association of coffee consumption and neurological disease. However, it is not known whether these associations are causal. We used Mendelian randomization (MR) study to assess the causal relationship of coffee intake with the risk of neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, and migraine. Single-nucleotide polymorphisms (SNPs) which had genetic statistical significance with coffee intake were used as instrumental variable (IV). Genetic instruments were stretched from the MRC-IEU (MRC Integrative Epidemiology Unit) analysis on the UK Biobank. We performed MR analyses using the inverse variance weighted (IVW) method as the main approach. Sensitivity analyses were further performed using MR-Egger and MR-PRESSO to assess the robustness. In the MR analysis, 40 SNPs were selected as IV, the F statistics for all SNPs ranged from 16 to 359. In IVW approach, our results provide genetic evidence supporting a potential causal association between coffee intake and a lower risk of migraine (OR = 0.528, 95% CI = 0.342-0.817, P = 0.004) and migraine with aura (OR = 0.374, 95% CI = 0.208-0.672, P = 0.001). However, we found no significant association between coffee intake and other neurological diseases along with their subtypes in this MR study. Using genetic data, our MR study found significant evidence supporting a causal association between coffee intake and migraine. This suggests that coffee consumption is likely a trigger or a prevention strategy for migraine.

Unveiling the role of gut-brain axis in regulating neurodegenerative diseases: A comprehensive review