The Endocannabinoid System in Alzheimer's Disease: A Network Meta-Analysis.

The findings concerning the association between endocannabinoid system (ECS) and Alzheimer's disease (AD) exhibited inconsistencies when examining the expression levels of endocannabinoids. This study aimed to provide a comprehensive summary of the studies regarding alterations of the ECS in AD. Six databases were thoroughly searched for literature to select relevant studies investigating the ECS in AD, including changes in cannabinoid receptors (CB1R and CB2R), endocannabinoids (2-AG and AEA), and their associated enzymes (FAAH and MAGL). Traditional meta-analysis evaluated the expression levels of the ECS in AD, and the results showed no significant differences in ECS components between healthy controls and AD patients. However, subgroup analysis revealed significantly lower expression levels of CB1R in AD than in controls, particularly in studies using western blot (SMD = -0.88, p < 0.01) and in studies testing CB1R of frontal cortex (SMD = -1.09, p < 0.01). For studies using HPLC, the subgroup analysis indicated significantly higher 2-AG levels in AD than in controls (SMD = 0.46, p = 0.02). Network meta-analysis examined the rank of ECS alterations in AD compared to controls, and the findings revealed that 2-AG and MAGL exhibited the largest increase and CB1R showed the largest decrease relative to the control group. Based on the findings of traditional meta-analysis and network meta-analysis, we proposed that AD patients may present decreased expression levels of CB1R and increased expression levels of 2-AG and its degrading enzyme MAGL. Our results may contribute to the growing body of research supporting the therapeutic potential of ECS modulation in the management of AD.

Clinical outcome assessments of disease burden and progression in late-onset GM2 gangliosidoses.

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials.

Dietary fibre confers therapeutic effects in a preclinical model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder involving psychiatric, cognitive and motor deficits, as well as peripheral symptoms, including gastrointestinal dysfunction. The R6/1 HD mouse model expresses a mutant human huntingtin transgene and has been shown to provide an accurate disease model. Recent evidence of gut microbiome disruption was shown in preclinical and clinical HD. Therefore, we aimed to assess the potential role of gut microbial modulation in the treatment of HD. The R6/1 HD mice and wild-type littermate controls were randomised to receive diets containing different amounts of fibre: high-fibre (10 % fibre), control (5 % fibre), or zero-fibre (0 % fibre), from 6 to 20 weeks of age. We characterized the onset and progression of motor, cognitive and affective deficits, as well as gastrointestinal function and gut morphological changes. Faeces were collected for gut microbiome profiling using 16S rRNA sequencing, at 14 and 20 weeks of age. When compared to the control diet, high-fibre diet improved the performance of HD mice in behavioral tests of cognitive and affective function, as well as the gastrointestinal function of both HD and wild-type mice. While the diets changed the beta diversity of wild-type mice, no statistical significance was observed at 14 or 20 weeks of age within the HD mice. Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC) models were performed to evaluate microbiota composition, which identified differences, including a decreased relative abundance of the phyla Actinobacteriota, Campylobacterota and Proteobacteria and an increased relative abundance of the families Bacteroidaceae, Oscillospiraceae and Ruminococcaceae in HD mice when compared to wild-type mice after receiving high-fibre diet. PICRUSt2 revealed that high-fibre diet also decreased potentially pathogenic functional pathways in HD. In conclusion, high-fibre intake was effective in enhancing gastrointestinal function, cognition and affective behaviors in HD mice. These findings indicate that dietary fibre interventions may have therapeutic potential in Huntington's disease to delay clinical onset, and have implications for related disorders exhibiting dysfunction of the gut-brain axis.

Adrenal insufficiency and the use of mineralocorticoid treatment in male patients with adrenoleukodystrophy; a retrospective analysis of an institutional database.

INTRODUCTION: Adrenoleukodystrophy (ALD) patients exhibit three primary clinical phenotypes: primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral demyelination due to the accumulation of saturated very long-chain fatty acids in the adrenal cortex and central nervous system white matter and axons. We investigated the diagnosis of adrenal insufficiency (AI) and the use of mineralocorticoid treatment in male ALD patients. METHODS: A retrospective chart review of electronic medical records was conducted for all ALD patients at a single institution between January 1, 2011, and December 6, 2021. RESULTS: Among the 437 ALD patients, 82% were male and 18% were female. Of the male ALD patients, 60% (213 out of 358) had a diagnosis of AI, and 39% (84 out of 213) of those with AI were prescribed mineralocorticoid replacement therapy. CONCLUSION: AI is highly prevalent among ALD patients, with approximately 40% of those with a diagnosis of AI undergoing mineralocorticoid replacement therapy. Further research is warranted to delineate the characteristics of patients predisposed to developing mineralocorticoid deficiency within the context of ALD and AI.

Combinations of physical and cognitive training for subcortical neurodegenerative diseases with physical, cognitive and behavioral symptoms: a systematic review.

BACKGROUND: The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies. METHODS: We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal. RESULTS: Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training. DISCUSSION: Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data. CONCLUSIONS: Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training.

Synaptic logistics: Competing over shared resources.

High turnover rates of synaptic proteins imply that synapses constantly need to replace their constituent building blocks. This requires sophisticated supply chains and potentially exposes synapses to shortages as they compete for limited resources. Interestingly, competition in neurons has been observed at different scales. Whether it is competition of receptors for binding sites inside a single synapse or synapses fighting for resources to grow. Here we review the implications of such competition for synaptic function and plasticity. We identify multiple mechanisms that synapses use to safeguard themselves against supply shortages and identify a fundamental neurologistic trade-off governing the sizes of reserve pools of essential synaptic building blocks.

Phytomedicine for neurodegenerative diseases: The road ahead.

Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.

Identification of Proteolysis Targeting Chimeras (PROTACs) for Lysine Demethylase 5 and Their Neurite Outgrowth-Promoting Activity.

Lysine demethylase 5 (KDM5) proteins are involved in various neurological disorders, including Alzheimer's disease, and KDM5 inhibition is expected to be a therapeutic strategy for these diseases. However, the pharmacological effects of conventional KDM5 inhibitors are insufficient, as they only target the catalytic functionality of KDM5. To identify compounds that exhibit more potent pharmacological activity, we focused on proteolysis targeting chimeras (PROTACs), which degrade target proteins and thus inhibit their entire functionality. We designed and synthesized novel KDM5 PROTAC candidates based on previously identified KDM5 inhibitors. The results of cellular assays revealed that two compounds, 20b and 23b, exhibited significant neurite outgrowth-promoting activity through the degradation of KDM5A in neuroblastoma neuro 2a cells. These results suggest that KDM5 PROTACs are promising drug candidates for the treatment of neurological disorders.

Neuroprotective potential of solanesol against tramadol induced zebrafish model of Parkinson's disease: insights from neurobehavioral, molecular, and neurochemical evidence.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and subsequent depletion of dopamine in the striatum. Solanesol, an alcohol that acts as a precursor to coenzyme Q10, possesses potential applications in managing neurological disorders with antioxidant, anti-inflammatory, and neuromodulatory potential. In this study, a zebrafish model was employed to investigate the effects of solanesol in tramadol induced PD like symptoms. Zebrafish were administered tramadol injections (50 mg/kg) over a 20-day period. Solanesol was administered at doses of 25, 50, and 100 mg/kg, three hours prior to tramadol administration from day 11 to day 20. Behavioral tests assessing motor coordination were conducted on a weekly basis using open field and novel diving tank apparatus. On day 21, the zebrafish were euthanized, and brain tissues were examined for markers of oxidative stress, inflammation, and neurotransmitters level. Chronic tramadol treatment resulted in motor impairment, reduced antioxidant enzyme levels, enhanced release of proinflammatory cytokines in the striatum, and disrupted neurotransmitter balance. However, solanesol administration mitigated these effects and exhibited a neuroprotective effect against neurodegenerative alterations in the zebrafish model of PD. This was evident through improvements in behavior, modulation of biochemical markers, attenuation of neuroinflammation, restoration of neurotransmitters level, and enhancement of mitochondrial activity. The histopathological study also confirmed that solanesol dose dependently restored neuronal cell density which confirmed its neuroprotective potential. Further investigations are required to elucidate the underlying mechanisms of solanesol neuroprotective effects and evaluate its efficacy in human patients.

Neuroprotective effects: Solanesol has shown significant neuroprotective effects in a zebrafish model of Parkinson's disease induced by chronic tramadol usage.Improved behavioral performance: Administration of solanesol resulted in improved motor coordination in the open field test (OFT) and novel diving apparatus in the tramadol-induced zebrafish model of PD.Decreased inflammation: Solanesol treatment significantly reduced pro-inflammatory cytokine levels in the tramadol-induced zebrafish model of PD, indicating its anti-inflammatory properties.Restored oxidative parameters: Solanesol administration restored oxidative stress parameters, as well as catecholamine and neurotransmitter levels in the tramadol-induced zebrafish model of PD.Histopathological improvement: Solanesol administration prevented histopathological alterations induced by tramadol, indicating its ability to protect against neuronal damage in the zebrafish model of PD.

Exploring Epigenetic Modifications as Potential Biomarkers and Therapeutic Targets in Glaucoma.

Glaucoma, a complex and multifactorial neurodegenerative disorder, is a leading cause of irreversible blindness worldwide. Despite significant advancements in our understanding of its pathogenesis and management, early diagnosis and effective treatment of glaucoma remain major clinical challenges. Epigenetic modifications, encompassing deoxyribonucleic acid (DNA) methylation, histone modifications, and non-coding RNAs, have emerged as critical regulators of gene expression and cellular processes. The aim of this comprehensive review focuses on the emerging field of epigenetics and its role in understanding the complex genetic and molecular mechanisms underlying glaucoma. The review will provide an overview of the pathophysiology of glaucoma, emphasizing the intricacies of intraocular pressure regulation, retinal ganglion cell dysfunction, and optic nerve damage. It explores how epigenetic modifications, such as DNA methylation and histone modifications, can influence gene expression, and how these mechanisms are implicated in glaucomatous neurodegeneration and contribute to glaucoma pathogenesis. The manuscript discusses evidence from both animal models and human studies, providing insights into the epigenetic alterations associated with glaucoma onset and progression. Additionally, it discusses the potential of using epigenetic modifications as diagnostic biomarkers and therapeutic targets for more personalized and targeted glaucoma treatment.

In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aß) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery.

Differences in Heart Rate Variability in the Frequency Domain between Different Groups of Patients.

Background and Objectives: Heart rate variability (HRV) is defined as a physiological variation in duration between sinus beats. The aim of this study was to research and analyze the HRV between various groups of patients. Materials and Methods: A retrospective study was conducted in an outpatient setting. Patients who had undergone a tilt-table test were selected for this study and were divided into three groups based on their self-reported health anamnesis: group 1 (n = 84, mean age 45.8 ± 17.8) consisted of patients with no known orthostatic intolerance or neurodegenerative disease, group 2 consisted of patients with a known or suspected orthostatic intolerance (n = 50, mean age 46.5 ± 18.6), and group 3 consisted of patients with a known or suspected neurodegenerative disorder (n = 29, mean age 55.6 ± 20.4). During the tilt-table test, HRV frequency-domain parameters-normalized low frequency (LFnu) and high frequency (HFnu), absolute powers-absolute low frequency (LF-RRI), absolute high frequency (HF-RRI), and LF/HF ratio-were recorded during 5 min rest in the supine position. Results: Group 1 had a reduced LFnu at 52.93% (SD: 18.00) compared to group 2 at 58.57% (18.06) and group 3 at 61.80% (SD: 17.74), and group 1 had increased HFnu: group 1-47.08% (SD: 17.97), group 2-41.41% (SD: 18.03), and group 3-38.16% (SD: 14.7). LFnu and HFnu differences were statistically significant (p < 0.05). LF-RRI was reported as follows: group 1-531.32 ms2 (SD: 578.57), group 2-346.2 ms2 (SD: 447.96), and group 3-143.21 ms2 (SD: 166.96). HF-RRI was reported as follows: group 1-835.87 ms2 (SD: 1625.42), group 2-297.46 ms2 (SD: 507.15), and group 3-70.83 ms2 (SD: 75.67). LF-RRI and HF-RRI comparisons between groups were statistically significant (p < 0.001). LF/HF ratios were reported as follows: group 1-1.91 (SD: 2.29), group 2-2.43 (SD: 2.33), and group 3-2.54 (SD: 2.17). LF/HF ratio comparisons between groups were statistically significant at p < 0.05. Conclusions: This study shows that patients with known or suspected orthostatic intolerance and neurodegenerative disorders have reduced HRV, possibly caused by reduced parasympathetic modulation. HRV in patients with known or suspected neurodegenerative disorders is reduced more severely than in patients with orthostatic disorders. Other studies in HRV have indicated a possible increase of risk in cardiovascular disorders in patients with reduced HRV, and therefore, HRV analysis could be a potential clinical diagnostic tool. However, the lack of universally agreed upon methodology, reference values, and possible external and internal factor influence hinders the introduction of HRV examinations into wider clinical practice.

Infantile Neuroaxonal Dystrophy: Case Report and Review of Literature.

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder affecting 1:1,000,000 children. It results from pathogenic variants in the PLA2G6 gene located on chromosome 22q13.1. The onset of symptoms usually occurs between 6 and 18 months, causing developmental regression leading to debilitating symptoms such as muscle weakness, dementia, and loss of basic skills. Eventually, it progresses to life-threatening symptoms, including breathing difficulties, which limit the life expectancy to 5-10 years. While potential genetic therapies for treatment are being developed, they are yet to be approved for use, and management remains essentially supportive. This case report is about a nine-year-old Pakistani girl with INAD. She presented with recurrent chest infections, developmental regression, loss of speech, paralysis, hypertension, and eventually breathing difficulties. Brain magnetic resonance imaging and genetic testing confirmed the diagnosis. This case posed diagnostic challenges in view of its overlapping clinical presentation. Through this report, we aim to raise awareness about this condition among practitioners, outline the importance of genetic counseling in susceptible couples, and suggest potential areas of further research.

SUMOylation in development and neurodegeneration.

In essentially all eukaryotes, proteins can be modified by the attachment of small ubiquitin-related modifier (SUMO) proteins to lysine side chains to produce branched proteins. This process of 'SUMOylation' plays essential roles in plant and animal development by altering protein function in spatially and temporally controlled ways. In this Primer, we explain the process of SUMOylation and summarize how SUMOylation regulates a number of signal transduction pathways. Next, we discuss multiple roles of SUMOylation in the epigenetic control of transcription. In addition, we evaluate the role of SUMOylation in the etiology of neurodegenerative disorders, focusing on Parkinson's disease and cerebral ischemia. Finally, we discuss the possibility that SUMOylation may stimulate survival and neurogenesis of neuronal stem cells.

Phytochemicals targeting nitric oxide signaling in neurodegenerative diseases.

Neurodegenerative diseases are a set of diseases in which slow and progressive neuronal loss occurs. Nitric oxide (NO) as a neurotransmitter performs key roles in the stimulation and blockade of various inflammatory processes. Although physiological NO is necessary for protection against a variety of pathogens, reactive oxygen species-mediated oxidative stress induces inflammatory cascades and apoptosis. Activation of glial cells particularly astrocytes and microglia induce overproduction of NO, resulting in neuroinflammation and neurodegenerative disorders. Hence, inhibiting the overproduction of NO is a beneficial therapeutic approach for numerous neuroinflammatory conditions. Several compounds have been explored for the management of neurodegenerative disorders, but they have minor symptomatic benefits and several adverse effects. Phytochemicals have currently gained more consideration owing to their ability to reduce the overproduction of NO in neurodegenerative disorders. Furthermore, phytochemicals are generally considered to be safe and beneficial. The mechanisms of NO generation and their implications in neurodegenerative disorders are explored in this review article, as well as several newly discovered phytochemicals that might have NO inhibitory activity. The current review could aid in the discovery of new anti-neuroinflammatory drugs that can suppress NO generation, particularly during neuroinflammatory and neurodegenerative conditions.

ATP7A-related copper transport disorders: A systematic review and definition of the clinical subtypes.

In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear genotype-phenotype correlation. We performed a systematic literature review by querying the MEDLINE and Embase databases identifying 143 relevant papers. We recorded data on the phenotype and genotype in 162 individuals with a molecularly confirmed ATP7A-related disorder in order to identify differentiating clinical criteria, evaluate genotype-phenotype correlations and propose management guidelines. Early seizures are specific for classical Menkes disease (CMD), that is characterized by early-onset neurodegenerative disease with high mortality rates. Ataxia is an independent indicator for atypical Menkes disease, that shows better survival rates than CMD. Bony exostoses, radial head dislocations, herniations and dental abnormalities are specific for occipital horn syndrome (OHS) that may further present with developmental delay and connective tissue manifestations. Intracranial tortuosity and bladder diverticula, both with high risk of complications, are common among all subtypes. Low ceruloplasmin is a more sensitive and discriminating biomarker for ATP7A-related disorders than serum copper. Truncating mutations are frequently associated with CMD, in contrast with splice site and intronic mutations which are more prevalent in OHS.

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus.

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

Traversing through the cell signaling pathways of neuroprotection by betanin: therapeutic relevance to Alzheimer's Disease and Parkinson's Disease.

Modulation of cell signaling pathways is the key area of research towards the treatment of neurodegenerative disorders. Altered Nrf2-Keap1-ARE (Nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1-Antioxidant responsive element) and SIRT1 (Sirtuin 1) cell signaling pathways are considered to play major role in the etiology and pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Strikingly, betanin, a betanidin 5-O-ß-D-glucoside compound is reported to show commendable anti-oxidative, anti-inflammatory and anti-apoptotic effects in several disease studies including AD and PD. The present review discusses the pre-clinical studies demonstrating the neuroprotective effects of betanin by virtue of its potential to ameliorate oxidative stress, neuroinflammation, abnormal protein aggregation and cell death. It highlights the direct linkage between the neuroprotective abilities of betanin and upregulation of the Nrf2-Keap1-ARE and SIRT1 signaling pathways. The review further hypothesizes the involvement of the betanin-Nrf2-ARE route in the inhibition of beta-amyloid aggregation through beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), one of the pivotal hallmarks of AD. The present review hereby for the first time elaborately discusses the reported neuroprotective abilities of betanin and decodes the Nrf2 and SIRT1 modulating potential of betanin as a primary mechanism of action behind, hence highlighting it as a novel drug candidate for the treatment of neurodegenerative diseases in the near future.

A Clinical Perspective on Bespoke Sensing Mechanisms for Remote Monitoring and Rehabilitation of Neurological Diseases: Scoping Review.

Neurological diseases including stroke and neurodegenerative disorders cause a hefty burden on the healthcare system. Survivors experience significant impairment in mobility and daily activities, which requires extensive rehabilitative interventions to assist them to regain lost skills and restore independence. The advent of remote rehabilitation architecture and enabling technology mandates the elaboration of sensing mechanisms tailored to individual clinical needs. This study aims to review current trends in the application of sensing mechanisms in remote monitoring and rehabilitation in neurological diseases, and to provide clinical insights to develop bespoke sensing mechanisms. A systematic search was performed using the PubMED database to identify 16 papers published for the period between 2018 to 2022. Teleceptive sensors (56%) were utilized more often than wearable proximate sensors (50%). The most commonly used modality was infrared (38%) and acceleration force (38%), followed by RGB color, EMG, light and temperature, and radio signal. The strategy adopted to improve the sensing mechanism included a multimodal sensor, the application of multiple sensors, sensor fusion, and machine learning. Most of the stroke studies utilized biofeedback control systems (78%) while the majority of studies for neurodegenerative disorders used sensors for remote monitoring (57%). Functional assessment tools that the sensing mechanism may emulate to produce clinically valid information were proposed and factors affecting user adoption were described. Lastly, the limitations and directions for further development were discussed.

Thrombin-Induced Microglia Activation Modulated through Aryl Hydrocarbon Receptors.

Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin is related to the development of neurodegeneration disorders. In this study, we investigated the role of AhR in the development of thrombin-induced neurodegenerative processes, especially those concerning microglia. The primary culture of either wild type or AhR deleted microglia, as well as BV-2 cell lines, was used for an in vitro study. Hippocampal slice culture and animals with either wild type or with AhR deleted were used for the ex vivo and in vivo studies. Simulations of ligand protein docking showed a strong integration between the thrombin and AhR. In thrombin-triggered microglia cells, deleting AhR escalated both the NO release and iNOS expression. Such effects were abolished by the administration of the AhR agonist. In thrombin-activated microglia cells, downregulating AhR increased the following: vascular permeability, pro-inflammatory genetic expression, MMP-9 activity, and the ratio of M1/M2 phenotype. In the in vivo study, thrombin induced the activation of microglia and their volume, thereby contributing to the deterioration of neurobehavior. Deleting AhR furthermore aggravated the response in terms of impaired neurobehavior, increasing brain edema, aggregating microglia, and increasing neuronal death. In conclusion, thrombin caused the activation of microglia through increased vessel permeability, expression of inflammatory response, and phenotype of M1 microglia, as well the MMP activity. Deleting AhR augmented the above detrimental effects. These findings indicate that the modulation of AhR is essential for the regulation of thrombin-induced brain damages and that the AhR agonist may harbor the potentially therapeutic effect in thrombin-induced neurodegenerative disorder.