The Growing Role of Telerehabilitation and Teleassessment in the Management of Movement Disorders in Rare Neurological Diseases: A Scoping Review.

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

The effect of multiple sclerosis therapy on gut microbiota dysbiosis: a longitudinal prospective study.

Gut microbiota has complex immune functions, related to different pathologies, including multiple sclerosis (MS).This study evaluated the influence of treatments on gut microbiota in people with MS (PwMS). The research comprised 60 participants, including 39 PwMS and 21 healthy controls (HC). Among the PwMS, 20 were prescribed a disease-modifying therapy (DMT), either interferon beta1a or teriflunomide, while 19 received a combination of classical DMT and an immunoglobulin Y (IgY) supplement. For each participant, two sets of gut samples were collected: one at the study's outset and another after two months. Alpha and beta diversity analyses revealed no significant differences between groups. In comparison to the HC, the MS group exhibited an increase in Prevotella stercorea and a decrease in Faecalibacterium prausnitzii. Following treatment, individuals with MS showed enrichment in Lachnospiraceae and Streptococcus. The second sample, compared to the first one, demonstrated an increase in Bifidobacterium angulatum and a decrease in Oscillospira for individuals with MS. Gut microbiota diversity in PwMS is not significantly different to HC.However, specific taxonomic changes indicate the presence of a dysbiosis state. The use of DMTs and immunoglobulin Y supplements may contribute to alterations in microbial composition, potentially leading to the restoration of a healthier microbiome.

Dysbiosis in Multiple Sclerosis: Can Immunoglobulin Y Supplements Help?

The role of gut microbiota in autoimmune disorders like multiple sclerosis is gaining attention. Multiple sclerosis is characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Alterations in gut microbiota have been linked to multiple sclerosis development, with decreased beneficial bacteria and increased harmful species. The gut-brain axis is a complex interface influencing bidirectional interactions between the gut and the brain. Dysbiosis, an imbalance in gut microbiota, has been associated with autoimmune diseases. The influence of gut microbiota in multiple sclerosis is reversible, making it a potential therapeutic target. Probiotics, prebiotics, and fecal microbiota transplantation have shown promise in multiple sclerosis treatment, with positive effects on inflammation and immune regulation. Immunoglobulin Y (IgY) supplements derived from chicken egg yolk have potential as nutraceuticals or dietary supplements. IgY technology has been effective against various infections, and studies have highlighted its role in modulating gut microbiota and immune responses. Clinical trials using IgY supplements in multiple sclerosis are limited but have shown positive outcomes, including reduced symptoms, and altered immune responses. Future research directions involve understanding the mechanisms of IgY's interaction with gut microbiota, optimal dosage determination, and long-term safety assessments. Combining IgY therapy with other interventions and investigating correlations between microbiota changes and clinical outcomes are potential avenues for advancing multiple sclerosis treatment with IgY supplements.

Levodopa-Carbidopa-Entacapone Intestinal Gel in Advanced Parkinson Disease: A Multicenter Real-Life Experience.

BACKGROUND: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021. STUDY QUESTION: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD? STUDY DESIGN: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania. MEASURES AND OUTCOMES: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted. RESULTS: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications. CONCLUSIONS: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen.

Sleep deprivation enhances amyloid beta peptide, p-tau and serotonin in the brain: Neuroprotective effects of nanowired delivery of cerebrolysin with monoclonal antibodies to amyloid beta peptide, p-tau and serotonin.

Sleep deprivation is quite frequent in military during combat, intelligence gathering or peacekeeping operations. Even one night of sleep deprivation leads to accumulation of amyloid beta peptide burden that would lead to precipitation of Alzheimer's disease over the years. Thus, efforts are needed to slow down or neutralize accumulation of amyloid beta peptide (AßP) and associated Alzheimer's disease brain pathology including phosphorylated tau (p-tau) within the brain fluid environment. Sleep deprivation also alters serotonin (5-hydroxytryptamine) metabolism in the brain microenvironment and impair upregulation of several neurotrophic factors. Thus, blockade or neutralization of AßP, p-tau and serotonin in sleep deprivation may attenuate brain pathology. In this investigation this hypothesis is examined using nanodelivery of cerebrolysin- a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies against AßP, p-tau and serotonin (5-hydroxytryptamine, 5-HT). Our observations suggest that sleep deprivation induced pathophysiology is significantly reduced following nanodelivery of cerebrolysin together with monoclonal antibodies to AßP, p-tau and 5-HT, not reported earlier.

Stress induced exacerbation of Alzheimer's disease brain pathology is thwarted by co-administration of nanowired cerebrolysin and monoclonal amyloid beta peptide antibodies with serotonin 5-HT6 receptor antagonist SB-399885.

Alzheimer's disease is one of the devastating neurodegenerative diseases affecting mankind worldwide with advancing age mainly above 65 years and above causing great misery of life. About more than 7 millions are affected with Alzheimer's disease in America in 2023 resulting in huge burden on health care system and care givers and support for the family. However, no suitable therapeutic measures are available at the moment to enhance quality of life to these patients. Development of Alzheimer's disease may reflect the stress burden of whole life inculcating the disease processes of these neurodegenerative disorders of the central nervous system. Thus, new strategies using nanodelivery of suitable drug therapy including antibodies are needed in exploring neuroprotection in Alzheimer's disease brain pathology. In this chapter role of stress in exacerbating Alzheimer's disease brain pathology is explored and treatment strategies are examined using nanotechnology based on our own investigation. Our observations clearly show that restraint stress significantly exacerbate Alzheimer's disease brain pathology and nanodelivery of a multimodal drug cerebrolysin together with monoclonal antibodies (mAb) to amyloid beta peptide (AßP) together with a serotonin 5-HT6 receptor antagonist SB399885 significantly thwarted Alzheimer's disease brain pathology exacerbated by restraint stress, not reported earlier. The possible mechanisms and future clinical significance is discussed.

Nanowired delivery of dl-3-n-butylphthalide with antibodies to alpha synuclein potentiated neuroprotection in Parkinson's disease with emotional stress.

Stress is one of the most serious consequences of life leading to several chronic diseases and neurodegeneration. Recent studies show that emotional stress and other kinds of anxiety and depression adversely affects Parkinson's disease symptoms. However, the details of how stress affects Parkinson's disease is still not well known. Traumatic brain injury, stroke, diabetes, post-traumatic stress disorders are well known to modify the disease precipitation, progression and persistence. However, show stress could influence Parkinson's disease is still not well known. The present investigation we examine the role of immobilization stress influencing Parkinson's disease brain pathology in model experiments. In ore previous report we found that mild traumatic brain injury exacerbate Parkinson's disease brain pathology and nanodelivery of dl-3-n-butylphthalide either alone or together with mesenchymal stem cells significantly attenuated Parkinson's disease brain pathology. In this chapter we discuss the role of stress in exacerbating Parkinson's disease pathology and nanowired delivery of dl-3-n-butylphthalide together with monoclonal antibodies to alpha synuclein (ASNC) is able to induce significant neuroprotection. The possible mechanisms of dl-3-n-butylphthalide and ASNC induced neuroprotection and suitable clinical therapeutic strategy is discussed.

Nanowired delivery of antibodies to tau and neuronal nitric oxide synthase together with cerebrolysin attenuates traumatic brain injury induced exacerbation of brain pathology in Parkinson's disease.

Concussive head injury (CHI) is one of the major risk factors for developing Parkinson's disease in later life of military personnel affecting lifetime functional and cognitive disturbances. Till date no suitable therapies are available to attenuate CHI or PD induced brain pathology. Thus, further exploration of novel therapeutic agents are highly warranted using nanomedicine in enhancing the quality of life of veterans or service members of US military. Since PD or CHI induces oxidative stress and perturbs neurotrophic factors regulation associated with phosphorylated tau (p-tau) deposition, a possibility exists that nanodelivery of agents that could enhance neurotrophic factors balance and attenuate oxidative stress could be neuroprotective in nature. In this review, nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies to neuronal nitric oxide synthase (nNOS) with p-tau antibodies was examined in PD following CHI in model experiments. Our results suggest that combined administration of nanowired antibodies to nNOS and p-tau together with cerebrolysin significantly attenuated CHI induced exacerbation of PD brain pathology. This combined treatment also has beneficial effects in CHI or PD alone, not reported earlier.

Co-administration of dl-3-n-butylphthalide and neprilysin is neuroprotective in Alzheimer disease associated with mild traumatic brain injury.

dl-3-n-Butylphthalide is a potent synthetic Chinese celery extract that is highly efficient in inducing neuroprotection in concussive head injury (CHI), Parkinson's disease, Alzheimer's disease, stroke as well as depression, dementia, anxiety and other neurological diseases. Thus, there are reasons to believe that dl-3-n-butylphthalide could effectively prevent Alzheimer's disease brain pathology. Military personnel during combat operation or veterans are often the victims of brain injury that is a major risk factor for developing Alzheimer's disease in their later lives. In our laboratory we have shown that CHI exacerbates Alzheimer's disease brain pathology and reduces the amyloid beta peptide (AßP) inactivating enzyme neprilysin. We have used TiO2 nanowired-dl-3-n-butylphthalide in attenuating Parkinson's disease brain pathology exacerbated by CHI. Nanodelivery of dl-3-n-butylphthalide appears to be more potent as compared to the conventional delivery of the compound. Thus, it would be interesting to examine the effects of nanowired dl-3-n-butylphthalide together with nanowired delivery of neprilysin in Alzheimer's disease model on brain pathology. In this investigation we found that nanowired delivery of dl-3-n-butylphthalide together with nanowired neprilysin significantly attenuated brain pathology in Alzheimer's disease model with CHI, not reported earlier. The possible mechanism and clinical significance is discussed based on the current literature.

Nicotine neurotoxicity exacerbation following engineered Ag and Cu (50-60 nm) nanoparticles intoxication. Neuroprotection with nanowired delivery of antioxidant compound H-290/51 together with serotonin 5-HT3 receptor antagonist ondansetron.

Nicotine abuse is frequent worldwide leading to about 8 millions people die every year due to tobacco related diseases. Military personnel often use nicotine smoking that is about 12.8% higher than civilian populations. Nicotine smoking triggers oxidative stress and are linked to several neurodegenerative diseases such as Alzheimer's disease. Nicotine neurotoxicity induces significant depression and oxidative stress in the brain leading to neurovascular damages and brain pathology. Thus, details of nicotine neurotoxicity and factors influencing them require additional investigations. In this review, effects of engineered nanoparticles from metals Ag and Cu (50-60 nm) on nicotine neurotoxicity are discussed with regard to nicotine smoking. Military personnel often work in the environment where chances of nanoparticles exposure are quite common. In our earlier studies, we have shown that nanoparticles alone induces breakdown of the blood-brain barrier (BBB) and exacerbates brain pathology in animal models. In present investigation, nicotine exposure in with Ag or Cu nanoparticles intoxicated group exacerbated BBB breakdown, induce oxidative stress and aggravate brain pathology. Treatment with nanowired H-290/51 a potent chain-breaking antioxidant together with nanowired ondansetron, a potent 5-HT3 receptor antagonist significantly reduced oxidative stress, BBB breakdown and brain pathology in nicotine exposure associated with Ag or Cu nanoparticles intoxication. The functional significance of this findings and possible mechanisms of nicotine neurotoxicity are discussed based on current literature.

Spinal cord injury induced exacerbation of Alzheimer's disease like pathophysiology is reduced by topical application of nanowired cerebrolysin with monoclonal antibodies to amyloid beta peptide, p-tau and tumor necrosis factor alpha.

Hallmark of Alzheimer's disease include amyloid beta peptide and phosphorylated tau deposition in brain that could be aggravated following traumatic of concussive head injury. However, amyloid beta peptide or p-tau in spinal cord following injury is not well known. In this investigation we measured amyloid beta peptide and p-tau together with tumor necrosis factor-alpha (TNF-α) in spinal cord and brain following 48 h after spinal cord injury in relation to the blood-spinal cord and blood-brain barrier, edema formation, blood flow changes and cell injury in perifocal regions of the spinal cord and brain areas. A focal spinal cord injury was inflicted over the right dorsal horn of the T10-11 segment (4 mm long and 2 mm deep) and amyloid beta peptide and p-tau was measured in perifocal rostral (T9) and caudal (T12) spinal cord segments as well as in the brain areas. Our observations showed a significant increase in amyloid beta peptide in the T9 and T12 segments as well as in remote areas of brain and spinal cord after 24 and 48 h injury. This is associated with breakdown of the blood-spinal cord (BSCB) and brain barriers (BBB), edema formation, reduction in blood flow and cell injury. After 48 h of spinal cord injury elevation of amyloid beta peptide, phosphorylated tau (p-tau) and tumor necrosis factor-alpha (TNF-α) was seen in T9 and T12 segments of spinal cord in cerebral cortex, hippocampus and brain stem regions associated with microglial activation as seen by upregulation of Iba1 and CD86. Repeated nanowired delivery of cerebrolysin topically over the traumatized segment repeatedly together with monoclonal antibodies (mAb) to amyloid beta peptide (AßP), p-tau and TNF-α significantly attenuated amyloid beta peptide, p-tau deposition and reduces Iba1, CD68 and TNF-α levels in the brain and spinal cord along with blockade of BBB and BSCB, reduction in blood flow, edema formation and cell injury. These observations are the first to show that spinal cord injury induces Alzheimer's disease like symptoms in the CNS, not reported earlier.

Nanodelivery of histamine H3 receptor inverse agonist BF-2649 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury.

Military personnel are often victims of spinal cord injury resulting in lifetime disability and decrease in quality of life. However, no suitable therapeutic measures are still available to restore functional disability or arresting the pathophysiological progression of disease in victims for leading a better quality of life. Thus, further research in spinal cord injury using novel strategies or combination of available neuroprotective drugs is urgently needed for superior neuroprotection. In this regard, our laboratory is engaged in developing TiO2 nanowired delivery of drugs, antibodies and enzymes in combination to attenuate spinal cord injury induced pathophysiology and functional disability in experimental rodent model. Previous observations show that histamine antagonists or antioxidant compounds when given alone in spinal cord injury are able to induce neuroprotection for short periods after trauma. In this investigation we used a combination of histaminergic drugs with antioxidant compound H-290/51 using their nanowired delivery for neuroprotection in spinal cord injury of longer duration. Our observations show that a combination of H3 receptor inverse agonist BF-2549 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury. These observations suggests that histamine receptors are involved in the pathophysiology of spinal cord injury and induce superior neuroprotection in combination with an inhibitor of lipid peroxidation H-290/51, not reported earlier. The possible mechanisms and significance of our findings in relation to future clinical approaches in spinal cord injury is discussed.

Association among VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 polymorphisms and acute ischemic stroke.

Acute ischemic stroke is a major cause of morbidity and mortality worldwide, and genetic factors play a role in the risk of stroke. Single nucleotide polymorphisms (SNPs) in the VKORC1, CYP4F2, and GGCX genes have been linked to clinical outcomes, such as bleeding and cardiovascular diseases. This study aimed to investigate the association between specific polymorphisms in these genes and the risk of developing the first episode of acute ischemic stroke in patients without a known embolic source. This retrospective, cross-sectional, observational, analytical, case-control study included adult patients diagnosed with acute ischemic stroke. The SNPs in VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 genes were genotyped and analyzed together with the demographic and clinical factors of the 2 groups of patients. The presence of SNPs in VKORC1 or CYP4F2 genes significantly increased the risk of ischemic stroke in the context of smoking, arterial hypertension, and carotid plaque burden. The multivariate logistic model revealed that smoking (odds ratio [OR] = 3.920; P < .001), the presence of carotid plaques (OR = 2.661; P < .001) and low-density lipoprotein cholesterol values >77 mg/dL (OR = 2.574; P < .001) were independently associated with stroke. Polymorphisms in the VKORC1 and CYP4F2 genes may increase the risk of ischemic stroke in patients without a determined embolic source. Smoking, the presence of carotid plaques, and high low-density lipoprotein cholesterol levels were reconfirmed as important factors associated with ischemic stroke.

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer's Disease Brain Pathology Exacerbated by Sleep Deprivation.

Sleep deprivation induces amyloid beta peptide and phosphorylated tau deposits in the brain and cerebrospinal fluid together with altered serotonin metabolism. Thus, it is likely that sleep deprivation is one of the predisposing factors in precipitating Alzheimer's disease (AD) brain pathology. Our previous studies indicate significant brain pathology following sleep deprivation or AD. Keeping these views in consideration in this review, nanodelivery of monoclonal antibodies to amyloid beta peptide (AßP), phosphorylated tau (p-tau), and tumor necrosis factor alpha (TNF-α) in sleep deprivation-induced AD is discussed based on our own investigations. Our results suggest that nanowired delivery of monoclonal antibodies to AßP with p-tau and TNF-α induces superior neuroprotection in AD caused by sleep deprivation, not reported earlier.

Nanodelivery of Histamine H3/H4 Receptor Modulators BF-2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson's Disease.

Parkinson's disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AßP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AßP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that TiO2 nanowired BF-2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of monoclonal antibodies (mAb) to AßP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AßP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD.