Search Results (98)

Neurofilament light chain (NfL), an abundant cytoskeletal protein in neurons, has emerged as a promising serum biomarker that indicates non-specific neuronal damage secondary to various neurologic diseases, including multiple sclerosis (MS). Emerging evidence suggests that serum NfL levels correlate with future disability, brain atrophy, predict new disease activity, and decrease in response to various disease-modifying therapies. As research continues to validate NfL’s potential role in clinical practice, the need for a practical model to conceptualize and visualize its relevance to MS pathology becomes evident—not only for healthcare providers but also for patients. To address this, we propose the Neurofoundational Model (NFM), which likens a neuron to a home, with various parts of the home representing distinct regions of the central nervous system (CNS). In this model, the home (neuron) experiences scenarios such as a fire, an earthquake, and a slow flood, representing distinct MS disease states. A fire illustrates an MS relapse with good recovery, where serum NfL levels rise during the relapse and subsequently return near baseline. An earthquake represents an MS relapse with poor recovery, where NfL levels increase and remain elevated above baseline. Finally, a slow flood depicts MS in progressive stages, characterized by sustained and gradually increasing serum NfL levels without abrupt clinical changes. This approach offers a clear and relatable visualization for clinicians and patients alike, illustrating the dynamics of serum NfL levels during CNS damage caused by demyelination. By integrating this model into clinical practice, we aim to enhance understanding and communication regarding the role of NfL in MS pathology and its potential utility as a biomarker. Full article

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS), characterized by inflammation, demyelination, and neurodegeneration, resulting in the disruption of axonal signal conduction. Optic neuritis (ON) occurs in over 70% of MS cases, highlighting the involvement of the optic nerve in the progression of the disease. Optic nerve atrophy secondary to the inflammatory episode can be observed during fundoscopy as pallor in the temporal quadrant or of the entire optic disc. Our study aims to evaluate the diagnostic capacity of fundus ophthalmoscopy when compared with the temporal thickness of the pRNFL (peripapillary retinal nerve fiber layer) measured using optical coherence tomography (OCT). Methods: We analyzed 88 eyes from 44 relapsing remitting MS patients using fundus photography (FP) and OCT optic disc measurements, correlating the temporal pallor of the optic disc seen in fundus photographs (FPs) with structural parameters obtained using OCT. Results: Our analysis revealed the significant capacity of optic disc pallor grading using FPs in MS patients in order to discriminate between normal and quadrants with pallor (p = 0.006) or strong pallor (p = 0.003) and between ones with light pallor and moderate pallor (p = 0.002) or strong pallor (p = 0.001), while being unable to clearly differentiate between normal quadrants and ones with light pallor (p = 0.608) or between pallor and strong pallor (p = 0.33). Conclusions: Fundoscopy and FP are useful screening tools in evaluating optic nerve atrophy in MS patients that could be used to assess neurodegeneration because of their universal availability. With the proposed inclusion of the optic disc as the fifth part of the CNS, the optic nerve will benefit from multiple exploratory techniques in order to increase the understanding of disease progression and patient quality of life. Full article

Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment. Full article

Amyotrophic lateral sclerosis (ALS), commonly known as motor neuron disease, is a neurodegenerative disorder characterized by the progressive degeneration of both upper and lower motor neurons. This pathological process results in muscle weakness and can culminate in paralysis. To date, the precise etiology of ALS remains unclear. However, a burgeoning body of research indicates that axonal dysfunction is a pivotal element in the pathogenesis of ALS and significantly influences the progression of disease. Dysfunction of axons in ALS can result in impediments to nerve impulse transmission, leading to motor impairment, muscle atrophy, and other associated complications that severely compromise patients’ quality of life and survival prognosis. In this review, we concentrate on several key areas: the ultrastructure of axons, the mechanisms of axonal degeneration in ALS, the impact of impaired axonal transport on disease progression in ALS, and the potential for axonal regeneration within the central nervous system (CNS). Our objective is to achieve a more holistic and profound understanding of the multifaceted role that axons play in ALS, thereby offering a more intricate and refined perspective on targeted axonal therapeutic interventions. Full article

Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system (CNS) but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN∆7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. We provide essential new ultrastructural data on focal and segmental lesions in the myofibrillar contractile apparatus. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation–contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the growing body of evidence indicating the existence of intrinsic alterations in the skeletal muscle in SMA and further reinforces the relevance of this peripheral tissue as a key therapeutic target for the disease. Full article

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). In most patients, the disease starts with an acute onset followed by a remission phase, subsequent relapses and a later transition to steady chronic progression. In a minority of patients, this progressive phase develops from the beginning. MS relapses are characterized predominantly by the de novo formation of an inflammatory CNS lesion and the infiltration of immune cells, whereas the pathological features of MS progression include slowly expanding lesions, global brain atrophy and an inflammatory response predominantly mediated by macrophages/microglia. Importantly, this CNS-intrinsic pathophysiology appears to initiate early during the relapsing–remitting disease phase, while it turns into the key clinical MS feature in later stages. Currently approved disease-modifying treatments for MS are effective in modulating peripheral immunity by dampening immune cell activity or preventing the migration of immune cells into the CNS, resulting in the prevention of relapses; however, they show limited success in halting MS progression. In this manuscript, we first describe the pathological mechanisms of MS and summarize the approved therapeutics for MS progression. We also review the treatment options for progressive MS (PMS) that are currently under investigation. Finally, we discuss potential targets for novel treatment strategies in PMS. Full article

(1) Objective: This study investigated the relationship between long-term particulate matter (PM_2.5) exposure and optic disc parameters—vertical cup-to-disc ratio (vCDR), vertical optic disc diameter (vDD), and vertical optic cup diameter (vCD)—in patients with type 2 diabetes mellitus (T2DM). (2) Methods: A cross-sectional analysis was conducted using data from 65,750 T2DM patients in the 2017–2018 Shanghai Cohort Study of Diabetic Eye Disease (SCODE). Optic disc parameters were extracted from fundus images, and PM_2.5 exposure was estimated using a random forest model incorporating satellite and meteorological data. Multivariate linear regression models were applied, adjusting for confounders including age, gender, body mass index, blood pressure, glucose, time of T2DM duration, smoking, drinking, and physical exercise. (3) Results: A 10 μg/m³ increase in PM_2.5 exposure was associated with significant reductions in vCDR (−0.008), vDD (−42.547 μm), and vCD (−30.517 μm) (all p-values < 0.001). These associations persisted after sensitivity analyses and adjustments for other pollutants like O₃ and NO₂. (4) Conclusions: Long-term PM_2.5 exposure is associated with detrimental changes in optic disc parameters in patients with T2DM, suggesting possible optic nerve atrophy. Considering the close relationship between the optic nerve and the central nervous system, these findings may also reflect broader neurodegenerative processes. Full article

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disorder and shares many radiological and clinical features with other more prevalent myelopathies. Here, we quantified spinal cord and brain volumes in adults with HAM/TSP in comparison with healthy volunteers (HVs) and individuals diagnosed with relapsing–remitting or progressive multiple sclerosis (RRMS or P-MS). Clinical disability and MRI were assessed in 24 HVs, 43 HAM/TSP subjects, and 46 MS subjects. Spinal cord cross-sectional area (SCCSA) and brain tissue volumes were measured and compared. HAM/TSP subjects had significantly lower SCCSA corresponding to cervical levels 2 and 3 (C2–3) (54.0 ± 8 mm²), cervical levels 4 and 5 (C4–5) (57.8 ± 8 mm²), and thoracic levels 4 to 9 (T4–9) (22.7 ± 4 mm²) and significantly elevated brain white matter hyperintensity (WMH) fraction (0.004 ± 0.008) compared to the HVs (C2–3: 69.4 ± 8 mm², C4–5: 75.1 ± 9 mm², T4–9: 34.1 ± 4 mm²; all p < 0.0001; and WMH: 0.0005 ± 0.0007; p < 0.001). In the HAM/TSP subjects, SCCSA at all levels but not WMH showed a significant correlation with clinical disability scores. WMH in HAM/TSP subjects, therefore, may not be related to clinical disability. SCCSA in our limited RRMS cohort was higher than the HAM/TSP cohort (C2–3: 67.6 ± 8 mm², C4–5: 72.7 ± 9 mm², T4–9: 33.4 ± 5 mm²; all p < 0.0001) and WMH was lower than in P-MS subjects (p = 0.0067). Principal component analysis suggested that SCCSA and WMH may be used to differentiate HAM/TSP from MS. Understanding these differences msay help establish early diagnostic criteria for HAM/TSP patients. Full article

Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of the art: The most pronounced OL is usually associated with Dementia with Lewy Bodies (DLB). While the view about the normosmic course of Multiple System Atrophy (MSA) remains unchanged, research indicates that mild OL may occur in a subset of patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). This might be linked to the deposition of abnormal protein aggregates in the central nervous system. Clinical significance: The aim of this review is to discuss the role of OL and its degree and pattern in the pathogenesis and course of APs. Olfactory testing could serve as a non-invasive, quick screening tool to differentiate between APs and project disease progression. Future directions: There is a need for further evaluation of this topic. This may lead to the development of standardized olfactory testing protocols that could be implemented in clinical practice, making differential diagnosis of APs more convenient. Understanding differences in the sense of smell could create an avenue for more targeted therapeutic strategies. Full article

The blood–brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE), and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. At the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, which induce antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS through autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert–Eaton myasthenic syndrome, and they were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage. Full article

Background/Objectives: Bladder outlet obstruction (BOO) resulting from benign prostate enlargement (BPE) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with central nervous system (CNS) diseases, such as spinal cord injury (SCI), Parkinson’s disease (PD), cerebrovascular accident (CVA) and multiple systemic atrophy (MSA), commonly experience lower urinary tract dysfunction. Men who suffer from CNS diseases may also experience symptoms related to BPE and BOO, which pose an additional burden to their overall clinical status and result in the need for catheter use and a deterioration in quality of life. The aim of this study was to identify if prostate surgery will benefit men with CNS diseases who have been diagnosed with BPE-related BOO. Methods: The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. EMBASE, MEDLINE, Cochrane systematic reviews, Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov were searched from 1946 up to July 2023 for peer-reviewed publications addressing the primary outcome (success rate) and the secondary outcomes (postoperative changes in incontinence episodes, urodynamic parameters, questionnaire scores, and quality of life). In addition, the perioperative outcomes (adverse events and the need for further medical or surgical therapy) were reported. Results: A total of 1572 abstracts were screened, and 13 studies involving 1144 patients were eligible for inclusion. Six studies assessed the effect of prostate surgery for BPE-related BOO in SCI, four studies in CVA, two studies in PD, and one study in the MSA population. All studies were considered to have a high risk of bias. Transurethral resection of the prostate (TURP) was the most common de-obstruction procedure, followed by prostatic artery embolism and open prostatectomy. The overall pooled success rate was calculated as 81.4% (65–100%) in SCI, 27.1% (9–70%) in PD, and 66.7% (50–79%) in CVA populations. The risk of de novo incontinence was 24.7–50% in SCI, 20% in PD, 21–50% in CVA, and 60% in MSA population. In patients with SCI with BPE-related BOO, prostate surgery improved mean bladder compliance and detrusor filling pressure and resolved detrusor overactivity in up to 50% of patients. Improvement of free flow rate, voided volume, and post-void residual was observed in all patients. Patients with CVA had an increased risk of perioperative mortality compared to non-CVA patients, and the risk of postoperative complications was inversely proportional to the timing of the CVA insult since surgery. Conclusions: This systematic review provides an overview of the available evidence on the outcome of prostate surgery in patients with neurologic diseases and BPE-related BOO. Identifying the optimal practice was challenging due to the limited availability of high-quality studies and the high variability of the reported outcomes. Properly selected patients with neurological diseases may benefit from prostate surgery, provided that preoperative investigations indicate BPE-related BOO. Full article

Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota–gut–brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut–brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer’s disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer’s neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson–Konovalov disease (WD), multisystem atrophy (MSA), Huntington’s chorea (HC), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut–brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases. Full article

Background/Objectives: Increasing evidence shows an involvement of brain plasticity mechanisms in both motor and central manifestations of neuromuscular disorders (NMDs). These mechanisms could be specifically addressed with neuromodulation or rehabilitation protocols. The aim of this scoping review is to summarise the evidence on plasticity mechanisms’ involvement in NMDs to encourage future research. Methods: A scoping review was conducted searching the PubMed and Scopus electronic databases. We selected papers addressing brain plasticity and central nervous system (CNS) studies through non-invasive brain stimulation techniques in myopathies, muscular dystrophies, myositis and spinal muscular atrophy. Results: A total of 49 papers were selected for full-text examination. Regardless of the variety of pathogenetic and clinical characteristics of NMDs, studies show widespread changes in intracortical inhibition mechanisms, as well as disruptions in glutamatergic and GABAergic transmission, resulting in altered brain plasticity. Therapeutic interventions with neurostimulation techniques, despite being conducted only anecdotally or on small samples, show promising results; Conclusions: despite challenges posed by the rarity and heterogeneity of NMDs, recent evidence suggests that synaptic plasticity may play a role in the pathogenesis of various muscular diseases, affecting not only central symptoms but also strength and fatigue. Key questions remain unanswered about the role of plasticity and its potential as a therapeutic target. As disease-modifying therapies advance, understanding CNS involvement in NMDs could lead to more tailored treatments. Full article

Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases. Full article

Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes. Full article