A Mutual Nexus Between Epilepsy and α-Synuclein: A Puzzle Pathway.

Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship.

Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease that affects various parts of the central nervous system. Fatigue, a common symptom, transient, prolonged, or chronic experienced by individuals with MS, can significantly impact daily functioning. It can be associated with underlying pathological processes or can have an idiopathic cause, such as chronic fatigue syndrome (CFS). The study aimed to assess the presence and etiology of fatigue in MS patients and its relationship with CFS. MATERIALS AND METHODS: This cross-sectional study was conducted in the Eastern Province of Saudi Arabia. Data were collected using a questionnaire from a sample of 225 MS patients receiving care at our university hospital. The questionnaire included the Centers for Disease Control and Prevention (CDC) criteria for diagnosing CFS and the Expanded Disability Status Scale to evaluate fatigue in MS patients. RESULTS: Of the total of 225 MS patients who participated in this study, 87.1% were diagnosed with relapsing-remitting MS, 6.7% with primary progressive MS, 3.6% with clinically isolated syndrome, and 2.7% with secondary progressive MS. About 53% had experienced fatigue that persisted for over 6 months. Analysis of CFS diagnosis revealed that 7.3% of patients met both CDC criteria and self-reported answers while 17.5% reported having CFS despite not meeting the CDC criteria. These findings highlight a significant lack of agreement between patient-reported diagnoses and established criteria, indicating poor agreement (P = 0.028). CONCLUSION: The study found an association between CFS and MS, and a significant impact on daily functioning. The study revealed lack of agreement between patient-reported diagnoses and established criteria for CFS. This emphasizes the need for a standardized approach to diagnosis and evaluation of fatigue in MS patients.

Endovascular thrombectomy for acute ischemic stroke in Saudi Arabia: A single-center experience.

PURPOSE: This study aimed to investigate the outcomes of endovascular thrombectomy-treated patients in King Fahad Medical City, Riyadh, Saudi Arabia. METHODS: A retrospective cohort study of acute ischemic stroke patients treated with endovascular thrombectomy. Patients were included in the study between January 2015 and December 2022. Good outcomes were defined as a modified Rankin Scale (mRS) of 0-2 at 90 days. Multivariate logistic regression analysis was performed to identify the independent factors associated with good outcomes. RESULTS: During the study period, 369 patients with acute ischemic stroke (mean ± SD age, 61/- 15.1 yrs; 55.4 % male) underwent mechanical thrombectomy. Median National Institute of Health Stroke Scale (NIHSS) 15. Intravenous thrombolysis was administered to 34.5 % of the patients. Successful recanalization in the anterior circulation was achieved in 84.8 % of patients. Data from mRS performed after 90 days in the anterior circulation were available for 71.2 % of the patients. Of these, 41 % showed a good outcome, and the mortality rate was 22.4 %. The significant factors associated with good outcomes were age, NIHSS score, Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and short arterial puncture to recanalization. CONCLUSION: The number of patients who underwent endovascular thrombectomy has increased over time. The treatment outcomes and mortality were comparable with those of previous endovascular thrombectomy registries despite the high prevalence of DM, lower ASPECT score, and prolonged onset-to-recanalization time.

Role of Brain Liver X Receptor in Parkinson's Disease: Hidden Treasure and Emerging Opportunities.

Parkinson's disease (PD) is a neurodegenerative disease due to the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). The liver X receptor (LXR) is involved in different neurodegenerative diseases. Therefore, the objective of the present review was to clarify the possible role of LXR in PD neuropathology. LXRs are the most common nuclear receptors of transcription factors that regulate cholesterol metabolism and have pleiotropic effects, including anti-inflammatory effects and reducing intracellular cholesterol accumulation. LXRs are highly expressed in the adult brain and act as endogenous sensors for intracellular cholesterol. LXRs have neuroprotective effects against the development of neuroinflammation in different neurodegenerative diseases by inhibiting the expression of pro-inflammatory cytokines. LXRs play an essential role in mitigating PD neuropathology by reducing the expression of inflammatory signaling pathways, neuroinflammation, oxidative stress, mitochondrial dysfunction, and enhancement of BDNF signaling.In conclusion, LXRs, through regulating brain cholesterol homeostasis, may be effectual in PD. Also, inhibition of node-like receptor pyrin 3 (NLRP3) inflammasome and nuclear factor kappa B (NF-κB) by LXRs could effectively prevent neuroinflammation in PD. Taken together, LXRs play a crucial role in PD neuropathology by inhibiting neuroinflammation and associated degeneration of DNs.

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer's disease: a new perspective.

Alzheimer's disease (AD) is the most common type of dementia associated with amyloid beta (Aß) deposition. Dysfunction of the neuronal clearance pathway promotes the accumulation of Aß. The plasminogen-activating system (PAS) is controlled by various enzymes like tissue plasminogen activators (tPA). Neuronal tPA enhances the conversion of plasminogen to plasmin, which cleaves Aß; this function is controlled by many inhibitors of PAS, including a plasminogen-activating inhibitor (PAI-1) and neuroserpin. Therefore, the objective of the present narrative review was to explore the potential role of tPA/neuroserpin in the pathogenesis of AD. PAI-1 activity is increased in AD, which is involved in accumulating Aß. Progressive increase of Aß level during AD neuropathology is correlated with the over-production of PAI-1 with subsequent reduction of plasmin and tPA activities. Reducing plasmin and tPA activities promote Aß by reducing Aß clearance. Neuroserpin plays a critical role in the pathogenesis of AD as it regulates the expression and accumulation of Aß. Higher expression of neuroserpin inhibits the neuroprotective tPA and the generation of plasmin with subsequent reduction in the clearance of Aß. These observations raise conflicting evidence on whether neuroserpin is neuroprotective or involved in AD progression. Thus, neuroserpin over-expression with subsequent reduction of tPA may propagate AD neuropathology.

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aß). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aß. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aß and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aß. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aß clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.

Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator.

Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy's involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy.

The Molecular Pathway of p75 Neurotrophin Receptor (p75NTR) in Parkinson's Disease: The Way of New Inroads.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease of the brain. PD is characterized by motor and non-motor symptoms. The p75 neurotrophin receptor (p75NTR) is a functional receptor for different growth factors including pro-brain derived neurotrophic factor (pro-BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Consequently, this review aimed to illustrate the detrimental and beneficial role of p75NTR in PD. Diverse studies showed that p75NTR and its downstream signaling are intricate in the pathogenesis of PD. Nevertheless, pro-apoptotic and pro-survival pathways mediated by p75NTR in PD were not fully clarified. Of note, p75NTR plays a critical role in the regulation of dopaminergic neuronal survival and apoptosis in the CNS. Particularly, p75NTR can induce selective apoptosis of dopaminergic neurons and progression of PD. In addition, p75NTR signaling inhibits the expression of transcription factors which are essential for the survival of dopaminergic neurons. Also, p75NTR expression is connected with the severity of dopaminergic neuronal injury. These verdicts implicate p75NTR signaling in the pathogenesis of PD, though the underlying mechanistic pathways remain not elucidated. Collectively, the p75NTR signaling pathway induces a double-sword effect either detrimental or beneficial depending on the ligands and status of PD neuropathology. Therefore, p75NTR signaling seems to be protective via phosphoinositide 3-kinase (PI3K)/AKT and Bcl-2 and harmful via activation of JNK, caspase 3, nuclear factor kappa B (NF-κB), and RhoA pathways.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

The potential link between acromegaly and risk of acute ischemic stroke in patients with pituitary adenoma: a new perspective.

Acromegaly is an endocrine disorder due to the excess production of growth hormone (GH) from the anterior pituitary gland after closed epiphyseal growth plates. Acromegaly is mainly caused by benign GH-secreting pituitary adenoma. Acute ischemic stroke (AIS) is one of the most common cardiovascular complications. It ranks second after ischemic heart disease (IHD) as a cause of disability and death in high-income countries globally. Thus, this review aimed to elucidate the possible link between acromegaly and the development of AIS. The local effects of acromegaly in the development of AIS are related to the development of pituitary adenoma and associated surgical and radiotherapies. Pituitary adenoma triggers the development of AIS through different mechanisms, particularly aneurysmal formation, associated thrombosis, and alteration of cerebral microcirculation. Cardiovascular complications and mortality were higher in patients with pituitary adenoma. The systemic effect of acromegaly-induced cardio-metabolic disorders may increase the risk for the development of AIS. Additionally, acromegaly contributes to the development of endothelial dysfunction (ED), inflammatory and oxidative stress, and induction of thrombosis that increases the risk for the development of AIS. Moreover, activated signaling pathways, including activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB), nod-like receptor pyrin 3 (NLRP3) inflammasome, and mitogen-activated protein kinase (MAPK) in acromegaly may induce systemic inflammation with the development of cardiovascular complications mainly AIS. Taken together, acromegaly triggers the development of AIS through local and systemic effects by inducing the formation of a cerebral vessel aneurysm, the release of pro-inflammatory cytokines, the development of oxidative stress, ED, and thrombosis correspondingly.

Assessment of Knowledge and Perception Regarding Deep Brain Stimulation Among Medical Students in Saudi Arabia.

BACKGROUND:  Deep brain stimulation (DBS) is a neurosurgical procedure approved for treating psychiatric and movement disorders, including Parkinson's disease (PD), essential tremor, dystonia, and other neurological conditions. The widespread use of DBS may not be reflected in the medical education curricula in Saudi universities, thus jeopardizing future patients' access to it. This study aims to investigate the knowledge and attitudes of medical students toward DBS as a therapeutic option. METHOD: A descriptive cross-sectional questionnaire-based study was conducted. The survey was distributed on online platforms to acquire responses from different regions of Saudi Arabia. The target population was medical students in the preclinical and clinical phases of medical education from different regions of Saudi Arabia. RESULTS: A total of 1075 medical students from various medical schools in Saudi Arabia were included. More than half of the students aged 21 to 23 (50.1%) were females (63.2%). More than half of the students have correctly recognized DBS as a Food and Drug Administration (FDA)-approved treatment (59.7%). Only 20.1% of the students stated that they received adequate education/training about DBS. About 53.8% of the students had self-rated their knowledge as poor, whereas 20.6% had rated their knowledge as good. A negative bias was more observed among the older students and students with a family history of DBS treatment. Half of the participants (54.1%) indicated that DBS is associated with severe adverse effects. A significant association between the level of knowledge about DBS and the academic level was observed. CONCLUSION: Almost half of the medical students had poor knowledge and unfavorable attitude toward DBS in Saudi Arabia. The current medical curricula are incommensurable with the clinical implications of DBS, which may deny future patients from such an effective therapeutic option. We recommend incorporating DBS teaching sessions to enhance future physicians' awareness and understanding of the benefits of this intervention.

Primary Hypothyroidism and Alzheimer's Disease: A Tale of Two.

Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer's disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aß) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aß and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true.

Risk Factors for Mortality in Patients With Cerebral Palsy: A Systematic Review and Meta-Analysis.

Cerebral palsy (CP) is a developmental and physical disorder with different degrees of severity. Since CP manifests itself in early childhood, numerous research studies have concentrated on children with CP. Patients with CP encounter different severity of motor impairments attributed to the damage or disturbance to the fetal or infant developing brain, which begins in early childhood and persists through adulthood. Patients with CP are more prone to mortality compared to the general population. This systematic review and meta-analysis aimed to assess the risk factors that predict and influence mortality in patients with CP. Systematic search for studies assessing the risk factors for mortality in CP patients that were conducted from 2000 to 2023 in Google Scholar, PubMed, and Cochrane Library was performed. R-One Group Proportion was used for statistical analysis and Newcastle-Ottawa Quality Assessment Scale (NOS) for quality appraisal. Of the 1791 total database searches, nine studies were included. Based on the NOS tool for quality appraisal, seven studies were of moderate quality, and two studies were rated as of high quality. The risk factors included pneumonia and other respiratory infections, neurological disorders, circulatory diseases, gastrointestinal infections, and accidents. Pneumonia (OR = 0.40, 95% CI = 0.31 - 0.51), neurological disorders (OR = 0.11, 95% CI = 0.08 - 0.16), respiratory infections (OR = 0.36, 95% CI = 0.31 - 0.51), cardiovascular and circulatory diseases (OR = 0.11, 95% CI = 0.04 - 0.27), gastrointestinal and metabolic causes (OR = 0.12, 95% CI = 0.06 - 0.22), and accidents (OR = 0.05, 95% CI = 0.04 - 0.07) were the risk factors assessed. It was concluded that multiple factors predict the risk of mortality in patients with CP. Pneumonia and other respiratory infections are associated with a high risk of mortality. Cardiovascular and circulatory diseases, gastrointestinal and metabolic disorders, and accidents are strongly linked to mortality in CP patients.

Intramuscular Versus Intravenous Treatment of Status Epilepticus: A Systematic Review.

Status epilepticus is a neurological emergency associated with high morbidity and mortality with fatal outcomes if not treated well. The goal of this study was to compare the intramuscular and intravenous treatment of individuals with status epilepticus. A search was performed on Scopus, PubMed, Embase, and Web of Science databases for articles published in the English language in peer-reviewed publications up to March 1, 2023. Studies were included if the treatment of status epileptics was compared either directly or indirectly between intramuscular and intravenous methods. In addition, relevant papers were manually screened for in the reference lists of the included studies. Non-duplicate articles were identified. Finally, five articles were included in the analysis, of which four were randomized controlled trials and one was a retrospective cohort study. The intramuscular midazolam group's time until the first seizure stopped was significantly shorter than the intravenous diazepam group's time (7.8 versus 11.2 minutes, respectively; p = 0.047). Moreover, the percentage of patients admitted was significantly lower in the intramuscular group than in the intravenous group (p = 0.01), but the lengths of stay in the intensive care unit and the hospital did not differ significantly between the groups. Regarding seizure recurrence, the intramuscular group had fewer incidences of recurrent seizures. Finally, there were no appreciable differences in safety outcomes between the two treatment arms. During the analysis, different outcomes reported after the use of intramuscular and intravenous treatments in managing patients with status epilepticus were categorized. This categorization led to a clear view of the efficacy and safety of intramuscular versus intravenous treatments in managing status epilepticus patients. The information at hand indicates that intramuscular therapy is just as successful as intravenous therapy in treating people with status epilepticus. The availability, adverse effect profile, logistics of administration, cost, and whether it is included in hospital formularies are some of the factors to be taken into consideration when choosing the drug administration technique.

An Assessment of Dementia Knowledge and Its Associated Factors Among Health College Students in Saudi Arabia.

Background Dementia is a public health concern and the main cause of impairment and dependency among the elderly worldwide. It is characterized by a progressive decline in cognition, memory, and all domains of quality of life with preserving the level of consciousness. Accurate measurement of dementia knowledge among future health professionals is required to improve targeted educational initiatives and supportive care of patients. This study aimed to assess knowledge of dementia and its associated factors among health college students in Saudi Arabia. Methods A descriptive, cross-sectional study was conducted among health college students from various regions in Saudi Arabia. Data on sociodemographic characteristics and dementia knowledge were gathered using a standardized study questionnaire Dementia Knowledge Assessment Scale (DKAS) distributed on different social media platforms. Data analysis was carried out using IBM SPSS Statistics for Windows, Version 24.0 (IBM Corp., Armonk, NY, USA) statistical software. A P-value of <0.05 was considered significant. Results A total of 1,613 participants were included in the study. The mean age was 20.5 ± 2.5 years (range 18-25 years). The majority of them were males (64.9%), and females represented 35.1%. The mean knowledge score of the participants was 13.68 ± 3.18 (out of 25). According to DKAS subscales, we found that the respondents scored the highest in care considerations (4.17 ± 1.30) and the lowest in risks and health promotion (2.89 ± 1.96). Furthermore, we found that the participants with no previous dementia exposure had a significantly higher level of knowledge than those with previous dementia exposure. In addition, we found that both genders, aged 19, 21, 22, 23, 24, and 25 years; the geographic distribution of respondents; and previous dementia exposure significantly affected the DKAS score. Conclusions Our findings showed that health college students in Saudi Arabia had poor knowledge about dementia. Ongoing health education and comprehensive academic training are recommended to improve their knowledge and provide competent care for dementia patients.