Identification of four novel mutations in VSP13A in Iranian patients with Chorea-acanthocytosis (ChAc).

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder characterized by a variety of involuntary movements, predominantly chorea, and the presence of acanthocytosis in peripheral blood smears. ChAc is caused by mutations in the vacuolar protein sorting-associated protein 13A (VPS13A) gene. The aim of the present study was to conduct a clinical and genetic analysis of five patients with suspected ChAc in Iran. This study included five patients who were referred to the genetic department of the Endocrinology and Metabolism Research Institute between 2020 and 2022, with a suspicion of ChAc. Clinical features and the presence of characteristic MRI findings were evaluated in the patients. Whole-exome sequencing (WES) followed by Sanger sequencing was employed to identify the disease-causing variants. The functional effects of novel mutations were analyzed by specific bioinformatics prediction tools. WES and data analysis revealed the presence of five distinct VPS13A mutations in the patients, four of which were novel. These included one nonsense mutation (p.L984X), and three splice site mutations (c.755-1G>A, c.144+1 G>C, c.2512+1G>A). All mutations were validated by Sanger sequencing, and in silico analysis predicted that all mutations were pathogenic. This study provides the first molecular genetic characteristics of Iranian patients with ChAc, identifying four novel mutations in the VPS13A gene. These findings expand the VPS13A variants spectrum and confirm the clinical variability in ChAc patients.

Outcome predictors in anterior and posterior ischemic strokes: a study based on the Iranian SITS registry.

Ischemic stroke is the major form of stroke with two separate vascular territories. Many risk factors are related to stroke outcomes in both territories. The present descriptive research was carried out on the basis of data obtained from the Safe Implementation of Treatments in Stroke (SITS) registry on Iranian intravenous thrombolysis ischemic stroke cases. Vascular territory involved in each case and three-month excellent outcome, functional independence, mortality rate, and brain hemorrhage occurrence were determined. Univariable and multivariable logistics regression analyses were utilized in order to investigate association of ischemic stroke outcomes with the vascular territory involved and other related factors. Among 1566 patients 95.4% was anterior circulation stroke patients and 4.6% was posterior circulation stroke cases. There is no significant association between vascular territory with mortality (OR of PCS vs ACS: 0.74, 95% CI 0.37-1.46), excellent functional outcome (OR 0.72, 95% CI 0.44-1.19), functional outcome (OR 0.86, 95% CI 0.52-1.42) and local hemorrhage (OR 0.98, 95% CI 0.30-3.21). Among major risk factors, age, diabetes, NIHSS score and admission duration, increased significantly odds of three-month mortality, excellent outcome, and functional independence in the multivariate analysis. The highest of odds was in NIHSS score with a dose-response association. The vascular territory was not an outcome predictor in ischemic strokes. The most important predictor was baseline NIHSS.

Safety and Outcomes of Intravenous Thrombolytic Therapy in Ischemic Stroke Patients with COVID-19: CASCADE Initiative.

BACKGROUND: There is little information regarding the safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke and COVID-19. METHODS: This multicenter study included consecutive stroke patients with and without COVID-19 treated with IV-tPA between February 18, 2019, to December 31, 2020, at 9 centers participating in the CASCADE initiative. Clinical outcomes included modified Rankin Scale (mRS) at hospital discharge, in-hospital mortality, the rate of hemorrhagic transformation. Using Bayesian multiple regression and after adjusting for variables with significant value in univariable analysis, we reported the posterior adjusted odds ratio (OR, with 95% Credible Intervals [CrI]) of the main outcomes. RESULTS: A total of 545 stroke patients, including 101 patients with COVID-19 were evaluated. Patients with COVID-19 had a more severe stroke at admission. In the study cohort, 85 (15.9%) patients had a hemorrhagic transformation, and 72 (13.1%) died in the hospital. After adjustment for confounding variables, discharge mRS score ≥2 (OR: 0.73, 95% CrI: 0.16, 3.05), in-hospital mortality (OR: 2.06, 95% CrI: 0.76, 5.53), and hemorrhagic transformation (OR: 1.514, 95% CrI: 0.66, 3.31) were similar in COVID-19 and non COVID-19 patients. High-sensitivity C reactive protein level was a predictor of hemorrhagic transformation in all cases (OR:1.01, 95%CI: 1.0026, 1.018), including those with COVID-19 (OR:1.024, 95%CI:1.002, 1.054). CONCLUSION: IV-tPA treatment in patients with acute ischemic stroke and COVID-19 was not associated with an increased risk of disability, mortality, and hemorrhagic transformation compared to those without COVID-19. IV-tPA should continue to be considered as the standard of care in patients with hyper acute stroke and COVID-19.

Low-dose versus standard-dose alteplase for intravenous thrombolysis in patients with acute ischemic stroke in Iran: Results from the safe implementation of treatments in stroke registry.

Background: Rates of intracranial hemorrhage (ICH) after intravenous thrombolysis (IVT) differ depending on ethnicity, one reason that few Eastern countries have approved a lower dose of alteplase. Data in this regard are scarce in the Middle Eastern region. Methods: The present retrospective study was performed on data extracted from the Safe Implementation of Treatments in Stroke (SITS) registry. Computed tomography (CT) image analysis was based on the SITS-Monitoring Study (SITS-MOST) definition for symptomatic ICH (SICH). Functional outcome at 3 months was assessed using the modified Rankin Scale (mRS). Multivariate logistic regression including adjusted analysis was used for comparison between groups. Results: Of 6615 patients, 1055 were enrolled. A total of 86% (n = 906) received a standard dose and 14% (n = 149) received a low dose of alteplase. Favorable 3-month outcome was achieved in 481 (53%) patients in the standard group and 71 (48%) patients in the low-dose group [adjusted odds ratio (AOR) = 1.24, 95% confidence interval (CI): 0.87-1.75, P = 0.218]. SICH occurred in 14 (1.5%) patients in the standard group and 3 (2%) patients in the low-dose group [odds ratio (OR) = 2.77, 95% CI: 0.36-21.04, P = 0.120]. At 3 months, mortality occurred in 145 (16.0%) patients in the standard group and 29 (19.4%) patients in the low-dose group (OR = 1.22, 95% CI: 0.78-1.91, P = 0.346). Conclusion: Low-dose compared to standard-dose alteplase for patients with acute ischemic stroke (AIS) was not associated with fewer hemorrhagic events and there was no significant difference in the favorable 3-month outcome (mRS: 0-2) or mortality rate.

The correlation of serum adiponectin and insulin resistance with the presence and severity of dementia in non-obese Alzheimer's patients.

BACKGROUND AND AIMS: Alteration in the insulin signaling could contribute to the development of Alzheimer's disease (AD) through metabolic or inflammatory processes, adipokines could affect insulin dysregulation. This study aimed to investigate whether there is a correlation between serum adiponectin level alteration and insulin resistance with the presence and severity of AD, compared to normal controls. METHODS: This analytical observational study was conducted on 60 non-overweight and non-diabetic participants who were assigned to AD patients (n = 34) and healthy volunteers (n = 26). The diagnosis and severity of dementia were evaluated by the same protocol, and the Mini-Mental Score Exam (MMSE) questionnaire was utilized to collect the data. Moreover, adiponectin concentration, fasting blood sugar, and plasma insulin levels were measured using enzyme-linked immunosorbent assay. Furthermore, the homeostasis model assessment for insulin resistance (HOMA-IR) was utilized in this study. RESULTS: The mean ages of the AD patients and control participants were 71.35 and 70.46, respectively. In addition, the mean values of the serum adiponectin level of the participants were 9660 and 12,730 ng/mL in control and AD groups, respectively (P ≤ 0.05). Additionally, the insulin resistance (IR) was 2.90 and 5.10 in the control and AD groups, respectively (P ≤ 0.05). According to the results, there was a significant positive correlation between serum adiponectin level and HOMA-IR in the AD group; however, no significant correlation was observed between serum adiponectin level and MMSE score in this group. The MMSE score of AD patients significantly decreased by 1.2 times with an increase in each score of the IR (P ≤ 0.05). CONCLUSION: A significant direct positive correlation was observed between the serum adiponectin level and IR among the AD patients. However, a significant decrease in cognition levels was detected following an increase in IR scores of the AD patients.

Prevalence of Multiple Sclerosis (MS) in Zanjan Province of Iran.

BACKGROUND: The prevalence of multiple sclerosis (MS) varies in different geographical regions and has dramatically increased in Iran. Revealing the high prevalence rate draws the attention of policymakers and helps them allocate necessary resources. The aim of this study is to determine the prevalence of MS in Zanjan province of Iran. METHODS: We included all registered residents of Zanjan province with MS on the prevalence day (July 31, 2019). All cases met the McDonald criteria. All registered cases in Zanjan MS society were identified as index cases. Data regarding patient's national code, gender, age, age at the first symptom onset, city of residence, marital status, education level, occupation, ethnicity, family history of MS and the time span between symptom's onset and disease diagnosis were recorded. RESULTS: We identified 758 patients, 551 of whom (72.7%) were female. The mean age at the first symptom onset was 28.9 ±8.7 years old. The crude prevalence was 71.6 per 100,000 population (95% CI 66.6-76.9). The disease was most prevalent in Zanjan city (100.5 per 100,000). The gender-specific prevalence per 100,000 population was 105.4 for women (95% CI: 96.8-114.6) and 38.7 for men (95% CI: 33.6-44.1), with female to male ratio of 2.6. The standardized mortality ratio (SMR) was calculated as expected/observed for both men and women as 2.3 (207/88.2) (551/234.1). CONCLUSIONS: Our data confirm that the MS prevalence rate is high in Zanjan province of Iran.

Stroke Care Trends During COVID-19 Pandemic in Zanjan Province, Iran. From the CASCADE Initiative: Statistical Analysis Plan and Preliminary Results.

BACKGROUND: The emergence of the COVID-19 pandemic has significantly impacted global healthcare systems and this may affect stroke care and outcomes. This study examines the changes in stroke epidemiology and care during the COVID-19 pandemic in Zanjan Province, Iran. METHODS: This study is part of the CASCADE international initiative. From February 18, 2019, to July 18, 2020, we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in Valiasr Hospital, Zanjan, Iran. We used a Bayesian hierarchical model and an interrupted time series analysis (ITS) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the National Institutes of Health Stroke Scale (NIHSS)], disability [measured by the modified Rankin Scale (mRS)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. We compared in-hospital mortality between study periods using Cox-regression model. RESULTS: During the study period, 1,026 stroke patients were hospitalized. Stroke hospitalization rates per 100,000 population decreased from 68.09 before the pandemic to 44.50 during the pandemic, with a significant decline in both Bayesian [Beta: -1.034; Standard Error (SE): 0.22, 95% CrI: -1.48, -0.59] and ITS analysis (estimate: -1.03, SE = 0.24, p < 0.0001). Furthermore, we observed lower admission rates for patients with mild (NIHSS < 5) ischemic stroke (p < 0.0001). Although, the presentation time and door-to-needle time did not change during the pandemic, a lower proportion of patients received thrombolysis (-10.1%; p = 0.004). We did not see significant changes in admission rate to the stroke unit and in-hospital mortality rate; however, disability at discharge increased (p < 0.0001). CONCLUSION: In Zanjan, Iran, the COVID-19 pandemic has significantly impacted stroke outcomes and altered the delivery of stroke care. Observed lower admission rates for milder stroke may possibly be due to fear of exposure related to COVID-19. The decrease in patients treated with thrombolysis and the increased disability at discharge may indicate changes in the delivery of stroke care and increased pressure on existing stroke acute and subacute services. The results of this research will contribute to a similar analysis of the larger CASCADE dataset in order to confirm findings at a global scale and improve measures to ensure the best quality of care for stroke patients during the COVID-19 pandemic.

Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE).

BACKGROUND AND PURPOSE: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic. METHODS: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center. CONCLUSION: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.

The association between serum 25-hydroxyvitamin D level and subclinical atherosclerosis in healthy population.

Background: Subclinical atherosclerosis is the asymptomatic phase of carotid atherosclerosis, and its early diagnosis is important to prevent cerebrovascular diseases. Although the vitamin D plays a role in the structure of vessels, the association between the serum level of vitamin D and subclinical atherosclerosis has not been well-studied. We aimed to investigate the association between serum vitamin D level and carotid artery intima-media thickness (CIMT) in Iranian population. Methods: One hundred individuals with the age range from 20 to 50 years with no history of cardiovascular risk factors were selected for the analysis. Measurements of serum 25-hydroxyvitamin D3 [25(OH) D3] concentration and CIMT were made. Confounding factors such as diabetes, hypertension (HTN), smoking, alcohol, tobacco, dyslipidemia, cardiovascular disease (CVD), high body mass index (BMI), history of drug intake especially calcium, vitamin D, statins, and anti-hypertensive drugs were considered and then excluded from our study. Results: The mean serum vitamin D level was 15.55 ± 0.42 ng/ml, whereas in the increased intima-media thickness (IMT), it was 12.50 ± 9.50 ng/ml. 55% of the subjects were diagnosed with subclinical atherosclerosis (IMT ≥ 0.75 mm). Mean IMT was 0.74 ± 0.12 mm; however, it was higher (0.86 ± 0.30) in severe vitamin D deficiency group. The analysis showed an association between serum 25(OH) D3 level and CIMT (P = 0.002). 44% of those participants with subclinical atherosclerosis had also a severe vitamin D deficiency, while only 13% of normal people had a severe vitamin D deficiency. Also, a correlation was observed between severe vitamin D deficiency and the presence of plaque or higher IMT. Conclusion: Serum 25(OH) D3 level was inversely correlated with CIMT in our investigated subjects with no cardiovascular risk factor.

Altered plasma visfatin levels and insulin resistance in patients with Alzheimer's disease.

Central insulin resistance is involved in the pathophysiology of Alzheimer's disease (AD). Visfatin (VIS), an adipokine secreted from peripheral adipose tissue, is involved in energy balance and weight control. Besides its metabolic roles, VIS possesses insulin-mimetic, anti-apoptotic, and neuroprotective properties. In this study, we assessed the presence of a correlation between plasma VIS level and insulin resistance or AD. Sixty participants were enrolled in this study; 34 patients with AD and 26 healthy subjects. All subjects underwent comprehensive evaluations including Mini-mental score exam (MMSE) for the diagnosis of dementia. Subjects with MMSE score < 24 were added to the AD group, while healthy subjects should have a MMSE score > 27. Fasting blood sugar (FBS) and insulin levels were measured by enzyme-linked immunosorbent assay. The results indicate a significant elevation in FBS from 103 ± 3.0 to 147 ± 7.6 in AD patients (p ≤ 0.001). Additionally, 71% of AD patients developed insulin resistance, as the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index increased from 2.9 ± 0.5 in healthy subjects to 5.2 ± 0.7 in AD patients (p ≤ 0.05). Body mass index and serum insulin level did not show a significant alteration, but serum VIS levels were significantly (p ≤ 0.01) lower in AD patients (11.15 ± 1.9 ng/ml) in comparison to control group (21.09 ± 2.3 ng/ml). There is a negative correlation between plasma VIS level and the HOMA-IR index (p < 0.05). The results of this study present clear evidence for systemic insulin resistance and decreased serum VIS level in non-obese, non-overweight patients with moderate to severe AD.