Folic Acid Treatment for Patients with Vascular Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND: As the life expectancy of elderly people has drastically increased, the incidence of cardiovascular and cerebrovascular diseases in this population has proportionally grown. Vascular cognitive impairment (VCI) refers to all forms of cognitive disorder associated with cerebrovascular disease. Homocysteine has recently been recognized as a contributor to the pathomechanisms involved in cognitive impairment. B vitamins, such as folic acid, are known to be effective in lowering homocysteine levels. AIM OF THE STUDY: To evaluate the efficacy of folic acid in patients with VCI. METHODS: We conducted a systematic review and meta-analysis of research on folic acid treatments for VCI. Only randomized controlled trials studies that compared the efficacy of folic acid to placebo or other interventions were considered, irrespective of publication status, year of publication, and languages. Two independent reviewers searched the Medline via Ovid, EMBASE and Cochrane Central Register of Controlled Trials (Central) journal databases up to July 2021 and independently appraised the included studies. We used mean difference outcome with 95% confidence intervals (CI) to calculate the change of Mini-Mental State Examination (MMSE), cognitive function domain, and concentration of homocysteine. RESULTS: We found three studies comparing folic acid with placebo and one study comparing folic acid with other interventions. There is only slight evidence that the MMSE score in patients who received Folic Acid increased 0.3 point higher compared to the placebo group after 24 months (95% CI:-0.12-0.37; p=0.31). There is very strong evidence that the concentration of Homocysteine in the Folic Acid group became 6.16 µmol/L lower compared to the placebo group after 6 months (95% CI:2.32-8.21 lower; p<0.001). CONCLUSIONS: Our review shows the effectiveness of folic acid in lowering plasma homocysteine concentration after 6 months period compared to placebo. However, this effect is not accompanied by improvement in cognitive function.

Effectiveness of physiotherapy interventions in brain plasticity, balance and functional ability in stroke survivors: A randomized controlled trial.

BACKGROUND: Brain injuries such as strokes cause damage and death of the neuron cells. Physiotherapy interventions help to improve patient's performance and ability. However, this is only theorized but the impact of the physiotherapy intervention on brain plasticity is not known. OBJECTIVE: The present study aimed to investigate the effect of physiotherapy interventions on brain neuroplasticity by evaluating the brain plasticity regeneration, balance and functional ability. METHODS: A randomized controlled trial was conducted with 64 stroke patients from three hospitals in the Surakarta region, Indonesia. Control groups (n = 32) received conventional physiotherapy and intervention groups (n = 32) received neurorestoration protocol, which both lasted for seven days. Efficacy of the interventions were measured on brain-derived neurotropic factor serum analysis, Berg Balance Scale and Barthel Index, respectively. RESULTS: Both groups showed improvements in all parameters but only balance and functional performance had a statistically significant outcome. CONCLUSION: Neurorestoration protocol that combined several established physiotherapy interventions was effective in improving balance and functional ability of stroke patients in only a seven days period.

Determining the association between polymorphisms of the DAT1 and DRD4 genes with attention deficit hyperactivity disorder in children from Java Island.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3'UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6-13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allele between both groups (p > 0.05). No association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes found in Indonesian children. This data suggest that DAT1 and DRD4 do not contribute to etiology of ADHD in Indonesian children. Further studies are needed to clarify association between VNTR polymorphism of DAT1 and DRD4 genetic with ADHD of Indonesian children in larger sample size and family based study.

Decision Tree Clinical Algorithm for Screening of Mild Cognitive Impairment in the Elderly in Primary Health Care: Development, Test of Accuracy, and Time-Effectiveness Analysis.

Mild cognitive impairment (MCI) is predicted to be a common cognitive impairment in primary health care. Early detection and appropriate management of MCI can slow the rate of deterioration in cognitive deficits. The current methods for early detection of MCI have not been satisfactory for some doctors in primary health care. Therefore, an easy, fast, accurate and reliable method for screening of MCI in primary health care is needed. This study intends to develop a decision tree clinical algorithm based on a combination of simple neurological physical examination and brief cognitive assessment for distinguishing elderly with MCI from normal elderly in primary health care. This is a diagnostic study, comparative analysis in elderly with normal cognition and those presenting with MCI. We enrolled 212 elderly people aged 60.04-79.92 years old. Multivariate statistical analysis showed that the existence of subjective memory complaints, history of lack of physical exercise, abnormal verbal semantic fluency, and poor one-leg balance were found to be predictors of MCI diagnosis (p ≤ 0.001; p = 0.036; p ≤ 0.001; p = 0.013). The decision trees clinical algorithm, which is a combination of these variables, has a fairly good accuracy in distinguishing elderly with MCI from normal elderly (accuracy = 89.62%; sensitivity = 71.05%; specificity = 100%; positive predictive value = 100%; negative predictive value = 86.08%; negative likelihood ratio = 0.29; and time effectiveness ratio = 3.03). These results suggest that the decision tree clinical algorithm can be used for screening of MCI in the elderly in primary health care.

The Effectiveness of Early Mobilization Time on Balance and Functional Ability after Ischemic Stroke.

BACKGROUND: Early mobilisation (EM) after-ischemic stroke is a motor learning intervention aimed to restore nerve cells and to improve balance and functional ability. Unfortunately, the study of when this intervention began has not been widely studied. AIM: On this study was compared the effect of EM started at 24 hours and 48 hours after an ischemic stroke on balance and functional ability. MATERIAL AND METHODS: Randomized controlled trial involving 40 patients on 2 groups meeting predefined inclusion criteria. The levels of balance were measured using the Berg Balance Scale, and the functional ability was measured using the Barthel Index, at 5th and 7th day. RESULTS: A significant difference was observed in both balance (p = 0.038) and functional ability (p = 0.021) obtained on the 7th day of assessment between both groups. A significant difference on the 5th day was observed only in the functional ability (p = 0.002) and not in the balance (p = 0.147), between the groups. CONCLUSION: EM started at 24 hours after the ischemic stroke has been found to have a better impact on balance and functional ability compared to that at 48 hours.

Comparison of Mean VEGF-A Expression Between Acute Ischemic Stroke Patients and Non-Ischemic Stroke Subjects.

BACKGROUND: Glucose and oxygen supply to neurons are disrupted during acute ischemic stroke, resulting in hypoxia. This event, in turn, activates the transcription of hypoxia-inducible factor (HIF-1), which is responsible for activating genes responsible for angiogenesis, including vascular endothelial growth factor (VEGF). VEGF and their receptor systems exert complex mechanisms of angiogenesis, including the stimulator, inhibitors, angiogenic and modulator. VEGF-A is the primary regulator of angiogenesis, both during physiological and pathological conditions. Nevertheless, the role of VEGF on the prognosis of hypoxia remains controversial. AIM: The purpose of this study was to address if there is any difference between the mean expression of VEGF-A between acute ischemic patients and non-ischemic stroke subjects. METHODS: This was an observational study with a cross-sectional design, the population in this research is the acute ischemic stroke patients and non-ischemic stroke subjects, which were admitted on Emergency Room and later treated in the Stroke Unit, Dr Sardjito General Hospital, Yogyakarta, Indonesia. Subjects were recruited using the purposive method, yielding a total of 64 subjects on both groups. Diagnosis of acute ischemic stroke was established using a head CT scan. Patients who meet the inclusion criteria and willing to participate in the study were asked to provide informed consent. Laboratory analysis was conducted during the first 24 hours after being treated at Stroke Unit, Dr Sardjito General Hospital, Yogyakarta, Indonesia, with venous blood was withdrawn VEGF-A levels between acute ischemic stroke and non-ischemic stroke subjects were subsequently compared. Categorical variables (including gender) were tested using either chi-square or Fisher exact test. Interval data was examined using student t-test if data distribution was normal. RESULTS: As many as 35 acute ischemic stroke and 35 non-ischemic stroke patients were included in the study, among whom were 18 men (51.43%) and 17 women (48.57%) among stroke patients and 21 (60%) men and 14 (40%) women among subjects without stroke. The average of the subject's age on stroke and non-ischemic stroke group was 58.51 and 48.57 years old. VEGF-A levels were significantly higher in the non-stroke group (561.77 ± 377.92) compared with stroke group (397.78 ± 181.53) with p = 0.02. CONCLUSION: expression of VEGF-A in acute ischemic stroke group was lower when compared with the non-stroke group.

Association between Increased Matrix Metalloproteinase-9 (MMP-9) Levels with Hyperglycaemia Incidence in Acute Ischemic Stroke Patients.

BACKGROUND: Hyperglycemia is common in acute stroke patients. Hyperglycemia can induce the production of reactive oxygen species, causing increased activity of matrix metalloproteinase-9 (MMP-9). AIM: This study aimed to determine an association between the increased levels of MMP-9 and the incidence of hyperglycemia in acute ischemic stroke patients. METHODS: This is a case-control study. Acute ischemic stroke patients admitted to the Stroke Unit of a reference hospital in Yogyakarta, Indonesia was divided into the hyperglycemic and non-hyperglycemic group. Demographic and clinical characteristics of each subject were recorded, and blood levels of MMP-9 were measured. Seventy-one patients were recruited, 40 subjects in the hyperglycemic group and 31 subjects in the non-hyperglycemic group. RESULTS: The median levels of blood MMP-9 level in the hyperglycemic and non-hyperglycemic group were 974.37 and 748.48 ng/mL, respectively, and the difference was statistically not significant (95% CI, 191.24-2849.53; p = 0.07). When the calculated cut-off point of 600.99 ng/mL was used, the proportion of patients with higher MMP-9 levels was significantly more in the hyperglycemic group compared with the ones in the non-hyperglycemic group (82.5% and 54.8%, respectively; OR = 3.88; p = 0.011). CONCLUSION: We concluded that the proportion of patients with MMP-9 level >600.99 ng/mL was significantly higher in acute ischemic stroke patients with hyperglycemia.

Vascular Endothelial Growth Factor 936 C/T Gene Polymorphism in Indonesian Subjects with Diabetic Polyneuropathy.

AIM: This study aimed to confirm the role of f VEGF gene 936 C/T polymorphism and Diabetic Polyneuropathy (DPN) in the Indonesian population as well as to investigate its relationship with VEGF-A level and the role of vascular risk factors. MATERIAL AND METHODS: This was a cross-sectional study involving 152 subjects. Clinical symptoms and signs of DPN were examined using DNE and DNS scoring followed by nerve conduction study. All subjects underwent anthropometric, clinical examination and laboratory procedures to obtain body mass index, HbA1C level, lipid profile, Polymorphism of +936 C/T VEGF gene (PCR-RFLP technique), and VEGF-A plasma level (ELISA). Statistical analysis using a t-test or Mann-Whitney was performed to assess continuous data and Chi-square for categorical data. Multivariate logistic regressions were also performed to determine the relationship between independent variables and DPN. RESULTS: Sixty-nine (45.4%) fulfilled the diagnostic criteria of DPN. There was a significant association between CT + TT genotype and DPN (OR 0.35 95%CI 0.16-0.79 p = 0.01). Multivariate logistic regression showed that plasma VEGF-A level (OR = 1.003; 95% CI = 1.000-1.007; p = 0.03), diabetes duration (OR = 1.108; 95% CI = 1.045-1.175; p = 0.001), and CT+TT genotype (OR = 0.347; 95%CI = 0.148-0.817; p = 0.013) were associated with DPN. Sub-group analysis on subjects with HbA1C level ≥7% showed that VEGF-A (OR = 1.011; 95%CI = (1.004-1.017; p = 0.03), diabetes duration (OR = 1.245; 95% CI = 1.117-1.388; p < 0.001), CT + TT genotype (OR = 0.259; 95%CI = 0.074-0.911p = 0.035), with an adition of HDL (OR = 0.916; 95% CI = 0.857-0.978; p = 0.009) were significant predictors of DPN while LDL (OR = 1.017; 95% CI = 1.000-1.035; p = 0.053) acted as modifying factor. CONCLUSION: It appeared that CT + TT genotype of VEGF +936 gene might act as a protecting factor for DPN while VEGF-A, diabetes duration, HDL, and LDL acted as risk factors especially on subjects with HbA1C level ≥ 7.

The role of insulin receptor substrate 1 gene polymorphism Gly972Arg as a risk factor for ischemic stroke among Indonesian subjects.

OBJECTIVE: The identification of new genetic-associated risk factor of ischemic stroke could improves strategies for stroke prevention. This study aims to identify insulin receptor substrate 1 (IRS-1) gene polymorphism Gly972Arg as the risk factor for ischemic stroke among Indonesian subjects. The case-control study was conducted by matching the gender and race on 85 cases of patients with ischemic stroke and 86 healthy non-stroke control subjects. Ischemic stroke was established by the complete neurology examination and brain computed tomography scan or magnetic resonance imaging. Polymerase chain reaction-Restriction Fragment Length Polymorphism was performed to analyze IRS-1 gene Gly972Arg genotype. RESULTS: There were 85 ischemic stroke cases and 86 control subjects. The distribution of nucleotide IRS-1 gene polymorphism Gly972Arg in the ischemic stroke vs health controls for GG were 32.2% vs 41.5%, for GR were 16% vs 7.6%, and for RR were 0.5% vs 1.9%. IRS-1 gene polymorphism Gly972Arg was found as significant risk factor for ischemic stroke [odds ratio of 2.6 (1.27-5.27); CI 95%, p = 0.008]. Conclusively, the IRS-1 gene polymorphism Gly972Arg should be considered as an important factor in the prevention and treatment of ischemic stroke.

Cytidine 5'-diphosphocholine administration prevents peripheral neuropathic pain after sciatic nerve crush injury in rats.

BACKGROUND: Cytidine 5'-diphosphocholine (citicoline) has been shown to have beneficial effects in central nervous system injury as well as in motoric functional recovery after peripheral nerve injury. This study aimed to examine the effect of citicoline on prevention of neuropathic pain in a rat model of sciatic nerve crush injury. METHODS: Forty experimental rats were divided into four groups. In three groups, the right sciatic nerves were crushed in the mid-thigh region, and a gelatin sponge moistened with 0.4 or 0.8 mL of 100 µmol/L citicoline, or saline 0.4 mL in the control group, was applied. The fourth group of rats was sham-operated, ie the sciatic nerve was exposed with no crush. Functional assessments were performed 4 weeks after crush injury. von Frey filaments (100 g threshold) were used to assess neuropathic pain. In addition, the sciatic functional index and extensor postural thrust (EPT) tests were used to assess motoric function. RESULTS: The crush/citicoline 0.4 mL group had a lower percentage of pain (23.53%, n=17) compared with the crush/saline group (53.33%, n=15, P<0.005). The crush/citicoline 0.4 mL group also showed better motoric recovery, as seen in stronger EPT results (P<0.001). However, the sciatic functional index analysis did not show significant differences between groups (P=0.35). The crush/citicoline 0.8 mL group showed a higher percentage of pain (66.67%, n=18) and less EPT recovery. These results may be explained by more severe nerve injury due to compression with a larger administered volume. CONCLUSION: In situ administration of 0.4 mL of 100 µmol/L citicoline prevents the occurrence of neuropathic pain and induces motoric recovery, evaluated by EPT test, 4 weeks after sciatic nerve injury.

Effectiveness of Gotu Kola Extract 750 mg and 1000 mg Compared with Folic Acid 3 mg in Improving Vascular Cognitive Impairment after Stroke.

This study aimed to determine the effectiveness of gotu kola (Centella asiatica) in improving cognitive function in patients with vascular cognitive impairment (VCI). This study uses a quasi-experimental design. Subjects in this study were patients with poststroke cognitive impairment who were treated at two hospitals in Yogyakarta, Indonesia. The number of subjects was 48: 17 subjects were treated with 1000 mg/day of gotu kola extract, 17 subjects treated with 750 mg/day of gotu kola extract, and 14 subjects treated with 3 mg/day of folic acid for 6 weeks. A Montreal Cognitive Assessment-Indonesian version (MoCA-Ina) was conducted at the beginning of treatment and after 6 weeks of therapy. It was found that all trials effectively improved poststroke VCI based on MoCA-Ina scores over the course of the study. There is no significant difference in ΔMoCA-Ina (score at the 6th week of treatment - score at the beginning) mean score among the three groups, indicating that gotu kola is as effective as folic acid in improving poststroke VCI. Gotu kola was shown to be more effective than folic acid in improving memory domain. This study suggested that gotu kola extract is effective in improving cognitive function after stroke.

Attention Deficit/Hyperactivity Disorder (ADHD): age related change of completion time and error rates of Stroop test.

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children throughout the world. The Stroop test has been widely used for the evaluation of ADHD symptoms. However, the age-related change of the Stroop test results has not been fully clarified until now. METHODS: Sixty-five ADHD and 70 age-matched control children aged 6-13 years were enrolled in this study. ADHD was diagnosed based on DSM-IV criteria. We examined the completion time and error rates of the Congruent Stroop test (CST) and Incongruent Stroop test (IST) in ADHD and control children. RESULTS: No significant difference was observed in the completion time for CST or IST between the ADHD and control children at 6-9 years old. However, ADHD children at 10-13 years old showed significantly delayed completion time for the CST and IST compared with controls of the same age. As for the error rates of the CST and IST, ADHD and control children at 6-9 years old showed no difference. However, error rates of CST and IST in the ADHD children at 10-13 years were significantly higher than those of control of the same age. CONCLUSIONS: Age may influence the results of Stroop test in ADHD children. For the ages of 10-13 years old, the Stroop test clearly separates ADHD children from control children, suggesting that it may be a useful screening tool for ADHD among preadolescent children.