The impact of medial temporal and parietal atrophy on cognitive function in dementia.

Although medial temporal atrophy (MTA) and parietal atrophy (Koedam score) have been used to diagnose Alzheimer's disease (AD), early detection of other dementia types remains elusive. The study aims to investigate the association between these brain imaging markers and cognitive function in dementia. This cross-sectional study collected data from the Memory Clinic of Dr. Sardjito General Hospital Yogyakarta, Indonesia from January 2020 until December 2022. The cut-off value of MTA and Koedam score was set with Receiver Operating Curve. Multivariate analysis was performed to investigate the association between MTA and Koedam score with cognitive function. Of 61 patients, 22.95% had probable AD, 59.01% vascular dementia, and 18.03% mixed dementia. Correlation test showed that MTA and Koedam score were negatively associated with Montreal Cognitive Assessment-Indonesian Version (MoCA-INA) score. MTA score ≥ 3 (AUC 0.69) and Koedam score ≥ 2 (AUC 0.67) were independently associated with higher risk of poor cognitive function (OR 13.54, 95% CI 1.77-103.43, p = 0.01 and OR 5.52, 95% CI 1.08-28.19, p = 0.04). Higher MTA and Koedam score indicate worse cognitive function in dementia. Future study is needed to delineate these findings as prognostic markers of dementia severity.

Symptom-based scoring technique by machine learning to predict COVID-19: a validation study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) surges, such as that which occurred when omicron variants emerged, may overwhelm healthcare systems. To function properly, such systems should balance detection and workloads by improving referrals using simple yet precise and sensitive diagnostic predictions. A symptom-based scoring system was developed using machine learning for the general population, but no validation has occurred in healthcare settings. We aimed to validate a COVID-19 scoring system using self-reported symptoms, including loss of smell and taste as major indicators. METHODS: A cross-sectional study was conducted to evaluate medical records of patients admitted to Dr. Sardjito Hospital, Yogyakarta, Indonesia, from March 2020 to December 2021. Outcomes were defined by a reverse-transcription polymerase chain reaction (RT-PCR). We compared the symptom-based scoring system, as the index test, with antigen tests, antibody tests, and clinical judgements by primary care physicians. To validate use of the index test to improve referral, we evaluated positive predictive value (PPV) and sensitivity. RESULTS: After clinical judgement with a PPV of 61% (n = 327/530, 95% confidence interval [CI]: 60% to 62%), confirmation with the index test resulted in the highest PPV of 85% (n = 30/35, 95% CI: 83% to 87%) but the lowest sensitivity (n = 30/180, 17%, 95% CI: 15% to 19%). If this confirmation was defined by either positive predictive scoring or antigen tests, the PPV was 92% (n = 55/60, 95% CI: 90% to 94%). Meanwhile, the sensitivity was 88% (n = 55/62, 95% CI: 87% to 89%), which was higher than that when using only antigen tests (n = 29/41, 71%, 95% CI: 69% to 73%). CONCLUSIONS: The symptom-based COVID-19 predictive score was validated in healthcare settings for its precision and sensitivity. However, an impact study is needed to confirm if this can balance detection and workload for the next COVID-19 surge.

Psychometric properties of Indonesian version of sleep condition indicator for screening poststroke insomnia.

BACKGROUND: No study has examined the psychometric properties of the sleep condition indicator (SCI) for screening poststroke insomnia in the Indonesian population. We aimed to develop the Indonesian version of the sleep condition indicator (ISCI) and to examine its psychometric properties for screening adult patients in late sub-acute and chronic periods after stroke. METHODS: This was a cross-sectional study with two stages. In the first stage, the English version of the SCI was translated into the ISCI using standard procedures. The psychometric properties of the ISCI were tested in the second stage. Internal consistency and test-retest reliability of ISCI were used to evaluate reliability. A confirmatory factor analysis (CFA) was performed to test construct validity. To test concurrent and convergent validity, the Indonesian version of the insomnia severity index (ISI-INA), generalized anxiety disorder questionnaire (IGAD-7), and patient health questionnaire (IPHQ-9) were used. A receiver operating characteristic (ROC) analysis was conducted to calculate the optimal cutoff score of the ISCI on the basis of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for insomnia. RESULTS: A total of 160 adults with a diagnosis of stroke for more than 3 months were included (median age of 58.5 years, 31% met the DSM-5 criteria for insomnia). The ISCI had a satisfactory Cronbach's alpha of 0.89 and test-retest reliability of 0.78. The CFA revealed that the ISCI exhibited a satisfactory model fit and was associated with the ISI-INA, IGAD-7, and IPHQ-9 (r = -0.81, -0.32, and -0.52, respectively; all P < .001). The ROC test revealed that the optimal cutoff point of ≤23 yielded the highest sensitivity (94%) and specificity (97%). CONCLUSION: The study results revealed that the 8-item ISCI is a reliable and valid screening tool for detecting insomnia symptoms according to the DSM-5 criteria in the chronic period after stroke.

Measurement of Social Strain in People with Dementia: A Preliminary Study of the Reliability and Validity of the Negative Relationship Quality Questionnaire in Indonesia.

People with dementia (PWD) may exhibit symptoms that negatively affect their relationships with their families or friends which could cause social strain. The Negative Relationship Quality (NRQ) questionnaire can be used to measure social strain in PWD. There has never been an Indonesian adaptation of the NRQ. This preliminary study aimed to measure the validity and reliability of the NRQ among PWD in Indonesia (NRQ-INA). This study used a cross-sectional design. Forward−backward translation methods were conducted first. Pearson's correlation and factor analysis were employed for the validity test. Cronbach's alpha and test−retest were used to determine reliability. The NRQ-INA has four parallel items related to social strain that are divided into three subscales and asked to spouse/partner, family members, and friends, leading to a total of 12 questions. The results of validity testing from 60 respondents showed that all items in the NRQ-INA were strongly valid with correlation coefficients (r) of >0.8 (p < 0.01). Factor analysis showed a convergence with the variance explained of more than 50% for all items in each subscale, which also indicated that NRQ-INA had acceptable construct validity to measure social strain. Cronbach's alpha values (α) were 0.926, 0.942, and 0.938 for the subscales of spouse, friends, and family members, respectively. The correlations of test−retest reliability for all items were >0.7 (p < 0.01), demonstrating a reliable NRQ-INA measurement. In conclusion, NRQ-INA had a good validity and reliability to measure social strain in PWD. Further study of the concurrent validity among PWD is still needed.

Dementia in a patient with autoimmune disease and hypercoagulable state worsened by COVID-19 vaccination: A case report.

Background: Systemic autoimmune disorders are associated with an increased risk of hypercoagulability. The hypercoagulable state in people with systemic autoimmune disorders has lately gained attention. Presentation of case: We presented a 44-year-old male with a chief complaint of progressive difficulty concentrating, memory impairment, and weakness in all limbs. Seven months before admission to our Memory Clinic, the patient began to have infrequent short-term memory loss and sometimes got lost when he went for a drive. Three months later, he complained of feeling dizzy when in a crowd, being unable to watch television for a long time, and easily forgetting. Computed tomography (CT) scan showed brain infarction. After receiving the first dose of COVID-19 vaccine (Sinovac), the patient had difficulty communicating verbally and could only point at objects, as well as tetraparesis. These conditions severely intervened in his daily activities. The patient was then referred to an immunologist and diagnosed with autoimmune disease. In our Memory Clinic, his performances of attention, memory, language, visuospatial, and executive function were very poor. We diagnosed him with autoimmune dementia. The administration of methylprednisolone, mycophenolate mofetil, vitamin D3, donepezil, and memantine could improve his condition. Discussion: Autoimmune disease can cause microvascular thrombosis and microembolism at the central nervous system level, which would cause vascular damage and cognitive impairment leading to brain infarction and dementia. Conclusion: There seems to be a link between autoimmune disease, hypercoagulable state, and dementia, although the magnitude of this link and the underlying processes are not fully understood.

Awareness of Being at Risk of Stroke and Its Determinant Factors among Hypertensive Patients in Banyumas, Indonesia.

Background: The global burden of stroke is still high, particularly in developing countries, with hypertension serving as the main risk factor. The awareness of stroke among hypertensive patients is crucial for stroke prevention. This study was aimed at identifying the awareness of being at risk of stroke and its determinant factors among hypertensive patients in Banyumas, Indonesia. Methods: This was a cross-sectional study conducted in Primary Health Centers (PHCs) in Banyumas Regency, Indonesia, from April to August 2019. A simple random sampling technique was used to select the representatives' PHCs. Hypertensive patients who came regularly to the PHCs were consecutively recruited. Data were collected through a self-reported questionnaire and medical records. The main outcome was the level of participants' awareness of being at risk of stroke. Multivariate logistic regression analysis was performed to measure determinant factors associated with the level of awareness. Results: Out of 457 patients investigated, 77.46% had a low level of awareness. Low knowledge of hypertension, low income, and no history of previous stroke were associated with a low-level of awareness (odds ratio (OR) 1.942, 95% CI 1.195-3.158, p 0.007; OR 2.321, 95% CI 1.326-4.064, p 0.003; and OR 6.033, 95% CI 2.450-14.858, p < 0.001, respectively). Conclusion: Majority of hypertensive patients were unaware of being at risk of stroke. Knowledge of hypertension, income, and history of previous stroke are factors that may influence the awareness of being at risk of stroke among them. This emphasizes the need to provide better campaigns and education programs to raise the awareness of stroke in a community setting, particularly for the population at risk.

Development and validation of the World Health Organization disability Assessment Schedule 2.0 (WHODAS 2.0) Indonesian version in stroke survivors.

PURPOSE: Stroke is the third most common cause of disability worldwide. In order to effectively study the disability status experienced by stroke survivors, it is important to identify reliable and valid tools to measure disability that can be administered to this population. No previous study had been conducted on the Indonesian version of the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). The aim of this study was to develop and validate the Indonesian version of the WHODAS 2.0 for stroke survivors in Indonesia. METHODS: Following translation and back-translation, the Indonesian version of the WHODAS 2.0 was administered to 183 stroke survivors. We used all six domains of the WHODAS 2.0, with the exception of four items of "work or school activities" in domain 5. Internal consistency was measured by Cronbach's alpha, the inter-rater reliability was measured by interclass correlations (ICCs), and the construct validity was tested with an exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). RESULTS: The range of Cronbach's alpha was 0.86-0.92, which indicated excellent reliability, and ICC was very good at 0.87-0.99. The EFA and CFA for the main 32-item questionnaire exhibited a total variance of 95% (KMO) and a p value of <0.05. The factor loadings per items were >0.4, and all the model fit indices were acceptable. CONCLUSIONS: The WHODAS 2.0 was adapted for use in Indonesia and showed good results for all six domains. Therefore, the Indonesian version of the WHODAS 2.0 can be applied to assess disability in Indonesian stroke survivors.Implications for rehabilitationThe WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) was developed as a single, generic instrument for assessing the health status and disability in different cultures and settings.In this study, we adapted and validated an Indonesian version of the WHODAS 2.0 for stroke survivors in Indonesia.The WHODAS 2.0 was adapted for use in Indonesia and showed good results for all six domains.The Indonesian version of the WHODAS 2.0 can be applied to assess disability in Indonesian stroke survivors.

HDACi protects against vascular cognitive impairment from CCH injury via induction of BDNF-related AMPA receptor activation.

We previously showed a hydroxamic acid-based histone deacetylase inhibitor (HDACi), compound 13, provides neuroprotection against chronic cerebral hypoperfusion (CCH) both in vitro under oxygen-glucose deprivation (OGD) conditions and in vivo under bilateral common carotid artery occlusion (BCCAO) conditions. Intriguingly, the protective effect of this HDACi is via H3K14 or H4K5 acetylation-mediated differential BDNF isoform activation. BDNF is involved in cell proliferation and differentiation in development, synaptic plasticity and in learning and memory related with receptors or synaptic proteins. B6 mice underwent BCCAO and were randomized into 4 groups; a sham without BCCAO (sham), BCCAO mice injected with DMSO (DMSO), mice injected with HDACi-compound 13 (compound 13) and mice injected with suberoylanilide hydroxamic acid (SAHA). The cortex and hippocampus of mice were harvested at 3 months after BCCAO, and levels of BDNF, AMPA receptor and dopamine receptors (D1, D2 and D3) were studied using Western blotting analysis or immunohistochemistry. We found that the AMPA receptor plays a key role in the molecular mechanism of this process by modulating HDAC. This protective effect of HDACi may be through BDNF; therefore, activation of this downstream signalling molecule, for example by AMPA receptors, could be a therapeutic target or intervention applied under CCH conditions.

Roles and Problems of Stroke Caregivers: A Qualitative Study in Yogyakarta, Indonesia.

Background: Caregivers play a central role in post-stroke patients' care. However, the role of and problems managed by caregivers have not been widely studied, particularly in Indonesia. This study aims to explore the roles and problems of caregivers in post- stroke patients' care. Method: This was a qualitative study. Seven caregivers of post-stroke patients from the homecare clinic of Dr Sardjito General Hospital were purposely selected during January 2017 to June 2018. Focus group discussions were conducted to explore the roles and problems of caregiving. Results: Themes related to caregivers' roles were: connecting patients with medical personnel and other family members, maintaining patients' health conditions by fulfilling basic needs and assisting rehabilitation, as well as maintaining patients' psychological conditions by encouraging conversation, telling jokes, or recreation. On the other hand, themes related to caregivers' problems were: lack of knowledge caused by education inadequacy, underappreciated and unconcerned family, suboptimal service including limited physiotherapy and pharmacy resource, unthorough administration, lack of communication, physical limitations, and burnout, as well as uncooperative patients. Conclusions: Caregivers play essential roles as communicators and help to maintain patient's health conditions. Common problems are related to a lack of knowledge about strokes and a lack of attention from family. Further research to study the effects of these findings on the quality of life of both patient and their caregiver, as well as how to handle the caregiver issues should be investigated.

Higher level of acute serum VEGF and larger infarct volume are more frequently associated with post-stroke cognitive impairment.

BACKGROUND: Serum vascular endothelial growth factor (VEGF) and infarct volume detected by brain imaging have been associated with stroke outcome. However, the relationship of these two variables with post-stroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between acute serum VEGF levels and infarct volume with PSCI in ischemic stroke patients. METHODS: Fifty-six first-ever ischemic stroke patients who were hospitalized in Dr. Sardjito General Hospital Yogyakarta, Indonesia were prospectively recruited. Serum VEGF level was taken on day 5 of stroke onset and measured by ELISA. Infarct volume was calculated manually from head CT scan by expert radiologist. PSCI was assessed after 3 months follow up by using Montreal Cognitive Assessment-Indonesian version (MoCA-INA). We performed a ROC curve analysis to determine the cut-off point of VEGF level and infarct volume. Multivariate logistic regression analysis was performed to measure the contribution of VEGF level and infarct volume to PSCI after controlling covariates (demographic and clinical data). RESULTS: The mean age of PSCI and non-PSCI patients was 61.63% ± 8.47 years and 58.67% ± 9.01 years, respectively (p = 0.221). No differences observed for vascular risk factors, infarct location, and NIHSS in both groups. Multivariate logistic regression showed that patients with higher VEGF level alone (≥519.8 pg/ml) were 4.99 times more likely to have PSCI than those with lower VEGF level (OR = 4.99, 95% CI = 1.01-24.7, p = 0.048). In addition, patients with larger infarct volume alone (≥0.054 ml) were also more frequently associated with PSCI (OR = 7.71, 95% CI = 1.39-42.91, p = 0.019). CONCLUSIONS: Acute ischemic stroke patients with higher serum VEGF level (≥519.8 pg/ml) and larger infarct volume (≥0.054 ml) were more likely to have PSCI 3 months after stroke. These findings may contribute to predict PSCI earlier and thus better prevention strategy could be made.

HDAC inhibitor protects chronic cerebral hypoperfusion and oxygen-glucose deprivation injuries via H3K14 and H4K5 acetylation-mediated BDNF expression.

Vascular dementia (VaD) is the second most common cause of dementia, but the treatment is still lacking. Although many studies have reported that histone deacetylase inhibitors (HDACis) confer protective effects against ischemic and hypoxic injuries, their role in VaD is still uncertain. Previous studies shown, one HDACi protected against cognitive decline in animals with chronic cerebral hypoperfusion (CCH). However, the underlying mechanisms remain elusive. In this study, we tested several 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates, which act as HDACis in the CCH model (in vivo), and SH-SY5Y (neuroblastoma cells) with oxygen-glucose deprivation (OGD, in vitro). We identified a compound 13, which exhibited the best cell viability under OGD. The compound 13 could increase, in part, the protein levels of brain-derived neurotrophic factor (BDNF). It increased acetylation status on lysine 14 residue of histone 3 (H3K14) and lysine 5 of histone 4 (H4K5). We further clarified which promoters (I, II, III, IV or IX) could be affected by histone acetylation altered by compound 13. The results of chromatin immunoprecipitation and Q-PCR analysis indicate that an increase in H3K14 acetylation leads to an increase in the expression of BDNF promoter II, while an increase in H4K5 acetylation results in an increase in the activity of BDNF promoter II and III. Afterwards, these cause an increase in the expression of BDNF exon II, III and coding exon IX. In summary, the HDACi compound 13 may increase BDNF specific isoforms expression to rescue the ischemic and hypoxic injuries through changes of acetylation on histones.

Correction: Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0221750.].

Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion.

The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1ß, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30-50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1ß, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1ß, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.

Obesity Is Less Frequently Associated with Cognitive Impairment in Elderly Individuals: A Cross-Sectional Study in Yogyakarta, Indonesia.

Obesity is one of the factors associated with cognitive impairment. However, obesity may differently affect cognitive function in different age groups, and scarce data are available from low- and middle-income countries. This cross-sectional study aimed to identify the association between obesity and cognitive impairment among 143 elderly individuals in Yogyakarta. We recorded the sociodemographic factors and some comorbidities, also measured the body mass index as a parameter of obesity, cognitive function using Montreal Cognitive Assessment-Indonesia, mood condition and depression status using geriatric depression scale-short form, as well as the daily life function using Activity of Daily Living and Instrumental Activity of Daily Living. After adjustment for the sociodemographic and comorbidities, we found that subjects with older age were more likely to have cognitive impairment (odds ratio [OR] 3.544, 95%CI: 1.36-9.22, p < 0.01) and compared with elderly individuals with normal weight, obese elderly individuals were 40% less likely to have cognitive impairment (OR 0.604, 95%CI: 0.39-0.95, p < 0.05). This study suggests that obesity in elderly individuals is less frequently associated with cognitive impairment. These findings support the reverse causation mechanism related to body mass index (BMI) and cognitive impairment in low/middle-income countries.

Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.

BACKGROUND: Several clinical trials reported that clopidogrel was superior to aspirin in secondary stroke prevention by reducing the risk of major adverse cardiovascular events (MACE). We aimed to compare the efficacy of clopidogrel with aspirin in reducing one-year risk of MACE based on real-world evidence from Taiwan Health Insurance Database. METHODS: We identified ischemic stroke patients between 2000 and 2012 who took aspirin or clopidogrel within 7 days of stroke onset for 1-year follow-up. The primary outcome was one-year MACE including recurrent stroke, acute myocardial infarction, and death. Propensity score matching and conditional Cox proportional hazards regression were conducted to control the confounding factors. RESULTS: From 9,089 ischemic stroke patients, we found 654 patients on aspirin and 465 patients on clopidogrel who met the selective inclusion criteria. After propensity score matching, 379 patients were selected from each group. The clopidogrel group had a 1.78-fold MACE risk compared with the aspirin group at one-year follow-up (95% CI = 1.41-2.26, p<0.01). The MACE-free rate in the aspirin group was 15.74% higher than in the clopidogrel group at one-year follow-up. Sub-analysis of the three components of MACE showed that clopidogrel conferred higher risk of recurrent stroke (OR 1.43, 95% CI = 1.06-1.92, p 0.02) and acute myocardial infarction (OR 3.72, 95% CI = 1.04-13.3, p 0.04), but no different risk of death than that of aspirin. CONCLUSIONS: Among first-ever ischemic stroke patients, secondary stroke prevention using clopidogrel was associated with higher rates of MACE than aspirin. Aspirin might have better efficacy in secondary stroke prevention and was associated with lower risk of MACE. The real-world evidence raises the need to re-assess the current therapeutic options in secondary stroke prevention applying aspirin vs. clopidogrel.