Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Altered Gut Microbiota in Korean Children with Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and behavioral impairments. Recent studies have suggested that gut microbiota play a critical role in ASD pathogenesis. Herein, we investigated the fecal microflora of Korean ASD children to determine gut microbiota profiles associated with ASD. Specifically, fecal samples were obtained from 54 children with ASD and 38 age-matched children exhibiting typical development. Systematic bioinformatic analysis revealed that the composition of gut microbiota differed between ASD and typically developing children (TDC). Moreover, the total amounts of short-chain fatty acids, metabolites produced by bacteria, were increased in ASD children. At the phylum level, we found a significant decrease in the relative Bacteroidetes abundance of the ASD group, whereas Actinobacteria abundance was significantly increased. Furthermore, we found significantly lower Bacteroides levels and higher Bifidobacterium levels in the ASD group than in the TDC group at the genus level. Functional analysis of the microbiota in ASD children predicted that several pathways, including genetic information processing and amino acid metabolism, can be associated with ASD pathogenesis. Although more research is needed to determine whether the differences between ASD and TDC are actually related to ASD pathogenesis, these results provide further evidence of altered gut microbiota in children with ASD, possibly providing new perspectives on the diagnosis and therapeutic approaches for ASD patients.

A Preliminary Study to Determine Comprehensive Research and Development Plans for Promoting Mental Health Services.

OBJECTIVES: The aim of this study was to analyze research and development projects in mental health services in Korea, using priority evaluation of mental health promotion policies to determine direction of the service. METHODS: An online survey was conducted that targeted experts in the mental health service regarding promotion of mental health in Korea in 2016. The survey was based on 32 policy projects that resulted from 12 strategies according to 4 policy objectives. RESULTS: Analysis of 32 mental health projects were assessed regarding the possibility of technology development success, magnitude of the ripple effect, and necessity of a national response. It was observed that 3 policy projects relevant to suicide, had a high relative priority. This was followed by policies for improvement of health insurance and the medical benefit cost system, and policies for reinforcement of crisis psychological support such as those for disaster victims. CONCLUSION: The prioritization of mental health services should place an emphasis on promotion of a healthy mental lifestyle, rehabilitation support for patients with serious mental illness, and reinforcement of social safety networks for suicide prevention.

Changes in antipsychotic drug usage and factors affecting the use of typical drugs based on nationwide health insurance data in South Korea.

OBJECTIVES: To determine changes in antipsychotic drug usage in all South Korean patients with schizophrenia in 2011-2015 and factors affecting their utilisation in 2015. DESIGN AND SETTING: Retrospective cohort study using health insurance claims data on patients with schizophrenia in South Korea in 2011-2015. PARTICIPANTS: All treated patients with schizophrenia in South Korea in 2011-2015. The number of patients with schizophrenia was 171 302 in 2011, 175 488 in 2012, 177 763 in 2013, 180 079 in 2014 and 183 427 in 2015. MAIN OUTCOME MEASURES: Changes in antipsychotic drug usage and factors affecting the use of antipsychotics. RESULTS: Among patients with schizophrenia, there were tendencies of decreased use of antipsychotic combination therapy of typical drugs (from 11.5% to 7.5%) but increased use of combination therapy of atypical drugs (from 21.8% to 29.0%). Factors affecting the use of typical drugs were sex, age, geographical region, type of benefits/insurances and type of medical institutions. Use of typical antipsychotics was increased by age (OR=1.02, 95% CI 1.02 to 1.02). It was higher in men (OR=1.27, 95% CI 1.23 to 1.30) than that in women. It was higher in Medicaid benefiters (OR=4.49, 95% CI 4.35 to 4.64) than that in patients with health insurance. Use of typical drugs was higher among patients treated in general hospitals (OR=1.46, 95% CI 1.32 to 1.64), primary hospitals (OR=3.25, 95% CI 2.95 to 3.59), long-term care hospitals (OR=3.00, 95% CI 2.59 to 3.49) and clinics (OR=8.87, 95% CI 8.06 to 9.76) compared with that in tertiary care hospitals. Compared with metropolitan region, higher use of typical antipsychotics was seen in Gangwon (OR=1.14, 95% CI 1.05 to 1.25), Jeolla (OR=1.32, 95% CI 1.26 to 1.39) and Gyeongsang (OR=1.14, 95% CI 1.10 to 1.18) provinces. CONCLUSIONS: Results of this study confirmed changes of antipsychotic drug usage from typical to atypical antipsychotics in the treatment of schizophrenia and identified factors affecting the use of typical drugs, in contrast with current treatment trend in South Korea. These results may be used in the improvement of a medical system.

Correction to: Risk factors for relapse in patients with first-episode schizophrenia: analysis of the Health Insurance Review and Assessment Service data from 2011 to 2015.

[This corrects the article DOI: 10.1186/s13033-018-0187-1.].

Analysis of the Health Insurance Review and Assessment Service data from 2011 to 2015.

BACKGROUND: Schizophrenia is a recurrent, debilitating disease that is rarely curable. Rapid intervention after the first episode of schizophrenia has been shown to positively affect the prognosis. Unfortunately, basic data is scarce on first-episode schizophrenia in Korean patients making it difficult to create a comprehensive list of risk factors for relapse. This study aims to investigate the demographic characteristics and institutional factors of patients with first-episode schizophrenia in order to identify risk factors for relapse. METHODS: Data from the Health Insurance Review & Assessment Service (HIRA) was used for this study to represent the Korean patient population. To identify factors affecting relapse, we explored gender, age, geographic location, medical benefits, type of medical institution, type of medication used, medication adherence, and the severity of symptoms. Data analysis was performed using the Cox proportional hazard model. RESULTS: The number of patients diagnosed with first-episode schizophrenia in Korea over a 2-year period was 4567 of which 1265 (27.7%) patients experienced a relapse during the observational period. Factors affecting relapse included age, type of medical institution, type of medication used, medication adherence, and type of treatment (inpatient or outpatient) after the initial diagnosis, which varied depending upon the severity of symptoms. CONCLUSIONS: It was found that environmental and institutional factors as well as the type of medical treatment were crucial in determining whether patients with first-episode schizophrenia subsequently relapsed. The results of this study can be utilized as source material for directing therapeutic interventions and improving mental health policies in the future.

Mental health services and R&D in South Korea.

World Health Organization has asserted that mental illness is the greatest overriding burden of disease in the majority of developed countries, and that the socioeconomic burden of mental disease will exceed that of cancer and cardiovascular disorders in the future. The life-time prevalence rate for mental disorders in Korea is reported at 27.6 %, which means three out of 10 adults experience mental disorders more than once throughout their lifetime. Korea's suicide rate has remained the highest among Organization for Economic Cooperation and Development (OECD) nations for 10 consecutive years, with 29.1 people out of every 100,000 having committed suicide. Nevertheless, a comprehensive study on the mental health services and the Research and Development (R&D) status in Korea is hard to find. Against this backdrop, this paper examines the mental health services and the R&D status in Korea, and examines their shortcomings and future direction. The paper discusses the mental health service system, budget and human resources, followed by the mental health R&D system and budget. And, by a comparison with other OECD countries, the areas for improvement are discussed and based on that, a future direction is suggested. This paper proposes three measures to realize mid and long-term mental health promotion services and to realize improvements in mental health R&D at the national level: first, establish a national mental health system; second, forecast demand for mental health; and third, secure and develop mental health professionals.

Economic and clinical benefits of galantamine in the treatment of mild to moderate Alzheimer's disease in a Korean population: a 52-week prospective study.

To evaluate the impact of galantamine treatment on the function, caregiver time, and resource used in the treatment of patients with mild to moderate Alzheimer's disease (AD), costs and outcomes were evaluated during a 52-week prospective, randomized, double-blind, community-controlled trial of galantamine. Patients received either galantamine treatment (n=72) or no treatment (n=66). The analysis was performed from a societal perspective. Galantamine treatment reduced time spent caring for the patients and maintained improved functional capacity, whereas, when no treatments were given, a great increase in caregiver time and progressive functional deteriorations were observed. Saved caregiver time was equivalent to 113 working days per year. After 52 weeks, mean total annual costs per patient were 14,735,000 Korea Won (KRW) (USD 12,315) for patients with galantamine treatment and 25,325,000 KRW (USD 21,166) for patients without treatment. Adjusted annual cost saving of galantamine treatment was 6,428,000 KRW (USD 5,372) when compared to no treatment (p=0.0089). Galantamine had a beneficial effect not only to slow functional decline in patients with mild to moderate AD, but also to save a substantial amount of costs, closely related to reduction in caregiver burden and decrease in caregiver time.

Survey of medication adherence in patients with schizophrenia--Korean ADHES data.

BACKGROUND: This study evaluated the partial adherence to medication in schizophrenic patients in Korea. METHODS: The Adherence in Schizophrenia (ADHES) survey was conducted worldwide, including Asian countries. Through questionnaires for clinicians, caregivers and patients, information about medication adherence in patients with schizophrenia and factors affecting adherence were identified. This survey involved 131 psychiatrists from 80 psychiatry clinics and 2824 patients with schizophrenia were enrolled. RESULTS: Partial adherence in patients with schizophrenia was prevalent (over 60%) in Korea. From the psychiatrists' point of view, the most prevalent factors associated with partial adherence in their patients were poor awareness of the illness (85%) and embarrassment at having to take medication daily (80%). Psychiatrists believed that most patients (83%) needed help from someone to remind them to take the medication regularly. Of patients, 57% reported feeling upset at having to take medication daily and 76% of caregivers reported preferring long-acting medications. CONCLUSION: Based on the study results, a specific strategy to deal successfully with the prevalent partial adherence to medication in patients with schizophrenia should be developed, and long-acting medication may be one solution to improve partial adherence problems.

Comparative efficacy of risperidone versus haloperidol on behavioural and psychological symptoms of dementia.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) cannot be regarded as a single clinical syndrome, but rather as a heterogeneous group of symptoms, each of which can be considered as possible targets for therapy. OBJECTIVE: To compare the efficacy of risperidone and haloperidol on specific manifestations of BPSD. METHODS: A post-hoc analysis was conducted using data from an 18-week, randomized, double-blind, crossover head-to-head trial of risperidone vs haloperidol in treating 114 nursing-home residents with BPSD. Dependent variables were item scores of the Korean versions of the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD-K) and Cohen-Mansfield Agitation Inventory (CMAI-K). RESULTS: On the BEHAVE-AD-K, risperidone was significantly more effective than haloperidol in treating wandering (p = 0.0496), agitation (p = 0.0091), diurnal rhythm disturbances (p = 0.0137), anxiety regarding upcoming events (p = 0.0002), and other anxieties (p = 0.0088). On the CMAI-K, risperidone was significantly more effective in treating physical sexual advances (p = 0.0202), pacing and aimless wandering (p = 0.0123), intentional falling (p = 0.0398), hoarding things (p = 0.0499), performing repetitious mannerisms (p = 0.0048), repetitive sentence or questions (p = 0.0025), complaining (p = 0.0101), and negativism (p = 0.0027). Haloperidol was not significantly superior to risperidone on any individual item in either scale. CONCLUSIONS: When comparing treatment effects on individual symptoms frequently occurring in patients with dementia, risperidone significantly improved symptoms of agitation, wandering, diurnal rhythm disturbance and anxieties, among other symptoms, compared with haloperidol.

Effect of the apolipoprotein E epsilon4 allele on the efficacy and tolerability of galantamine in the treatment of Alzheimer's disease.

OBJECTIVE: To investigate the effect of the apolipoprotein E (ApoE) epsilon4 allele on the efficacy and tolerability of galantamine treatment. METHODS: A total of 202 patients with mild to moderate Alzheimer's disease participated in a 16-week, prospective, multi-center, randomized, double-blind galantamine trial in a Korean population. Patients were assessed at baseline and after 4, 8 and 16 weeks of randomized treatment using the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog/11), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the Disability Assessment for Dementia Scale (DAD), the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and adverse events. ApoE genotypes were determined for all subjects. RESULTS: Of the 202 subjects, 115 carried at least one ApoE epsilon4 allele and 87 did not. In both ApoE epsilon4 carriers and ApoE epsilon4 noncarriers, significant improvements were detected relative to baseline on ADAS-cog/11, CIBIC-plus, DAD and BEHAVE-AD. ApoE epsilon4 noncarriers showed better improvement in mean total BEHAVE-AD score and mean psychosis (delusions and hallucinations) subscale score than ApoE epsilon4 carriers. The incidence of weight loss was significantly higher in ApoE epsilon4 carriers (n = 11; 9.6%) than in ApoE epsilon4 noncarriers (n = 1; 1.2%) during this 16-week study, even though 92% of patients who complained of weight loss completed this 16-week trial successfully. CONCLUSION: ApoE epsilon4 genotype does not affect galantamine-related improvements in cognition, global rating, function and behavior. Longer prospective studies with larger patient populations are required to confirm these new findings.

Risperidone dosing pattern and clinical outcome in psychosis: an analysis of 1713 cases.

BACKGROUND: In treating patients with psychosis, practicing clinicians use various dosing strategies of antipsychotic medications, including risperidone. To evaluate the outcome of different risperidone dosing strategies in clinical practice, we undertook a large, prospective, naturalistic study in which daily dosage was determined freely by local standards of care. METHOD: In a 6-week trial between December 2000 and January 2002, 1713 patients with DSM-IV schizophrenia and related psychoses were treated with risperidone, with the dose, daily changes in dose, and weekly changes in Brief Psychiatric Rating Scale score documented. Cluster analysis was performed to identify homogeneous dosing patterns among the heterogeneous total population. RESULTS: Of the 6 dosing patterns identified by cluster analysis, a 2-week titration cluster, with a starting dose of 1.8 mg/day titrated to a maximum dose of 4.7 mg/day at day 14, and a 1-week titration cluster, with a starting dose of 2.6 mg/day titrated to a maximum dose of 5.4 mg/day at day 7, showed superior clinical outcomes compared with the other clusters, in which titrations were slower and higher. CONCLUSION: Our results indicate that the current consensus regarding risperidone dosing is appropriate for clinical practice, whereas a slower titration schedule does not guarantee a better clinical outcome, thus emphasizing the need for appropriate early titration.

Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study.

Mood stabilizers and atypical antipsychotics are commonly combined for the treatment of bipolar mania. The aim of this study was to compare the effectiveness and tolerability of topiramate and divalproex in combination with risperidone for treating acute mania patients in a naturalistic treatment setting. Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study. In order to assess the efficacy and the extrapyramidal symptoms (EPS), the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI) and Simpson-Angus Rating Scale (SARS) were measured at the baseline and at weeks 1, 3 and 6. From the baseline to the endpoint, the YMRS and CGI scores were reduced by 67.9% and 56.6% in the topiramate plus risperidone group (TPMG). The YMRS and CGI scores were also reduced by 63.7% and 58.2% in the divalproex plus risperidone group (DVPG). The weight and body mass index (BMI) increased significantly by 3.6% and 3.3% from the baseline to the endpoint in the DVPG, while they decreased by 0.5% and 0.4%, respectively, with no significant difference in the TPMG. There were no serious adverse events in either group. Despite the methodological limitations, topiramate was effective and tolerable for treating acute mania and may also be a promising alternative to a weight-gain liable mood stabilizer (MS) such as divalproex.

A prospective, double-blind, community-controlled comparison of three doses of galantamine in the treatment of mild to moderate Alzheimer's disease in a Korean population.

BACKGROUND: With the Korean population rapidly aging and the number of Koreans with Alzheimer's disease(AD) steadily growing, treatment of AD is becoming an increasing concern. Galantamine hydrobromide, a dual acetylcholinesterase inhibitor and allosteric modulator of nicotinic receptors, is being studied in the treatment of the disease. OBJECTIVE: This study compared the efficacy and tolerability of 3 doses of galantamine in a Korean population with mild to moderate AD. METHODS: In this prospective, multicenter, double-blind, community-controlled, comparative study, patients with mild to moderate AD were randomized to receive galantamine 8, 16, or 24 mg/d; patients were evaluated at baseline (week 0) and after 4, 8, and 16 weeks of treatment. A 4-week dose-titration schedule was used in the 16-and 24-mg/d groups. Also included were patients with AD from a community control group who were untreated and assessed at baseline and week 16. The primary efficacy outcome was change in cognitive function, as measured with the Korean version of the AD Assessment Scale-11-item cognitive subscale (ADAS-cog/11-K); secondary efficacy measures included changes in functional capacity, behavioral symptoms, and global impression (clinical response), as measured with the Korean versions of the Disability Assessment for Dementia Scale (DAD-K), Behavior Pathology in AD Rating Scale (BEHAVE-AD-K), and Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus-K). RESULTS: A total of 300 patients (228 women, 72 men) were enrolled (76, 78, 80, and 66 patients in the 8-, 16-,24-mg/d and community control groups, respectively). Significant differences in demographic characteristics were found between the galantamine and community control groups for age, sex, and duration of formal education (P = 0.042, P = 0.049, and P < 0.001, respectively). Results demonstrated a robust dose-response relationship between ADAS-cog/11-K and galantamine dosage compared with baseline and controls at 16 weeks. Mean (SE) improvements ranged from 3.7 (0.8) to 5.6 (0.8) points in the galantamine groups, whereas the control group deteriorated by 4.7 (0.5) points (P < 0.001). Similarly, significant improvements in all 3 treatment groups were observed in mean DAD-K, BEHAVE-AD-K, and CIBIC-plus-K scores (P < 0.001, P < 0.005, and P < 0.001, respectively). Galantamine was relatively well tolerated. CONCLUSIONS: This study found that galantamine effected significant benefits on the cognitive, functional, and behavioral symptoms of mild to moderate AD in this population of Korean patients. The tolerability results suggest that galantamine is well tolerated in these patients. Inc.

A randomized, double-blind, crossover comparison of risperidone and haloperidol in Korean dementia patients with behavioral disturbances.

OBJECTIVE: Behavioral disturbances in dementia are extremely prominent and distressful, and often result in serious physical, social, and economic consequences. The authors compared the efficacy and tolerability of risperidone and haloperidol in the treatment of behavioral and psychological symptoms of dementia (BPSD) in institutionalized elderly Korean patients with Alzheimer disease, vascular dementia, or mixed dementia. METHODS: This was an 18-week double-blind, crossover study involving 120 patients who were randomly assigned to receive flexible doses (0.5-1.5 mg/day) of risperidone or haloperidol. BPSD were assessed using the Korean version of the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD-K), the Korean version of the Cohen-Mansfield Agitation Inventory (CMAI-K), and the Clinical Global Impression of Change scale (CGI-C). Safety and tolerability assessments included the Extrapyramidal Symptom Rating Scale and the incidence of adverse events. RESULTS: Both risperidone and haloperidol were efficacious in alleviating BPSD. However, when receiving risperidone, patients showed significantly greater improvement than when receiving haloperidol in the total and subscale scores of the BEHAVE-AD-K, the total and subscale scores of the CMAI-K, and the scores on the CGI-C scale. Also, risperidone had an additional benefit on aggressiveness and anxieties/phobias. The risk of antipsychotic-induced parkinsonism throughout this study was significantly lower with risperidone than with haloperidol. CONCLUSION: Risperidone had a favorable efficacy and tolerability profile compared with haloperidol in the treatment of BPSD in this patient population.

Risperidone in combination with mood stabilizers for acute mania: a multicentre, open study.

The primary aims of this study were (i) a replication of the effectiveness and tolerability of risperidone in the treatment of patients with acute mania in a very large cohort in a naturalistic treatment setting and (ii) to extend the data on the effect and tolerability of risperidone in the treatment of patients with acute mania to an Asian population. A total of 909 patients fulfilling DSM-IV criteria of bipolar disorder (current manic and hypomanic episode) entered this large, open, multicentre study. The Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI) and Simpson-Angus Rating Scale (SARS) were measured at baseline and weeks 1, 3 and 6, for the assessment of effectiveness and extrapyramidal symptoms. This study showed a statistically significant reduction of scores on the YMRS and CGI-severity (mean change=-23.5+/-11.8, P<0.0001; mean change=-2.7+/-1.5, P<0.0001, respectively) from baseline to endpoint (week 6). The number of patients with a 50% reduction or more in the YMRS and CGI-severity scores was 693 (77.8%) and 630 (70.7%) at endpoint, respectively. There were no statistically significant increments of scores on SARS. Risperidone was generally well tolerated. The present larger open study indicates that risperidone add-on therapy is effective and tolerable in treatment of bipolar disorder, replicating results in various controlled and uncontrolled studies from Western countries.

Risperidone use in Korean patients with Alzheimer's disease: optimal dosage and effect on behavioural and psychological symptoms, cognitive function and activities of daily living.

BACKGROUND: This study aimed to investigate the effect of risperidone on the behavioural and psychological symptoms (BPS), cognitive function and activities of daily living (ADL) of Alzheimer's disease (AD). The optimal dose of risperidone in Korean patients with AD was determined with respect to both efficacy and safety profiles. METHODS: This was an 8 week prospective, open-labelled study with risperidone. The following efficacy measures were implemented: Behaviour Pathology in Alzheimer's Disease Rating Scale, Korean version for BPS; Korean version of mini-mental state examination for cognitive function; Barthel activities of daily living and blessed dementia rating scale for ADL; and global deterioration scale for global assessment of severity. Adverse events were recorded using the UKU side effect rating scale. RESULTS: Forty-eight patients completed the study. Risperidone was effective in reducing the BPS without affecting the cognitive and ADL domains of AD symptomatology. Risperidone dosages of 0.25 or 0.5 mg/day were most frequently administered and demonstrated the most favourable outcomes by efficacy and safety measures. Risperidone treatment was generally well tolerated, although extrapyramidal symptoms were noted in a dose-dependent manner. CONCLUSIONS: These results suggest that low dosages of risperidone are effective and favourable in reduction of the BPS for Korean patients with AD.

Subjective memory impairment, cognitive function and depression--a community study in older Koreans.

Correlates of subjective memory impairment (SMI) were investigated using data from a community study of 1,204 individuals aged 65 or over in an urban and rural area of South Korea. SMI and depression were ascertained from the Geriatric Mental State Schedule and cognitive function from the Korean version of the Mini-Mental State Examination (MMSE-K). 686 participants had also completed the MMSE-K two years earlier. SMI was present in 22% of the sample and was associated with depression and lower MMSE-K scores. Depression and SMI were most strongly associated in the presence of cognitive impairment. SMI was weakly associated with previous cognitive decline and was not associated with APOE e4. SMI and cognitive impairment were most strongly associated in urban residents, particularly rural-to-urban migrants.