Pulse pressure is associated with decline in physical function in older adults.

OBJECTIVES: This study examined the associations between pulse pressure, hypertension, and the decline in physical function in a prospective framework. STUDY DESIGN: The Healthy Aging Longitudinal Study tracked a group of Taiwanese adults aged 55 or more over an average of 6.19 years to assess pulse pressure and decline in physical function, including in handgrip strength, gait speed, and 6-min walking distance, at baseline (2009-2013) and in the second phase of assessments (2013-2020). MAIN OUTCOME MEASURES: Pulse pressure was calculated as the difference between systolic and diastolic blood pressure values. Weakness, slowness, and low endurance were defined as decreases of ≥0.23 m/s (one standard deviation) in gait speed, ≥5.08 kg in handgrip strength, and ≥ 57.73 m in a 6-min walk, as determined from baseline to the second phase of assessment. Linear and logistic regressions were employed to evaluate the associations between pulse pressure, hypertension, and decline in physical function. RESULTS: Baseline pulse pressure was associated with future handgrip strength (beta = -0.017, p = 0.0362), gait speed (beta = -0.001, p < 0.0001), and 6-min walking distance (beta = -0.470, p < 0001). In multivariable models, only handgrip strength (beta = -0.016, p = 0.0135) and walking speed (beta = -0.001, p = 0.0042) remained significantly associated with future pulse pressure. Older adults with high systolic blood pressure (≥140 mmHg) and elevated pulse pressure (≥60 mmHg) exhibited a significantly increased risk of weakness (odds ratio: 1.30, 95 % confidence interval: 1.08-1.58), slowness (1.29, 1.04-1.59), and diminished endurance (1.25, 1.04-1.50) compared with the reference group, who exhibited systolic blood pressure of <140 mmHg and pulse pressure of <60 mmHg. CONCLUSIONS: Among older adults, pulse pressure is associated with a decline in physical function, especially in terms of strength and locomotion.

Suppression of the alpha, delta, and omicron variants of SARS-Cov-2 in Taiwan.

BACKGROUND: Taiwan was a coronavirus disease 2019 (COVID-19) outlier, with an extraordinarily long transmission-free record: 253 days without locally transmitted infections while the rest of the world battled wave after wave of infection. The appearance of the alpha variant in May 2021, closely followed by the delta variant, disrupted this transmission-free streak. However, despite low vaccination coverage (<1%), outbreaks were well-controlled. METHODS: This study analyzed the time to border closure and conducted one-sample t test to compare between Taiwan and Non-Taiwan countries prior to vaccine introduction. The study also collected case data to observe the dynamics of omicron transmission. Time-varying reproduction number,Rt, was calculated and was used to reflect infection impact at specified time points and model trends of future incidence. RESULTS: The study analyzed and compare the time to border closure in Taiwan and non-Taiwan countries. The mean times to any border closure from the first domestic case within each country were -21 and 5.98 days, respectively (P < .0001). The Taiwanese government invested in quick and effective contact tracing with a precise quarantine strategy in lieu of a strict lockdown. Residents followed recommendations based on self-discipline and unity. The self-discipline in action is evidenced in Google mobility reports. The central and local governments worked together to enact non-pharmaceutical interventions (NPIs), including universal masking, social distancing, limited unnecessary gatherings, systematic contact tracing, and enhanced quarantine measures. The people cooperated actively with pandemic-prevention regulations, including vaccination and preventive NPIs. CONCLUSIONS: This article describes four key factors underlying Taiwan's success in controlling COVID-19 transmission: quick responses; effective control measures with new technologies and rolling knowledge updates; unity and cooperation among Taiwanese government agencies, private companies and organizations, and individual citizens; and Taiwanese self-discipline.

Assessing the impact of public funding in alleviating participant reduction and improving the retention rate in methadone maintenance treatment clinics in Taiwan: an interrupted time series analysis.

BACKGROUND: Given the steady decline in patient numbers at methadone maintenance treatment (MMT) clinics in Taiwan since 2013, the government initiated Patients' Medical Expenditure Supplements (PMES) in January 2019 and the MMT Clinics Accessibility Maintenance Program (MCAM) in September 2019. This study aims to evaluate the impact of the PMES and MCAM on the enrollment and retention of patients attending MMT clinics and whether there are differential impacts on MMT clinics with different capacities. METHODS: The monthly average number of daily participants and 3-month retention rate from 2013 to 2019 were extracted from MMT databases and subjected to single interrupted time series analysis. Pre-PMES (from February 2013 to December 2018) was contrasted with post-PMES, either from January 2019 to December 2019 for clinics funded solely by the PMES or from January 2019 to August 2019 for clinics with additional MCAM. Pre-MCAM (from January 2019 to August 2019) was contrasted with post-MCAM (from September 2019 to December 2019). Based on the monthly average number of daily patients in 2018, each MMT clinic was categorized as tiny (1-50), small (51-100), medium (101-150), or large (151-700) for subsequent stratification analysis. RESULTS: In terms of participant numbers after the PMES intervention, a level elevation and slope increase were detected in the clinics at every scale except medium in MMT clinics funded solely by PMES. In MMT clinics with subsequent MCAM, a level elevation was only detected in small-scale clinics, and a slope increase in the participant numbers was detected in tiny- and small-scale clinics. The slope decrease was also detected in medium-scale clinics. In terms of the 3-month retention rate, a post-PMES level elevation was detected at almost every scale of the clinics, and a slope decrease was detected in the overall and tiny-scale clinics for both types of clinics. CONCLUSIONS: Supplementing the cost of a broad treatment repertoire enhances the enrollment of people with heroin use in MMTs. Further funding of human resources is vital for MMT clinics to keep up with the increasing numbers of participants and their retention.

Patients with first-episode psychosis in northern Taiwan: neurocognitive performance and niacin response profile in comparison with schizophrenia patients of different familial loadings and relationship with clinical features.

BACKGROUND: Examining patients with first-episode psychosis (FEP) provides opportunities to better understand the mechanism underlying these illnesses. By incorporating quantitative measures in FEP patients, we aimed to (1) determine the baseline distribution of clinical features; (2) examine the impairment magnitude of the quantitative measures by comparing with external controls and then the counterparts of schizophrenia patients of different familial loadings; and (3) evaluate whether these quantitative measures were associated with the baseline clinical features. METHODS: Patients with FEP were recruited from one medical center, two regional psychiatric centers, and two private clinics in northern Taiwan with clinical features rated using the Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale. Quantitative measurements included the Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), niacin response abnormality (NRA), and minor physical anomalies and craniofacial features (MPAs). To evaluate the relative performance of the quantitative measures in our FEP patients, four external comparison groups from previous studies were used, including three independent healthy controls for the CPT, WCST, and NRA, respectively, and one group of treatment-resistant schizophrenia patients for the MPAs. Additionally, patients from simplex families and patients from multiplex families were used to assess the magnitude of FEP patients' impairment on the CPT, WCST, and NRA. RESULTS: Among the 80 patients with FEP recruited in this study (58% female, mean age = 25.6 years, mean duration of untreated psychosis = 132 days), the clinical severity was mild to moderate (mean PANSS score = 67.3; mean PSP score = 61.8). Patients exhibited both neurocognitive and niacin response impairments (mean Z-scores: -1.24 for NRA, - 1.06 for undegraded d', - 0.70 for degraded d', - 0.32 for categories achieved, and 0.44 for perseverative errors) but did not show MPAs indicative of treatment resistance. Among these quantitative measures, three of the four neurocognitive indices were correlated with the baseline clinical features, whereas NRA did not show such correlation. CONCLUSIONS: This FEP study of Taiwanese patients revealed the presence of neurocognitive performance and niacin response and their different relationships with clinical features, rendering this sample useful for future follow-up and incorporation of multiomics investigation.

COVID-19 control measures unexpectedly increased the duration of stay at High Speed Rail stations during the first community outbreak in Taiwan.

During the COVID-19 pandemic, Taiwan has implemented strict border controls and community spread prevention measures. As part of these efforts, the government also implemented measures for public transportation. In Taiwan, there are two primary public transportation systems: Taiwan Railways (TR) is commonly utilized for local travel, while the Taiwan High-Speed Rail (THSR) is preferred for business trips and long-distance journeys due to its higher speed. In this study, we examined the impact of these disease prevention measures on the number of passengers and duration of stay in two major public transportation systems during the first community outbreak from April 29th to May 29th, 2021. Using data from a local telecommunications company, our study observed an expected decrease in the number of passengers after the cancellation of non-reserved seats at both TR and THSR stations across all 19 cities in the main island of Taiwan. Surprisingly, however, the duration of stay in some of the cities unexpectedly increased, especially at THSR stations. This unanticipated rise in the duration of stay has the potential to elevate contact probability among passengers and, consequently, the transmission rate. Our analysis shows that intervention policies may result in unforeseen outcomes, highlighting the crucial role of human mobility data as a real-time reference for policymakers. It enables them to monitor the impact of disease prevention measures and facilitates informed, data-driven decision-making.

Application of Artificial Intelligence in Infant Movement Classification: A Reliability and Validity Study in Infants Who Were Full-Term and Preterm.

OBJECTIVE: Preterm infants are at high risk of neuromotor disorders. Recent advances in digital technology and machine learning algorithms have enabled the tracking and recognition of anatomical key points of the human body. It remains unclear whether the proposed pose estimation model and the skeleton-based action recognition model for adult movement classification are applicable and accurate for infant motor assessment. Therefore, this study aimed to develop and validate an artificial intelligence (AI) model framework for movement recognition in full-term and preterm infants. METHODS: This observational study prospectively assessed 30 full-term infants and 54 preterm infants using the Alberta Infant Motor Scale (58 movements) from 4 to 18 months of age with their movements recorded by 5 video cameras simultaneously in a standardized clinical setup. The movement videos were annotated for the start/end times and presence of movements by 3 pediatric physical therapists. The annotated videos were used for the development and testing of an AI algorithm that consisted of a 17-point human pose estimation model and a skeleton-based action recognition model. RESULTS: The infants contributed 153 sessions of Alberta Infant Motor Scale assessment that yielded 13,139 videos of movements for data processing. The intra and interrater reliabilities for movement annotation of videos by the therapists showed high agreements (88%-100%). Thirty-one of the 58 movements were selected for machine learning because of sufficient data samples and developmental significance. Using the annotated results as the standards, the AI algorithm showed satisfactory agreement in classifying the 31 movements (accuracy = 0.91, recall = 0.91, precision = 0.91, and F1 score = 0.91). CONCLUSION: The AI algorithm was accurate in classifying 31 movements in full-term and preterm infants from 4 to 18 months of age in a standardized clinical setup. IMPACT: The findings provide the basis for future refinement and validation of the algorithm on home videos to be a remote infant movement assessment.

Beyond the waves: Unraveling pandemic outcomes with genomic insights and immunity analysis - Evidence from 14 countries.

OBJECTIVE: Although the World Health Organization and many governments have recategorized COVID-19 as a generally mild to moderately severe disease, consecutive pandemic waves driven by immune escape variants have underscored the need for timely and accurate prediction of the next outbreak. Nevertheless, little attention has been paid to translating genomic data and infection- and vaccine-induced immunity into direct estimates. METHODS: We retrieved epidemiologic and genomic data shortly before pandemic waves across 14 developed countries from late 2021 to mid-2022 and examined associations between early-stage variant competition, infection- and vaccine-induced immunity, and the time intervals between wave peaks. We applied regression analysis and the generalized estimating equation method to construct an inferential model. RESULTS: Each per cent increase in the proportion of a new variant was associated with a 1.0% reduction in interpeak intervals on average. Curvilinear associations between vaccine-induced immunity and outcome variables were observed, suggesting that reaching a critical vaccine distribution rate may decrease the caseload of the upcoming wave. CONCLUSIONS: By leveraging readily accessible pre-outbreak genomic and epidemiologic data, our results not only substantiate the predictive potential of early variant fractions but also propose that immunity acquired through infection alone may not sufficiently mitigate transmission. Conversely, a rapid and widespread vaccination initiative appears to be correlated with a decrease in disease incidence.

Analysis across Taiwan Biobank, Biobank Japan, and UK Biobank identifies hundreds of novel loci for 36 quantitative traits.

Genome-wide association studies (GWASs) have identified tens of thousands of genetic loci associated with human complex traits. However, the majority of GWASs were conducted in individuals of European ancestries. Failure to capture global genetic diversity has limited genomic discovery and has impeded equitable delivery of genomic knowledge to diverse populations. Here we report findings from 102,900 individuals across 36 human quantitative traits in the Taiwan Biobank (TWB), a major biobank effort that broadens the population diversity of genetic studies in East Asia. We identified 968 novel genetic loci, pinpointed novel causal variants through statistical fine-mapping, compared the genetic architecture across TWB, Biobank Japan, and UK Biobank, and evaluated the utility of cross-phenotype, cross-population polygenic risk scores in disease risk prediction. These results demonstrated the potential to advance discovery through diversifying GWAS populations and provided insights into the common genetic basis of human complex traits in East Asia.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Interregional mobility in different age groups is associated with COVID-19 transmission in the Taipei metropolitan area, Taiwan.

Before vaccines were introduced, mobility restriction was one of the primary control measures in the early stage of the coronavirus disease 2019 (COVID-19) pandemic. Because different age groups face disproportionate health risks, differences in their mobility changes affect the effectiveness of pandemic control measures. This study aimed to investigate the relationship between multiscale mobility patterns in different age groups and COVID-19 transmission before and after control measures implementation. Data on daily confirmed case numbers, anonymized mobile phone data, and 38 socioeconomic factors were used to construct negative binomial regression models of these relationships in the Taipei metropolitan area in May 2021. To avoid overfitting, the socioeconomic factor dimensions were reduced by principal component analysis. The results showed that inter-district mobility was a greater promoter of COVID-19 transmission than was intra-district mobility (coefficients: pre-alert, 0.52 and 0.43; post-alert, 0.41 and 0.36, respectively). Moreover, both the inter-district mobility of people aged 15-59 and ≥ 60 years were significantly related to the number of confirmed cases (coefficients: pre-alert, 0.82 and 1.05; post-alert, 0.48 and 0.66, respectively). The results can help agencies worldwide formulate public health responses to emerging infectious diseases.

The use of premixed drugs in commodity packets in the population: prevalence and correlates revealed by the 2018 National Survey of Substance Use in Taiwan.

BACKGROUND: Administering premixed drugs in commodity packets was first reported in Asia in 2015, but there continues to be a dearth of related population-based data. This study aimed at examining (1) the prevalence of drug packet use in the population and (2) the sociodemographic profiles, particularly gender distribution, of drug packet users. METHODS: Data were derived from a survey of 18,626 Taiwanese civilians, aged 12-64 years, using stratified, multi-stage, random sampling in 2018. Participants anonymously completed a computer-assisted self-interview on tablet computers which covered the use and problematic use of illicit drugs/inhalants, prescription drugs and other psychoactive substances, among others. RESULTS: Approximately 1.46% of respondents had a lifetime use of illicit drugs, with drugs in commodity packets (0.18%) being ranked the fifth-most commonly used illicit drugs, higher than nitrous oxide (0.14%) and heroin (0.09%). Ten formats of drug packets were endorsed by users. Approximately 81.6% of persons with drug packet use had a lifetime use of other illicit drugs. The correlates of the use of drugs in commodity packets were similar to those of the exclusive use of other drugs except that there was a lack of gender differences in the use of drugs in commodity packets but not in the exclusive use of other drugs. CONCLUSION: Drugs in commodity packets have become a common way of administering illicit drugs in the population in Taiwan, and there were no gender differences among users. Our findings have implications for more efficient drug testing and culturally appropriate intervention for drug packet use.

Emergence and Persistent Dominance of SARS-CoV-2 Omicron BA.2.3.7 Variant, Taiwan.

Since April 2022, waves of SARS-CoV-2 Omicron variant cases have surfaced in Taiwan and spread throughout the island. Using high-throughput sequencing of the SARS-CoV-2 genome, we analyzed 2,405 PCR-positive swab samples from 2,339 persons and identified the Omicron BA.2.3.7 variant as a major lineage within recent community outbreaks in Taiwan.

Characterization of clinical features and comorbidities between bipolar affective disorder with and without depressive episodes.

BACKGROUNDS: A proportion of patients with bipolar disorder (BD) manifests with only unipolar mania (UM). This study examined relevant clinical features and psychosocial characteristics in UM compared with depressive-manic (D-M) subgroups. Moreover, comorbidity patterns of physical conditions and psychiatric disorders were evaluated between the UM and D-M groups. METHODS: This clinical retrospective study (N = 1015) analyzed cases with an average of 10 years of illness duration and a nationwide population-based cohort (N = 8343) followed up for 10 years in the Taiwanese population. UM was defined as patients who did not experience depressive episodes and were not prescribed adequate antidepressant treatment during the disease course of BD. Logistic regression models adjusted for relevant covariates were used to evaluate the characteristics and lifetime comorbidities in the two groups. RESULTS: The proportion of UM ranged from 12.91% to 14.87% in the two datasets. Compared with the D-M group, the UM group had more psychotic symptoms, fewer suicidal behaviors, a higher proportion of morningness chronotype, better sleep quality, higher extraversion, lower neuroticism, and less harm avoidance personality traits. Substantially different lifetime comorbidity patterns were observed between the two groups. CONCLUSIONS: Patients with UM exhibited distinct clinical and psychosocial features compared with patients with the D-M subtype. In particular, a higher risk of comorbid cardiovascular diseases and anxiety disorders is apparent in patients with D-M. Further studies are warranted to investigate the underlying mechanisms for diverse presentations in subgroups of BDs.

Contribution of Testing Strategies and Contact Tracing towards COVID-19 Outbreaks Control: A Mathematical Modeling Study.

This modeling study considers different screening strategies, contact tracing, and the severity of novel epidemic outbreaks for various population sizes, providing insight into multinational containment effectiveness of emerging infectious diseases, prior to vaccines development. During the period of the ancestral SARS-Cov-2 virus, contact tracing alone is insufficient to achieve outbreak control. Although universal testing is proposed in multiple nations, its effectiveness accompanied by other measures is rarely examined. Our research investigates the necessity of universal testing when contact tracing and symptomatic screening measures are implemented. We used a stochastic transmission model to simulate COVID-19 transmission, evaluating containment strategies via contact tracing, one-time high risk symptomatic testing, and universal testing. Despite universal testing having the potential to identify subclinical cases, which is crucial for non-pharmaceutical interventions, our model suggests that universal testing only reduces the total number of cases by 0.0009% for countries with low COVID-19 prevalence and 0.025% for countries with high COVID-19 prevalence when rigorous contact tracing and symptomatic screening are also implemented. These findings highlight the effectiveness of testing strategies and contact tracing in reducing COVID-19 cases by identifying subclinical cases.

Assessing the Brighton Collaboration Case Definition of Sensorineural Hearing Loss in Ghana.

The Brighton Collaboration has developed a case definition to assess sensorineural hearing loss (SNHL) as an adverse event of special interest for Lassa fever vaccines. We applied the level of diagnostic certainty (LOC) criteria to 300 SNHL patients aged 18 to 59 years at a tertiary hospital in Ghana from January 2017 through June 2020 and evaluated the applicability of this definition. Most SNHL cases were assessable (85.0%) and assigned level 1 LOC (84.3%); missing information on otoscopy (86.7%) was the main reason for being unable to classify cases. Consistency of LOC classification between assessors was 99.3%. Cases with electronic medical records (EMRs) were less assessable than those with paper records (30.9% versus 93.8%). These findings indicate that the SNHL definition would be applicable to retrospectively ascertain and classify cases in resource-limited settings. Developing an EMR template to document otoscopy results may improve the feasibility at this hospital to ascertain SNHL.

Developing a Sensitive Platform to Measure 5-Methyltetrahydrofolate in Subjects with MTHFR and PON1 Gene Polymorphisms.

Inadequate levels of 5-methyltetrahydrofolate (5-MTHF) and the T variant of MTHFR C677T have been suggested to be associated with an increased risk of developing mental illness, whereas the PON1 SNP variant provides a protective role. However, reports validating the methodology for plasma 5-MTHF levels in schizophrenia patients are limited. A sensitive LC−MS/MS system using an amide column and calibration curve was determined by dialyzed human plasma, and applied to schizophrenia patients and healthy controls in Taiwan, and the differences between the subgroups were discussed. This analysis system meets regulation criteria, and the lower limit of quantification for 5-MTHF levels was 4 nM from 200 µL plasma, within 7 min. The mean plasma 5-MTHF levels in schizophrenia patients (n = 34; 11.70 ± 10.37 nM) were lower than those in the healthy controls (n = 42; 22.67 ± 11.12 nM) significantly (p < 0.01). 5-MTHF concentrations were significantly lower in male carriers than in female carriers (18.30 ± 10.37 nM vs. 24.83 ± 11.01 nM, p < 0.05), especially in subjects who were MTHFR CT/PON1 Q allele carriers. In conclusion, this quantitative system, which employed sensitive and simple processing methods, was successfully applied, and identified that schizophrenic patients had significantly lower levels of 5-MTHF. Lower plasma 5-MTHF concentrations were observed in male subjects.

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship.

Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

Mitochondrial DNA methylation profiling of the human prefrontal cortex and nucleus accumbens: correlations with aging and drug use.

BACKGROUND: Despite the brain's high demand for energy, research on its epigenetics focuses on nuclear methylation, and much of the mitochondrial DNA methylation remains seldom investigated. With a focus on the nucleus accumbens (NAcc) and the prefrontal cortex (PFC), we aimed to identify the mitochondrial methylation signatures for (1) distinguishing the two brain areas, (2) correlating with aging, and (3) reflecting the influence of illicit drugs on the brain. RESULT: We collected the brain tissue in the NAcc and the PFC from the deceased individuals without (n = 39) and with (n = 14) drug use and used whole-genome bisulfite sequencing to cover cytosine sites in the mitochondrial genome. We first detected differential methylations between the NAcc and the PFC in the nonusers group (P = 3.89 × 10-9). These function-related methylation differences diminished in the drug use group due to the selective alteration in the NAcc. Then, we found the correlation between the methylation levels and the chronological ages in the nonusers group (R2 = 0.34 in the NAcc and 0.37 in the PFC). The epigenetic clocks in illicit drug users, especially in the ketamine users, were accelerated in both brain regions by comparison with the nonusers. Finally, we summarized the effect of the illicit drugs on the methylation, which could significantly differentiate the drug users from the nonusers (AUC = 0.88 in the NAcc, AUC = 0.94 in the PFC). CONCLUSION: The mitochondrial methylations were different between different brain areas, generally accumulated with aging, and sensitive to the effects of illicit drugs. We believed this is the first report to elucidate comprehensively the importance of mitochondrial DNA methylation in human brain.