A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue.

TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and differential exon usage are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. In this brief report, we identified markers of TDP-43 loss of function by depleting TARDBP from post-mortem human brain pericytes, a manipulable in vitro primary human brain cell model, and identifying differential exon usage events with bulk RNA-sequencing analysis. We present these data in an interactive database (https://www.scotterlab.auckland.ac.nz/research-themes/tdp43-lof-db-v2/) together with seven other TDP-43-depletion datasets we meta-analysed previously, for user analysis of differential expression and splicing signatures. Differential exon usage events that were validated by qPCR were then compiled into a 'differential exon usage panel' with other well-established TDP-43 loss-of-function exon markers. This differential exon usage panel was investigated in ALS and control motor cortex tissue to verify whether, and to what extent, TDP-43 loss of function occurs in ALS. We find that profiles of TDP-43-regulated cryptic exons, changed exon usage and changed 3' UTR usage discriminate ALS brain tissue from controls, verifying that TDP-43 loss of function occurs in ALS. We propose that TDP-43-regulated splicing events that occur in brain tissue will have promise as predictors of disease.

Impacts of the COVID-19 lockdown on self-reported mood and self-rated health of community-dwelling adults with chronic illness.

AIM: To determine whether self-reported mood or self-rated health were affected in community-dwelling adults with chronic illness following COVID-19 lockdown. METHODS: This was a repeated cross-sectional study using secondary data. We included New Zealanders aged 40+ who underwent International Residential Instrument (interRAI) assessments in the year prior to COVID-19 lockdown (25 March 2019-24 March 2020) or in the year following COVID-19 lockdown (25 March 2020-24 March 2021). Pairwise comparisons were made between each pre-lockdown quarter and its respective post-lockdown quarter to account for seasonality patterns. Data from 45,553 (pre-lockdown) and 45,349 (post-lockdown) assessments were analysed. Outcomes (self-reported mood, self-rated health) were stratified by socio-demographic variables. RESULTS: Self-reported mood improved in the first quarter post-lockdown among those aged 80+, as well as among women, people of European ethnicity, those living alone and those living in more deprived areas. Self-rated health improved in these same groups, as well as among those aged 65-79, and among men. No differences in self-reported mood or self-rated health were found in the second, third, or fourth quarters post-lockdown. CONCLUSIONS: Self-reported mood and self-rated health of community-dwelling adults with chronic illness were not negatively affected following COVID-19 lockdown, and temporarily improved among some sub-groups. However, the longer-term impacts of the COVID-19 pandemic need to be closely monitored.

PSA-NCAM Regulatory Gene Expression Changes in the Alzheimer's Disease Entorhinal Cortex Revealed with Multiplexed in situ Hybridization.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. OBJECTIVE: To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. METHODS: We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. RESULTS: In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. CONCLUSION: We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.

Progressive Spread of Beta-amyloid Pathology in an Olfactory-driven Amyloid Precursor Protein Mouse Model.

Years before Alzheimer's disease (AD) is diagnosed, patients experience an impaired sense of smell, and ß-amyloid plaques accumulate within the olfactory mucosa and olfactory bulb (OB). The olfactory vector hypothesis proposes that external agents cause ß-amyloid to aggregate and spread from the OB to connected downstream brain regions. To reproduce the slow accumulation of ß-amyloid that occurs in human AD, we investigated the progressive accumulation of ß-amyloid across the brain using a conditional mouse model that overexpresses a humanized mutant form of the amyloid precursor protein (hAPP) in olfactory sensory neurons. Using design-based stereology, we show the progressive accumulation of ß-amyloid plaques within the OB and cortical olfactory regions with age. We also observe reduced OB volumes in these mice when hAPP expression begins prior-to but not post-weaning which we tracked using manganese-enhanced MRI. We therefore conclude that the reduced OB volume does not represent progressive degeneration but rather disrupted OB development. Overall, our data demonstrate that hAPP expression in the olfactory epithelium can lead to the accumulation and spread of ß-amyloid through the olfactory system into the hippocampus, consistent with an olfactory system role in the early stages of ß-amyloid-related AD progression.

Anti-dementia medication use in Aotearoa New Zealand: An exploratory study using health data from the Integrated Data Infrastructure (IDI).

OBJECTIVE: Anti-dementia medications such as acetylcholinesterase inhibitors are an important part of the management pathway for dementia. However, there are limited data in New Zealand that have examined the rates and patterns of use of funded anti-dementia medication and how use differs with ethnicity, age and sex. METHODS: This was a retrospective population-based descriptive study. Using the Integrated Data Infrastructure, we identified individuals of all ages coded for a diagnosis of dementia and estimated the proportion dispensed funded anti-dementia medication - donepezil tablets and rivastigmine patches - between 1 July 2016 and 30 June 2020. Rates of medication use in five main ethnic groups (Maori, Pacific peoples, Asian, European, and Middle Eastern, Latin American and African) in the <65, 65-79 and 80 and over (80+) age groups were compared and also between males and females in all sub-groups. Log-binomial models were used to calculate relative risks to determine any differences in anti-dementia medication use in the five ethnic groups and the three age groups and between males and females in each of the four study years. RESULTS: Overall, one-third of the dementia population received a funded anti-dementia medication in the total population (all ages) between 2016 and 2020. Donepezil tablets were dispensed in 31.6-34.0% and rivastigmine patches in 1.4-2.1% across the four study years. Compared to people of European ethnicity, Maori, Pacific peoples, and Middle Eastern, Latin American and African groups were less likely to be dispensed an anti-dementia medication (Maori: relative risk = 0.79-0.81, p < 0.0001; Pacific peoples: relative risk = 0.72-0.74, p < 0.0001; Middle Eastern, Latin American and African: relative risk = 0.73-0.78, p < 0.05). Compared to the age 80+ group, the 65-79 age group was more likely (relative risk = 1.50-1.54, p < 0.0001), while the age <65 group was less likely (relative risk = 0.67-0.71, p < 0.0001) to be dispensed an anti-dementia medication. There were no statistically significant differences in anti-dementia medication use between males and females. CONCLUSION: This study provides important information about funded anti-dementia medication use in New Zealand and how this differs by ethnicity, age and sex. Despite higher dementia prevalence in Maori and Pacific peoples, these groups were less likely to receive funded anti-dementia medication.

Incidence of Young Onset Dementia in Waikato, New Zealand: A Population-Based Study.

BACKGROUND: There is limited epidemiological research on the incidence of young onset dementia (YOD). Estimates of YOD incidence in New Zealand are extrapolated from international studies that do not reflect New Zealand's population and ethnic diversity. OBJECTIVE: To determine the incidence of YOD in the geographical area served by the Waikato District Health BoardMethods: All new inpatient and outpatient in the age range 30-64 years with a documented diagnosis of dementia at Waikato Hospital between 1 January 2014 -31 December 2016 were identified. Incidence rates were calculated by 5-year age-band, sex, and ethnicity. RESULTS: 64 incident cases of YOD were included. Incidence rates for all cause YOD were 13.3 (95% CI 10.3-17.0) and 22.7 (95% CI 17.5-29.1) per 100,000 person-years in the age range 30-64 years and 45-64 years respectively. The incidence rate in Maori (20.0, 95% CI 11.4-32.4) was higher compared to non-Maori (12.0, 95% CI 8.9-15.9), but this difference was not statistically significant (p = 0.09). CONCLUSION: The incidence of YOD in this study is similar to global estimates. Incidence may be higher in Maori compared to non-Maori, highlighting the need for culturally appropriate approaches to dementia prevention, intervention, and care.

Prevalence of young-onset dementia: nationwide analysis of routinely collected data.

INTRODUCTION: Young-onset dementia prevalence is understudied internationally. Previous studies have been limited by low case numbers, reliance on single sources of routinely collected health data for case identification and inclusion of a limited age range. Our objective was to determine the 1-year period prevalence of diagnosed dementia in people aged 0-64 in the entire New Zealand population using routinely collected health data. METHODS: A population-based descriptive study was carried out in New Zealand (population 4.8 million) using routinely collected deidentified health data from 2016 to 2020. Dementia cases in seven linked health datasets in the New Zealand Integrated Data Infrastructure were identified using diagnostic codes and/or use of antidementia medication. Prevalence for each of the four study years was calculated by age, sex and ethnicity. RESULTS: From a total population of 4 027 332-4 169 754 individuals aged 0-64, we identified 3396-3474 cases of 'all-cause' dementia in each of the study years (prevalence crude range: 83-84/100 000 people aged 0-64; 139-141/100 000 people aged 30-64 years; 204-207/100 000 people aged 45-64 years). Age-standardised prevalence was higher in males than females. Age-standardised and sex-standardised prevalence was higher in Maori and Pacific People than European and Asian. DISCUSSION: By using a large study population and multiple national health datasets, we have minimised selection bias and estimated the national prevalence of diagnosed young-onset dementia with precision. Young-onset dementia prevalence for the total New Zealand population was similar to reported global prevalence, validating previous estimates. Prevalence differed by ethnicity, which has important implications for service planning.

Piloting online training in the Pacific-Ophelia project for child and adolescent mental health.

INTRODUCTION: In June 2020, St Vincent's Mental Health, Fiji National University, and the Royal Australian and New Zealand College of Psychiatrists, Faculty of Child and Adolescent Psychiatry collaborated to deliver online, specialized child and adolescent mental health (CAMH) training to Pacific-based healthcare workers. This accompanying research aimed to understand the telehealth model and structures that would sustain an engaged community of practice and support the development of professional networks across the Pacific. METHOD: Quantitative and qualitative feedback was analyzed to understand participation and self-rated measures of skills, knowledge, and confidence in providing health care for children and young people, as well as experiences of training, including access, engagement, and applicability of the initiative to the Pacific Islands health care organizations. RESULTS: Ophelia Training was able to meet the stated learning objectives. The data from all stakeholders identifies the value of a telehealth initiative incorporating training, technical assistance, knowledge networks, and professional coaching as a capacity building approach. CONCLUSION: This program offers an integration of research and practice. This regional approach to understanding telehealth capacity for Pacific Island mental health services is valuable for informing decision-making with respect to clinical care, management, workforce training and policy. It also provided an opportunity to improve health inequalities, by improving access to CAMH training via telehealth.

The Pasifika Veilomani Project: a pilot online training programme for healthcare workers in managing gender-based violence and family violence and sharing experiences.

OBJECTIVE: Pacific Island Countries (PICs) record high rates of gender-based violence (GBV). COVID-19 has significantly increased the number of GBV cases globally. This research aims to understand educational pathways for PICs' healthcare workers (HCWs) to strengthen GBV clinical practices in the Pasifika Veilomani (sharing the love) project. METHOD: A literature review, content experts' discussion and review of stakeholder governance documents were used to inform the design of the telehealth training. HCWs were invited to share experiences, further exploring the capacity of online learning to meet clinical practice needs. RESULTS: Global health guidance was adapted by Pacific experts to deliver a 12-week multidisciplinary course. One hundred and thirty-six participants from nine PICs registered and participated in the telehealth sessions. Despite internet and technical difficulties, participants' responses were positive. Results indicated the online training improved their confidence, helped them to reflect on practice and that more training would be valued. CONCLUSIONS: The Pasifika Veilomani Project engaged HCW and clinical leaders to inform current practices, education, and public health approaches on GBV as a public health priority. This project demonstrates the potential for engaging and supporting HCW remotely across challenging geographic, service and cultural domains in the context of COVID-19 social and service demands.

Dementia prevalence estimation among the main ethnic groups in New Zealand: a population-based descriptive study of routinely collected health data.

OBJECTIVE: Estimates of dementia prevalence in New Zealand (NZ) have previously been extrapolated from limited Australasian studies, which may be neither accurate nor reflect NZ's unique population and diverse ethnic groups. This study used routinely collected health data to estimate the 1-year period prevalence for diagnosed dementia for each of the 4 years between July 2016 and June 2020 in the age 60+ and age 80+ populations and for the four main ethnic groups. DESIGN: A population-based descriptive study. SETTING: Seven national health data sets within the NZ Integrated Data Infrastructure (IDI) were linked. Diagnosed dementia prevalence for each year was calculated using the IDI age 60+ and age 80+ populations as the denominator and also age-sex standardised to allow comparison across ethnic groups. PARTICIPANTS: Diagnosed dementia individuals in the health datasets were identified by diagnostic or medication codes used in each of the data sets with deduplication of those who appeared in more than one data set. RESULTS: The crude diagnosed dementia prevalence was 3.8%-4.0% in the age 60+ population and 13.7%-14.4% in the age 80+ population across the four study years. Dementia prevalence age-sex standardised to the IDI population in the last study period of 2019-2020 was 5.4% for Maori, 6.3% for Pacific Islander, 3.7% for European and 3.4% for Asian in the age 60+ population, and 17.5% for Maori, 22.2% for Pacific Islander, 13.6% for European and 13.5% for Asian in the age 80+ population. CONCLUSIONS: This study provides the best estimate to date for dementia prevalence in NZ but is limited to those people who were identified as having dementia based on data from the seven included data sets. The findings suggest that diagnosed dementia prevalence is higher in Maori and Pacific Islanders. A nationwide NZ community-based dementia prevalence study is much needed to confirm the findings of this study.

Sociodemographic and Clinical Characteristics of 1350 Patients With Young Onset Dementia: A Comparison With Older Patients.

OBJECTIVE: To determine the sociodemographic and clinical characteristics of a large cohort of patients with young onset dementia (YOD) (aged below 65), and whether they differ from older (age 65+) adults with dementia. METHODS: Retrospective cross-sectional study. Participants were New Zealanders who were assessed with International Residential Assessment Instrument (interRAI) assessments (including community-dwelling adults and those in long-term care) from 2016 to 2019 and had a diagnosis of dementia. Outcomes were sociodemographic and clinical characteristics captured in the interRAI assessment. RESULTS: People with YOD were more likely to be male, of non-European ethnicity, and live in a dwelling other than a private home or be homeless. They were more likely to exhibit problematic behaviors and neuropsychiatric symptoms but were less frail and less dependent for activities of daily living. Financial strain and loneliness were more common in people with YOD. Carers of people with YOD were more likely to feel distress, anger, or depression, and families of people with YOD were more likely to feel overwhelmed. CONCLUSIONS: YOD patients have different needs than older adults with dementia. These differences must be considered by clinicians and organizations that provide care and support to people living with dementia.

fISHing with immunohistochemistry for housekeeping gene changes in Alzheimer's disease using an automated quantitative analysis workflow.

In situ hybridization (ISH) is a powerful tool that can be used to localize mRNA expression in tissue samples. Combining ISH with immunohistochemistry (IHC) to determine cell type provides cellular context of mRNA expression, which cannot be achieved with gene microarray or polymerase chain reaction. To study mRNA and protein expression on the same section we investigated the use of RNAscope® ISH in combination with fluorescent IHC on paraffin-embedded human brain tissue. We first developed a high-throughput, automated image analysis workflow for quantifying RNA puncta across the total cell population and within neurons identified by NeuN+ immunoreactivity. We then applied this automated analysis to tissue microarray (TMA) sections of middle temporal gyrus tissue (MTG) from neurologically normal and Alzheimer's Disease (AD) cases to determine the suitability of three commonly used housekeeping genes: ubiquitin C (UBC), peptidyl-prolyl cis-trans isomerase B (PPIB) and DNA-directed RNA polymerase II subunit RPB1 (POLR2A). Overall, we saw a significant decrease in total and neuronal UBC expression in AD cases compared to normal cases. Total expression results were validated with RT-qPCR using fresh frozen tissue from 5 normal and 5 AD cases. We conclude that this technique combined with our novel automated analysis pipeline provides a suitable platform to study changes in gene expression in diseased human brain tissue with cellular and anatomical context. Furthermore, our results suggest that UBC is not a suitable housekeeping gene in the study of post-mortem AD brain tissue.

RNA Quality in Post-mortem Human Brain Tissue Is Affected by Alzheimer's Disease.

Gene expression studies of human post-mortem brain tissue are useful for understanding the pathogenesis of neurodegenerative disease. These studies rely on the assumption that RNA quality is consistent between disease and neurologically normal cases; however, previous studies have suggested that RNA quality may be affected by neurodegenerative disease. Here, we compared RNA quality in human post-mortem brain tissue between neurologically normal cases (n = 14) and neurodegenerative disease cases (Alzheimer's disease n = 10; Parkinson's disease n = 11; and Huntington's disease n = 9) in regions affected by pathology and regions that are relatively devoid of pathology. We identified a statistically significant decrease in RNA integrity number (RIN) in Alzheimer's disease tissue relative to neurologically normal tissue (mixed effects model, p = 0.04). There were no statistically significant differences between neurologically normal cases and Parkinson's disease or Huntington's disease cases. Next, we investigated whether total RNA quality affected mRNA quantification, by correlating RIN with qPCR threshold cycle (CT). CT values for all six genes investigated were strongly correlated with RIN (p < 0.05, Pearson correlation); this effect was only partially mitigated by normalization to RPL30. Our results indicate that RNA quality is decreased in Alzheimer's disease tissue. We recommend that RIN should be considered when this tissue is used in gene expression analyses.

Art-making in mental health - a Fijian pilot study.

OBJECTIVE: A pilot art-making and mental health recovery project addressed consumer and carer mental health and well-being in Suva, Fiji. METHOD: Using feedback surveys, the project evaluated initial training, and a 12-month art programme for consumers, carers and staff across several mental health services. RESULTS: First person and stakeholder group reports from the project reflected broad-scale approval for the novel modality and its potential for continued application in keeping with local cultural values. A broad stakeholder base was involved in planning and participation, aligned with the values of inclusive recovery-oriented mental health service approaches. CONCLUSIONS: These results suggest that the programme can add value to mental health care being provided for people with a mental illness in Fiji.

Impact of COVID-19 on the health and psychosocial status of vulnerable older adults: study protocol for an observational study.

BACKGROUND: Many countries around the world have adopted social distancing as one of the public health measures to reduce COVID-19 transmissions in the community. Such measures could have negative effects on the mental health of the population. The aims of this study are to (1) track the impact of COVID-19 on self-reported mood, self-rated health, other health and psychosocial indicators, and health services utilization of people who have an interRAI assessment during the first year of COVID-19; (2) compare these indicators with the same indicators in people who had an interRAI assessment in the year before COVID-19; and (3) report these indicators publicly as soon as data analysis is completed every 3 months. METHODS: interRAI COVID-19 Study (iCoS) is an observational study on routinely collected national data using the interRAI Home Care and Contact Assessment, which are standardized geriatric assessment tools mandated for all people assessed for publicly funded home support services and aged residential care in New Zealand. Based on the 2018/19 figures, we estimated there are 36,000 interRAI assessments per annum. We will compare the four post-lockdown quarters (from 25th March 2020) with the respective pre-lockdown quarters. The primary outcomes are self-reported mood (feeling sad, depressed or hopeless: 0 = no, 1 = yes) and self-rated health (0 = excellent, 1 = good, 2 = fair, 3 = poor). We will also analyze sociodemographics, other secondary health and psychosocial indicators, and health services utilization. Descriptive statistics will be conducted for primary outcomes and other indicators for each of the eight quarters. We will compare the quarters using regression models adjusted for demographic characteristics using weights or additional variables. Key health and psychosocial indicators will be reported publicly as soon as data analysis is completed for each quarter in the 12-month post-lockdown period by using a data visualization tool. DISCUSSION: This rapid translation of routinely collected national interRAI data will provide a means to monitor the health and psychosocial well-being of vulnerable older New Zealanders. Insights from this study can be shared with other countries that use interRAI and prepare health and social services for similar epidemics/pandemics in the future.

Identification of a dysfunctional microglial population in human Alzheimer's disease cortex using novel single-cell histology image analysis.

In Alzheimer's disease (AD), microglia are affected by disease processes, but may also drive pathogenesis. AD pathology-associated microglial populations have been identified with single-cell RNA-Seq, but have not been validated in human brain tissue with anatomical context. Here, we quantified myeloid cell markers to identify changes in AD pathology-associated microglial populations. We performed fluorescent immunohistochemistry on normal (n = 8) and AD (n = 8) middle temporal gyri, co-labelling the pan-myeloid cell marker, Iba1, with one of 11 markers of interest (MOIs): CD45, HLA-DR, CD14, CD74, CD33, CD206, CD32, CD163, P2RY12, TMEM119, L-Ferritin. Novel image analyses quantified the single-cell abundance of Iba1 and each MOI. Each cell was gated into one Iba1-MOI population (Iba1low MOIhigh, Iba1high MOIhigh, or Iba1high MOIlow) and the abundance of each population was compared between AD and control. Triple-labelling of L-Ferritin and Iba1 with a subset of MOIs was performed to investigate L-Ferritin-MOI co-expression on Iba1low cells. Iba1low MOIhigh myeloid cell populations delineated by MOIs CD45, HLA-DR, CD14, CD74, CD33, CD32, and L-Ferritin were increased in AD. Further investigation of the Iba1low MOIhigh populations revealed that their abundances correlated with tau, but not amyloid beta, load in AD. The Iba1low microglial population highly expressed L-Ferritin, reflecting microglial dysfunction. The L-Ferritinhigh CD74high HLA-DRhigh phenotype of the Iba1low population mirrors that of a human AD pathology-associated microglial subpopulation previously identified using single-cell RNA-Seq. Our high-throughput immunohistochemical data with anatomical context support the microglial dysfunction hypothesis of AD.

Quantitative immunohistochemical analysis of myeloid cell marker expression in human cortex captures microglia heterogeneity with anatomical context.

Current immunohistochemical methods of studying microglia in the post-mortem human brain do not capture the heterogeneity of microglial function in response to damage and disease. We therefore investigated the expression of eight myeloid cell proteins associated with changes in function alongside Iba1. To study the myeloid cells we used immunohistochemistry on post-mortem human middle temporal gyrus sections from neurologically normal individuals. First we investigated co-labelling between the classical 'activation' marker, HLA-DR and each of the other markers of interest. Significant co-labelling between HLA-DR with CD206, CD32, CD163, or L-Ferritin was observed, although complete overlap of expression of HLA-DR with aforementioned markers was not observed. A qualitative assessment also demonstrated that perivascular macrophages expressed higher levels of the markers of interest we investigated than microglia, suggesting perivascular macrophages show a more phagocytic and antigen presentation state in the human brain. To determine whether the markers of interest were expressed in different functional states, the immunoreactivity for each marker was qualitatively assessed on microglial morphologies. Degenerating marker, L-Ferritin, was specific for dystrophic microglia. We demonstrate that microglial heterogeneity can be investigated in immunohistochemically stain post-mortem human tissue by integrating the single-cell abundance of proteins and cell morphology to infer function.

Effectiveness of a culturally adapted biopsychosocial intervention (POHON SIHAT) in improving self-efficacy in patients with diabetes attending primary healthcare clinics in Putrajaya, Malaysia: study protocol of a randomised controlled trial.

INTRODUCTION: People with diabetes are often associated with multifaceted factors and comorbidities. Diabetes management frameworks need to integrate a biopsychosocial, patient-centred approach. Despite increasing efforts in promotion and diabetes education, interventions integrating both physical and mental health components are still lacking in Malaysia. The Optimal Health Programme (OHP) offers an innovative biopsychosocial framework to promote overall well-being and self-efficacy, going beyond education alone and has been identified as relevant within the primary care system. Following a comprehensive cultural adaptation process, Malaysia's first OHP was developed under the name 'Pohon Sihat' (OHP). The study aims to evaluate the effectiveness of the mental health-based self-management and wellness programme in improving self-efficacy and well-being in primary care patients with diabetes mellitus. METHODS AND ANALYSIS: This biopsychosocial intervention randomised controlled trial will engage patients (n=156) diagnosed with type 2 diabetes mellitus (T2DM) from four primary healthcare clinics in Putrajaya. Participants will be randomised to either OHP plus treatment as usual. The 2-hour weekly sessions over five consecutive weeks, and 2-hour booster session post 3 months will be facilitated by trained mental health practitioners and diabetes educators. Primary outcomes will include self-efficacy measures, while secondary outcomes will include well-being, anxiety, depression, self-care behaviours and haemoglobin A1c glucose test. Outcome measures will be assessed at baseline, immediately postintervention, as well as at 3 months and 6 months postintervention. Where appropriate, intention-to-treat analyses will be performed. ETHICS AND DISSEMINATION: This study has ethics approval from the Medical Research and Ethics Committee, Ministry of Health Malaysia (NMRR-17-3426-38212). Study findings will be shared with the Ministry of Health Malaysia and participating healthcare clinics. Outcomes will also be shared through publication, conference presentations and publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03601884.

Plasma MicroRNAs Are Altered Early and Consistently in a Mouse Model of Tauopathy.

Pathological accumulation of tau protein in brain cells is the hallmark of a group of neurodegenerative diseases called tauopathies. Accumulation of tau protein begins years before the onset of symptoms, which include deficits in cognition, behavior and movement. The pre-symptomatic phase of tauopathy may be the best time to deliver disease-modifying treatments, but this is only possible if prognostic, pre-symptomatic biomarkers are identified. Here we describe the profiling of blood plasma microRNAs in a mouse model of tauopathy, in order to identify biomarkers of pre-symptomatic tauopathy. Circulating RNAs were isolated from blood plasma of 16-week-old and 53-week-old hTau mice and age-matched wild type controls (n = 28). Global microRNA profiling was performed using small RNA sequencing (Illumina) and selected microRNAs were validated using individual TaqMan RT-qPCR. The area under the receiver operating characteristic curve (AUC) was used to evaluate discriminative accuracy. We identified three microRNAs (miR-150-5p, miR-155-5p, miR-375-3p) that were down-regulated in 16-week-old hTau mice, which do not yet exhibit a behavioral phenotype and therefore represent pre-symptomatic tauopathy. The discriminative accuracy was AUC 0.98, 0.95 and 1, respectively. Down-regulation of these microRNAs persisted at 53 weeks of age, when hTau mice exhibit cognitive deficits and advanced neuropathology. Bioinformatic analysis showed that these three microRNAs converge on pathways associated with neuronal signaling and phosphorylation of tau. Thus, these circulating microRNAs appear to reflect neuropathological change and are promising candidates in the development of biomarkers of pre-symptomatic tauopathy.

Beyond psychiatry: motivations for considering an Australian wellbeing program within Malaysian health services.

OBJECTIVES: To explore the relevance and adaptability of the Optimal Health Program for mental and primary healthcare providers in Malaysia. METHODS: Evaluate stakeholder engagement and training programme for psychiatrists, family medicine specialists, public health specialists, physicians, clinical psychologists, counsellors, and representatives from a patient support group. Evaluate the programme for applicability, as well as participant's knowledge and confidence in using key components. RESULTS: The training was very well received in terms of content, training materials and facilitation style. Development of culturally specific materials will be needed. Improvement in the self-rating measurement for knowledge and confidence in using key Optimal Health Program components was reported at the completion of the 2-day training. CONCLUSIONS: The Optimal Health Program has potential as a comprehensive socio-culturally responsive self-management programme that is relevant within mental health services and adaptable for task-sharing of mental health care in Malaysia.