Liesbeth Aerts

Background: Apathy (loss of motivation or goal‐directed behaviour) and depression each confer risk for dementia, cardiovascular disease and mortality in older adults. The mechanisms by which these neuropsychiatric symptoms are linked with health outcomes are not yet understood. Health behaviours may be one pathway, yet their potential links with apathy have received scant attention, whereas depression has been consistently associated with unhealthier behaviours including physical inactivity. Depression and apathy may be confounded, thus it is critical to determine their potential differential associations with health behaviours. This study thus aims to investigate whether apathy and depressive symptoms in older adults were associated with a broad battery of health behaviours.Method: Community‐dwelling participants from the Sydney Memory and Ageing Study (n = 1,030) aged 70‐90 without dementia completed assessments including the Geriatric Depression Scale, from which apathy (GDS‐3A) and depression (GDS‐12D) subscores were obtained. To investigate cross‐sectional associations with self‐reported physical activity, diet, current and lifetime alcohol consumption and smoking, linear or logistic regressions predicted the outcomes from apathy and depression, controlling for age, sex, education, global cognition and chronic conditions.Result: Greater apathy (but not depressive symptoms) was significantly associated with current physical inactivity (fewer hours/week weighted by intensity, p < .001) and frequent alcohol consumption (>2x weekly, p <.05). Depressive symptoms alone predicted poorer current adherence to Australian Dietary Guidelines (ADG‐2013, p <.05) and smoking (p <.001). Higher levels of both apathy and depressive symptoms were significantly associated with a past period of “heavier” alcohol consumption (p <.05); neither were related with lifetime history of smoking nor lifetime abstinence from alcohol.Conclusion: Apathy and depression were differentially associated with health behaviours. Presence of these symptoms in older adults may act as a barrier to engagement in healthier lifestyle activities, which are known to have numerous benefits for health and cognitive outcomes. These novel findings should be further examined longitudinally and with objective measures and alternative apathy assessment. Apathy should be considered along with depression as key determinants of health behaviours when designing health promotion interventions targeting older adults, and in models of dementia risk reduction.

Introduction: Antipsychotic medications are commonly used to manage behavioural and psychological symptoms of dementia despite their side effects and harms. While the Halting Antipsychotic Use in Long‐Term care (HALT) deprescribing trial was successful at reducing antipsychotic use, 19% of participants had their antipsychotics represcribed or never reached a dose of zero. The aim of this study was to investigate the reasons for represcription of antipsychotic medication and factors associated with ongoing antipsychotic use, relating to care staff requests and perceived behavioural changes.Materials and methods: Thirty‐nine of 133 HALT participants never ceased their antipsychotic medication or were represcribed a regular or pro re nata (PRN) antipsychotic after initial deprescribing. The views of nursing staff, general practitioner, and family on the circumstances leading up to these outcomes were collected via a questionnaire‐based approach. This information was triangulated with observation and detailed file audit (including progress notes, medical notes, medication charts, incident reports, and hospital discharge summaries). A consensus panel reconstructed the represcribing context.Results: Nurses were the most common drivers of represcribing (63.2%), followed by family members (39.5%), GPs (23.7%), specialists (13.2%), and hospital staff (10.5%). There were multiple drivers for antipsychotic use in 46.2% of participants. Increased agitated and aggressive behaviours were the most commonly reported reasons for represcribing even though these changes were not identified over time on objective measures. Consent and dosage practices remained poor despite education.Discussion: Nursing staff are the key drivers of deprescribing particularly in response to perceived worsening agitation and aggression among male residents. The train‐the‐trainer model used in the HALT trial may have been insufficient on its own to improve staff competence and confidence in applying nonpharmacological approaches when responding to behaviour change.

Increasing recognition that apathy is one of the most prevalent behavioral and psychological symptoms of dementia and causes substantial caregiver distress has led to trials evaluating psychosocial and pharmacological treatments of apathy in dementia. We evaluated evidence of the efficacy of pharmacotherapies for apathy in dementia from studies since 2013. Previously reported benefits of acetylcholinesterase inhibitors and memantine were not replicated in recent studies. Antidepressants had mixed results with positive effects for apathy shown only for agomelatine, while stimulants, analgesics, and oxytocin study results were inconclusive. For some approaches, such as antipsychotic review, positive effects were found only in combination with nonpharmacological approaches. Relatively few studies assessed apathy outcomes specifically, complicating interpretation of potentially positive treatment effects; none dissected outcomes for emotional, motivational and behavioral components of apathy. Better trial design and more detailed analysis are needed in order to evaluate outcomes of pharmacological treatments for apathy.

Mutations in the gene encoding the mitochondrial kinase PINK1 cause early-onset familial Parkinson’s disease. To understand the biological function of PINK1 and its role in the pathogenesis of Parkinson’s disease, it is useful to study its kinase activity towards substrates both in vivo and in vitro. For in vitro kinase assays, a purified Triboleum castaneum PINK1 insect orthologue is often employed, because it displays higher levels of activity when compared to human PINK1. We show, however, that the activity requirements, and more importantly the substrate specificity, differ between both orthologues. While Triboleum castaneum PINK1 readily phosphorylates the PINKtide peptide and Histone H1 in vitro, neither of these non-physiological substrates is phosphorylated by human PINK1. Nonetheless, both Tc and human PINK1 phosphorylate Parkin and Ubiquitin, two physiological substrates of PINK1. Our results show that the substrate selectivity differs among PINK1 orthologues, an important consideration that should be taken into account when extrapolating findings back to human PINK1.

PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1] is a serine/threonine kinase targeted to mitochondria and implicated in early-onset recessive Parkinson's disease (PD). Through the phosphorylation of its downstream targets, PINK1 regulates multiple mitochondrial processes, including ATP production, stress-response and mitochondrial dynamics and quality control. The orchestration of such a wide array of functions by an individual kinase requires a fine-tuned and versatile regulation of its activity. PINK1 proteolytic processing, trafficking and localization, as well as different post-translational modifications, affect its activity and function. Unravelling the regulatory mechanisms of PINK1 is essential for a full comprehension of its kinase function in health and disease.