Theses (MSc. Medical and Health Sciences)

Medication reviews form the backbone of pharmacotherapy optimisation among the older population. Acknowledging the association of frailty and quality of life with medication appropriateness is beneficial in optimising medications among the elderly. This study developed an individualised approach to medication management among older people residing in aged care facilities, and assessed their frailty and quality of life. The approach is centred on medication appropriateness and comprises a five-step medication review algorithm that is supplemented with a 10-component tool, the Medication Appropriateness Index-Geriatric version (MAI-G). The MAI-G incorporates geriatric components and is useful in quantifying medication appropriateness. The components in the MAl-G closely correspond to components in the algorithm to allow for quick and unequivocal extrapolation. The algorithm and MAI-G were implemented in a 6-month prospective study among 202 residents aged 65 years and above across 17 aged care facilities in Klang Valley, Malaysia. The mean age ± standard deviation of the participants was 76.81 ± 7.79 years, with females dominating the study population (62.4%). The number of inappropriate medications detected by the MAI-G decreased from 0.83 ± 0.93 at baseline, to 0.76 ± 0.92 at 6- months. The proportion of inappropriate medications detected by the MAl-G that were not detected by the MAl was high, 39.7% at baseline, 34.8% at 3-months and 34.3% at 6-months. Interestingly frailty and quality of life status improved at 6-months although there was no statistically significant association between medication appropriateness and the risk of reporting frailty (OR 4.64, 95% CI: 0.83-25.76), or medication appropriateness and the risk of reporting poor quality of life, at 6-months (OR 1.60, 95% CI: 0.47-5.49). This study provides an overview of the frailty and quality of life status of aged care residents in Malaysia, and suggests that urgent attention from health care professionals is warranted, to improve their health care, particularly the prescribing of potentially inappropriate medications. The findings support the need for a comprehensive medication review process that is supplemented by a medication appropriateness quantification tool which is geriatric-specific.

Alzheimer’s disease (AD), the major cause of dementia, affects elderly population worldwide. Beta amyloid (Aβ) plagues are the main cause in the AD pathology, and removing the plagues is a constant challenge in the treatment of AD. Recently, depletion of receptor interacting protein kinase 1 (RIPK1) activity in murine AD models has been shown to reduce amyloid burden, memory deficits and the levels of inflammatory cytokines. Moreover, inhibition of RIPK1 has been shown to promote microglial degradation of Aβ in vitro. Necroptosis, a programmed form of necrosis, executed by mixed lineage kinase domain-like (MLKL) protein and activated by RIPK1 and RIPK3, has been shown to be involved in AD. However, the role of RIPK1 in Aβ-induced necroptosis is yet to be deciphered. In this study, SH-SY5Y human neuroblastoma cells treated with Aβ 1-40 or Aβ 1-42 was used as an AD model. Caspase activity assay and co-administration with caspase inhibitor or autophagy inhibitor showed that Aβ-induced neuronal cell death was independent of apoptosis and autophagy pathways. Furthermore, immunoblotting assay showed that Aβ-treated cells and cells overexpressing amyloid precursor protein (APP) activated iii RIPK1/MLKL-dependant necroptosis pathway. Moreover, depletion of RIPK1 expression rescued the cells from Aβ-induced neuronal cell death. In addition, ectopic expression of RIPK1 was found to prolong the stability of the endogenous APP. Transcriptomic analysis showed that the expression of RIPK1 was increased in AD patients, particularly in the hippocampus, entorhinal cortex and temporal cortex. Taken together, the present findings show that Aβ is able to activate necroptosis in an RIPK1-MLKL dependent manner, suggesting that RIPK1 plays an important role in the development of AD.