There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Karen Mate |
| Institution: | University of Newcastle |
| Department: | School of Biomedical Sciences and Pharmacy |
| Country: | |
| Proposed Analysis: | Drugs should be prescribed with caution in older patients, as they are more sensitive to adverse effects and drug clearance is reduced. The Beers Criteria, developed and updated by the American Geriatrics Society [1], list a number of potentially inappropriate medications that should be avoided in older adults. Our proposed studies will focus on two aspects of medication use, anticholinergic load and cytochrome P450 (CYP) inhibitor-substrate interactions, and their effects over time on cognition, activities of daily living and adverse events. Anticholinergics It is specifically recommended that anticholinergic medication is avoided in people with dementia, as it may further impair their cognitive function. Anticholinergic burden can develop insidiously over time, as patients are subjected to increasingly complex medication regimens to manage multi-morbidities. The scientific literature has focussed on the effects of individual drugs with marked anticholinergic activity [1-3], with less recognition of the cumulative effect of multiple drugs with lower individual anticholinergic activities, which can contribute, on average, 70% to the total anticholinergic burden [4]. The ADNI protocol, which excludes a number of strong anticholinergic medications at the screening stage, provides a unique dataset to examine (i) the effects of low level anticholinergic medications and (ii) the accumulation of anticholinergic load over time in an elderly cohort of known dementia status. This is of particular interest, as our recent cross-sectional study of community-dwelling elderly patients in Australia [4] found that anticholinergic medication(s) were used more frequently in people with dementia, with a mean anticholinergic load almost double that of people without dementia. • What is the magnitude of load contributed by low level anticholinergic medications in people with normal cognition (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimers dementia (AD) • Are people with normal cognition, EMCI, LMCI or AD more likely to accumulate an increased anticholinergic burden over time? • Does an increase in anticholinergic burden or anticholinergic exposure over time affect cognition, activities of daily living or the likelihood of an adverse event in people with normal cognition, EMCI, LMCI or AD? CYP Enzyme-Drug-Gene Interactions The elderly are also at increased risk for adverse effects resulting from drug interactions involving the cytochrome (CYP) metabolising enzymes, a superfamily of monooxygenases, due to their impaired drug clearance and the higher incidence of polypharmacy in this population. Different gene variants of CYP enzymes exhibit different metabolic activities which have a bearing on the severity of potential interactions. Potentially serious or fatal adverse effects may occur when high plasma levels of a substrate drug result from the co-administration of a drug that inhibits its metabolism. On the other hand, drugs that are inducers of a particular enzyme may result in reduced plasma levels of a co-administered substrate drug and therefore, reduced efficacy. The potential for these interactions to result in adverse effects will be diminished or exacerbated by the CYP genotype of the individual, which will determine whether they are a “fast”, “intermediate” or “poor” metaboliser. • What is the incidence of CYP inhibitor drug interactions with anticholinergic (and other) CYP substrate drugs in people with normal cognition (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimers dementia (AD)? • What specific CYP substrate-inhibitor adverse interactions are most likely to result in adverse events in people with normal cognition, EMCI, LMCI or AD? • Can pharmacogenomics predict adverse outcomes associated with CYP substrate-inhibitor interactions? References [1] American Geriatrics Society 2015 Beers Criteria Update Expert Panel (2015) American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. JAGS doi: 10.1111/jgs.13702. [Epub ahead of print] [2] Sera, L.C. and M.L. McPherson, Pharmacokinetics and pharmacodynamic changes associated with aging and implications for drug therapy. Clin Geriatr Med, 2012. 28(2): 273-86. [3] Mannesse, C.K., et al., Contribution of adverse drug reactions to hospital admission of older patients. Age Ageing, 2000. 29(1): 35-9. [4] Mate, K.E., et al (2015) Impact of multiple low-level anticholinergic medications on anticholinergic load of community-dwelling elderly with and without dementia. Drugs Aging 32(2):159-67. |
| Additional Investigators |
