A study of mechanisms linking type 2 diabetes mellitus and dementia
thesisposted on 2017-02-27, 05:32 authored by Moran, Christopher
Background: Dementia is highly prevalent in older age, accounts for a significant proportion of age-related disability, and is one of the most expensive disorders affecting older Australians. T2DM affects about 85% of all people with diabetes and occurs more commonly in older age. T2DM increases the risk of vascular dementia and Alzheimer’s dementia (AD) although there may be substantial overlap of the two pathologies. The underlying pathways between T2DM and dementia may involve neurodegeneration, vascular disease, or both, with several common intermediary mechanisms. Aims & methods: The broad aim of this thesis was to study the disease pathways that underlie the association between T2DM and dementia. The majority of the research presented was conducted within the Cognition and Type 2 Diabetes in Older Tasmanians (CDOT) study. A further study was conducted in a second sample, derived from the United States’ Alzheimer’s disease Neuroimaging Initiative (ADNI). Results: The main novel results of my thesis are summarised below: 1. Brain atrophy is a key mediator of T2DM-related cognitive impairment and the regional distribution of brain atrophy seen in T2DM appears similar to that seen in early AD. 2. Tissue advanced glycation is associated with brain atrophy in T2DM (and in those without T2DM) and may partially mediate the association between T2DM and brain atrophy. 3. T2DM is associated with excess production of CSF phosphorylated tau, and this partially mediates the association between T2DM and reduced cortical thickness, providing the first in-vivo evidence mechanistically linking T2DM with neurodegenerative AD-type pathology. 4. Retinal vascular architecture and retinopathy (subclinical markers of small cerebral vessel disease) were not associated with MRI biomarkers of T2DM-related brain disease, raising speculation about the relative importance of vascular pathways leading to brain disease in people with T2DM receiving good glycaemic and vascular risk control. Conclusions: Brain atrophy is a key mediator of diabetes-related cognitive impairment and mechanisms similar to that seen in AD may play a role in T2DM-related cognitive impairment. These findings do not exclude the possibility that cerebrovascular disease or other non-AD-type processes contribute to T2DM-related cognitive impairment. A greater understanding of the mechanisms linking T2DM and dementia may facilitate development of new avenues for treatment of dementia.
Awards: Vice-Chancellor’s Commendation for Doctoral Thesis Excellence in 2015.