Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology.

OBJECTIVE: To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. METHODS: Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. RESULTS: Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT308AKT1/total AKT1, but not with pS307IRS-1/total IRS-1 or the density of cells stained positive for pS616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. INTERPRETATION: Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.

Metformin, age-related cognitive decline, and brain pathology.

The objective of this study was to evaluate the relation of metformin with change in cognition and brain pathology. During a mean of 8 years (SD = 5.5) of annual follow-up visits, 262/3029 participants were using metformin at any time during the study. Using a linear-mixed effect model adjusted for age, sex, and education, metformin users had slower decline on a score of global cognition compared to non-users (estimate = 0.017, SE = 0.007, p = 0.027). Analyses of cognitive domains showed a slower decline in episodic memory and semantic memory specifically. In sensitivity analysis, when examining any diabetes medication use vs none, no association was observed of any diabetes medication use with cognitive function. In the autopsy subset of 1584 participants, there was no difference in the level of Alzheimer's disease (AD) pathology or the presence of infarcts (of any size or location) between groups of metformin users vs non-users. However, in additional analyses, metformin users had higher odds of subcortical infarcts, and lower odds of atherosclerosis and arteriosclerosis.

The impact of incident stroke on cognitive trajectories in later life.

BACKGROUND: Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals. METHODS: 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke. RESULTS: During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants. CONCLUSIONS: These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention.