Insulin resistance is a causal factor in pre-diabetes and type 2 diabetes (T2D), and also increases the risk of developing Alzheimer’s disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fluorodeoxyglucose positron emission tomography (FDG PET) in parietotemporal, frontal, and cingulate cortex are also associated with increased AD risk, and can be observed years before dementia onset.
We examined whether greater insulin resistance as indexed by the homeostasis model assessment (HOMA-IR) would be associated with reduced resting CMRglu in areas known to be vulnerable in AD in a sample of cognitively normal adults with newly diagnosed pre-diabetes or T2D (P-D/T2D). We also determined whether P-D/T2D adults have abnormal patterns of CMRglu during a memory encoding task.
Randomized crossover design of resting and activation [F-18] FDG-PET.
University Imaging Center and VA Clinical Research Unit.
Participants included 23 older adults (mean age±SEM=74.4±1.4) with no prior diagnosis of or treatment for diabetes, but who met American Diabetes Association glycemic criteria for pre-diabetes (n=11) or diabetes (n=12) based on fasting or 2-h oral glucose tolerance test (OGTT) glucose values, and 6 adults (mean age±SEM=74.3±2.8) with normal fasting glucose and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment (MCI).
Fasting participants rested with eyes open in a dimly lit room and underwent resting and cognitive activation [F-18]FDG PET imaging on separate days, in randomized order, at 9 am. Following a 30-min transmission scan, subjects received an intravenous injection of 5 mCi [F-18]FDG, and the emission scan commenced 40 min post-injection. In the activation condition, a 35-min memory encoding task was initiated at the time of tracer injection. Subjects were instructed to remember a repeating list of 20 words that were randomly presented in series through earphones. Delayed free recall for items on the word list was assessed once the emission scan was complete.
Main Outcome Measures
HOMA-IR was calculated for each participant using fasting glucose and insulin values obtained during OGTT screening, and then correlated with CMRglu values obtained during the resting scan. Resting CMRglu values were also subtracted from CMRglu values obtained during the memory encoding/activation scan to examine task-related patterns of CMRglu.
Greater insulin resistance as indexed by HOMA-IR was associated with an AD-like pattern of reduced CMRglu in frontal, temporal-parietal, and cingulate regions in adults with P-D/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-h OGTT glucose concentration, or apolipoprotein E-ε4 allele carriage. During the memory encoding task, normal adults showed activation in right anterior and inferior prefrontal cortex, right inferior temporal cortex, and medial and posterior cingulate regions. Compared to the normal group, adults with P-D/T2D showed a different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.
Our results suggest that insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of MCI.