Insulin resistance was associated with a pattern of reduced CMRglu in frontal, temporal-parietal, and cingulate regions in cognitively intact adults with P-D/T2D. This pattern of hypometabolism has also been observed in patients with MCI and AD, in middle-aged non-demented carriers of the APOE-ε4 genetic risk factor, and in pre-symptomatic adults with the AD-causative presenilin-1 gene.5,17
In our sample, the relationship between CMRglu and insulin resistance indexed by HOMA-IR was independent of age, 2-h OGTT glucose concentration, or APOE-ε4 allele carriage. Adults with P-D/T2D also showed a different activation pattern during a memory encoding task compared with normal adults, characterized by more widespread activation. Our participants received careful neuropsychological assessment and were not cognitively impaired according to current criteria for MCI.9
However, their ability to recall words encoded during scanning was reduced relative to adults who were not insulin resistant, despite being of similar age and education levels. Taken together, these results suggest that increased 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.
Although reduced CMRglu has been reported in several rodent models of diabetes,18,19
few human studies have examined this possibility in T2D, and none in P-D. In an early FDG-PET study in humans, a small sample of Pima Indians with T2D (n=4) showed no overall differences compared with caucasian participants without T2D.20
Regional differences were not examined, however, and the diabetic group was heterogenous with respect to treatment. Nagamachi et al. examined cerebral blood flow (CBF) using SPECT in adults with T2D with no evidence of cerebral infarction on CT.21
They reported reduced CBF in all cortical areas, with prominent reduction in frontal areas for more severely affected patients who were treated with insulin. Generalized reductions in CBF and CMRglu were related to an atrophy index for a group of subjects with microvascular disease and treated diabetes.22
In contrast, participants in our study had milder, newly-diagnosed P-D or T2D, and had never received treatment for diabetes. Thus, the AD-like pattern of hypometabolism we observed is likely related to the underlying pathophysiology of insulin resistance and diabetes, as opposed to secondary effects of diabetic treatment.
The identification of specific metabolic factors that are associated with abnormal CMRglu patterns may elucidate important pathogenetic pathways. Reiman et al. investigated the relationship between cholesterol and CMRglu in late middle-aged adults of varying APOE genotypes.23
They reported an AD-like pattern of temporo-parietal and frontal hypometabolism that was more prominent in APOE-ε4 carriers than in non-carriers. In our study, the relationship between insulin resistance and CMRglu was not mediated by APOE-ε4 carriage status, suggesting that insulin resistance and APOE-ε4 carriage may be independent factors associated with AD-related CMRglu abnormalities. This possibility has been suggested in other studies in which factors related to insulin resistance and APOE genotype have been shown to be independent risk factors for AD. Support for insulin resistance-related CMRglu reductions was also provided by a recent study in which a cognitively mixed group of adults showed reduced frontal CMRglu that was associated with increased cardiovascular risk, as assessed by the Framingham Cardiovascular Risk Profile.24
This index includes components such as diabetes, hypertension, cholesterol, and age, and is strongly related to measures of insulin resistance.25
There are several possible mechanisms through which insulin resistance may affect CMRglu.26
Insulin resistance is associated with reduced insulin levels and/or activity in the CNS, due to reduced transport of insulin across the BBB in the context of chronically elevated peripheral insulin levels, or to reduced CNS insulin signalling. Insulin modulation affects brain glucose utilization in animal models,7,27
and thus reduced insulin levels or activity may interere with this process. Insulin resistance is also associated with impaired cerebrovascular function which may affect glucose delivery to the CNS, even in the absence of frank infarcts.1
Other indirect effects on neurotransmitter modulation may negatively impact glucose utilization.1
A final potential mechanism with direct relevance to AD concerns the relationship between insulin and Aβ. Increased Aβ burden has been linked to reduced CMRglu, and insulin modulates levels of Aβ, in part through its effects on Aβ clearance.1,28
Interesting differences in activation patterns were observed during the memory encoding task for normal and P-D/T2D groups. For normal adults, activation was observed in Brodmann areas 10, 45, and 47 in right frontal cortex, in right inferior temporal cortex, and in medial and posterior cingulate regions. This right-sided lateralization may initially appear surprising given that the encoding paradigm used auditorally-presented verbal stimuli. Several reviews have noted however, that lateralization patterns during encoding differ for older adults and include regions observed in our study.16
Furthermore, selective right prefrontal activation, particularly involving Brodmann area 10, has been noted in a variety of verbal memory tasks.29
These patterns may reflect different strategic approaches to encoding, or recruitment of different regions as a compensatory mechanism for age-related metabolic dysfunction. Additionally, because it was necessary to obtain a resting scan to explore relationships of basal CMRglu with insulin resistance, task activation was compared to a resting state, rather than to a control task that accounted for non-specific attentional and working memory demands; consequently, activation includes cognitive processes in addition to memory encoding, processes that may preferentially activate right hemisphere neurocognitive networks. Use of a matched control task in future studies may more clearly delineate activation patterns due specifically to encoding processes. It is also worth noting that our normal group may be healthier than control groups included in many neuroimaging studies; it is likely that many studies of “normal” older adults include adults with undiagnosed P-D/T2D in their sample, as it is estimated that as more than 50% of adults over the age of 60 with these conditions are unaware of their abnormal glycemic status,30
and screening OGTTs are not routinely administered. The inclusion of such subjects undoubtedly contributes to heterogenous results in neuroimaging studies of older adults.
In contrast to the pattern observed for the normal group, the P-D/T2D group showed more diffuse activation that included bilateral medial and inferior frontal regions that were adjacent to regions activated for normal adults. The P-D/T2D group also showed activation of subcortical regions (right putamen, left thalamus) and right cerebellar vermis. Diffuse activation or hyperactivation of areas not typically engaged in a cognitive task have been reported in adults with prodromal or early AD as well as in non-symptomatic APOE-ε4 carriers, and may be a compensatory mechanism that is invoked following dysfunction of the neuroarchitectural network that typically would support a cognitive task.31,32
A recent meta-analysis reported that patients with AD showed extensive prefrontal activation during memory encoding tasks, including activation in Brodmann area 11, as well as thalamic and cerebellar activation, a pattern very similar to that observed in our P-D/T2D group.33
Postive correlations were also observed between recall and CMRglu for several stereotactically defined globally-normalized VOIs that included frontal, parietal, temporal, and posterior cingulate cortices.
Our results suggest that insulin resistance may be a risk factor for AD in part due to detrimental effects on CMRglu. Screening for insulin resistance may thus provide a relatively low-cost, non-invasive means for identifying adults at risk, as well as providing a rationale for examining the potential benefits of interventions directed at improving insulin resistance. Many such interventions, such as exercise, are low-risk, with numerous documented health benefits, and improve cognitive function in adults with MCI and AD.34
Our results also provide a strong rationale for further study of the mechanisms underlying the association between insulin resistance and reduced CMRglu.