However, in a 25-year follow-up of the Honolulu-Asia Aging Study, men who had higher levels of high-sensitivity CRP earlier in life had an increased RR of dementia later in life.40 Compared with men in the lowest quartile of CRP, men in the upper 3 quartiles had a 3-fold significantly increased RR of all dementias combined, as well as for AD and vascular dementia. Thus, it is possible that—as with midlife obesity—long-term rather than short-term exposure to high levels of inflammation may be most relevant to the risk of late-life cognitive decline and dementia.
Finally, there may be additional connections of metabolic syndrome to late-life cognitive dysfunction. For example, obesity, insulin resistance, and diabetes have been associated with depression, and inflammation may play a mechanistic role in the development of depression.41-45 A relationship between depressed mood and psychological distress and dementia has also been found (depression may not be merely an early manifestation of dementia).46 Indeed, depression and diabetes-related risk factors may have complex interactions that affect late-life cognition, which warrant further study.47,48
Metabolic risk factors have substantial implications for public health. Obesity is increasing among younger people, including children, and insulin resistance is increasingly prevalent in young and middle-aged adults. The Table provides an overview of increased hyperinsulinemia prevalence from 1984 through 2002.49 Although advancing age is still the most prominent risk factor for cognitive decline and dementia, the escalating prevalence of obesity, insulin resistance (including frank diabetes), and attendant metabolic problems could create a scenario in which the burden of late-life cognitive disorders will actually be far greater than that which would be anticipated by virtue of the age shift alone.
Fortunately, these metabolic risk factors are readily modifiable. Regular physical activity, healthy diet, and weight reduction/control can decrease the risk of obesity and metabolic problems. Physical activity promotes insulin sensitivity, reduces hyperinsulinemia, and lowers levels of inflammatory markers.50,51 Dietary replacement of high glycemic index carbohydrates (eg, refined sugars, products made with white flour) with minimally refined cereals and whole grains reduces the risk of insulin resistance and diabetes.52 Finally, obesity provokes insulin resistance; thus, a strategy of maintaining a healthy weight and avoiding weight gain during adulthood is considered “the cornerstone of diabetes prevention.”6
A potential adjunct to these prevention strategies is the development of pharmacotherapies that target diabetes-related biology and offer either enhancement or protection of late-life cognitive function. Some preliminary work shows promise in this regard. For example, Watson and colleagues53 reported on the potential role of a class of diabetes drugs called peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists. These drugs enhance insulin sensitivity and appear to reduce blood levels of inflammatory markers, such as CRP and IL-6, even in persons without diabetes.54
At the end of a double-blind, placebo-controlled, 6-month study of 30 patients with mild AD or amnestic mild cognitive impairment, those who received rosiglitazone (a PPAR-γ agonist) demonstrated better performance on a task of delayed recall than placebo recipients.53 However, the recent alarm about the adverse cardiovascular profile of rosiglitazone may limit exploration of such alternative uses for PPAR-γ agonists, and researchers may turn their attention to the development of other insulin-sensitizing interventions.55
As exploration of pharmacological options continues, clinical psychiatrists can adopt a proactive role in addressing the numerous nonpharmacological means of reducing the likelihood of adverse cognitive aging effects of diabetes-related factors with their patients. Specifically, psychiatrists can aim to incorporate focused counseling on pertinent life-style modifications into their work:
• Recommendations for regular physical activity sufficient to break a sweat (30 minutes a day, 3 to 5 times a week)
• Referral to nutrition consultation and/or weight management programs for patients who are overweight or obese
• Diligent monitoring of metabolic factors (eg, levels of fasting glucose, lipids, hemoglobin A1c) for patients at high risk for obesity or metabolic syndrome
In summary, a growing body of research indicates that diabetes-related risk factors pose potent threats to healthy cognitive aging, even in the absence of actual diabetes. Psychiatrists can play their part in dementia prevention by monitoring closely the cognitive function of their older patients who already have diabetes, and encouraging patients of all ages to address modifiable risk factors for obesity, insulin resistance, and diabetes.
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