Effects of insulinic therapy on cognitive impairment in patients with Alzheimer disease and diabetes mellitus type-2.
ABSTRACT Type-2 Diabetes Mellitus (DM-2) is an important risk factor for Alzheimer disease (AD) and vascular dementia (VD). The role of insulinic therapy on cognitive decline is controversial.
To evaluate cognitive impairment in patients with AD and DM-2 treated with either oral antidiabetic drugs or combination of insulin with other diabetes medications.
104 patients with mild-to-moderate AD and DM-2 were divided into two groups, according to antidiabetic pharmacotherapy: group A, patients treated with oral antidiabetic drugs and group B, patients treated with insulin combined with other oral antidiabetic medications. Cognitive functions were assessed by the Mini Mental State Examination (MMSE) and the Clinician's Global Impression (CGI), with a follow-up of 12 months.
At the end of the study, the MMSE scores showed a significant worsening in 56.5% patients of group A and in 23.2% patients of group B, compared to baseline MMSE scores (P=.001). Also CGI-C scores showed a significant worsening for all domains after 12 months in group A vs group B (P=.001). The two groups were matched for body mass index, serum lipids, triglycerides, Apo epsilon4 allele and smoke habit. Conversely, ischemic heart disease and hypertension were significantly higher in group B (P=.002). After adjustment for this risk variables, our results remained significant (P=.001).
Our study suggests that insulinic therapy could be effective in slowing cognitive decline in patients with AD.
Article: Consequences of Aberrant Insulin Regulation in the Brain: Can Treating Diabetes be Effective for Alzheimer's Disease.[show abstract] [hide abstract]
ABSTRACT: There is an urgent need for new ways to treat Alzheimer's disease (AD), the most common cause of dementia in the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the course of the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactions between diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and are frequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This is currently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinical and biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucose metabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidence from a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported by a number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions were induced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brains demonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition, diabetes induces its own distinct features of neuropathology different from AD. There are common pathological features to be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence that vascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II) diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors and affect insulin signaling and cell survival. It has even been suggested that AD could be considered as "type 3 diabetes" since insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycation endproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproducts plays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβ peptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have been conducted, further understanding the common pathological processes of diabetes and AD are needed to determine whether these diseases share common therapeutic targets.DNA research: an international journal for rapid publication of reports on genes and genomes 12/2011; 9(4):693-705. · 1.73 Impact Factor
Article: Recommended measures for the assessment of cognitive and physical performance in older patients with dementia: a systematic review.[show abstract] [hide abstract]
ABSTRACT: AIM/GOAL: To recommend a set of neuropsychological and physical exercise tests for researchers to assess cognition and physical fitness in clinical trials with older patients with dementia; to create consensus, decrease heterogeneity, and improve research quality. METHODS: A literature search (2005-2011) yielded 89 randomized controlled trials. To provide information on test recommendations the frequency of test use, effect size of the test outcome, study quality, and psychometric properties of tests were analyzed. RESULTS: Fifty-nine neuropsychological tests (cognitive domains: global cognition, executive functioning, memory, and attention) and 10 exercise tests (physical domains: endurance capacity, muscle strength, balance, and mobility) were found. Conclusion: The Severe Impairment Battery, Mini Mental State Examination, and Alzheimer Disease Assessment Scale - cognitive subscale were recommended to measure global cognition. The Verbal Fluency Test Category/Letters, Clock Drawing Test, and Trail Making Test-B were recommended to measure executive functioning. No specific memory test could be recommended. The Digit Span Forward, Digit Span Backward, and Trail Making Test-A were recommended to measure attention. As physical exercise tests, the Timed Up and Go and Six Meter Walk for mobility, the Six Minute Walk Distance for endurance capacity, and the Tinetti Balance Scale were recommended.Dementia and geriatric cognitive disorders extra. 01/2012; 2(1):589-609.
Article: Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease.[show abstract] [hide abstract]
ABSTRACT: Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) to induce experimental diabetes in AD transgenic mice (5XFAD model) and investigated how insulin deficiency affects the β-amyloidogenic processing of amyloid precursor protein (APP). Two and half months after 5XFAD mice were treated with STZ (90 mg/kg, i.p., once daily for two consecutive days), they showed significant reductions in brain insulin levels without changes in insulin receptor expression. Concentrations of cerebral amyloid-β peptides (Aβ40 and Aβ42) were significantly increased in STZ-treated 5XFAD mice as compared with vehicle-treated 5XFAD controls. Importantly, STZ-induced insulin deficiency upregulated levels of both β-site APP cleaving enzyme 1 (BACE1) and full-length APP in 5XFAD mouse brains, which was accompanied by dramatic elevations in the β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA levels were not affected, whereas phosphorylation of the translation initiation factor eIF2α, a mechanism proposed to mediate the post-transcriptional upregulation of BACE1, was significantly elevated in STZ-treated 5XFAD mice. Meanwhile, levels of GGA3, an adapter protein responsible for sorting BACE1 to lysosomal degradation, are indistinguishable between STZ- and vehicle-treated 5XFAD mice. Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains. Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.PLoS ONE 01/2012; 7(3):e32792. · 4.09 Impact Factor