Journal of Alzheimer's Disease - Volume 59, issue 2

Article Type: Editorial

DOI: 10.3233/JAD-179004

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 387-388, 2017

Authors: Martins, Ralph N.

Article Type: Editorial

DOI: 10.3233/JAD-170309

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 389-392, 2017

Authors: Sutherland, Greg T. | Lim, Julia | Srikanth, Velandai | Bruce, David G.

Article Type: Review Article

Abstract: Diabetes and dementia are two diseases that increased dramatically in most societies in direct proportion to increases in average life expectancy. The two conditions are strongly associated and there is much hope that understanding this association will unlock the enigma that is the pathogenesis of dementia. Previous studies suggest that type 2 diabetes is a risk factor for all-cause dementia, vascular dementia and Alzheimer’s disease. However these estimates may not necessarily have taken into account the overlap in dementia pathologies or the competing risk of death. Although the link between diabetes and vascular disease is intuitive, it is now becoming …clear that type 2 diabetes is also associated with reduced brain volumes and with progression of brain atrophy, apparently independent of its relation with cerebrovascular disease. This raises the possibility that type 2 diabetes may also contribute to neurodegeneration, and particularly tau pathology. Prospective studies that record extensive multimodal in-vivo biomarkers and conduct rigorous postmortem neuropathological examination are certainly required to tease apart these complex pathways. However monitoring cognitive outcomes from current observational studies and randomized clinical trials of new diabetes treatments could be equally valuable in reducing the dementia epidemic. Show more

Keywords: Alzheimer’s disease, dementia, diabetes, epidemiology

DOI: 10.3233/JAD-161194

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 393-403, 2017

Authors: Moran, Chris | Beare, Richard | Phan, Thanh | Starkstein, Sergio | Bruce, David | Romina, Mizrahi | Srikanth, Velandai

Article Type: Review Article

Abstract: Diabetes mellitus is associated with an elevated risk of cognitive impairment and dementia. Cerebrovascular disease and neurodegeneration are two major pathways that may explain the effect of diabetes on the brain and therefore deserve investigation. Neuroimaging provides an effective way to investigate the contribution of these pathways in vivo , guiding further mechanistic research and providing biomarkers for clinical correlation or interventional studies. In this paper, we present a narrative review of the state of play with neuroimaging evidence in studies of people with diabetes mellitus, how these data are useful in understanding mechanistic links between diabetes and brain impairment, …and possible ways that the field may develop in the future. Show more

Keywords: Alzheimer’s disease, dementia, diabetes, neuroimaging

DOI: 10.3233/JAD-161166

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 405-419, 2017

Authors: Bharadwaj, Prashant | Wijesekara, Nadeeja | Liyanapathirana, Milindu | Newsholme, Philip | Ittner, Lars | Fraser, Paul | Verdile, Giuseppe

Article Type: Review Article

Abstract: A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer’s disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in …reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β protein, insulin, tau, type 2 diabetes

DOI: 10.3233/JAD-161192

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 421-432, 2017

Authors: Huynh, Kevin | Martins, Ralph N. | Meikle, Peter J.

Article Type: Review Article

Abstract: Lipids are a diverse class of hydrophobic and amphiphilic molecules which make up the bulk of most biological systems and are essential for human life. The role of lipids in health and disease has been recognized for many decades, as evidenced by the early identification of cholesterol as an important risk factor of heart disease and the development and introduction of statins as a one of the most successful therapeutic interventions to date. While several studies have demonstrated an increased risk of dementia, including Alzheimer’s disease (AD), in those with diabetes mellitus, the nature of this risk is not well …understood. Recent developments in the field of lipidomics, driven primarily by technological advances in high pressure liquid chromatography and particularly mass spectrometry, have enabled the detailed characterization of the many hundreds of individual lipid species in mammalian systems and their association with disease states. Diabetes mellitus and AD have received particular attention due to their prominence in Western societies as a result of the ongoing obesity epidemic and the aging populations. In this review, we examine how these lipidomic studies are informing on the relationship between lipid metabolism with diabetes and AD and how this may inform on the common pathological pathways that link diabetes risk with dementia. Show more

Keywords: Alzheimer’s disease, diabetes mellitus, lipid metabolism, mass spectrometry, risk

DOI: 10.3233/JAD-161215

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 433-444, 2017

Authors: Asih, Prita R. | Tegg, Michelle L. | Sohrabi, Hamid | Carruthers, Malcolm | Gandy, Samuel E. | Saad, Farid | Verdile, Giuseppe | Ittner, Lars M. | Martins, Ralph N.

Article Type: Review Article

Abstract: Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal …aging, and although there is no significant increase in cerebral Aβ deposition in T2DM, the extent of Aβ accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk. Show more

Keywords: Alzheimer’s disease, men, testosterone, type-2 diabetes, women

DOI: 10.3233/JAD-161259

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 445-466, 2017

Authors: Dhananjayan, Karthik | Gunawardena, Dhanushka | Hearn, Nerissa | Sonntag, Tanja | Moran, Chris | Gyengesi, Erika | Srikanth, Velandai | Münch, Gerald

Article Type: Research Article

Abstract: Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-γ and LPS (5 + 5 and 10 + 10 IFN-γ U/ml or μg/ml LPS), and extracellular MGO concentration was …determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48 h, increasing 2.86-fold (3.14±0.4 μM) at 5 U/ml IFN-γ +5 μg/ml LPS, and 4.74-fold (5.46±0.30 μM) at 10 U/ml IFN-γ +10 μg/ml LPS compared to the non-activated controls (1.15±0.02 μM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline. Show more

Keywords: Cognitive decline, inflammation, methylglyoxal, type 2 diabetes mellitus, vascular complications

DOI: 10.3233/JAD-161152

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 467-479, 2017

Authors: Fernando, Warnakulasuriya M.A.D.B. | Somaratne, Geeshani | Goozee, Kathryn G. | Williams, Shehan | Singh, Harjinder | Martins, Ralph N.

Article Type: Review Article

Abstract: Dementia and diabetes mellitus are prevalent disorders in the elderly population. While recognized as two distinct diseases, diabetes has more recently recognized as a significant contributor to risk for developing dementia, and some studies make reference to type 3 diabetes, a condition resulting from insulin resistance in the brain. Alzheimer’s disease, the most common form of dementia, and diabetes, interestingly, share underlying pathological processes, commonality in risk factors, and, importantly, pathways for intervention. Tea has been suggested to possess potent antioxidant properties. It is rich in phytochemicals including, flavonoids, tannins, caffeine, polyphenols, boheic acid, theophylline, theobromine, anthocyanins, gallic acid, and …finally epigallocatechin-3-gallate, which is considered to be the most potent active ingredient. Flavonoid phytochemicals, known as catechins, within tea offer potential benefits for reducing the risk of diabetes and Alzheimer’s disease by targeting common risk factors, including obesity, hyperlipidemia, hypertension, cardiovascular disease, and stroke. Studies also show that catechins may prevent the formation of amyloid-β plaques and enhance cognitive functions, and thus may be useful in treating patients who have Alzheimer’s disease or dementia. Furthermore, other phytochemicals found within tea offer important antioxidant properties along with innate properties capable of modulating intracellular neuronal signal transduction pathways and mitochondrial function. Show more

Keywords: Alzheimer’s disease, cognitive impairment, diabetes, phytochemicals, tea

DOI: 10.3233/JAD-161200

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 481-501, 2017

Authors: Callisaya, Michele | Nosaka, Kazunori

Article Type: Review Article

Abstract: Cognitive impairment and dementia are common contributors to institutionalization and loss of quality of life in older people. Both type 2 diabetes mellitus (T2DM) and physical inactivity are prevalent and important modifiable risk factors for developing dementia. Physical activity is recommended in the management of T2DM, and there is growing evidence that exercise, a subgroup of physical activity, is also beneficial for maintaining and improving brain structure and function. This paper reviews the evidence for a benefit of exercise on T2DM related cognitive impairment and dementia. In addition, the type (e.g., aerobic, resistance), intensity, duration, and frequency of exercise are …discussed. This review shows that although exercise has known benefits on the mechanisms linking T2DM to dementia, there are very few randomized controlled trials examining whether this is the case. It is concluded that the uptake of exercise for the brain has great potential to improve quality of life and provide significant cost savings, but further research is warranted to clarify the effects of exercise on T2DM and those on dementia. Show more

Keywords: Aerobic exercise, brain health, cognitive function, eccentric exercise, physical activity, resistance exercise

DOI: 10.3233/JAD-161154

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 503-513, 2017