Journal of Alzheimer's Disease - Volume 42, issue 2

Authors: Desai, Gauri S. | Zheng, Chen | Geetha, Thangiah | Mathews, Suresh T. | White, B. Douglas | Huggins, Kevin W. | Zizza, Claire A. | Broderick, Tom L. | Babu, Jeganathan Ramesh

Article Type: Review Article

Abstract: Epidemiological and observational studies indicate a positive correlation between type 2 diabetes (T2DM) and dementia, with an increased risk of dementia and Alzheimer's disease (AD) associated with insulin-treated diabetes patients. The purpose of this review is to reveal the molecular mechanisms that connect physiological and pathological processes commonly observed in T2DM and AD. Conformational modifications in peptide residues, such as amyloid-β peptide in AD and amylin in T2DM have been shown to instigate formation of insoluble protein aggregates that get deposited in extracellular spaces of brain and pancreatic tissue thus disrupting their normal function. Impaired insulin signaling plays a critical …role in AD pathogenesis by reducing IRS-associated PI3 kinase activity and increasing GSK-3β activity. GSK-3β has been suggested to be a component of the γ-secretase complex and is involved in amyloid-β protein precursor processing. GSK-3β along with CDK5 is responsible for hyperphosphorylation of tau leading to the formation of neurofibrillary tangles. In summary, there is evidence to believe that a molecular link connects AD and T2DM and has potential for further investigation toward development of an effective therapeutic target. Show more

Keywords: Alzheimer's disease, amyloid-β, insulin receptor, neurofibrillary tangle, type 2 diabetes

DOI: 10.3233/JAD-140018

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 347-356, 2014

Authors: Farías, Gonzalo A. | Guzmán-Martínez, Leonardo | Delgado, Carolina | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: Alzheimer's disease is a growing health problem worldwide. The pharmaceutical industry has not recently developed any new drugs that have had a significant impact on the natural history of the disease, so considerable attention has been given to nutraceuticals and nutritional bioactive compounds that can be obtained directly from diet or supplementation. These compounds may be able to modify physiopathological processes responsible for neurodegeneration and/or to have pro-cognitive properties. Here, we review current knowledge on the role of diet modifications, lipid and carbohydrates consumption, vitamin supplementation, and the possible effects of antioxidant and nutraceutical compounds with neuroprotective activity, in the …prevention and treatment of Alzheimer's disease and related disorders. Show more

Keywords: Alzheimer's disease, antioxidants, clinical trials, food supplements, nutraceuticals, vitamins

DOI: 10.3233/JAD-132741

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 357-367, 2014

Authors: Femminella, Grazia Daniela | Rengo, Giuseppe | Komici, Klara | Iacotucci, Paola | Petraglia, Laura | Pagano, Gennaro | de Lucia, Claudio | Canonico, Vincenzo | Bonaduce, Domenico | Leosco, Dario | Ferrara, Nicola

Article Type: Review Article

Abstract: Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer's disease are also implicated in autonomic nervous system regulation, and it has been hypothesized that the deficit in central cholinergic function observed in Alzheimer's disease could likely lead to autonomic dysfunction. Several feasible tests can be used in clinical practice for the assessment of parasympathetic and sympathetic functions, especially in terms of cardiovascular autonomic modulation. In this review, we describe the different tests available and the evidence from the literature which …indicate a definite presence of autonomic dysfunction in dementia at various degrees. Importantly, the recognition of dysautonomia, besides possibly being an early marker of dementia, would help prevent the disabling complications which increase the risk of morbidity, institutionalization, and mortality in these individuals. Show more

Keywords: Alzheimer's disease, autonomic nervous system, baroreflex, functional recovery, orthostatic hypotension

DOI: 10.3233/JAD-140513

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 369-377, 2014

Authors: Macdonald, Ian R. | Rockwood, Kenneth | Martin, Earl | Darvesh, Sultan

Article Type: Short Communication

Abstract: Cholinesterase inhibitors are the standard of care for Alzheimer's disease (AD). Acetylcholinesterase (AChE) catalyzes the hydrolysis of the cholinergic neurotransmitter acetylcholine. However, the related enzyme butyrylcholinesterase (BuChE) also breaks down acetylcholine and is likewise targeted by the same clinical cholinesterase inhibitors. The lack of clinical efficacy for the highly specific and potent AChE inhibitor, (−) huperzine A, is intriguing, given the known cholinergic deficit in AD. Based on the proven efficacy of inhibitors affecting both cholinesterases and the apparent failure of specific AChE inhibition, focused BuChE inhibition seems important for more effective treatment of AD. Therefore, BuChE-selective inhibitors provide promise …for improved benefit. Show more

Keywords: Acetylcholinesterase, bisnorcymserine, butyrylcholinesterase, donepezil, (−) huperzine A, rivastigmine

DOI: 10.3233/JAD-140219

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 379-384, 2014

Authors: Ishibashi, Kenji | Miura, Yoshiharu | Oda, Keiichi | Ishiwata, Kiichi | Ishii, Kenji

Article Type: Short Communication

Abstract: Increased plasma glucose levels can cause the regional reduction of fluorine-18-labeled fluorodeoxyglucose (18 F-FDG) uptake in the posterior cingulate, precuneus, and/or temporoparietal cortices as an Alzheimer's disease (AD)-like pattern. However, the association of such an AD-like pattern of cerebral 18 F-FDG uptake with AD pathophysiology is unknown. We report a case of a 70-year-old patient with mild cognitive impairment, and show that the AD-like pattern of cerebral 18 F-FDG uptake during a hyperglycemic state could be reversible and is not associated with amyloid-β accumulation. Our case concludes that the AD-like pattern is dependent on the plasma glucose level and independent …of AD pathophysiology. Show more

Keywords: 11C-PiB, 18F-FDG, hyperglycemia, PET

DOI: 10.3233/JAD-140639

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 385-389, 2014

Authors: Oldmeadow, Christopher | Holliday, Elizabeth G. | McEvoy, Mark | Scott, Rodney | Kwok, John B.J. | Mather, Karen | Sachdev, Perminder | Schofield, Peter | Attia, John

Article Type: Short Communication

Abstract: There are a growing number of large cohorts of older persons with genome-wide genotyping data available, but APOE is not included in any of the common microarray platforms. We compared directly measured APOE genotypes with those imputed using microarray data and the “1000 Genomes” dataset in a sample of 320 Caucasians. We find 90% agreement for ε2/ε3/ε4 genotypes and 93% agreement for predicting ε4 status, yielding kappa values of 0.81 and 0.84, respectively. More stringent thresholds around allele number estimates can increase this agreement to 90–97% and kappas of 0.90–0.93.

Keywords: Agreement, APOE, concordance, dementia, genotyping

DOI: 10.3233/JAD-140846

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 391-393, 2014

Authors: Stockburger, Carola | Gold, Vicki A.M. | Pallas, Thea | Kolesova, Natalie | Miano, Davide | Leuner, Kristina | Müller, Walter E.

Article Type: Research Article

Abstract: Recent data suggest that the combined effect of oxidative stress due to aging and slightly elevated amyloid-β (Aβ) levels initiate Alzheimer's disease (AD) long before the clinical onset. Investigations of this early phase are hampered by the lack of cellular or animal models reflecting this scenario. We used SH-SY5Y cells stably transfected with an additional copy of the human AβPP gene and artificial aging by complex I inhibition. These cells show slightly elevated Aβ levels, moderately decreased ATP levels, impaired mitochondrial membrane potential, and decreased mitochondrial respiration. Assessing mitochondrial dynamics with three different methods reveals a distinct shift toward mitochondrial …fission and fragmentation in SH-SY5Y AβPPwt cells. We also performed electron cryo-tomography of isolated mitochondria to reveal that there were no major differences between SH-SY5Y control and SH-SY5Y AβPPwt mitochondria with respect to swelling or loss of cristae. Dystrophic neurites are an early pathological feature of AD. Interestingly, SH-SY5Y AβPPwt cells exhibit significantly longer neurites, likely due to substantially elevated levels of sAβPPα. Complex I inhibition also shows substantial effects on mitochondrial dynamics, impairs neuritogenesis, and elevates Aβ levels in both cell types. In SH-SY5Y AβPPwt cells, these defects were more pronounced due to a relatively elevated Aβ and a reduced sAβPPα production. Our findings suggest that the progression from low Aβ levels to the beginning of AD takes place in the presence of oxidative stress during normal aging. This mechanism not only results from additive effects of both mechanisms on mitochondrial function but might also be additionally aggravated by altered amyloidogenic processing. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β, mitochondrial dynamics, mitochondrial function

DOI: 10.3233/JAD-140381

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 395-411, 2014

Authors: Saint-Aubert, Laure | Sagot, Catherine | Wallon, David | Hannequin, Didier | Payoux, Pierre | Nemmi, Federico | Bezy, Catherine | Chauveau, Nicolas | Campion, Dominique | Puel, Michèle | Chollet, François | Pariente, Jérémie

Article Type: Research Article

Abstract: We report the case of a 65-year-old woman, clinically diagnosed with the logopenic variant of primary progressive aphasia (PPA), and carrier of C9ORF72 expansion, despite cerebrospinal fluid biomarkers suggesting Alzheimer's disease (AD). She underwent structural MRI, metabolic PET, and amyloid PET imaging using florbetapir. Comparison with healthy controls revealed widespread hypometabolism, left sided cortical atrophy, and an increased cortical amyloid load. No difference in amyloid binding was found between the patient and predemential AD patients. This case provides evidence of amyloidopathy in a carrier of C9ORF72 expansion exhibiting a clinical profile of the logopenic variant of PPA.

Keywords: Alzheimer's disease, C9ORF72 expansion, florbetapir, logopenic primary aphasia

DOI: 10.3233/JAD-140222

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 413-420, 2014

Authors: Kim, Eosu | Jung, Young-Sang | Kim, Hyunjeong | Kim, Jin-Sup | Park, Minsun | Jeong, Jihyeon | Lee, Su Kyoung | Yoon, Ho-Geun | Hwang, Geum-Sook | Namkoong, Kee

Article Type: Research Article

Abstract: Discovery of biomarkers in peripheral blood is a crucial step toward the early diagnosis and repetitive monitoring of treatment response for Alzheimer's disease (AD). Metabolomics is a promising technology that can identify unbiased biomarkers. To explore potential blood biomarkers for AD via metabolic profiling with high-resolution magic angle spinning nuclear magnetic resonance techniques, we identified changes in peripheral blood metabolomic profiles in response to amyloid-β (Aβ)-induced neuroinflammation and co-treatment with gallate, a phytochemical known to have anti-neuroinflammatory properties. Alzheimer's-like (AL) model mice were produced by intracerebroventricular infusion of Aβ and compared with normal control mice with infusion of vehicle. AL …mice were treated with either gallate (treated AL mice) or vehicle (untreated AL mice). Metabolomic analyses of both whole blood and plasma showed a clear separation between untreated AL mice and the other two groups, with levels of several metabolites involved in energy metabolism, including pyruvate and creatine, being significantly reduced in untreated AL mice compared with control and treated AL mice. Gallate treatment suppressed Aβ-induced overproduction of the inflammatory cytokine tumor necrosis factor-α in the hippocampus and normalized plasma levels of the affected metabolites. These results suggest that plasma levels of several metabolites could be indicative of both brain pathology and therapeutic responses, supporting the possibility of a close relationship between central neuroinflammation and systemic metabolic disturbance. These findings also suggest the potential of NMR-based metabolomics as a method to identify novel plasma biomarkers for AD, which could be confirmed by future translational research with human patients. Show more

Keywords: Alzheimer's disease, biomarker, creatine, metabolomics, neuroinflammation, NMR, plasma, pyruvate

DOI: 10.3233/JAD-132165

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 421-433, 2014

Authors: Conway, Megan | Nafar, Firoozeh | Straka, Tatjana | Mearow, Karen

Article Type: Research Article

Abstract: Upregulation of heat shock proteins, such as Hsp70 and HspB1/Hsp27, have been associated with an amelioration of the deficits in animal models of Alzheimer's disease (AD). HspB1 is reported to be increased in AD brains and to accumulate in plaques, but whether this localization is an attempt by HspB1 to ameliorate the detrimental effects of amyloid-β (Aβ) on cells or part of the disease process is unknown. Here we explore the potential effects of the HspB1 on amyloid-β protein precursor (AβPP) processing and distribution within HEK293 stable cell lines expressing either AβPPwt or AβPPsw. We compare AβPP production, distribution, and …release of proteolytic products (including Aβ40 and Aβ42 ) to determine possible modifications in the presence of HspB1. We also investigate whether HspB1 interacts with Aβ or its precursor, AβPP, and whether, through this interaction, it is able to alter AβPP processing or release of Aβ peptide. Coexpression of HspB1 resulted in increased cellular holoAβPP as well as C-terminal fragments. Further, expression of HspB1 attenuated the release of Aβ42 from the AβPPsw cells. In summary, we have shown that expression of HspB1 alters AβPP expression and processing in cell lines expressing AβPPwt and AβPPsw. Furthermore, the presence of HspB1 decreased the amount of Aβ42 released by the cell lines. Thus in addition to its effects on protecting cells from the potentially toxic effects of Aβ, HspB1 also appears to be involved in modulating cellular levels of AβPP, although an understanding of the underlying mechanisms requires further investigation. Show more

Keywords: AβPPwt, AβPPsw, cell line, protein expression, small heat shock protein

DOI: 10.3233/JAD-140348

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 435-450, 2014