Journal of Alzheimer's Disease - Volume 32, issue 2

Authors: Arendash, Gary W.

Article Type: Review Article

Abstract: The universal failure of pharmacologic interventions against Alzheimer's disease (AD) appears largely due to their inability to get into neurons and the fact that most have a single mechanism-of-action. A non-invasive, neuromodulatory approach against AD has consequently emerged: transcranial electromagnetic treatment (TEMT). In AD transgenic mice, long-term TEMT prevents and reverses both cognitive impairment and brain amyloid-β (Aβ) deposition, while TEMT even improves cognitive performance in normal mice. Three disease-modifying and inter-related mechanisms of TEMT action have been identified in the brain: 1) anti-Aβ aggregation, both intraneuronally and extracellularly; 2) mitochondrial enhancement; and 3) increased neuronal activity. Long-term TEMT appears …safe in that it does not impact brain temperature or oxidative stress levels, nor does it induce any abnormal histologic/anatomic changes in the brain or peripheral tissues. Future TEMT development in both AD mice and normal mice should involve head-only treatment to discover the most efficacious set of parameters for achieving faster and even greater cognitive benefit. Given the already extensive animal work completed, translational development of TEMT could occur relatively quickly to “proof of concept” AD clinical trials. TEMT's mechanisms of action provide extraordinary therapeutic potential against other neurologic disorders/injuries, such as Parkinson's disease, traumatic brain injury, and stroke. Show more

Keywords: AD transgenic mice, amyloid-β, cognitive benefits, electromagnetic treatment, mitochondrial function, neuronal activity, transcranial

DOI: 10.3233/JAD-2012-120943

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 243-266, 2012

Authors: Girão da Cruz, M. Teresa | Jordão, Jessica | DaSilva, Kevin A. | Ayala-Grosso, Carlos A. | Ypsilanti, Athéna | Weng, Ying-Qi | LaFerla, Frank M. | McLaurin, JoAnne | Aubert, Isabelle

Article Type: Short Communication

Abstract: Accumulation of amyloid-β peptides (Aβ) and cholinergic degeneration are hallmarks of Alzheimer's disease (AD). In a triple transgenic mouse model of AD (3xTg-AD), soluble Aβ42 levels were detected in the septum by 2 months of age, reaching their highest levels at 3–6 months and decreasing at 12 months. Deficits in the number of septal cholinergic neurons and the length of hippocampal cholinergic axons were observed starting at 4 months in 3xTg-AD mice. Our results show that septal Aβ and septohippocampal cholinergic pathology in 3xTg-AD mice occur at an early stage of disease.

Keywords: Amyloid-β peptides, choline acetyltransferase, cholinergic neurons, gamma-aminobutyric acid, medial septal nucleus

DOI: 10.3233/JAD-2012-100732

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 267-272, 2012

Authors: Olsson, Bob | Malmeström, Clas | Basun, Hans | Annas, Peter | Höglund, Kina | Lannfelt, Lars | Andreasen, Niels | Zetterberg, Henrik | Blennow, Kaj

Article Type: Short Communication

Abstract: Microglia is thought to be important in Alzheimer's disease. Therefore, our aim was to investigate the usefulness of the microglial marker chitotriosidase in clinical trials. Chitotriosidase was analyzed in cerebrospinal fluid from Alzheimer's disease patients on acetylcholine esterase inhibitors (AChEI) and in cerebrospinal fluid from multiple sclerosis patients before and after natalizumab treatment. Chitotriosidase activity was extremely stable during treatment with the non-inflammatory drug AChEI. However, the immunomodulatory treatment with natalizumab led to lower chitotriosidase activity. Thus, chitotriosidase may be useful in clinical trials where microglia is targeted or as a safety biomarker in other trials where the brain is …a bystander organ. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, chitotriosidase, multiple sclerosis, stability

DOI: 10.3233/JAD-2012-120931

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 273-276, 2012

Authors: Di Domenico, Fabio | Barone, Eugenio | Mancuso, Cesare | Perluigi, Marzia | Cocciolo, Annalisa | Mecocci, Patrizia | Butterfield, D. Allan | Coccia, Raffaella

Article Type: Research Article

Abstract: Several studies showed increased oxidative and nitrosative stress in plasma from patients with Alzheimer's disease (AD), however, little and controversial knowledge has emerged about the antioxidant functionality of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in blood. The current study reports increased levels of both HO-1 and BVR-A in plasma from probable AD patients, as a result of the increased oxidative environment. However, the increase of oxidative stress in plasma result also in the increase of BVR-A 3-nitrotyrosine levels and the decrease of BVR-A phosphotyrosine levels and reductase activity, suggesting that nitrosative stress play the prominent oxidative role in plasma during …AD. Our data on HO-1/BVR-A status in plasma closely correlate with recent reports in hippocampus of subjects with AD and arguably its early form, mild cognitive impairment. Moreover, we show that alterations on HO-1/BVR-A system are tightly connected with cognitive decline indexed by Mini-Mental Status Exam scores. We hypothesize that the HO-1/BVR-A system status in plasma might reflect the ongoing situation in the brain, offering an important biochemical tool for the potential prediction of AD at the earliest stages of the disease. Show more

Keywords: Alzheimer disease's, bilirubin, biliverdin reductase-A, heme oxygenase-1, oxidative/nitrosative stress

DOI: 10.3233/JAD-2012-121045

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 277-289, 2012

Authors: Bitel, Claudine L. | Kasinathan, Chinnaswamy | Kaswala, Rajesh H. | Klein, William L. | Frederikse, Peter H.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the major age-dependent disease of the brain, but what instigates late-onset AD is not yet clear. Epidemiological, animal model, and cell biology findings suggest links between AD and diabetes. Although AD pathology is accelerated by diabetes in mice engineered to accumulate human-sequence amyloid-β (Aβ) peptides, they do not adequately model non-inherited AD. We investigated AD-type pathology induced solely by diabetes in genetically unmodified rabbits which generate human-sequence Aβ peptides. After 15 weeks, alloxan-treated diabetic rabbits with expected high blood glucose showed ~5-fold increase in Aβ40 /Aβ42 in cortex and hippocampus, and significantly, generated Aβ-derived assemblies …found in human AD. Deposits of these putative pathogenic toxins were detected by Aβ/Aβ oligomer antibodies in brain parenchyma and surrounding vasculature, also co-localizing with markedly elevated levels of RAGE. Soluble brain extracts showed diabetes-induced buildup of Aβ oligomers on dot-blots. Phospho-tau also was clearly elevated, overlapping with βIII-tubulin along neuronal tracts. Indications of retina involvement in AD led to examination of AD-type pathology in diabetic retinas and showed Aβ accumulation in ganglion and inner nuclear cell layers using Aβ/oligomer antibodies, and RAGE again was elevated. Our study identifies emergence of AD pathology in brain and retina as a major consequence of diabetes; implicating dysfunctional insulin signaling in late-onset AD, and a potential relationship between Aβ-derived neurotoxins and retinal degeneration in aging and diabetes, as well as AD. AD-type pathology demonstrated in genetically unmodified rabbits calls attention to the considerable potential of the model for investigation of AD pathogenesis, diagnostics, and therapeutics. Show more

Keywords: Alzheimer's disease, amyloid-β, brain, diabetes, oligomers, retina

DOI: 10.3233/JAD-2012-120571

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 291-305, 2012

Authors: Lopes, Marcos Antonio | Ferrioli, Eduardo | Nakano, Eduardo Yoshio | Litvoc, Júlio | Bottino, Cássio Machado Campos

Article Type: Research Article

Abstract: Although several surveys have been conducted around the world, few surveys have investigated the prevalence of dementia in Latin America. The aim of this study was to estimate dementia prevalence in a community sample in Ribeirão Preto, Brazil, and to evaluate its distribution across several socio-demographic and clinical characteristics and habits. The population was aged 60 years and older and a representative sample from three different social regions. The screening instruments used in the first phase were the Mini-Mental State Examination, the Fuld Object-Memory Evaluation, the Informant Questionnaire on Cognitive Decline in the Elderly, and the Bayer Activities of Daily …Living Scale. In the second phase, the Cambridge Examination was employed to diagnose dementia according to the DSM-IV criteria. The estimate of dementia prevalence was adjusted for screening instrument performance, using the positive and negative predictive values. The data were weighted to compare frequencies, considering the sampling and the non-response effect, and subjected to multivariate analysis. In all, 1.145 elderly subjects were evaluated (mean age: 70.9 years), of whom 63.4% were female and 52.8% had up to 4 years of schooling (participation rates at the first and the second phases were 62.6 and 60%, respectively). The observed and estimated prevalences of dementia were 5.9% and 12.5%, respectively (n = 68). Alzheimer's disease was the main cause (60.3%). Dementia was associated with old age, low education, stroke, absence of arthritis, and not reading books. The estimated prevalence of dementia was higher than the prevalence previously found. Associated factors confirmed the importance of intellectual activities in prevention. Show more

Keywords: Aging, Alzheimer's disease, dementia, epidemiology, prevalence

DOI: 10.3233/JAD-2012-120847

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 307-316, 2012

Authors: Wu, Jinglong | Yang, Jiajia | Yu, Yinghua | Li, Qi | Nakamura, Naoya | Shen, Yong | Ohta, Yasuyuki | Yu, Shengyuan | Abe, Koji

Article Type: Research Article

Abstract: The human brain can anatomically combine task-relevant information from different sensory pathways to form a unified perception; this process is called multisensory integration. The aim of the present study was to test whether the multisensory integration abilities of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) differed from those of normal aged controls (NC). A total of 64 subjects were divided into three groups: NC individuals (n = 24), MCI patients (n = 19), and probable AD patients (n = 21). All of the subjects were asked to perform three separate audiovisual integration tasks and were instructed to …press the response key associated with the auditory, visual, or audiovisual stimuli in the three tasks. The accuracy and response time (RT) of each task were measured, and the RTs were analyzed using cumulative distribution functions to observe the audiovisual integration. Our results suggest that the mean RT of patients with AD was significantly longer than those of patients with MCI and NC individuals. Interestingly, we found that patients with both MCI and AD exhibited adequate audiovisual integration, and a greater peak (time bin with the highest percentage of benefit) and broader temporal window (time duration of benefit) of multisensory enhancement were observed. However, the onset time and peak benefit of audiovisual integration in MCI and AD patients occurred significantly later than did those of the NC. This finding indicates that the cognitive functional deficits of patients with MCI and AD contribute to the differences in performance enhancements of audiovisual integration compared with NC. Show more

Keywords: Alzheimer's disease, audiovisual integration, cognitive functional deficits, mild cognitive impairment, performance enhancement

DOI: 10.3233/JAD-2012-111070

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 317-328, 2012

Authors: Roberts, Rosebud O. | Roberts, Lewis A. | Geda, Yonas E. | Cha, Ruth H. | Pankratz, V. Shane | O'Connor, Helen M. | Knopman, David S. | Petersen, Ronald C.

Article Type: Research Article

Abstract: High caloric intake has been associated with an increased risk of cognitive impairment. Total caloric intake is determined by the calories derived from macronutrients. The objective of the study was to investigate the association between percent of daily energy (calories) from macronutrients and incident mild cognitive impairment (MCI) or dementia. Participants were a population-based prospective cohort of elderly persons who were followed over a median 3.7 years (interquartile range, 2.5–3.9) of follow-up. At baseline and every 15 months, participants (median age, 79.5 years) were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis …of MCI, normal cognition, or dementia. Participants also completed a 128-item food-frequency questionnaire at baseline; total daily caloric and macronutrient intakes were calculated using an established database. The percent of total daily energy from protein (% protein), carbohydrate (% carbohydrate), and total fat (% fat) was computed. Among 937 subjects who were cognitively normal at baseline, 200 developed incident MCI or dementia. The risk of MCI or dementia (hazard ratio, [95% confidence interval]) was elevated in subjects with high % carbohydrate (upper quartile: 1.89 [1.17–3.06]; p for trend = 0.004), but was reduced in subjects with high % fat (upper quartile: 0.56 [0.34–0.91]; p for trend = 0.03), and high % protein (upper quartile 0.79 [0.52–1.20]; p for trend = 0.03) in the fully adjusted models. A dietary pattern with relatively high caloric intake from carbohydrates and low caloric intake from fat and proteins may increase the risk of MCI or dementia in elderly persons. Show more

Keywords: Caloric intake, community-based, dementia, dietary carbohydrates, dietary fats, dietary proteins, energy intake, mild cognitive impairment, prospective studies

DOI: 10.3233/JAD-2012-120862

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 329-339, 2012

Authors: Maioli, Silvia | Puerta, Elena | Merino-Serrais, Paula | Fusari, Laura | Gil-Bea, Francisco | Rimondini, Roberto | Cedazo-Minguez, Angel

Article Type: Research Article

Abstract: The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice …on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment. Show more

Keywords: Alzheimer's disease, apoE4, Arc, BDNF, β-catenin, carbohydrates, memory impairment, mice

DOI: 10.3233/JAD-2012-120697

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 341-355, 2012

Authors: Tranah, Gregory J. | Nalls, Michael A. | Katzman, Shana M. | Yokoyama, Jennifer S. | Lam, Ernest T. | Zhao, Yiqiang | Mooney, Sean | Thomas, Fridtjof | Newman, Anne B. | Liu, Yongmei | Cummings, Steven R. | Harris, Tamara B. | Yaffe, Kristine | The Health, Aging and Body Composition Study

Article Type: Research Article

Abstract: Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increased neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) …among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10–12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia (OR = 1.86, 95% CI = 1.23, 2.82, p = 0.0008) and haplogroup J participants experienced a statistically significant 8-year decline in 3MS (β = −0.14, 95% CI = −0.27, −0.03, p = 0.0006), both compared with common haplogroup H. The m.15244A>G, p.G166G, CytB variant was associated with a significant decline in DSST score (β = −0.58, 95% CI −0.89, −0.28, p = 0.00019) and the m.14178T>C, p.I166V, ND6 variant was associated with a significant decline in 3MS score (β = −0.87, 95% CI −1.31, −3.86, p = 0.00012). Finally, we sequenced the complete ~16.5 kb mtDNA from 135 Health ABC participants and identified several highly conserved and potentially functional nonsynonymous variants unique to 22 dementia cases and aggregate sequence variation across the hypervariable 2-3 regions that influences 3MS and DSST scores. Show more

Keywords: Cognitive function, dementia, DNA sequencing, mitochondria, mtDNA, oxidative phosphorylation

DOI: 10.3233/JAD-2012-120466

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 357-372, 2012