Journal of Alzheimer's Disease - Volume 34, issue 1

Authors: Froestl, Wolfgang | Pfeifer, Andrea | Muhs, Andreas

Article Type: Review Article

Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, …in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years. Show more

Keywords: Amyloid-β aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products, peptides, psychostimulants, tau, vaccines

DOI: 10.3233/JAD-121729

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 1-114, 2013

Authors: Caldeira, Gladys L. | Ferreira, I. Luisa | Rego, A. Cristina

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the major cause of dementia in the world. Abnormal extracellular accumulation of amyloid-β (Aβ) peptide and tau hyperphosphorylation, forming neurofibrillary tangles in the brain, are hallmarks of the disease. Oxidative stress, neuroinflammation, and mitochondrial and synaptic dysfunction are also observed in AD and often correlated to intracellular Aβ. This peptide results from the cleavage of the amyloid-β protein precursor by β- and γ-secretases and tends to be secreted after its production. However, secreted Aβ can be internalized by the interaction with membrane receptors, namely N-methyl-D-aspartate receptors, advanced glycation end products receptors, and/or alpha 7 nicotinic acetylcholine …receptors. Inside the cell, Aβ interacts with several organelles, including mitochondria and nucleus, and there is growing evidence pointing to a possible role of Aβ in the regulation of gene transcription. Accordingly, transcriptional deregulation was observed in several AD models and human samples from AD patients through modified expression, phosphorylation levels, function, and subcellular localization of some transcription factors, resulting in the suppression of neuroprotective transcription both in the nucleus and the mitochondria. In this review we focus on key transcription regulators related with mitochondrial biogenesis and antioxidant defenses that seem to be altered in AD models and also on the role of intranuclear Aβ in the pathogenesis of the disease. Show more

Keywords: Antioxidant defenses, CREB, intranuclear Aβ, mitochondrial biogenesis, Nrf2, PGC-1α, transcription factors

DOI: 10.3233/JAD-121444

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 115-131, 2013

Authors: Montañés, María | Casabona, Diego | Sarasa, Leticia | Pesini, Pedro | Sarasa, Manuel

Article Type: Short Communication

Abstract: Alzheimer's disease is characterized by the abnormal aggregation of amyloid-β (Aβ)1-40 and Aβ1-42 peptides into fibrils. In this work, we analyzed the kinetics of Aβ1-40 and Aβ1-42 fibril formation in vitro using Thioflavin T fluorescence. We synthesized high-purity peptides and performed a hexafluoro-2-propanol pre-treatment to yield uniform peptide solutions as starting materials. We found that the aggregation is clearly affected by the presence of sub-millimolar quantities of antibodies against the C-terminal region of the peptides. Because the fibrillization of these peptides is closely related to the pathogenesis of Alzheimer's disease, blocking this process may provide significant …therapeutic benefit. Show more

Keywords: Aggregation, Alzheimer's disease, Thioflavin T

DOI: 10.3233/JAD-120850

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 133-137, 2013

Authors: Perez, David L. | Dickerson, Bradford C. | McGinnis, Scott M. | Sapolsky, Daisy | Johnson, Keith | Searl, Meghan | Daffner, Kirk R.

Article Type: Short Communication

Abstract: Primary progressive aphasia (PPA) is a language predominant neurodegenerative disorder that has three recognized variants: nonfluent/agrammatic, semantic, and logopenic. This report describes a 60-year-old man who presented with a progressive decline in verbal output that does not fit the currently accepted PPA subtypes. The patient exhibited a paucity of verbal output and impaired phonemic fluency with minimal associated language, cognitive, or behavioral deficits. Focal cortical thinning/hypometabolism of the left superior frontal region and a cerebrospinal fluid profile not consistent with Alzheimer's disease pathology were identified. This case of isolated progressive dynamic aphasia extends the current boundaries of PPA diagnostic variants.

Keywords: Cerebrospinal fluid, magnetic resonance imaging, neurodegenerative disease, PET scan, primary progressive aphasia

DOI: 10.3233/JAD-121861

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 139-144, 2013

Authors: Dwyer, Rebecca | Skrobot, Olivia Anna | Dwyer, James | Munafo, Marcus | Kehoe, Patrick Gavin

Article Type: Research Article

Abstract: Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer's disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. We conducted a systematic review of all published genetic association studies of forms of sporadic VCI prior to 6 July 2012. An initial pool of 229 gene association studies yielded 104 papers (72 polymorphisms from 47 genes) that met inclusion criteria for analysis. Systematic meta-analysis was conducted on 6 polymorphisms (which had 3 or more published case-control cohorts from 69 papers) in the APOE, ACT, ACE, MTHFR, PON1, and PSEN-1 genes. Associations …of increased risk for VCI were found for APOE ε4 (1.818 (95% CI = 1.611–2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061–1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI = 0.783–0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI. It also shows the utility of meta-analysis as a tool to identify potential candidate genes from numerous individual small-scale studies of diseases where sample recruitment may be limited for a variety of practical reasons. Show more

Keywords: Association, cognitive impairment, dementia, gene, meta-analysis, vascular

DOI: 10.3233/JAD-121069

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 145-154, 2013

Authors: Mizwicki, Mathew T. | Liu, Guanghao | Fiala, Milan | Magpantay, Larry | Sayre, James | Siani, Avi | Mahanian, Michelle | Weitzman, Rachel | Hayden, Eric Y. | Rosenthal, Mark J. | Nemere, Ilka | Ringman, John | Teplow, David B.

Article Type: Research Article

Abstract: As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2 -vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. …The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology. Show more

Keywords: Alzheimer's disease, amyloid-β, 1α,25-dihydroxyvitamin D3, phagocytosis, resolvin D1

DOI: 10.3233/JAD-121735

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 155-170, 2013

Authors: Rembach, Alan | Doecke, James D. | Roberts, Blaine R. | Watt, Andrew D. | Faux, Noel G. | Volitakis, Irene | Pertile, Kelly K. | Rumble, Rebecca L. | Trounson, Brett O. | Fowler, Christopher J. | Wilson, William | Ellis, Kathryn A. | Martins, Ralph N. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Masters, Colin L | AIBL research group | Bush, Ashley I.

Article Type: Research Article

Abstract: Background: Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer’s disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. Methods: Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. …Results: There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003). Conclusion: Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD. Show more

Keywords: Alzheimer's disease, biomarkers, ceruloplasmin, copper, serum

DOI: 10.3233/JAD-121474

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 171-182, 2013

Authors: Dal-Ré, Rafael | Fauria, Karine | Gramunt, Nina | Molinuevo, José Luis

Article Type: Research Article

Abstract: This study describes the main characteristics of ongoing observational studies on Alzheimer's disease (AD) to help identify any important research gaps. A search through the WHO International Clinical Trials Registry Platform and on the Primary Registries was conducted on 9 June 2012. The descriptors ‘recruiting’ or ‘open’ were used to describe a study's recruitment status. 62 studies are being conducted in 18 countries (Australia, Far-East, Middle-East, North America, and Western Europe). The US and France are involved in 55% of these studies. The studies aimed to recruit 20 to 10,000 participants, lasting 8 months to 24 years; 46% are case-control, …whereas 44% are cohort studies; 60% and 34% are longitudinal and cross-sectional, respectively. The majority are sponsored by hospitals, universities, medical centers, or public health systems (63%), and are conducted in single centers (55%). 37 use imaging (MRI, PET, SPECT), 18 conduct lumbar puncture, 21 collect DNA and/or RNA, and 15 collect ApoE genotyping. 17 studies are medium-term prospective disease progression studies, the majority to assess mild cognitive impairment (MCI) or/and AD progression; only 3 are on cognitively normal older people at risk (2 studies, n = 180) or not (1 study, n < 200) of developing MCI. Observational studies are being conducted in few countries, with very few in low and middle-income countries where the majority of AD patients live. There is a remarkable interest in disease progression studies; however, longitudinal, long-term studies, on cognitively normal middle-age individuals, of key importance to try to fully understand the preclinical phase of AD, are lacking. Show more

Keywords: Alzheimer's disease, clinical research, ClinicalTrial.gov, ICTPR, non-interventional studies, observational studies, registries, worldwide

DOI: 10.3233/JAD-121525

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 183-190, 2013

Authors: Zieschang, Tania | Schwenk, Michael | Oster, Peter | Hauer, Klaus

Article Type: Research Article

Abstract: Evidence for sustainability of motor training effects in people with dementia is lacking. To examine whether the substantial improvements in motor performance achieved through a three-month specialized, standardized motor training were sustained, the participants of the randomized controlled trial were re-evaluated nine months after training had ceased. As part of a comprehensive study, participants with confirmed mild to moderate dementia underwent a progressive resistance and functional group training specifically developed for patients with dementia (intervention, n = 40) compared to a low-intensity motor placebo activity (control, n = 51). Primary and secondary outcome measures for maximal strength and function were …measured before the start of the training (T1), directly after training ceased (T2), three months after training ceased (T3) and—the focus of this paper—nine months after training ceased (T4). Even after nine months without training, the gains in functional performance were sustained with significant group differences in the primary endpoint (five-chair-rise, relative change: IG: −8.54 ± 22.57 versus CG: +10.70 ± 45.89 s, p = 0.014, effect size ηp 2 = 0.067). Other functional tests, such as walking speed and POMA (Tinetti), confirmed this result in the secondary analysis. Strength, as measured by the primary endpoint 1-Repetition Maximum (1RM) was still elevated (time effect for T1 versus T4: 148.68 ± 57.86 versus 172.79 ± 68.19 kg, p < 0.001, effect size ηp 2 = 0.157), but between-group differences disappeared (relative change: maximal strength, IG: 22.75 ± 40.66 versus CG: 15.60 ± 39.26, p = 0.369). The study found that intensive dementia-specific motor training sustainably improved functional performance of patients with dementia nine months after cessation of training. Show more

Keywords: Dementia, frail older adults, randomized controlled trial, resistance training

DOI: 10.3233/JAD-120814

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 191-202, 2013

Authors: Tang, Maoping | Wang, Zhaoxia | Zhou, Ying | Xu, Wangjie | Li, Shengtian | Wang, Lianyun | Wei, Dongqing | Qiao, Zhongdong

Article Type: Research Article

Abstract: This study focused on a promising drug candidate, N-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenyl-acrylamide (gx-50), a compound extracted from Sichuan pepper (Zanthoxylum Bungeanum), to determine whether it would be an effective therapeutic for Alzheimer's disease (AD) via biological experiments. In vivo, we determined the pharmacokinetic profile of gx-50 and evaluated the effect of gx-50 on the cognitive abilities of amyloid-β protein precursor transgenic (AβPP-Tg) mice by Morris water maze testing. In addition, we examined the effects of gx-50 on amyloid-β (Aβ) oligomers in the brains of AβPP-Tg mice by immunohistochemistry. In vitro, we observed a direct effect of gx-50 on Aβ oligomers by atomic force …microscopy, detected the neuroprotective effects of gx-50 by western blotting and cell apoptosis assays, and measured its effects on intracellular calcium currents by laser confocal microscopy. Experiments in vivo showed that gx-50 could penetrate the blood brain barrier and improve the cognitive abilities of mice. Moreover, gx-50 treatment decreased the accumulation of Aβ oligomers in the cerebral cortex. The results in vitro demonstrated that gx-50 could disassemble Aβ oligomers, inhibit Aβ-induced neuronal apoptosis and apoptotic gene expression, and reduce neuronal calcium toxicity. These results strongly suggest that gx-50 is a potential candidate drug for treating AD. Show more

Keywords: Alzheimer's disease, depolymerized amyloid plaque, memory improvement, neuroprotective effect

DOI: 10.3233/JAD-121831

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 203-213, 2013