Journal of Alzheimer's Disease - Volume 28, issue 2

Authors: Haas, Christopher

Article Type: Review Article

Abstract: Therapeutic options for Alzheimer's disease are currently limited to symptomatic treatment that only provides modest and temporary maintenance of cognitive and memory functions, without altering disease progression. Although a variety of therapeutics targeting amyloid production or plaque degradation as well as tau hyperphosphorylation and aggregation have been proposed, examined in pre-clinical models and introduced into clinical trials, many have failed to provide significant therapeutic benefit. Concerns over the adequacy of currently used pre-clinical models, in addition to questions pertaining to the timing of therapeutic administration, vis-à-vis synaptic and neuronal loss have been raised, and are further complicated by the genetic …diversity of individual patients. This review will provide a brief overview of Alzheimer's disease pathophysiology and the currently approved therapeutics, while the main section will focus on therapeutics currently evaluated in pre-clinical models and clinical trials. Show more

Keywords: Alzheimer's disease, amyloid-β, drug therapy, humans, investigational drugs, pathophysiology, tau

DOI: 10.3233/JAD-2011-110986

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 241-281, 2012

Authors: Skulachev, Vladimir P.

Article Type: Article Commentary

Abstract: Much experimental evidence suggests that age-related brain pathologies are most often mediated by reactive oxygen species primarily originating from mitochondria (mROS). Two papers with such evidence have been recently published in the Journal of Alzheimer's Disease (Stefanova et al., J Alzheimers Dis 21, 476–491, 2010; Lloret et al., J Alzheimers Dis, doi: 10.3233/JAD-2011-110890). In the first paper, it was shown that appearance of a typical behavioral trait of aging in rats (that old animals do not enter an open arm in a maze) was completely reversed by ten weeks treatment of the old rats with the mitochondria-targeted antioxidant SkQ1. In …the second article, the authors identified molecular mechanisms by which amyloid-β-induced mROS can mediate hyperphosphorylation of the tau protein, a key event in Alzheimer's disease. Conventional antioxidants prevented such hyperphosphorylation. In this article, I will summarize the present state of the art in this field. I conclude that mitochondria-targeted rechargeable antioxidants are promising as tools to treat brain pathologies developing in elderly humans. Show more

Keywords: Alzheimer's disease, behavior, hippocampus, mitochondria-targeted antioxidant, plastoquinone, stroke

DOI: 10.3233/JAD-2011-111391

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 283-289, 2012

Authors: Insua, Daniel | Corredoira, Angélica | González-Martínez, Ángela | Suárez, María-Luisa | Santamarina, Germán | Sarasa, Manuel | Pesini, Pedro

Article Type: Short Communication

Abstract: The canine cognitive dysfunction syndrome (CDS) has been identified as a natural model for Alzheimer's disease (AD). We have used unbiased stereology to estimate the total number of basal forebrain cholinergic neurons expressing the nerve growth factor p75NTR receptor in young, aged cognitively-unimpaired (CU) and aged cognitively-impaired (CI) dogs. Aged-CI dogs showed a ∼20% decrement (p = 0.009) in p75NTR neurons compared to both the young and the aged-CU animals. These results suggest that the basal forebrain cholinergic system is affected in dogs with CDS and provide additional support for the use this canine syndrome as a model …for AD research. Show more

Keywords: Aging, Alzheimer's disease, basal forebrain cholinergic neurons (BFCN), p75NTR, unbiased stereology

DOI: 10.3233/JAD-2011-110905

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 291-296, 2012

Authors: Ramos, Maria C. | Sierra, Saleta | Ramirez, Carlos | Velasco, Javier | Burgos, Javier S.

Article Type: Short Communication

Abstract: This work describes a novel mechanism of neuroprotection by simvastatin: the modulation of seladin-1, an enzyme involved in Alzheimer's disease. Genomic and proteomic studies in human neuronal cells showed seladin-1 production to be increased in a dose- and time-dependent manner by simvastatin. This was confirmed in mice by immunohistochemical and qRT-PCR studies.

Keywords: Alzheimer's disease, brain, cholesterol, neuroprotection, seladin-1, simvastatin

DOI: 10.3233/JAD-2011-111118

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 297-301, 2012

Authors: Antonell, Anna | Gelpi, Ellen | Sánchez-Valle, Raquel | Martínez, Ramiro | Molinuevo, José L. | Lladó, Albert

Article Type: Short Communication

Abstract: AβPP locus duplications have been recently identified in early-onset Alzheimer's disease. We describe a patient who initiated memory problems and behavioral disturbances at 57 years, with a progressive cognitive decline, who died at the age of 68 years with dementia. Neuropathological examination revealed a temporobasal hemorrhage, extensive Alzheimer-type pathology, and severe cerebral amyloid angiopathy. We observed a chromosomal 21 region duplication spanning 0.59 Mb, which comprised JAM2, ATP5J, GABPA, and AβPP genes. We propose a replication based mutational mechanism (single Fork-Stalling and Template-Switching) or a recombination based one (non-homologous end-joining repair) for the AβPP locus duplication in this case.

Keywords: Alzheimer's disease, amyloid-β protein precursor (AβPP), cerebral amyloid angiopathy (CAA), chromosomal duplication, chromosome breakpoint

DOI: 10.3233/JAD-2011-110911

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 303-308, 2012

Authors: Maruszak, Aleksandra | Pepłońska, Beata | Safranow, Krzysztof | Chodakowska-Żebrowska, Małgorzata | Barcikowska, Maria | Żekanowski, Cezary

Article Type: Research Article

Abstract: Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combination with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14–16T), long a (La; 20–22T), long b (Lb; 26–30T), and very long (VL; 31–39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some …analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years. Show more

Keywords: Alzheimer's disease, APOE, association study, haplotype, late-onset Alzheimer's disease, longevity, TOMM40

DOI: 10.3233/JAD-2011-110743

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 309-322, 2012

Authors: Boutoleau-Bretonnière, Claire | Lebouvier, Thibaud | Delaroche, Odile | Lamy, Estelle | Evrard, Christelle | Charriau, Tiphaine | Bretonnière, Cédric | Damier, Philippe | Derkinderen, Pascal | Vercelletto, Martine

Article Type: Research Article

Abstract: The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp …of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis. Show more

Keywords: Alzheimer's disease, biomarkers, dementia, emission-computed, frontotemporal dementia, magnetic resonance imaging, neuropsychological tests, single-photon, tomography, vascular dementia

DOI: 10.3233/JAD-2011-110761

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 323-336, 2012

Authors: Baig, Shabnam | Palmer, Laura E. | Owen, Michael J. | Williams, Julie | Kehoe, Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Clusterin, a multifunctional lipoprotein is expressed in a number of tissues but expression is particularly high in the brain, where it binds to amyloid-β (Aβ), possibly facilitating Aβ transport into the bloodstream. Its concentration in peripheral blood was identified as a potential biomarker for Alzheimer's disease (AD) and predicted retention of 11 C–Pittsburgh Compound B in the temporal lobe. Single-nucleotide polymorphisms in the clusterin gene, CLU, are associated with the risk of developing AD. We measured clusterin mRNA levels in control and AD brains and investigated the relationship of the clusterin protein to soluble, insoluble, and plaque-associated Aβ. Clusterin mRNA …levels were unchanged when normalized to GAPDH but modestly increased in the frontal and temporal cortex in AD in relation to NSE and MAP-2. Levels of NSE and MAP-2 mRNA were reduced in the AD frontal cortex. Clusterin protein concentration was unchanged and did not correlate with the amount of Aβ present. In the frontal cortex, clusterin concentration was higher in APOE ε4-negative brains but no effect of APOE was detected in the temporal cortex or thalamus. Overall clusterin mRNA and protein levels are unaltered in the neocortex in AD and clusterin concentration does not reflect Aβ content. The increase in clusterin noted in peripheral blood in AD may reflect increased passage of this chaperone protein across the blood-brain barrier but further work is needed to determine how CLU variants influence the development of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, clusterin

DOI: 10.3233/JAD-2011-110473

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 337-344, 2012

Authors: Yang, ShaoNan | Wang, ShengQing | Peng, Nan | Xie, ZhaoHong | Wang, Ping | Zhao, CuiPing | Wei, LiFei | Yang, Hui | Zhao, BaoXiang | Miao, JunYing | Bi, JianZhong

Article Type: Research Article

Abstract: Excessive extracellular deposition of amyloid-β peptides (Aβ) is a characteristic pathologic feature of Alzheimer's disease (AD). Accumulating evidence indicates that macroautophagy is involved in the pathogenesis of AD, but the exact role of macroautophapy is still unclear. We investigated whether Aβ25-35 could cause reactive oxygen species (ROS) accumulation, decrease the activity of Na+ , K+ -ATPase, trigger an autophagy process, and inhibit the growth of PC12 cells and examined the effect of a new autophagy modulator, butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3 H)-one (3BDO). 3BDO could block the decrease in cell viability induced by Aβ25-35 by inhibiting ROS accumulation and …the decrease in activity of Na+ , K+ -ATPase and the autophagy process. In addition, 3BDO modulated the autophagy progress via a mammalian target of rampamycin-dependent pathway. 3BDO has a protective effect against the cytotoxicity induced by Aβ25-35 and might be a promising tool for AD research. Show more

Keywords: Alzheimer disease, amyloid-β, autophagy, Na+, K+-ATPase, mTOR, reactive oxygen species

DOI: 10.3233/JAD-2011-110863

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 345-356, 2012

Authors: Becerra, Judith | Fernández, Thalía | Roca-Stappung, Milene | Díaz-Comas, Lourdes | Galán, Lídice | Bosch, Jorge | Espino, Marbella | Moreno, Alma J | Harmony, Thalía

Article Type: Research Article

Abstract: In normal elderly subjects, the best electroencephalogram (EEG)-based predictor of cognitive impairment is theta EEG activity abnormally high for their age. The goal of this work was to explore the effectiveness of a neurofeedback (NFB) protocol in reducing theta EEG activity in normal elderly subjects who present abnormally high theta absolute power (AP). Fourteen subjects were randomly assigned to either the experimental group or the control group; the experimental group received a reward (tone of 1000 Hz) when the theta AP was reduced, and the control group received a placebo treatment, a random administration of the same tone. The results …show that the experimental group exhibits greater improvement in EEG and behavioral measures. However, subjects of the control group also show improved EEG values and in memory, which may be attributed to a placebo effect. However, the effect of the NFB treatment was clear in the EG, although a placebo effect may also have been present. Show more

Keywords: Cognitive impairment, electroencephalogram (EEG) biofeedback, global deterioration scale, healthy aging, neurofeedback, placebo, quantitative electroencephalogram (QEEG)

DOI: 10.3233/JAD-2011-111055

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 357-367, 2012