Journal of Alzheimer's Disease - Volume 31, issue 3

Authors: Mamelak, Mortimer

Article Type: Review Article

Abstract: A reduction in cerebral glucose utilization is one of the earliest signs of Alzheimer's disease. Although the exact cause of this reduction is not known, gathering evidence suggests that it is part of a complex metabolic adaptation to oxidative stress during which glycolysis and oxidative phosphorylation are turned down, glucose metabolism is shifted to the pentose phosphate pathway to generate antioxidant reducing factors such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, and the gamma-aminobutyric acid (GABA) shunt is activated to provide glutamate as an alternate source of energy. In the face of these adaptive metabolic changes, the Alzheimer brain …runs short of energy and begins to digest itself. The very early induction of macroautophagy attests to the search for nutrients. In clinical trials, antioxidants alone have not been effectively able to influence the course of the disease as these agents do not meet the energy and nutritional requirements of the brain. Evidence is presented that gammahydroxybutyrate, a natural product of the GABA shunt, can provide the necessary energy, carbon, and antioxidant power and that its use may be able to delay the onset and progress of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, cerebral glucose metabolism, GABA shunt, gammahydroxybutyrate (sodium oxybate), histone deacetylase inhibition, ketone bodies, macroautophagy, oxidative stress, pentose phosphate pathway

DOI: 10.3233/JAD-2012-120370

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 459-474, 2012

Authors: Jiang, Teng | Yu, Jin-Tai | Tan, Lan

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common progressive dementia in the elderly and places an enormous burden on the individual and society. Presently, the treatments for AD are only symptomatic and do not halt the progression of the disease. With the recent advances in the understanding of the pathogenesis of AD in past years, numerous therapies which could modify the disease process are under active investigation. These therapies could attenuate or even reverse the neurodegenerative process by interfering with the underlying pathogenesis including amyloid-β production, tau hyperphosphorylation, oxidative stress, inflammation, and excitotoxicity. In this review, new disease-modifying therapies which reduce …amyloid-β production, prevent tau hyperphosphorylation, and provide neuroprotective effects are described, including the results of in vitro and in vivo studies and clinical trials. Some typical therapies with disease-modifying effects have also been discussed. Show more

Keywords: Alzheimer's disease, amyloid, disease-modifying therapies, neuroprotection, tau protein

DOI: 10.3233/JAD-2012-120640

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 475-492, 2012

Authors: Ito, Shingo | Ménard, Michel | Atkinson, Trevor | Gaudet, Chantal | Brown, Leslie | Whitfield, James | Chakravarthy, Balu

Article Type: Research Article

Abstract: The p75 neurotrophin receptor (p75NTR) has been thought to play a critical role in amyloid-β peptide (Aβ)-mediated neurodegeneration and Aβ metabolism in Alzheimer's disease (AD) brains. Our previous report showed that membrane-associated p75NTR protein expression was significantly increased in the hippocampi of two different strains of transgenic AD mice and was associated with the age-dependent elevation of Aβ1-42 levels. Here, we provide evidence that the Aβ1-42 oligomers known as ADDLs (Aβ-derived diffusible ligands) induce p75NTR protein expression through insulin-like growth factor 1 receptor (IGF-1R) phosphorylation in SH-SY5Y human neuroblastoma cells. An in vivo microinjection study demonstrated that microinjected …ADDLs increased the p75NTR protein expression by 1.4-fold in the ipsilateral hippocampus compared to the contralateral hippocampus. In addition, ADDLs microinjected into mouse hippocampi facilitated IGF-1R phosphorylation within 30 min and the co-administration of picropodophyllin, an IGF-1R kinase inhibitor, blocked ADDLs-induced p75NTR expression. We examined the possible involvement of IGF-1R in the increased p75NTR protein expression in the hippocampi of 6-month-old AβPPswe/PS1dE9 AD model mice that had accumulated significant amounts of Aβ1-42 and showed significantly higher p75NTR expression than age-matched wild-type mice. We found that IGF-1R phosphorylation in these transgenic mice was higher than that in the wild-type mice. These findings indicate that Aβ1-42 oligomers stimulate the p75NTR protein expression in the hippocampus through IGF-1R signaling. Thus, Aβ1-42 oligomers-mediated IGF-1R activation may trigger an increase in p75NTR protein expression in the hippocampus of AD brain during the early stages of disease development. Show more

Keywords: Alzheimer's disease, amyloid-β oligomer, hippocampus, IGF-1R, p75NTR, Trk-A

DOI: 10.3233/JAD-2012-120046

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 493-506, 2012

Authors: Schultz, Timothy | Yang, Eric | Farnum, Michael | Lobanov, Victor | Verbeeck, Rudi | Raghavan, Nandini | Samtani, Mahesh N. | Novak, Gerald | Shi, Yingqi | Narayan, Vaibhav | DiBernardo, Allitia

Article Type: Research Article

Abstract: One of the challenges in developing a viable therapy for Alzheimer's disease has been demonstrating efficacy within a clinical trial. Using this as motivation, we sought to re-examine conventional clinical trial practices in order to determine whether efficacy can be better shown through alternative trial designs and novel analysis methods. In this work, we hypothesize that the confounding factors which hamper the ability to discern a treatment signal are the variability in observations as well as the insidious nature of the disease. We demonstrate that a two-phase trial design in which drug dosing is administered after a certain level of …disease severity has been reached, coupled with a method to account more accurately for the progression of the disease, may allow us to compensate for these factors, and thus enable us to make treatment effects more apparent. Utilizing data from two previously failed trials which involved the evaluation of galantamine for indication in mild cognitive impairment, we were able to demonstrate that a clear treatment effect can be realized through both visual and statistical means, and propose that future trials may be more likely to show success if similar methods are utilized. Show more

Keywords: Cholinesterase inhibitors, clinical trials as topic, disease progression, dose-response relationship, drug, synchronization

DOI: 10.3233/JAD-2012-120286

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 507-516, 2012

Authors: Rami, Lorena | Sala-Llonch, Roser | Solé-Padullés, Cristina | Fortea, Juan | Olives, Jaume | Lladó, Albert | Peña-Gómez, Cleofe | Balasa, Mircea | Bosch, Bea | Antonell, Anna | Sanchez-Valle, Raquel | Bartrés-Faz, David | Molinuevo, Jose L.

Article Type: Research Article

Abstract: In this study functional magnetic resonance imaging (fMRI) is used to investigate the functional brain activation pattern in the preclinical stage of AD (pre-AD) subjects during a visual encoding memory task. Thirty subjects, eleven in the pre-AD stage, with decreased cerebrospinal fluid levels of Aβ42 (<500 pg/ml), and 19 controls with normal Aβ42 levels (CTR) were included. fMRI was acquired during a visual encoding task. Data were analyzed through an Independent Component Analysis (ICA) and region-of-interest-based univariate analysis of task-related BOLD signal change. From the ICA decomposition, we identified the main task-related component, which included the activation of …visual associative areas and prefrontal executive regions, and the deactivation of the default-mode network. The activation was positively correlated with task performance in the CTR group (p < 0.0054). Within this pattern, subjects in the pre-AD stage had significantly greater activation of the precuneus and posterior cingulate cortex during encoding. Subjects in the pre-AD stage present distinct functional neural activity before the appearance of clinical symptomatology. These findings may represent that subtle changes in functional brain activity precede clinical and cognitive symptoms in the AD continuum. Present findings provide evidence suggesting that fMRI may be a suitable biomarker of preclinical AD. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, cognition, diagnosis, functional magnetic resonance imaging, preclinical phases

DOI: 10.3233/JAD-2012-120223

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 517-526, 2012

Authors: Hedskog, Louise | Brohede, Jesper | Wiehager, Birgitta | Pinho, Catarina Moreira | Revathikumar, Priya | Lilius, Lena | Glaser, Elzbieta | Graff, Caroline | Karlström, Helena | Ankarcrona, Maria

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) gene remains the most strongly established risk factor for late onset Alzheimer's disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length. Reported results are contradictory in regard to the very long poly-T variant that has been associated with both increased and decreased risk of LOAD. Our study aimed to elucidate the functional implication …of rs10524523 in an in vitro model of human fibroblast cells obtained from cognitively healthy APOE ε3/ε4 carriers harboring very long or short poly-T variants coupled to their APOE ε3 allele. We have studied (i) expression levels of TOM40 protein and mRNA, (ii) TOM40 mRNA splicing, and (iii) mitochondrial function and morphology; and we have found no significant differences in regards to very long or short poly-T variant. Show more

Keywords: Human fibroblast cell line, late-onset Alzheimer's disease (LOAD), mitochondria, TOMM40

DOI: 10.3233/JAD-2012-120580

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 527-536, 2012

Authors: Villa, Chiara | Ghezzi, Laura | Fenoglio, Chiara | Clerici, Francesca | Marcone, Alessandra | Benussi, Luisa | Ghidoni, Roberta | Gallone, Salvatore | Serpente, Maria | Cantoni, Claudia | Ridolfi, Elisa | Bonsi, Rossana | Cerami, Chiara | Cappa, Stefano | Binetti, Giuliano | Franceschi, Massimo | Rainero, Innocenzo | Mariani, Claudio | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Transcription factor Sp4 (Specificity protein 4) levels are increased in the brain of patients with Alzheimer's disease (AD), and Sp4 colocalizes with neurofibrillary tangles. Moreover, SP4 is a susceptibility gene for bipolar disorder and schizophrenia, which share many clinical features with frontotemporal lobar degeneration (FTLD). The distribution of three tagging single nucleotide polymorphisms(SNPs)—rs9639379, rs10272006, and rs6461569—has been determined in a population of 352 patients diagnosed clinically with AD, 290 patients with FTLD, and 341 age-matched controls. Expression analysis of SP4 was performed in peripheral blood mononuclear cells (PBMC). No significant differences in either allelic or genotypic frequency of the three …SNPs were found (p > 0.05), even stratifying according to gender and to the apolipoprotein E status. Significantly increased SP4 relative expression levels were observed in PBMC from patients with AD as compared with controls (7.132 ± 1.301 versus 3.396 ± 0.829, p < 0.050) and a similar trend was shown in patients with FTLD compared with controls (6.525 ± 1.500 versus 3.396 ± 0.829, p = 0.073). According to these results, SP4 gene does not act as a susceptibility factor either for AD or FTLD. However, Sp4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases. Show more

Keywords: Alzheimer's disease, expression, frontotemporal lobar degeneration, risk factor, SP4, specificity protein 4

DOI: 10.3233/JAD-2012-120379

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 537-542, 2012

Authors: Martínez-Martín, Pablo | Osa-Ruiz, Emma | Gómez-Conesa, Antonia | Olazarán, Javier | The RSGE-CD Validation Group

Article Type: Research Article

Abstract: A relationship between decline in mobility and walking performance and cognitive impairment exists in the elderly. Therefore, clinical assessment of gait and mobility may be relevant for diagnostic and therapeutic purposes. However, the rating scales used for evaluation of gait disorder in the context of cognitive deterioration were not designed or validated for that setting. The present study was aimed at checking the clinimetric properties of the Rating Scale for Gait Evaluation in Cognitive Deterioration (RSGE-CD), specifically developed for assessment of gait dysfunction across all stages of cognitive decline. Two hundred fifty six subjects were included in the study and …classified according to the Global Deterioration Scale (control, subjective/mild cognitive impairment, or dementia). Patients with dementia had a diagnosis of probable Alzheimer's disease (73%) or dementia of combined etiology (27%). Cognitive and functional evaluations, the Tinetti scale, and timed tests were simultaneously applied with the tested scale, which is composed of two subscales: Functional ability and Examination. Exploratory factor analysis showed one factor (70% of the variance). Floor effect and skewness were observed in the control group, whereas internal consistency (Cronbach's alpha = 0.88–0.95), inter-observer and test-retest reliability (intraclass correlation coefficients ≥0.97) were satisfactory. Convergent validity with the other measures was ≥0.60 and the discriminant validity according to classification of subjects by cognitive state and other aspects was also satisfactory (p = 0.0001). The RSGE-CD showed low standard errors of measurement. In this first validation study, the RSGE-CD showed satisfactory clinimetric attributes for assessing gait and mobility across the complete range of cognitive state. Show more

Keywords: Alzheimer's disease, assessment, cognitive deterioration, dementia, evaluation, gait, mild cognitive impairment, mobility, Rating Scale for Gait Evaluation in Cognitive Deterioration, RSGE-CD

DOI: 10.3233/JAD-2012-120271

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 543-553, 2012

Authors: Matos, Marco | Augusto, Elisabete | Machado, Nuno J. | dos Santos-Rodrigues, Alexandre | Cunha, Rodrigo A. | Agostinho, Paula

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-β (Aβ) peptides (mainly Aβ1-42 ). There is a precocious disruption of glutamatergic synapses in AD, in line with an ability of Aβ to decrease astrocytic glutamate uptake. Accumulating evidence indicates that caffeine prevents the burden of AD, likely through the antagonism of A2A receptors (A2A R) which attenuates Aβ-induced memory impairment and synaptotoxicity. Since A2A R also modulate astrocytic glutamate uptake, we now tested if A2A R blockade could prevent the decrease of astrocytic glutamate uptake caused by Aβ. In cultured astrocytes, …Aβ1-42 (1 μM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A2A R agonist, CGS 26180 (30 nM), and prevented by the A2A R antagonist, SCH 58261 (100 nM). Aβ1-42 also decreased D-aspartate uptake by 28 ± 4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A2A R. In accordance with the long term control of glutamate transporter expression by A2A R, Aβ1-42 enhanced the expression and density of astrocytic A2A R and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A2A R knockout mice. This impact of Aβ1-42 on glutamate transporters and uptake, dependent on A2A R function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Aβ1-42 . These results provide the first demonstration for a direct key role of astrocytic A2A R in the ability of Aβ-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD. Show more

Keywords: Adenosine, adenosine A2A receptor, Alzheimer's disease, astrocytes, excitotoxicity, gliosomes, glutamate transporters

DOI: 10.3233/JAD-2012-120469

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 555-567, 2012

Authors: Morgan, Gemma S. | Gallacher, John | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: Previous studies suggest that physical activity may be protective for dementia and cognitive impairment. We report findings comparing leisure-time and work-related physical activity from the Caerphilly Prospective study (CaPS) with dementia and cognitive impairment not dementia (CIND) after around 16 years of follow-up. We synthesized our results with a meta-analysis specifically testing if length of follow-up was associated with the size of any association. Age-adjusted models found no real association with dementia, and if anything increased risk for CIND (odds ratio (OR) highest versus lowest tertile 2.61, 95% CI 1.58 to 4.31), though this was attenuated after adjustment for other …confounders (OR highest versus lowest tertile 1.38, 95% CI 0.78 to 2.44). There was no evidence that this differed by type (vascular versus non-vascular) of cognitive disease. Meta-analysis of other published effect estimates showed a protective effect of physical activity on cognitive impairment (OR 0.66, 95% CI 0.52 to 0.85) but with significant heterogeneity which was partially explained by length of follow up (p = 0.03). A protective association was also seen for dementia (OR 0.78, 95% CI 0.65, 0.94), which did not appear to be related to follow-up length but there was evidence of small study bias (p = 0.002) suggesting an absence of small null studies. The apparent protective effects of physical activity on cognitive health may partially reflect reverse causation and current estimates may be overly optimistic in terms of cognitive benefits. Show more

Keywords: Cohort studies, dementia, meta-analysis, mild cognitive impairment, motor activity, review

DOI: 10.3233/JAD-2012-112171

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 569-580, 2012