Journal of Alzheimer's Disease - Volume 20, issue 2

Authors: Zhuo, Jia-Min | Kruger, Warren D. | Praticò, Domenico

Article Type: Research Article

Abstract: Diet-induced high circulating levels of homocysteine, also known as hyper-homocysteinemia (HHcy), is associated with an acceleration of Alzheimer's disease-like amyloidosis. Herp is a homocysteine-responsive stress protein, which has been shown to increase the formation of amyloid-β (Aβ) via interaction with presenilins in vitro. The aim of our paper was to investigate the functional role that Herp plays in HHcy-induced amyloidosis. Amyloidosis secondary to diet-induced HHcy in Tg2576 mice is associated with an increase of Herp protein and mRNA levels. By contrast, no other stress-related proteins are altered by the same diet regimen. Compared to wild type animals, brains from a …genetically induced HHcy mouse model did not manifest any significant change in Herp levels. Cells stably over-expressing human AβPP Swedish mutant incubated with high levels of homocysteine had an increase in Aβ formation, but no change in Herp level. Finally, over-expression of Herp did not result in any significant modification of Aβ levels. We conclude that the Herp protein pathway is unlikely to be directly involved in the pro-amyloidotic effect of HHcy. Show more

Keywords: Amyloid-β, amyloid-β metabolism, endoplasmatic reticulum stress, Tg2576, Tg-278Cbs-/-

DOI: 10.3233/JAD-2010-1394

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 569-576, 2010

Authors: García, Ana M. | Ramón-Bou, Nieves | Porta, Miquel

Article Type: Research Article

Abstract: The roles of smoking and alcohol on the development of Alzheimer's disease (AD) remain unclear. We performed a case-control study on the effects of both exposures before the age of onset of the disease in the cases (and same reference age for their age-matched controls) on disease risk. Interviews were conducted with population controls (n=246) and relatives of cases (n=176) identified through local Alzheimer's Disease Associations. Logistic regression models were built adjusting by gender, age, residence, education, economic situation, employment, and history of dementia in close relatives. Risk of AD was unaffected by any measure of tobacco consumption. Alcohol consumers …showed a lower risk of AD than never consumers (adjusted odds ratio, aOR = 0.53, 95% CI 0.32, 0.88), with differences by gender (women aOR =0.48, 95% CI 0.27, 0.84; men aOR=0.80, 95% CI 0.23, 2.80). Mean daily total consumption of alcohol and time consuming alcohol showed increasingly protective dose-response relationships in women. Lower AD risk was observed in alcohol drinkers of both genders who never smoked (aOR= 0.37, 95% CI 0.21, 0.65). All these associations were independent of the presence of apolipoprotein E4 allele(s) in the cases. Although the sample was small for some analyses addressing these interactions, our results suggest a protective effect of alcohol consumption, mostly in non-smokers, and the need to consider interactions between tobacco and alcohol consumption, as well as interactions with gender, when assessing the effects of smoking and/or drinking on the risk of AD. Show more

Keywords: Alcohol drinking, Alzheimer's disease, apolipoprotein E4, case-control studies, humans, smoking, Spain

DOI: 10.3233/JAD-2010-1399

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 577-586, 2010

Authors: Lehmann, Manja | Rohrer, Jonathan D. | Clarkson, Matthew J. | Ridgway, Gerard R. | Scahill, Rachael I. | Modat, Marc | Warren, Jason D. | Ourselin, Sebastien | Barnes, Josephine | Rossor, Martin N. | Fox, Nick C.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult to differentiate clinically due to overlapping symptoms. Subject classification in research studies is often based on clinical rather than pathological criteria which may mean some subjects are misdiagnosed and misclassified. Recently, methods measuring cortical thickness using magnetic resonance imaging have been suggested to be effective in differentiating between clinically-defined AD and frontotemporal dementia (FTD) in addition to showing disease-related patterns of atrophy. In this study we used FreeSurfer, a freely-available and automated software tool, to measure cortical thickness in 28 pathologically-confirmed AD patients, of which 11 had a typical …amnestic presentation and 17 an atypical presentation during life, 23 pathologically-confirmed FTLD subjects, and 25 healthy controls. Patients with AD pathology, irrespective of clinical diagnosis, showed reduced cortical thickness bilaterally in the medial temporal lobe, posterior cingulate gyrus, precuneus, posterior parietal lobe, and frontal pole compared with controls. We further showed that lower cortical thickness in the posterior cingulate gyrus, parietal lobe, and frontal pole is suggestive of AD pathology in patients with behavioral or language deficits. In contrast, lower cortical thickness in the anterior temporal lobe and frontal lobe is indicative of the presence of FTLD pathology in patients with a clinical presentation of FTD. Reduced cortical thickness in the posterior cingulate gyrus is characteristic of AD pathology in patients with typical and atypical clinical presentations of AD, and may assist a clinical distinction of AD pathology from FTLD pathology. Show more

Keywords: Alzheimer's disease, cortical thickness, FreeSurfer, magnetic resonance imaging, pathology

DOI: 10.3233/JAD-2010-1401

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 587-598, 2010

Authors: Söderqvist, Fredrik | Hardell, Lennart | Carlberg, Michael | Mild, Kjell Hansson

Article Type: Research Article

Abstract: Radiofrequency field (RF) exposure provided cognitive benefits in an animal study. In Alzheimer's disease (AD) mice, exposure reduced brain amyloid-β (Aβ) deposition through decreased aggregation of Aβ and increase in soluble Aβ levels. Based on our studies on humans on RF from wireless phones, we propose that transthyretin (TTR) might explain the findings. In a cross-sectional study on 313 subjects, we used serum TTR as a marker of cerebrospinal fluid TTR. We found a statistically significantly positive β coefficient for TTR for time since first use of mobile phones and desktop cordless phones combined (P=0.03). The electromagnetic field parameters were …similar for the phone types. In a provocation study on 41 persons exposed for 30 min to an 890-MHz GSM signal with specific absorption rate of 1.0 Watt/kg to the temporal area of the brain, we found statistically significantly increased serum TTR 60 min after exposure. In our cross-sectional study, use of oral snuff also yielded statistically significantly increased serum TTR concentrations and nicotine has been associated with decreased risk for AD and to upregulate the TTR gene in choroid plexus but not in the liver, another source of serum TTR. TTR sequesters Aβ, thereby preventing the formation of Aβ plaques in the brain. Studies have shown that patients with AD have lowered TTR concentrations in the cerebrospinal fluid and have attributed the onset of AD to insufficient sequestering of Aβ by TTR. We propose that TTR might be involved in the findings of RF exposure benefit in AD mice. Show more

Keywords: Blood-cerebrospinal barrier, cordless phone, DECT, dementia, mobile phone, nicotine, plexus choroideus

DOI: 10.3233/JAD-2010-1395

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 599-606, 2010

Authors: Chen, Ta-Fu | Huang, Rwei-Fen S. | Lin, Sey-En | Lu, Jyh-Feng | Tang, Ming-Chi | Chiu, Ming-Jang

Article Type: Research Article

Abstract: Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-β (Aβ) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Aβ accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies in the Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)_M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)_M (both p < 0.05). Analysis of Aβ40 …and Aβ42 showed lower brain loads in both treatment groups but this did not reach statistical significance. Histopathology analysis showed that Tg(+)_M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)_M (p< 0.005). DNA analysis revealed that in the Tg(+)M_+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)_M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Aβ production, and modification of brain gene expression. Show more

Keywords: Alzheimer's disease, folic acid, memantine, neuron protection, spatial learning, transgenic mice

DOI: 10.3233/JAD-2010-1396

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 607-615, 2010

Authors: Milward, Elizabeth A. | Bruce, David G. | Knuiman, Matthew W. | Divitini, Mark L. | Cole, Michelle | Inderjeeth, Charles A. | Clarnette, Roger M. | Maier, Graham | Jablensky, Assen | Olynyk, John K.

Article Type: Research Article

Abstract: The relationship of iron status with cognition and dementia risk in older people is contentious. We have examined the longitudinal relationship between serum ferritin and cognition in 800 community-dwelling Australians 60 years or older. Iron studies (serum iron, transferrin saturation, serum ferritin) were performed in 1994/5 and 2003/4 and clinical and cognitive assessments were conducted in 2003/4 for 800 participants of the Busselton Health Study. All participants completed the Cambridge Cognitive test (CAMCOG). Those with CAMCOG scores <84 underwent expert clinical review for cognitive disorders, including the Clinical Dementia Rating scale. Mean serum iron (18.3 μmol/l) and transferrin saturation (28.5%) …in 2003/4 did not differ significantly from 1994/5 whereas mean serum ferritin decreased from 162 μg/l in 1994/5 to 123 μg/l in 2003/4, possibly reflecting aging or dietary changes. No relationships were observed between serum iron or transferrin saturation and presence or absence of dementia (p> 0.05). In participants without dementia (n=749), neither serum ferritin in 1994/5 or 2003/4 nor change in serum ferritin between these times was related to total CAMCOG or executive function scores, with or without adjustment for gender, age, National Adult reading test, or stroke history (all p> 0.05). No relationships were observed between ferritin and cognition for participants with possible or probable dementia (n=51). All participants identified as HFE C282Y homozygous or with serum ferritin >1,000 ng/ml had normal CAMCOG scores. We conclude abnormal body iron stores (low or high) are unlikely to have clinically significant effects on cognition or dementia risk in community-dwelling older people. Show more

Keywords: Alzheimer's disease, cognition, dementia, ferritin, iron

DOI: 10.3233/JAD-2010-1402

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 617-623, 2010

Authors: Costa, Rui O. | Ferreiro, Elisabete | Cardoso, Sandra M. | Oliveira, Catarina R. | Pereira, Cláudia M.F.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previously we found that Aβ induces both mitochondrial and endoplasmic reticulum (ER) dysfunction leading to apoptosis, and now we address the relevance of ER-mitochondria crosstalk in apoptotic cell death triggered by Aβ peptide. Using mitochondrial DNA-depleted ρ0 cells derived from the human NT2 teratocarcinoma cell line, characterized by the absence of functional mitochondria, and the parental ρ+ cells, we report here that treatment with the synthetic Aβ1-40 peptide, or the classical ER stressors thapsigargin or brefeldin A, increases GRP78 expression levels and caspase activity, two …ER stress markers, and also depletes ER calcium stores. Significantly, we show that the presence of functional mitochondria is required for ER stress-mediated apoptotic cell death triggered by toxic insults such as Aβ. We found that the increase in the levels of the pro-apoptotic transcription factor GADD153/CHOP, which mediates ER stress-induced cell death, as well as caspase-9 and -3 activation and increased number of TUNEL-positive cells, occurs in treated parental ρ+ cells but is abolished in ρ0 cells. Our results strongly support the close communication between ER and mitochondria during apoptotic cell death induced by the Aβ peptide and provide insights into the molecular cascade of cell death in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, ER stress, mitochondria, rho0 cells

DOI: 10.3233/JAD-2010-091369

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 625-636, 2010

Authors: Head, Elizabeth | Pop, Viorela | Sarsoza, Floyd | Kayed, Rakez | Beckett, Tina L. | Studzinski, Christa M. | Tomic, Jennifer L. | Glabe, Charles G. | Murphy, M. Paul

Article Type: Research Article

Abstract: The study of Alzheimer's disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-β peptide (Aβ) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Aβ in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5–15.7 years, were studied. Aβ40 and Aβ42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral …hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Aβ42 were detected at a younger age, prior to increases in Aβ40 , and were correlated with an increased amyloid load. In the CSF, Aβ42 decreased with age while Aβ40 levels remained constant. The CSF Aβ42/40 ratio was also a good predictor of the amount of Aβ in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Aβ, whereas oligomers in the brain were correlated with SDS soluble Aβ42 . These findings indicate that the Aβ in the brain of the aged canine exhibits patterns that mirror Aβ deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor, beagle, cerebrospinal fluid, dog, oligomer

DOI: 10.3233/JAD-2010-1397

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 637-646, 2010

Authors: Ott, Brian R. | Cohen, Ronald A. | Gongvatana, Assawin | Okonkwo, Ozioma C. | Johanson, Conrad E. | Stopa, Edward G. | Donahue, John E. | Silverberg, Gerald D. | the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The frequent co-occurrence of Alzheimer's disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid-β peptide (Aβ) in CSF in preclinical and early AD. CSF biomarker data (Aβ, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived …as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Aβ in APOE ε4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Aβ in ε4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Aβ in preclinical AD. The basis for the apparent effect of APOE ε4 genotype on the relationship of ventricular volume to Aβ and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, MRI

DOI: 10.3233/JAD-2010-1406

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 647-657, 2010

Authors: Aisa, Bárbara | Gil-Bea, Francisco J. | Solas, Maite | García-Alloza, Mónica | Chen, Christopher P. | Lai, Mitchell K. | Francis, Paul T. | Ramírez, María Javier

Article Type: Research Article

Abstract: Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to …an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD. Show more

Keywords: BDNF, ChAT, cognitive deficits, frontal cortex (BA10), MMSE, plasticity, temporal cortex (BA20)

DOI: 10.3233/JAD-2010-1398

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 659-668, 2010