Journal of Alzheimer's Disease - Volume 28, issue 1

Authors: Polidori, M. Cristina | Pientka, Ludger

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is slowly but steadily undergoing a profound reshaping of the definition and approach caused by the frustrating gap between poorly controlled AD epidemiology and repeated lack of success in finding a cure. The frequently reported and currently accepted role of vascular pathology and vascular risk factors in AD pathophysiology in recent years is one major aspect of this need for a severe adjustment in the modus operandi in AD. A clue into the importance that the interdependence between AD and vascularity has gained in scientific opinion is the large amount of recent reviews, almost reaching that of …original papers, on the topic. Far from aiming to meta-analyze all in vitro, in vivo, and ex vivo experiments, animal model research, clinical investigations, and epidemiological surveys conducted so far on the vascular disease-AD axis, this work focus on selected aspects of it in the hope of identifying possible study designs to be applied to the vascular AD patient. Looking over the literature on AD-related vascular pathology, the need also emerges to find the right location of oxidative stress. Show more

Keywords: Alzheimer's disease, oxidative stress, vascular pathology

DOI: 10.3233/JAD-2011-111034

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 1-9, 2012

Authors: Ricci, Serafino | Fuso, Andrea | Ippoliti, Flora | Businaro, Rita

Article Type: Review Article

Abstract: Increasing evidence has been accumulating about the role of stress as an important challenge to the onset and progression of Alzheimer's disease (AD). The hippocampus, one of the areas of the brain damaged during AD, was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones, including cortisol, sympathetic and parasympathetic transmitters, cytokines, and metabolic hormones. The present review aims at summarizing neuroinflammatory mechanisms induced by stress, resulting in neuronal dysfunction and impaired neurogenesis. Lifestyle and environmental factors related to metabolic and inflammatory alterations observed in stressed subjects and thought to favor AD development …and progression, as well as the possible ways of prevention, are discussed. Show more

Keywords: Alzheimer's disease, cytokines, HPA axis, lifestyle, neurogenesis, stress

DOI: 10.3233/JAD-2011-110821

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 11-24, 2012

Authors: Michels, Andreas | Multhammer, Manuel | Zintl, Maria | Mendoza, Maria Cristina | Klünemann, Hans-Hermann

Article Type: Research Article

Abstract: To examine the relationship between apolipoprotein E ε4 (ApoE ε4) and psychiatric symptoms, we compared ε4/ε4, ε3/ε3, and ε3/ε4 subjects. 659 outpatients with memory complaints underwent comprehensive neuropsychiatric assessment interview and neurological examination and ApoE genotyping: 98 were ε4/ε4. 18.4% (n = 18) ε4/ε4, 19.3% (n = 45) ε3/ε4, and 5.4% (n = 14) ε3/ε3 presented with symptoms of anxiety (p = 0.00001). ε4/ε4 patients with mild cognitive impairment (MCI; p < 0.0001) and those with Alzheimer's disease with late onset (p = 0.0175) were the most frequently affected. For anxiety, there were no gender dependent differences in the two …homozygous groups, however, in the ε3/ε4 group, anxiety symptoms were evident in 7.3% (n = 8) of the male versus 30.1% (n = 37) of the female ε3/ε4 heterozygotes (p < 0.0001). Depression was found in 20.4% (n = 20) ε4/ε4 and 21.0% (n = 49) ε3/ε4 compared to 17.1% (n = 44) ε3/ε3 (p = 0.5181). Visual hallucinations were reported in 5.1% (n = 5) ε4/ε4 as opposed to 3.8% (n = 9) ε3/ε4 and 2.3% (n = 6) ε3/ε3 (p = 0.5278). We have seen a higher association of anxiety with the ApoE ε4 allele across all stages of disease and what may be a dosing effect in the early stage (MCI) for this ostensible risk, since we see a significantly higher frequency in the ApoE ε4 homozygotes when compared to the heterozygotes. Show more

Keywords: Anxiety, apolipoprotein E ε4 (ApoE ε4), ApoE ε4 homozygosity, delusion, depression, ε4/ε4 homozygosity, ε4/ε4 homozygous, hallucinations, psychiatric symptoms

DOI: 10.3233/JAD-2011-110554

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 25-32, 2012

Authors: Khalifat, Nada | Puff, Nicolas | Dliaa, Mariam | Angelova, Miglena I.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a degenerative disease of the central nervous system which causes irreversible damage to neuron structure and function. The main hypothesis concerning the cause of AD is excessive accumulation of amyloid-β peptides (Aβ). There has recently been a surge in studies on neuronal morphological and functional pathologies related to Aβ-induced mitochondrial dysfunctions and morphological alternations. What is the relation between the accumulation of Aβ in mitochondria, decreased production of ATP, and the large number of mitochondria with broken or scarce cristae observed in AD patients' neurons? The problem is complex, as it is now widely recognized that …mitochondria function determines mitochondrial inner membrane (IM) morphology and, conversely, that IM morphology can influence mitochondrial functions. In our previous work, we designed an artificial mitochondrial IM, a minimal model system (giant unilamellar vesicle) mimicking the IM. We showed experimentally that modulation of the local pH gradient at the membrane level of cardiolipin-containing vesicles induces dynamic membrane invaginations similar to the mitochondrial cristae. In the present work we show, using our artificial IM, that Aβ renders the membrane unable to support the formation of cristae-like structures when local pH gradient occurs, leading to the failure of this cristae-like morphology. Fluorescent probe studies suggest that the dramatic change of membrane mechanical properties is due to Aβ-induced lipid bilayer dehydration, increased ordering of lipids, loss of membrane fluidity, and possibly to Aβ-induced changes in dynamic friction between the two leaflets of the lipid membrane. Show more

Keywords: Alzheimer's disease, amyloid-β peptide (Aβ42), biophysical phenomena, fluorescence polarization, lipid bilayers, liposomes, micromanipulation, mitochondria, pH gradient, videomicroscopy

DOI: 10.3233/JAD-2011-110389

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 33-47, 2012

Authors: Bohrmann, Bernd | Baumann, Karlheinz | Benz, Jörg | Gerber, Francoise | Huber, Walter | Knoflach, Frédéric | Messer, Jürg | Oroszlan, Krisztina | Rauchenberger, Robert | Richter, Wolfgang F. | Rothe, Christine | Urban, Margit | Bardroff, Michael | Winter, Michael | Nordstedt, Christer | Loetscher, Hansruedi

Article Type: Research Article

Abstract: The amyloid-β lowering capacity of anti-Aβ antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-β removal is controversial, antibody-mediated sequestration of peripheral Aβ versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful Aβ immunotherapy, we hypothesized that high affinity antibody binding to amyloid-β plaques and recruitment of brain effector cells is required for most efficient amyloid clearance. Here we report the generation of a novel fully human anti-Aβ antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to …a conformational epitope expressed on amyloid-β fibrils using HuCAL® phage display technologies. In peptide maps, both N-terminal and central portions of Aβ were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal Aβ bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-Aβ1-11 complex. In functional assays gantenerumab induced cellular phagocytosis of human amyloid-β deposits in AD brain slices when co-cultured with primary human macrophages and neutralized oligomeric Aβ42 -mediated inhibitory effects on long-term potentiation in rat brain. In APP751swedish xPS2N141I transgenic mice, gantenerumab showed sustained binding to cerebral amyloid-β and, upon chronic treatment, significantly reduced small amyloid-β plaques by recruiting microglia and prevented new plaque formation. Unlike other Aβ antibodies, gantenerumab did not alter plasma Aβ suggesting undisturbed systemic clearance of soluble Aβ. These studies demonstrated that gantenerumab preferentially interacts with aggregated Aβ in the brain and lowers amyloid-β by eliciting effector cell-mediated clearance. Show more

Keywords: Alzheimer's disease, Aβ, amyloid-β, antibody, HuCAL®, immunotherapy

DOI: 10.3233/JAD-2011-110977

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 49-69, 2012

Authors: Chen, Shuang-Qing | Cai, Qing | Shen, Yu-Ying | Wang, Pei-Jun | Teng, Gao-Jun | Li, Ming-Hua | Zhang, Wei | Zang, Feng-Chao

Article Type: Research Article

Abstract: The aim of this work was to explore the applicable value of 1 H-MRS evaluation on the treatment of Alzheimer's disease (AD) with neural stem cell (NSC) transplantation by quantitative analysis of metabolite changes in the hippocampal area in AβPP/PS1 transgenic (tg) mice. The tg mice (n = 30) aged 12 months were randomized into two subgroups: One receiving NSCs and the other receiving PBS transplantation in the bilateral hippocampal CA1 region. The wild-type mice (n = 15) were used as the control group. 1 H-MRS was performed before transplantation and 6 weeks after transplantation to measure the change of …N-acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), choline (Cho), and creatine (Cr) in the hippocampus. Results showed NAA and Glu levels were increased and mI level was decreased in NSC group compared with the PBS group at six weeks after transplantation (p < 0.05). There was no significant difference in NAA and Glu (p > 0.05), and there was significant difference in mI (p < 0.05) between NSC and control groups. However, there was no significant difference in Cho before and after transplantation among the three groups (p > 0.05). Histology showed the number of neurons in the hippocampal CA1 region increased significantly in the NSC group than those in the PBS group (p < 0.05), and the number of astrocytes significantly decreased in the NSC group compared with the PBS group. Ultrastructure showed that the neurons in the NSC group were morphologically normal. In conclusion, 1 H-MRS can display intracranial metabolite changes before and after NSC transplantation in tg mice and has a applicable value in evaluating the therapeutic effect of NSCs on AD. Show more

Keywords: Magnetic resonance spectroscopy (MRS), neural stem cells (NSCs), transplantation

DOI: 10.3233/JAD-2010-110893

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 71-80, 2012

Authors: Farr, Susan A. | Price, Tulin O. | Dominguez, Ligia J. | Motisi, Antonio | Saiano, Filippo | Niehoff, Michael L. | Morley, John E. | Banks, William A. | Ercal, Nuran | Barbagallo, Mario

Article Type: Research Article

Abstract: Polyphenols are potent antioxidants found in extra virgin olive oil (EVOO); antioxidants have been shown to reverse age- and disease-related learning and memory deficits. We examined the effects of EVOO on learning and memory in SAMP8 mice, an age-related learning/memory impairment model associated with increased amyloid-β protein and brain oxidative damage. We administered EVOO, coconut oil, or butter to 11 month old SAMP8 mice for 6 weeks. Mice were tested in T-maze foot shock avoidance and one-trial novel object recognition with a 24 h delay. Mice which received EVOO had improved acquisition in the T-maze and spent more time with …the novel object in one-trial novel object recognition versus mice which received coconut oil or butter. Mice that received EVOO had improve T-maze retention compared to the mice that received butter. EVOO increased brain glutathione levels suggesting reduced oxidative stress as a possible mechanism. These effects plus increased glutathione reductase activity, superoxide dismutase activity, and decreased tissue levels of 4-hydroxynoneal and 3-nitrotyrosine were enhanced with enriched EVOO (3 × and 5 × polyphenols concentration). Our findings suggest that EVOO has beneficial effects on learning and memory deficits found in aging and diseases, such as those related to the overproduction of amyloid-β protein, by reversing oxidative damage in the brain, effects that are augmented with increasing concentrations of polyphenols in EVOO. Show more

Keywords: Extra virgin olive oil, learning, memory, object recognition, oxidative stress, SAMP8, T-maze

DOI: 10.3233/JAD-2011-110662

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 81-92, 2012

Authors: Calderón-Garcidueñas, Lilian | Kavanaugh, Michael | Block, Michelle | D'Angiulli, Amedeo | Delgado-Chávez, Ricardo | Torres-Jardón, Ricardo | González-Maciel, Angelica | Reynoso-Robles, Rafael | Osnaya, Norma | Villarreal-Calderon, Rodolfo | Guo, Ruixin | Hua, Zhaowei | Zhu, Hongtu | Perry, George | Diaz, Philippe

Article Type: Research Article

Abstract: Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% …had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrPC ) was seen in highly exposed subjects. The down-regulation of the PrPC is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrPC and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders. Show more

Keywords: Alzheimer's disease, air pollution, cellular prion protein, children, inflammasomes, neuroinflammation, oxidative stress, particulate matter

DOI: 10.3233/JAD-2011-110722

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 93-107, 2012

Authors: Saxton, Judith | Hofbauer, Robert K. | Woodward, Michael | Gilchrist, Nigel L. | Potocnik, Felix | Hsu, Hai-An | Miller, Michael L. | Pejović, Vojislav | Graham, Stephen M. | Perhach, James L.

Article Type: Research Article

Abstract: Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimer's disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10–19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement …on the FLCI (placebo: −0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: −5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers. Show more

Keywords: Alzheimer's disease, American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS), communication, drug therapy, Functional Linguistic Communication Inventory (FLCI), language, memantine, randomized controlled trial

DOI: 10.3233/JAD-2011-110947

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 109-118, 2012

Authors: Lewczuk, Piotr | Popp, Julius | Lelental, Natalia | Kölsch, Heike | Maier, Wolfgang | Kornhuber, Johannes | Jessen, Frank

Article Type: Research Article

Abstract: In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical …dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, biomarkers, cerebrospinal fluid

DOI: 10.3233/JAD-2011-110857

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 119-125, 2012

Authors: Chapuis, Julien | Vingtdeux, Valérie | Capiralla, Hemachander | Davies, Peter | Marambaud, Philippe

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is a type I transmembrane protein that undergoes maturation during trafficking in the secretory pathway. Proper maturation and trafficking of AβPP are necessary prerequisites for AβPP processing to generate amyloid-β (Aβ), the core component of Alzheimer's disease senile plaques. Recently, we reported that the glycosylphosphatidylinositol (GPI)-anchored protein growth arrest-specific 1 (Gas1) binds to and interferes with the maturation and processing of AβPP. Gas1 expression led to a trafficking blockade of AβPP between the endoplasmic reticulum (ER) and the Golgi. GPI-anchored proteins can exit the ER by transiting through raft subdomains acting as specialized sorting platforms. …Here, we show that Gas1 co-partitioned and formed a complex with AβPP in raft fractions, wherein Gas1 overexpression triggered immature AβPP accumulation. Pharmacological interference of ER to Golgi transport increased immature AβPP accumulation upon Gas1 expression in these raft fractions, which were found to be positive for the COPII protein complex component Sec31A, a specific marker for ER exit sites. Furthermore, a Gas1 mutant lacking the GPI anchor that could not transit through rafts was still able to form a complex with AβPP but did not lead to immature AβPP accumulation in rafts. Together these data show that Gas1 interfered with AβPP trafficking by interacting with AβPP to facilitate its translocation into specialized ER-associated rafts where immature AβPP accumulated. Show more

Keywords: AβPP, Alzheimer's disease, Gas1, lipid rafts, protein trafficking

DOI: 10.3233/JAD-2011-110434

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 127-135, 2012

Authors: Baker, Laura D. | Bayer-Carter, Jennifer L. | Skinner, Jeannine | Montine, Thomas J. | Cholerton, Brenna A. | Callaghan, Maureen | Leverenz, James B. | Walter, Brooke K. | Tsai, Elaine | Postupna, Nadia | Lampe, Johanna | Craft, Suzanne

Article Type: Research Article

Abstract: We previously showed that amyloid-β 1-42 (Aβ42 ) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-week dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aβ42 were modulated by high intensity physical activity (hi–PA). Normal older adults (n = 18, mean age = 68.6 ± 7.4 y) and adults with amnestic MCI (n = 23, mean age = 68.0 ± 6.5 y) received a low saturated fat/low glycemic index (LOW) diet or a high saturated fat/high glycemic index (HIGH) diet, and …CSF levels of Aβ42 , tau, and IL-8 were measured at baseline and week 4. Pre-study activity levels were assessed using a 7-d questionnaire, and weekly duration of hi–PA was quantified. At baseline, increased hi–PA in normals predicted lower CSF levels of tau (r = −0.54, p = 0.020) and IL-8 (r = −0.70, p = 0.025). Diet-induced effects on CSF Aβ42 during the intervention study were modulated by hi–PA, and the nature of this effect differed for normals and MCI (ANOVA, p = 0.039). That is, for normal adults, increased hi–PA attenuated the effects of the HIGH diet on CSF Aβ42 whereas in MCI, increased hi–PA potentiated the effects of the LOW diet. Our results suggest that normal adults who engage in hi–PA are less vulnerable to the pathological effects of an unhealthy diet, while in MCI, the benefit of a healthy diet on Aβ modulation is greatest when paired with hi–PA. Exercise may thus interact with diet to alter pathological processes that ultimately modify risk of Alzheimer's disease. Show more

Keywords: Aging, Alzheimer's disease, amyloid, biomarker, brain, diet, exercise, interleukin, mild cognitive impairment, tau

DOI: 10.3233/JAD-2011-111076

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 137-146, 2012

Authors: Gallagher, Joseph J. | Finnegan, Mary E. | Grehan, Belinda | Dobson, Jon | Collingwood, Joanna F. | Lynch, Marina A.

Article Type: Research Article

Abstract: There is a well-established literature indicating a relationship between iron in brain tissue and Alzheimer's disease (AD). More recently, it has become clear that AD is associated with neuroinflammatory and oxidative changes which probably result from microglial activation. In this study, we investigated the correlative changes in microglial activation, oxidative stress, and iron dysregulation in a mouse model of AD which exhibits early-stage amyloid deposition. Microfocus X-ray absorption spectroscopy analysis of intact brain tissue sections prepared from AβPP/PS1 transgenic mice revealed the presence of magnetite, a mixed-valence iron oxide, and local elevations in iron levels in tissue associated with amyloid-β-containing …plaques. The evidence indicates that the expression of markers of microglial activation, CD11b and CD68, and astrocytic activation, GFAP, were increased, and were histochemically determined to be adjacent to amyloid-β-containing plaques. These findings support the contention that, in addition to glial activation and oxidative stress, iron dysregulation is an early event in AD pathology. Show more

Keywords: Alzheimer's disease, iron, microglia, oxidative stress, spectrometry, X-ray fluorescence

DOI: 10.3233/JAD-2011-110614

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 147-161, 2012

Authors: Gustafson, Deborah R. | Bäckman, Kristoffer | Joas, Erik | Waern, Margda | Östling, Svante | Guo, Xinxin | Skoog, Ingmar

Article Type: Research Article

Abstract: Level of adiposity is linked to dementia in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index (BMI) and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. Longitudinal studies with sufficient follow-up are necessary to estimate trajectories that allow better understanding of the relationship between adiposity indices and dementia over the life course. We evaluated the natural history of BMI in relationship to clinical dementia over 37 years in the Prospective Population Study of Women (PPSW) in …Sweden. PPSW is a systematic sample of 1462 women born 1908, 1914, 1918, 1922, and 1930 and aged 38–60 years at baseline. Examinations occurred in 1968, 1974, 1980, 1992, 2000, and 2005. Statistical analyses were conducted using mixed effects regression models. Trajectories of BMI over 37 years as a function of age differed between women who did versus did not develop dementia. Women developing dementia evidenced a lesser increase in BMI from age 38 to 70 years. After age 70, the BMI slope decreased similarly (no “accelerated decline”) irrespective of dementia status. A lower BMI before and during dementia onset was observed. Women with similar BMI at mid-life exhibited a different pattern of BMI change as they approached late-life that was related to dementia onset. BMI may be a potential marker of dementia-related neuropathologies in the brain. Dementia is related to a common risk factor, BMI, from mid-to late-life. Show more

Keywords: Alzheimer's disease, adiposity, body mass index, dementia, epidemiology, longitudinal, obesity, population-based, risk factor, women

DOI: 10.3233/JAD-2011-110917

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 163-171, 2012

Authors: Elipenahli, Ceyhan | Stack, Cliona | Jainuddin, Shari | Gerges, Meri | Yang, Lichuan | Starkov, Anatoly | Beal, M. Flint | Dumont, Magali

Article Type: Research Article

Abstract: Coenzyme Q10 is a key component of the electron transport chain which plays an essential role in ATP production and also has antioxidant effects. Neuroprotective effects of coenzyme Q10 have been reported in both in vitro and in vivo models of neurodegenerative diseases. However, its effects have not been studied in cells or in animals with tau induced pathology. In this report, we administered coenzyme Q10 to transgenic mice with the P301S tau mutation, which causes fronto-temporal dementia in man. These mice develop tau hyperphosphorylation and neurofibrillary tangles in the brain. Coenzyme Q10 improved survival and behavioral deficits in the …P301S mice. There was a modest reduction in phosphorylated tau in the cortex of P301S mice. We also examined the effects of coenzyme Q10 treatment on the electron transport chain enzymes, the mitochondrial antioxidant enzymes, and the tricarboxylic acid cycle. There was a significant increase in complex I activity and protein levels, and a reduction in lipid peroxidation. Our data show that coenzyme Q10 significantly improved behavioral deficits and survival in transgenic mice with the P301S tau mutation, upregulated key enzymes of the electron transport chain, and reduced oxidative stress. Show more

Keywords: Coenzyme Q10, mitochondria, tauopathy, transgenic mice

DOI: 10.3233/JAD-2011-111190

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 173-182, 2012

Authors: Kaneai, Nozomi | Arai, Masaya | Takatsu, Hirokatsu | Fukui, Koji | Urano, Shiro

Article Type: Research Article

Abstract: One characteristic of age-related neurodegeneration is thought to be cognitive deficits caused by oxidative stress. Neurons in the brain are considered to be particularly vulnerable to oxidative stress, leading to neuronal oxidative damage and neurodegenerative disorders such as Alzheimer's disease (AD) and senile dementia. The process of fusing synaptic plasma membranes and synaptic vesicles involves particular proteins, such as the soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor (SNARE) proteins for docking both membranes, and is integral to neurotransmission. To elucidate whether oxidative stress induces denaturation of SNARE proteins, and whether vitamin E can counteract this process, changes in the expression …of synaptobrevin, synaptotagmin, SNAP-25, and syntaxin-1 in rat brain nerve terminals were analyzed using an immunoblotting method. The results showed that oxidative stress induced significant reductions in the levels synaptobrevin and synaptotagmin in synaptic vesicles. Similarly, marked decreases in the levels of SNAP-25 and syntaxin-1 in pre-synaptic plasma membranes were also observed. In the absence of oxidative stress, vitamin E-deficient rats exhibited similar decreases in these proteins. In contrast, it was found that decreases in SNARE proteins, except for SNAP-25, were not observed in vitamin E-supplemented rats, even when the rats were subjected to oxidative stress. These results suggest that reactive oxygen species generated by oxidative stress are detrimental to neurons, resulting in the oxidation of SNARE proteins, thereby disrupting neurotransmission. Additionally, vitamin E is capable of protecting against such neurodegeneration. Show more

Keywords: Neurotransmission, oxidative stress, SNARE protein, synaptic membrane fusion, vitamin E

DOI: 10.3233/JAD-2011-111133

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 183-189, 2012

Authors: Hooijmans, Carlijn R. | Pasker-de Jong, Pieternel C.M. | de Vries, Rob B.M. | Ritskes-Hoitinga, Merel

Article Type: Research Article

Abstract: To date, only a few randomized clinical trials (RCTs) have investigated the effects of omega-3 fatty acids (FA) on Alzheimer's disease (AD). Some of these studies demonstrated that patients with very mild AD or mild cognitive impairment benefit from omega-3 FA treatment, but none showed significant improvements in cognitive function in patients with moderate or advanced AD. All these RCTs had a relatively short duration of supplementation, however, and we hypothesized that this might be one of the reasons why no effects of omega-3 FA supplementation could be observed in patients with “moderate” or “advanced” AD. Animal studies offer better …possibilities for controlled long-term supplementation than clinical studies. Therefore, we performed a systematic review (SR) and meta-analysis of the literature that focused on effects of the relatively long-term omega-3 FA supplementation (minimum period; 10% of average total lifespan) on cognitive impairment, amyloid-β pathology, and neuronal loss in animal models of AD. This SR shows that long-term omega-3 FA supplementation decreased the omega-6/omega-3 FA ratio and reduced the amount of amyloid-β in experimental animal models of AD. Omega-3 FA supplementation also improved cognitive function; this effect appeared larger in rats compared to mice, and in males compared to females. Moreover, omega-3 FA supplementation diminished the amount of neuronal loss, especially in female animals. The results of this SR indicate that it might be worthwhile to perform new clinical trials with long-term omega-3 FA supplementation in AD patients. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, animal models, cognition, docosahexaenoic acid, omega-3 fatty acids, pathology, systematic review

DOI: 10.3233/JAD-2011-111217

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 191-209, 2012

Authors: Olazarán, Javier | Agüera-Ortiz, Luis | Osorio, Ricardo S. | León-Salas, Beatriz | Dobato, José Luis | Cruz-Orduña, Isabel | González, Belén | Valentí, Meritxell | Gil-Ruiz, Nuria | Frades, Belén | Ramos-García, M.I. | Martínez-Martín, Pablo

Article Type: Research Article

Abstract: The Alzheimer Center Reina Sofía Foundation (ACRSF) was envisaged to address the complex and multi-disciplinary research and care needs posed by Alzheimer's disease (AD) and other neurodegenerative dementias. Patients may be admitted at ACRSF either as inpatients (i.e., nursing home) or outpatients (i.e., day-care center). The research program includes clinical, social, biochemical, genetic, and magnetic resonance investigations, as well as brain donation. We present the inception of the clinical research protocol for the ACRSF, the early results, and the amendments to the protocol. Foreseen as distinct populations, inpatient and outpatient results are presented separately. Data were collected from 180 patients …(153 inpatients, 27 outpatients) (86% AD), with informed consent for participation in the research program of the ACRSF. Most patients (95%) had moderate to severe dementia. Nursing home patients were older, displayed marked gait dysfunction, and were significantly more dependent in the activities of daily living (ADL), compared to the day-care patients (p < 0.05). Some cognitive, ADL, and quality of life (QoL) scales were eliminated from the protocol due to floor effect or lack of specificity of contents for advanced dementia. New measurements were added for evaluation of cognition, apathy, agitation, depression, ADL, motor function, and QoL. The final assessment is expected to be sensitive to change in all the clinical aspects of advanced degenerative dementia, to promote multidisciplinary and, desirably, inter-center collaborative research and, eventually, to contribute to the improvement of treatment and care for these patients. Show more

Keywords: Alzheimer's disease, clinical research protocol, geriatric assessment, inpatients, nursing homes, outpatients, primary senile degenerative dementia

DOI: 10.3233/JAD-2011-110875

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 211-222, 2012

Authors: Marioni, Riccardo E. | van den Hout, Ardo | Valenzuela, Michael J. | Brayne, Carol | Matthews, Fiona E. | MRC Cognitive Function and Ageing Study

Article Type: Research Article

Abstract: Education and lifestyle factors linked with complex mental activity are thought to affect the progression of cognitive decline. Collectively, these factors can be combined to create a cognitive reserve or cognitive lifestyle score. This study tested the association between cognitive lifestyle score and cognitive change in a population-based cohort of older persons from five sites across England and Wales. Data came from 13,004 participants of the Medical Research Council Cognitive Function and Ageing Study who were aged 65 years and over. Cognition was assessed at multiple waves over 16 years using the Mini-Mental State Examination. Subjects were grouped into four …cognitive states (no impairment, slight impairment, moderate impairment, severe impairment) and cognitive lifestyle score was assessed as a composite measure of education, mid-life occupation, and current social engagement. A multi-state model was used to test the effect of cognitive lifestyle score on cognitive transitions. Hazard ratios for cognitive lifestyle score showed significant differences between those in the upper compared to the lower tertile with a more active cognitive lifestyle associating with: a decreased risk of moving from no to slight impairment (0.58, 95% CI (0.45, 0.74)); recovery from a slightly impaired state back to a non-impaired state (2.93 (1.35, 6.38)); but an increased mortality risk from a severely impaired state (1.28 (1.12, 1.45)). An active cognitive lifestyle is associated with a more favorable cognitive trajectory in older persons. Future studies would ideally incorporate neuroradiological and neuropathological data to determine if there is causal evidence for these associations. Show more

Keywords: All epidemiology, cognitive aging, cognitive reserve, education

DOI: 10.3233/JAD-2011-110377

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 223-230, 2012

Authors: Hansson, Oskar | Stomrud, Erik | Vanmechelen, Eugeen | Östling, Svante | Gustafson, Deborah R | Zetterberg, Henrik | Blennow, Kaj | Skoog, Ingmar

Article Type: Research Article

Abstract: Amyloid-β (Aβ) pathology is a major component in the mechanisms behind Alzheimer's disease (AD). Measurement of Aβ42 in cerebrospinal fluid predicts cognitive decline in patients with mild cognitive impairment and identifies AD in patients with dementia. However, studies on Aβ in plasma are contradictory. In this prospective population-based study, plasma Aβ42 and Aβ40 were measured at baseline in 730 adults aged 70 years or older and without dementia. After five years, plasma levels were analyzed again and participants were assessed for development of dementia. During follow-up, 53 individuals (7%) developed dementia of which 37 (5%) were classified …as AD. No difference in baseline plasma Aβ42 , Aβ40 , or Aβ42 /Aβ40 ratio levels were observed between converters to dementia or AD compared to the cognitively stable individuals. However, individuals with plasma Aβ40 levels above the median level for the group at baseline had an increased risk of developing dementia and AD during the follow-up, even after adjustment for age, gender, APOE genotype, and educational level (odds ratio = 2.2, 95% confidence interval = 1.0–4.7, p < 0.05). Neither plasma Aβ42 nor the Aβ42 /Aβ40 ratio influenced the risk of developing dementia or AD. Moreover, Aβ42 and Aβ40 levels increased over the 5 years, whereas the Aβ42 /Aβ40 ratio decreased (p < 0.001). In conclusion, this study suggests that measurement of plasma Aβ should not be used clinically to predict dementia or AD. However, plasma Aβ40 may possibly be regarded as a moderate risk marker comparable to other risk markers for AD such as first-degree family history of dementia. Show more

Keywords: Alzheimer's disease, amyloid-β 40, amyloid-β 42, biological markers, cohort studies, dementia, plasma

DOI: 10.3233/JAD-2011-111418

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 231-238, 2012

Article Type: Other

DOI: 10.3233/JAD-2011-111419

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 239-240, 2012