Journal of Alzheimer's Disease - Volume 54, issue 1

Article Type: Editorial

DOI: 10.3233/JAD-169005

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 1-2, 2016

Authors: Leighton, Patricia L.A. | Allison, W. Ted

Article Type: Review Article

Abstract: Prion disease research has contributed much toward understanding other neurodegenerative diseases, including recent demonstrations that Alzheimer’s disease (AD) and other neurodegenerative diseases are prion-like. Prion-like diseases involve the spread of degeneration between individuals and/or among cells or tissues via template directed misfolding, wherein misfolded protein conformers propagate disease by causing normal proteins to misfold. Here we use the premise that AD, amyotrophic lateral sclerosis, Huntington’s disease, and other similar diseases are prion-like and ask: Can we apply knowledge gained from studies of these prion-like diseases to resolve debates about classical prion diseases? We focus on controversies about what role(s) protein …loss-of-function might have in prion diseases because this has therapeutic implications, including for AD. We examine which loss-of-function events are recognizable in prion-like diseases by considering the normal functions of the proteins before their misfolding and aggregation. We then delineate scenarios wherein gain-of-function and/or loss-of-function would be necessary or sufficient for neurodegeneration. We consider roles of PrPC loss-of-function in prion diseases and in AD, and conclude that the conventional wisdom that prion diseases are ‘toxic gain-of-function diseases’ has limitations. While prion diseases certainly have required gain-of-function components, we propose that disease phenotypes are predominantly caused by deficits in the normal physiology of PrPC and its interaction partners as PrPC converts to PrPSc . In this model, gain-of-function serves mainly to spread disease, and loss-of-function directly mediates neuron dysfunction. We propose experiments and predictions to assess our conclusion. Further study on the normal physiological roles of these key proteins is warranted. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, amyotrophic lateral sclerosis, huntingtin protein, Huntington’s disease, prion diseases, protein misfolding diseases, superoxide dismutase 1, tau protein, tauopathies

DOI: 10.3233/JAD-160361

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 3-29, 2016

Authors: Ambrose, Charles T.

Article Type: Review Article

Abstract: Apart from chronic diseases (arthritis, diabetes, etc.), old age is generally characterized by three lesser ailments: muscle weakness, minor memory lapses, and cold intolerance. This trio of complaints may have a common, underlying cause, namely, the age-associated reduced microcirculation in muscles, brain, skin, and elsewhere in the body. The Angiogenesis Hypothesis proposes that old age is in part a deficiency disease due to the decline in angiogenic (AG) factors, resulting in a reduced capillary density (CD) throughout the body. Over fifty published papers document waning levels of AG factors and/or decreased CD in various organ systems of aged animals and …people, including those with Alzheimer’s disease. The deficiency of AG factors is analogous to that of certain hormones (e.g., testosterone) whose blood levels also decline with age. In theory, therapeutic angiogenesis employing recombinant AG factors is a tenable treatment for the lesser ailments of old age and may improve the later years of human life. An optimal administration route may be intranasal. Show more

Keywords: Aging, Alzheimer’s disease, angiogenesis, capillary density, cold intolerance, memory lapses, muscle weakness, vascular dementia

DOI: 10.3233/JAD-160303

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 31-43, 2016

Authors: Olsen, Ingar | Singhrao, Sim K.

Article Type: Review Article

Abstract: Inflammasomes are responsible for the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-18, and IL-33 and activation of inflammatory cell death, pyroptosis. They assemble in response to cellular infection and stress or to tissue damage, promote inflammatory reactions, and are important in regulating innate immunity particularly by acting as platforms for activation of caspase proteases. They appear to be involved in several pathological processes activated by microbes including Alzheimer’s disease (AD). Best characterized in microbial pathogenesis is the nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3) inflammasome. AD is a neurodegenerative condition in which the neuropathological hallmarks are the …deposition of amyloid-β (Aβ) and hyperphosphorylated tau protein coated neurofibrillary tangles. For decades, the role of the innate immune system in the etiology of AD was considered less important, but the recently discovered inflammatory genes by genome-wide association studies driving inflammation in this disease has changed this view. Innate immune inflammatory activity in the AD brain can result from the pathological hallmark protein Aβ as well as from specific bacterial infections that tend to possess weak immunostimulatory responses for peripheral blood myeloid cell recruitment to the brain. The weak immunostimulatory activity is a consequence of their immune evasion strategies and survival. In this review we discuss the possibility that inflammasomes, particularly via the NLR family of proteins NLRP3 are involved in the pathogenesis of AD. In addition, we discuss the plausible contribution of specific bacteria playing a role in influencing the activity of the NLRP3 inflammasome to AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-beta, bacteria, cytokines, inflammasome

DOI: 10.3233/JAD-160197

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 45-53, 2016

Authors: Chiasserini, Davide | Biscetti, Leonardo | Farotti, Lucia | Eusebi, Paolo | Salvadori, Nicola | Lisetti, Viviana | Baschieri, Francesca | Chipi, Elena | Frattini, Giulia | Stoops, Erik | Vanderstichele, Hugo | Calabresi, Paolo | Parnetti, Lucilla

Article Type: Research Article

Abstract: The variability of Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40 ), amyloid-β 1-42 (Aβ1-42 ), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n  = 28), mild cognitive impairment (MCI, n  = 77), and neurological controls (OND, n  = 35). MCI patients were evaluated yearly and cognitive functions were assessed by …Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r  = 0.83, p  < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42 /Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42 /Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD. The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42 /Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, cerebrospinal fluid, mild cognitive impairment, tau

DOI: 10.3233/JAD-160298

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 55-67, 2016

Authors: Ren, Ping | Lo, Raymond Y. | Chapman, Benjamin P. | Mapstone, Mark | Porsteinsson, Anton | Lin, Feng | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimer’s disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three-year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low-frequency fluctuations (ALFF) (0.01–0.08 Hz) and two subdivided bands (slow-4:0.027–0.073 Hz; slow-5:0.01–0.027 Hz). We calculated Aβ/pTau ratio using baseline cerebrospinal fluid pTau and Aβ1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in …the right putamen was significantly related to the memory decline over time and lower baseline Aβ/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Aβ/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Aβ/pTau ratio regardless of clinical diagnosis. Show more

Keywords: Amyloid-beta, low-frequency fluctuation, mild cognitive impairment, pTau, resting state fMRI, striatum

DOI: 10.3233/JAD-160368

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 69-78, 2016

Authors: Hülsemann, Maren | Zafiu, Christian | Kühbach, Katja | Lühmann, Nicole | Herrmann, Yvonne | Peters, Luriano | Linnartz, Christina | Willbold, Johannes | Kravchenko, Kateryna | Kulawik, Andreas | Willbold, Sabine | Bannach, Oliver | Willbold, Dieter

Article Type: Research Article

Abstract: Amyloid-β (Aβ) oligomers represent a promising biomarker for the early diagnosis of Alzheimer’s disease (AD). However, state-of-the-art methods for immunodetection of Aβ oligomers in body fluids show a large variability and lack a reliable and stable standard that enables the reproducible quantitation of Aβ oligomers. At present, the only available standard applied in these assays is based on a random aggregation process of synthetic Aβ and has neither a defined size nor a known number of epitopes. In this report, we generated a highly stable standard in the size range of native Aβ oligomers that exposes a defined number of …epitopes. The standard consists of a silica nanoparticle (SiNaP), which is functionalized with Aβ peptides on its surface (Aβ-SiNaP). The different steps of Aβ-SiNaP synthesis were followed by microscopic, spectroscopic and biochemical analyses. To investigate the performance of Aβ-SiNaPs as an appropriate standard in Aβ oligomer immunodetection, Aβ-SiNaPs were diluted in cerebrospinal fluid and quantified down to a concentration of 10 fM in the sFIDA (surface-based fluorescence intensity distribution analysis) assay. This detection limit corresponds to an Aβ concentration of 1.9 ng l–1 and lies in the sensitivity range of currently applied diagnostic tools based on Aβ oligomer quantitation. Thus, we developed a highly stable and well-characterized standard for the application in Aβ oligomer immunodetection assays that finally allows the reproducible quantitation of Aβ oligomers down to single molecule level and provides a fundamental improvement for the worldwide standardization process of diagnostic methods in AD research. Show more

Keywords: Alzheimer’s disease diagnosis, Aβ oligomer standards, assay standardization, biofunctionalized nanoparticles

DOI: 10.3233/JAD-160253

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 79-88, 2016

Authors: Li, Dong | Huang, Yan | Cheng, Bin | Su, Jie | Zhou, Wen-Xia | Zhang, Yong-Xiang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease, and effective therapeutic drugs in the clinic are still lacking. Ideally, AD progression could be stopped at an early stage, such as at the mild cognitive impairment (MCI) stage. MCI refers to the clinical condition between normal aging and dementia. Patients with MCI experience memory loss but do not meet the criteria for the diagnosis of clinically probable AD. However, few MCI animal models have been established. Here, we used in vivo long-term potentiation (LTP) recording and the Morris water maze (MWM) to evaluate the effects of intracerebroventricular injection of streptozotocin …(ICV-STZ) in mice. We found a relationship between cognitive behavior and LTP in vivo and determined the appropriate doses of STZ for a putative MCI animal model. Animals that received≥150μg of STZ exhibited cognitive impairment in the MWM test, and few changes in behavior tests were observed in animals receiving less than 150μg of STZ. In vivo LTP recordings revealed that the induction of LTP decreased significantly in STZ-treated animals, even at the lowest dose (25μg/mouse), in a dose-dependent manner. Pathology analysis revealed STZ-induced neuron loss in a dose-dependent manner, both in the cortex and in the hippocampus, as evidenced by a significantly decreased neuronal number in the cohort treated with 75μg of STZ/mouse. Our study indicated that a low dose (25μg/mouse) of STZ impaired neural plasticity; at a higher dose of 75μg/mouse STZ, further LTP deficits were noted along with induced neuronal loss in both the cortex and the hippocampus, which could be considered a possible MCI or pre-MCI animal model; and finally, at 150μg/mouse STZ, dementia was induced, feasibly indicating a state of AD. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, long-term potentiation, mild cognitive impairment, Morris water maze

DOI: 10.3233/JAD-150979

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 89-98, 2016

Authors: Durazzo, Timothy C. | Korecka, Magdalena | Trojanowski, John Q. | Weiner, Michael W. | O’ Hara, Ruth | Ashford, John W. | Shaw, Leslie M. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2 -isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2 -isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer’s disease (AD). Smoking and non-smoking CN (n  = 83), MCI (n  = 164), and probable AD (n  = 101) were compared on cerebrospinal fluid (CSF) iPF2α -III and 8,12, iso -iPF2α -VI F2 -isoprostane concentrations. Associations between F2 -isoprostane levels and hippocampal volumes were also evaluated. …In CN and AD, smokers had higher iPF2α -III concentration; overall, smoking AD showed the highest iPF2α -III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2α -III concentration. No group differences were apparent on 8,12, iso -iPF2α -VI concentration, but across AD, higher 8,12, iso -iPF2α -VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2 -isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan. Show more

Keywords: Alzheimer’s disease, cigarette smoking, F2-isoprostanes, hippocampus, mild cognitive impairment

DOI: 10.3233/JAD-160413

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 99-107, 2016

Authors: Calderón-Garcidueñas, Lilian

Article Type: Article Commentary

Abstract: Smoking has serious health effects. Cigarettes, including tobacco, marijuana, and electronic nicotine delivery systems are very effective ways to inhale harmful amounts of fine and ultrafine particulate matter. Does size matter? Yes, indeed! The smaller the particle you inhale, the higher the ability to produce reactive oxygen species and to readily access the brain. In this issue of the Journal of Alzheimer ’s Disease, Durazzo provides evidence of an association between active cigarette tobacco smoking in cognitively-normal elders and increased cerebral oxidative stress, while in actively smoking Alzheimer’s disease (AD) patients, the association was also seen with smaller left …and total hippocampal volumes. This paper has highly relevant results of interest across the US and the world because millions of people are active smokers and they have other genetic and environmental risk factors that could play a key role in the development/worsening of brain oxidative stress and neurodegeneration. Smoking basically anything producing aerosols with particulate matter in the fine and ultrafine size range is detrimental to your brain. Marijuana and e-cigarette use has grown steadily among adolescents and young adults. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD. Current knowledge also relates fine and ultrafine particles exposures influencing neurodevelopmental processes in utero. The results from Durazzo et al. should be put in a broader context, a context that includes evaluating the oxidative stress of nano-aerosols associated with cigarette emissions and their synergistic effects with air pollution exposures. AD is expected to increase in the US threefold by the year 2050, and some of these future AD patients are smoking and vaping right now. Understanding the impact of everyday exposures to long-term harmful consequences for brain health is imperative. Show more

Keywords: Air pollution, Alzheimer’s disease, cerebrospinal fluid, Mexico City, nanoparticles, oxidative stress, PM2.5, smoking

DOI: 10.3233/JAD-160510

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 109-112, 2016

Authors: Ułamek-Kozioł, Marzena | Kocki, Janusz | Bogucka-Kocka, Anna | Petniak, Alicja | Gil-Kulik, Paulina | Januszewski, Sławomir | Bogucki, Jacek | Jabłoński, Mirosław | Furmaga-Jabłońska, Wanda | Brzozowska, Judyta | Czuczwar, Stanisław J. | Pluta, Ryszard

Article Type: Research Article

Abstract: Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 …days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7–30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7–30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia. Show more

Keywords: Alzheimer’s disease, BECN 1, BNIP 3, brain ischemia, caspase 3, genes, rat, selective vulnerability, temporal cortex

DOI: 10.3233/JAD-160387

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 113-121, 2016

Authors: Allali, Gilles | Garibotto, Valentina | Assal, Frèdèric

Article Type: Research Article

Abstract: Background: Parkinsonism is frequent in neurological conditions affecting gait and cognition, such as idiopathic normal pressure hydrocephalus (iNPH) and iNPH mimics, but its discriminating value between these two groups is still unidentified. Objective: This study aims to compare the prevalence of parkinsonism between iNPH and iNPH mimics and its discriminating value. Methods: Among 141 patients with suspicion of iNPH (75.7±7.1 years; 31.2% women), seventy-nine presented a possible or probable iNPH according to standardized diagnostic criteria and the remaining sixty-two were classified as iNPH mimics. Presence of parkinsonism and other seminal clinical symptoms of iNPH were …systematically evaluated by a board-certified neurologist. Covariates include age, gender, comorbidities, and white matter disease burden using the age-related white matter changes scale. Logistic regressions were used to assess the association between parkinsonism and diagnostic groups. Results: Parkinsonism was present in 40.3% of iNPH mimics and 20.3% of iNPH (p -value: 0.015). The presence of parkinsonism, but not iNPH symptoms, was associated with the diagnosis of mimics in the adjusted model (adjusted odds ratio: 2.28; 95% CI: 1.06–4.93), even when age-related white matter changes were accounted for. Conclusion: Compared to iNPH, the increased prevalence of parkinsonism in patients with iNPH mimics in the absence of significant white matter disease suggest an underlying neurodegenerative mechanism. Show more

Keywords: Aging, mimics, normal pressure hydrocephalus, parkinsonism, white matter changes

DOI: 10.3233/JAD-160428

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 123-127, 2016

Authors: Tsolaki, Magda | Karathanasi, Elina | Lazarou, Ioulietta | Dovas, Kostas | Verykouki, Eleni | Karakostas, Anastasios | Georgiadis, Kostas | Tsolaki, Anthoula | Adam, Katerina | Kompatsiaris, Ioannis | Sinakos, Zacharias

Article Type: Research Article

Abstract: There is evidence to suggest the efficacy of Crocus (saffron) in the management of cognitive decline. This study examined the efficacy of Crocus in patients with amnesic and multi domain MCI (aMCImd). The participants included 17 patients on Crocus and 18 on a waiting list, who were examined with a short neuropsychological battery, MRI 3T, while some patients were examined via 256-channel electroencephalogram (HD-EEG) at baseline and after 12 months. The results showed that patients on Crocus had improved Mini-Mental State Examination scores (p  = 0.015), while the control group deteriorated. Also, MRI, EEG, and ERP showed improvement in specific domains. …This led us to conclude that Crocus is a good choice for management of aMCImd. Show more

Keywords: Crocus sativus, electroencephalography, magnetic resonance imaging, mild cognitive impairment, saffron

DOI: 10.3233/JAD-160304

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 129-133, 2016

Authors: Li, Yan | Chang, Lirong | Song, Yizhi | Gao, Xianghong | Roselli, Francesco | Liu, Jinping | Zhou, Wei | Fang, Yuan | Ling, Wei | Li, Hui | Almeida, Osborne F.X. | Wu, Yan

Article Type: Research Article

Abstract: Early-stage Alzheimer’s disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer’s disease, in which Aβ and NMDAR play significant roles, these observations are striking since neuronal GluN2A and …GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor β (β-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD. Show more

Keywords: Amyloid-beta, astrocyte, N-methyl-D-aspartate receptors, synaptotoxicity

DOI: 10.3233/JAD-160297

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 135-148, 2016

Authors: Connors, Michael H. | Ames, David | Boundy, Karyn | Clarnette, Roger | Kurrle, Sue | Mander, Alastair | Ward, John | Woodward, Michael | Brodaty, Henry

Article Type: Research Article

Abstract: Background: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival. Objective: To identify predictors of mortality in patients with MCI. Methods: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline. Results: 55 (30%) …patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality. Conclusion: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients’ risk. Show more

Keywords: Lifespan, longitudinal studies, mild cognitive impairment, mortality, risk factors, survival

DOI: 10.3233/JAD-160148

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 149-155, 2016

Authors: Mandecka, Monika | Budziszewska, Magdalena | Barczak, Anna | Pepłońska, Beata | Chodakowska-Żebrowska, Małgorzata | Filipek-Gliszczyńska, Anna | Nesteruk, Marta | Styczyńska, Maria | Barcikowska, Maria | Gabryelewicz, Tomasz

Article Type: Research Article

Abstract: In the course of Alzheimer’s disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-β1-42 (Aβ1-42 ), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer’s dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ …4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n  = 85), MCI (n  = 87), and AD-D (n  = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aβ1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ 4 carriers, who had lower levels of Aβ1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ 4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aβ1-42 , and the T-tau CSF biomarkers, but not by the APOE genotyping. Show more

Keywords: Alzheimer’s disease, APOE genotype, auditory verbal learning task, cerebrospinal fluid biomarkers, diagnosis, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-160176

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 157-168, 2016

Authors: Grinberg, Lea T. | Anghinah, Renato | Nascimento, Camila Fernandes | Amaro Jr, Edson | Leite, Renata P. | Martin, Maria da Graça M. | Naslavsky, Michel S. | Takada, Leonel T. | Filho, Wilson Jacob | Pasqualucci, Carlos A. | Nitrini, Ricardo

Article Type: Research Article

Abstract: The relationship between soccer and chronic traumatic encephalopathy (CTE) is not well established. We report clinicopathological correlations in an 83-year-old retired center-back soccer player, with no history of concussion, manifesting typical Alzheimer-type dementia. Examination revealed mixed pathology including widespread CTE, moderate Alzheimer’s disease, hippocampal sclerosis, and TDP-43 proteinopathy. This case adds to a few CTE cases described in soccer players. Furthermore, it corroborates that CTE may present clinically as typical Alzheimer-type dementia. Further studies investigating the extent to which soccer is a risk for CTE are needed.

Keywords: Alzheimer’s disease, autopsy, chronic post-traumatic encephalopathy, dementia, humans, soccer

DOI: 10.3233/JAD-160312

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 169-174, 2016

Authors: Sun, Jie | Cai, Rongrong | Huang, Rong | Wang, Pin | Tian, Sai | Sun, Haixia | Xia, Wenqing | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia. Objective: We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients. Methods: We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification. Results: There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among …diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r  = –0.638; p  < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r  = –0.266; p  = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p  < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level ≥2.59 mmol/L, or high density lipoproteins level ≤1.0 mmol/L for men and ≤1.3 mmol/L for women, or TG level ≥1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all p s < 0.05). Conclusions: CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients. Show more

Keywords: Cholesteryl ester transfer protein, dyslipidemia, memory decline, mild cognitive impairment, type 2 diabetes

DOI: 10.3233/JAD-160053

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 175-184, 2016

Authors: Heser, Kathrin | Bleckwenn, Markus | Wiese, Birgitt | Mamone, Silke | Riedel-Heller, Steffi G. | Stein, Janine | Lühmann, Dagmar | Posselt, Tina | Fuchs, Angela | Pentzek, Michael | Weyerer, Siegfried | Werle, Jochen | Weeg, Dagmar | Bickel, Horst | Brettschneider, Christian | König, Hans-Helmut | Maier, Wolfgang | Scherer, Martin | Wagner, Michael | for the AgeCoDe Study Group

Article Type: Research Article

Abstract: Background: Late-life depression is frequently accompanied by cognitive impairments. Objective: Whether these impairments indicate a prodromal state of dementia, or are a symptomatic expression of depression per se is not well-studied. Methods: In a cohort of very old initially non-demented primary care patients (n  = 2,709, mean age = 81.1 y), cognitive performance was compared between groups of participants with or without elevated depressive symptoms and with or without subsequent dementia using ANCOVA (adjusted for age, sex, and education). Logistic regression analyses were computed to predict subsequent dementia over up to six years of follow-up. The same analytical approach …was performed for lifetime major depression. Results: Participants with elevated depressive symptoms without subsequent dementia showed only small to medium cognitive deficits. In contrast, participants with depressive symptoms with subsequent dementia showed medium to very large cognitive deficits. In adjusted logistic regression models, learning and memory deficits predicted the risk for subsequent dementia in participants with depressive symptoms. Participants with a lifetime history of major depression without subsequent dementia showed no cognitive deficits. However, in adjusted logistic regression models, learning and orientation deficits predicted the risk for subsequent dementia also in participants with lifetime major depression. Conclusion: Marked cognitive impairments in old age depression should not be dismissed as “depressive pseudodementia”, but require clinical attention as a possible sign of incipient dementia. Non-depressed elderly with a lifetime history of major depression, who remained free of dementia during follow-up, had largely normal cognitive performance. Show more

Keywords: Cognition, dementia, depression, depressive symptoms, executive function, memory

DOI: 10.3233/JAD-160209

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 185-199, 2016

Authors: Johnson, Leigh A. | Gamboa, Adriana | Vintimilla, Raul | Edwards, Melissa | Hall, James | Weiser, Brent | Yadav, Menaka | Dickensheets, Tony | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Late life depression is a prodromal feature and a risk factor for Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating. Objective: Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans. Methods: Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and …endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis. Results: Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p  < 0.05) in women, with no significant differences on delay recall in either gender. Conclusion: DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline. Show more

Keywords: Alzheimer’s disease, cognitive decline, depression, endophenotype, Mexican American, mild cognitive impairment

DOI: 10.3233/JAD-150743

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 201-206, 2016

Authors: Calvo-Rodríguez, María | García-Durillo, Mónica | Villalobos, Carlos | Núñez, Lucía

Article Type: Research Article

Abstract: The most important risk factor for Alzheimer’s disease (AD) is aging. Neurotoxicity in AD has been linked to dyshomeostasis of intracellular Ca2+ induced by small aggregates of the amyloid-β peptide 1-42 (Aβ42 oligomers). However, how aging influences susceptibility to neurotoxicity induced by Aβ42 oligomers is unknown. In this study, we used long-term cultures of rat hippocampal neurons, a model of neuronal in vitro aging, to investigate the contribution of aging to Ca2+ dishomeostasis and neuron cell death induced by Aβ42 oligomers. In addition, we tested whether non-steroidal anti-inflammatory drugs (NSAIDs) and R-flurbiprofen prevent apoptosis …acting on subcellular Ca2+ in aged neurons. We found that Aβ42 oligomers have no effect on young hippocampal neurons cultured for 2 days in vitro (2 DIV). However, they promoted apoptosis modestly in mature neurons (8 DIV) and these effects increased dramatically after 13 DIV, when neurons display many hallmarks of in vivo aging. Consistently, cytosolic and mitochondrial Ca2+ responses induced by Aβ42 oligomers increased dramatically with culture age. At low concentrations, NSAIDs and the enantiomer R-flurbiprofen lacking anti-inflammatory activity prevent Ca2+ overload and neuron cell death induced by Aβ42 oligomers in aged neurons. However, at high concentrations R-flurbiprofen induces apoptosis. Thus, Aβ42 oligomers promote Ca2+ overload and neuron cell death only in aged rat hippocampal neurons. These effects are prevented by low concentrations of NSAIDs and R-flurbiprofen acting on mitochondrial Ca2+ overload. Show more

Keywords: Aβ42 oligomers, aging, Alzheimer’s disease, calcium, hippocampal neurons, mitochondria, non-steroidal anti-inflammatory drugs, NSAIDs, R-flurbiprofen

DOI: 10.3233/JAD-151189

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 207-221, 2016

Authors: Malpas, Charles B. | Vivash, Lucy | Genc, Sila | Saling, Michael M. | Desmond, Patricia | Steward, Christopher | Hicks, Rodney J. | Callahan, Jason | Brodtmann, Amy | Collins, Steven | Macfarlane, Stephen | Corcoran, Niall M. | Hovens, Christopher M. | Velakoulis, Dennis | O’Brien, Terence J.

Article Type: Research Article

Abstract: Background: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer’s disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain. Objective: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials. Methods: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled …trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14–26) were randomized to supranutritional (VEL015 10 mg tds [n  = 20]) and control (VEL015 320μg tds [n  = 10] or placebo [n  = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42 ). Results: Thirty-six (90%; [supranutritional n  = 18, control/placebo n  = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p  < 0.05). Conclusion: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks. Show more

Keywords: Alzheimer’s disease, clinical trial, dementia, sodium selenate

DOI: 10.3233/JAD-160544

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 223-232, 2016

Authors: Ettcheto, Miren | Petrov, Dmitry | Pedrós, Ignacio | Alva, Norma | Carbonell, Teresa | Beas-Zarate, Carlos | Pallas, Merce | Auladell, Carme | Folch, Jaume | Camins, Antoni

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ …signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α -secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42 , which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice. Show more

Keywords: Alzheimer’s disease, APPSwe/PS1dE9, hippocampus, insulin receptor, mitochondria, tau

DOI: 10.3233/JAD-160150

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 233-251, 2016

Authors: Middelstädt, Jennifer | Folkerts, Ann-Kristin | Blawath, Sabrina | Kalbe, Elke

Article Type: Research Article

Abstract: Background: Increasing evidence demonstrates the efficacy of cognitive stimulation (CS) in individuals with dementia. However, conducting studies in nursing homes engenders specific challenges that have limited the data gathered on this topic so far. Objective: The aim of this randomized controlled trial was to investigate the effects of CS on cognition, quality of life (QoL), behavioral symptoms, and activities of daily life in persons with dementia living in nursing homes. We further aimed to identify predictors of the intervention’s benefits. Methods: Seventy-one persons with mild to moderate dementia were randomly allocated to the experimental group …(EG; n  = 36) that visited a CS program twice weekly for eight weeks or to the control group (CG; n  = 35) that was receiving usual care. Neuropsychological tests were conducted before and after the intervention period and at six-week follow-up. Results: There were no significant interaction effects Time×Group for the outcome measures. However, regression analysis revealed that a low cognitive baseline level predicted cognitive improvements. Furthermore, a low baseline level of QoL predicted a QoL benefit. For both findings, depression was a significant moderator, meaning that persons with fewer depressive symptoms had a higher probability of showing improvements. Conclusion: This study provides data on profiles of patients who are most likely to profit from CS intervention in nursing-home settings and demonstrates that treatment of depression is of the utmost relevance for a positive outcome of CS. Living conditions will have to be considered more thoroughly in future research. Show more

Keywords: Cognitive stimulation, dementia, depression, intervention, nursing homes, quality of life

DOI: 10.3233/JAD-160181

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 253-268, 2016

Authors: Honda, Kazuhiro

Article Type: Research Article

Abstract: Background: An impairment of amyloid-β (Aβ) clearance has been suggested in Alzheimer’s disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. Objective: This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). Methods: Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were …excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain. Results: Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. Conclusion: In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA. Show more

Keywords: Alzheimer’s disease, carotid occlusion, cerebral amyloid angiopathy, cortical microbleeds, perivascular drainage

DOI: 10.3233/JAD-160499

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 269-274, 2016

Authors: Wang, Hao | Wang, Ying | Hong, Xiaoyu | Li, Shuiming | Wang, Yong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease with well-characterized pathological features. Yet the underlying mechanisms have not been resolved and an effective therapeutic approach is lacking. Cerebral hypoxia is considered a risk factor of AD. Objective: We tested whether oxygen supplementation can relieve AD symptoms and how it affects the expression levels of proteins in the lens. Methods: Triple transgenic AD model (3xTg-AD) mice were divided into oxygen treated (OT) and control (Ctrl) groups. Their cognitive performances were tested in a Morris water maze (MWM) paradigm. Then, their eye lens tissues were subjected to …quantitative proteomics analysis by the iTRAQ (isobaric tags for relative and absolute quantification) method. The up- and downregulated proteins were classified according to a Gene Ontology (GO) database in PANTHER. Behavioral and proteomic data were compared between the groups. Results: Mice in the OT group had better learning and memorizing performance compared with the Ctrl group in MWM test. Lenses from the OT group had 205 differentially regulated proteins, relative to lenses from the Ctrl group, including proteins that are involved in the clearance of amyloid β-protein. Conclusion: The results of this study indicate that oxygen treatment can improve cognitive function in AD model mice and alters protein expression in a manner consistent with improved redox regulation. Show more

Keywords: Alzheimer’s disease, iTRAQ, mass spectrometry, oxygen, proteomics, water maze

DOI: 10.3233/JAD-160263

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 275-286, 2016

Authors: van Steenoven, Inger | Aarsland, Dag | Weintraub, Daniel | Londos, Elisabet | Blanc, Frédéric | van der Flier, Wiesje M. | Teunissen, Charlotte E. | Mollenhauer, Brit | Fladby, Tormod | Kramberger, Milica G. | Bonanni, Laura | Lemstra, Afina W. | on behalf of the European DLB consortium

Article Type: Research Article

Abstract: Background: Concomitant Alzheimer’s disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers. Objective: We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB). Methods: We included 375 DLB patients, 164 Parkinson’s disease (PD) patients without dementia, and 55 …PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau. Results: A substantial proportion of DLB patients had abnormal values for CSF Aβ42 , t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF. Conclusion: A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB. Show more

Keywords: Amyloid beta-protein (1-42), biomarkers, cerebrospinal fluid, dementia with Lewy bodies, Lewy body disease, tau protein

DOI: 10.3233/JAD-160322

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 287-295, 2016

Authors: Yu, Lixia | Chen, Yuan | Wang, Weiguang | Xiao, Zhonghai | Hong, Yan

Article Type: Research Article

Abstract: Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer’s disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a …decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia. Show more

Keywords: Homocysteine, hypoxia, memory improvement, tau phosphorylation, vitamin B

DOI: 10.3233/JAD-160329

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 297-306, 2016

Authors: Martire, Sara | Fuso, Andrea | Mosca, Luciana | Forte, Elena | Correani, Virginia | Fontana, Mario | Scarpa, Sigfrido | Maras, Bruno | d’Erme, Maria

Article Type: Research Article

Abstract: Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer’s disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer’s transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. …Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer’s disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism. Show more

Keywords: Alzheimer’s disease, bioenergetic metabolism, mitochondria, PARP-1, PKM2

DOI: 10.3233/JAD-151040

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 307-324, 2016

Authors: Roalf, David R. | Quarmley, Megan | Mechanic-Hamilton, Dawn | Wolk, David A. | Arnold, Steven E. | Moberg, Paul J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The transition from mild cognitive impairment (MCI) to Alzheimer’s disease is characterized by a decline in cognitive performance in many domains. Cognitive performance profiles in MCI are heterogeneous, however, and additional insights into markers of incipient dementia are needed. Typically, studies focus on average or mean performance, but ignore consistency of performance across domains. WIV (within-individual variability) provides an index of this consistency and is a potential marker of cognitive decline. Objective: To use neurocognitive data from the Alzheimer’s Disease Neuroimaging Initiative cohort to measure neurocognitive variability. Methods: The utility of WIV was measured, …in addition to global neurocognitive performance (GNP), for identifying AD and MCI. In addition, the association between changes in neurocognitive variability and diagnostic transition over 12 months was measured. Results: As expected, variability was higher in AD and MCI as compared to healthy controls; GNP was lower in both groups as compared to healthy subjects. Global neurocognitive performance alone best distinguished those with dementia from healthy older adults. Yet, for individuals with MCI, including variability along with GNP improved diagnostic classification. Variability was higher at baseline in individuals transitioning from MCI to AD over a 12-month period. Conclusion: We conclude that variability offers complementary information about neurocognitive performance in dementia, particularly in individuals with MCI, and may provide beneficial information about disease transition. Show more

Keywords: ADNI, Alzheimer’s disease, intra-individual variability, mild cognitive impairment, neurocognitive function

DOI: 10.3233/JAD-160259

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 325-335, 2016

Authors: Jaakkimainen, R. Liisa | Bronskill, Susan E. | Tierney, Mary C. | Herrmann, Nathan | Green, Diane | Young, Jacqueline | Ivers, Noah | Butt, Debra | Widdifield, Jessica | Tu, Karen

Article Type: Research Article

Abstract: Background: Population-based surveillance of Alzheimer’s and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD. Objective: We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data …in identifying older adults with AD-RD over time. Methods: This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared. Results: The highest performing algorithm was “one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication” with sensitivity 79.3% (confidence interval (CI) 72.9–85.8%), specificity 99.1% (CI 98.8–99.4%), positive predictive value 80.4% (CI 74.0–86.8%), and negative predictive value 99.0% (CI 98.7–99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11. Conclusion: Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD. Show more

Keywords: Dementia, electronic medical records, family physician, health administrative algorithm

DOI: 10.3233/JAD-160105

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 337-349, 2016

Authors: Ho, Bo-Lin | Kao, Yi-Hui | Chou, Mei-Chuan | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background : Rivastigmine has been approved in the treatment of Alzheimer’s disease (AD) patients as it can inhibit acetyl- and butyryl-cholinesterase and provide neuroprotective effects involving the synapses. White matter changes (WMCs) are frequently observed in AD, and clinical-pathological correlations imply their possible impacts on cognitive function by interference with cortical and subcortical neuronal pathways. Objective: To evaluate the therapeutic effects of rivastigmine in AD patients with cerebral WMCs. Methods: Clinically diagnosed AD patients from Kaohsiung Municipal Ta-Tung hospital were recruited together with their cranial magnetic resonance imaging and a series of annual psychometric tests, including …Mini-Mental State Examination (MMSE) and sum of boxes of clinical dementia rating scale (CDR-SB). WMCs were rated through the modified Fazekas scale for the periventricular and deep WMCs. Results: In total, 87 AD patients treated with rivastigmine were enrolled. Patients at severe stage of WMCs, compared to mild stage ones, had significant improvement evaluated by MMSE (periventricular WMCs, p  = 0.025; deep WMCs, p  = 0.030), but not CDR-SB. Compared to the worsening group, the clinically improving group had a significant higher ratio of pre-existing hypertension in terms of cognitive performance [p  = 0.016, odds ratio (OR) = 3.48, 95% CI = 1.25–10.34], while having younger age (p  = 0.043, OR = 0.11, 95% CI = 0.01–1.12) in terms of global status. Conclusion: Rivastigmine may provide better benefits in cognitive function, but not global status, for AD patients with more advanced WMCs. The detailed mechanisms still have to be determined in future studies. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, rivastigmine, white matter changes

DOI: 10.3233/JAD-160364

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 351-357, 2016

Authors: Wang, Pingyue | Chen, Kewei | Yao, Li | Hu, Bin | Wu, Xia | Zhang, Jiacai | Ye, Qing | Guo, Xiaojuan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In recent years, increasing attention has been given to the identification of the conversion of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Brain neuroimaging techniques have been widely used to support the classification or prediction of MCI. The present study combined magnetic resonance imaging (MRI), 18 F-fluorodeoxyglucose PET (FDG-PET), and 18 F-florbetapir PET (florbetapir-PET) to discriminate MCI converters (MCI-c, individuals with MCI who convert to AD) from MCI non-converters (MCI-nc, individuals with MCI who have not converted to AD in the follow-up period) based on the partial least squares (PLS) method. Two types of PLS models (informed PLS and …agnostic PLS) were built based on 64 MCI-c and 65 MCI-nc from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The results showed that the three-modality informed PLS model achieved better classification accuracy of 81.40%, sensitivity of 79.69%, and specificity of 83.08% compared with the single-modality model, and the three-modality agnostic PLS model also achieved better classification compared with the two-modality model. Moreover, combining the three modalities with clinical test score (ADAS-cog), the agnostic PLS model (independent data: florbetapir-PET; dependent data: FDG-PET and MRI) achieved optimal accuracy of 86.05%, sensitivity of 81.25%, and specificity of 90.77%. In addition, the comparison of PLS, support vector machine (SVM), and random forest (RF) showed greater diagnostic power of PLS. These results suggested that our multimodal PLS model has the potential to discriminate MCI-c from the MCI-nc and may therefore be helpful in the early diagnosis of AD. Show more

Keywords: Classification, mild cognitive impairment, MRI, partial least squares, PET

DOI: 10.3233/JAD-160102

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 359-371, 2016

Authors: Rosenberg, Paul B. | Lanctôt, Krista L. | Herrmann, Nathan | Mintzer, Jacobo E. | Porsteinsson, Anton P. | Sun, Xiaoying | Raman, Rema

Article Type: Research Article

Abstract: Background: In a recent report, 76 weeks’ treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer’s disease (AD). Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). Methods: 1,537 participants with mild to moderate AD were randomized to 76 weeks’ treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer’s Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change …in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. Results: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. Conclusion: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD. Show more

Keywords: Alzheimer’s disease, amyloid, clinical trial, depression, neuropsychiatry

DOI: 10.3233/JAD-151113

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 373-381, 2016

Authors: Somers, Charisse | Struyfs, Hanne | Goossens, Joery | Niemantsverdriet, Ellis | Luyckx, Jill | De Roeck, Naomi | De Roeck, Ellen | De Vil, Bart | Cras, Patrick | Martin, Jean-Jacques | De Deyn, Peter-Paul | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer’s disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42 ), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P ). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination …with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, diagnosis, mild cognitive impairment, neuropathology, tau

DOI: 10.3233/JAD-151097

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 383-395, 2016

Authors: Lou, Wutao | Shi, Lin | Wong, Adrian | Chu, Winnie C.W. | Mok, Vincent C.T. | Wang, Defeng

Article Type: Research Article

Abstract: Disruptions of the functional brain network and cerebral blood flow (CBF) have been revealed in patients with mild cognitive impairment (MCI). However, the neurophysiological mechanism of hypoperfusion as well as the reorganization of the intrinsic whole brain network due to the neuropathology of MCI are still unclear. In this study, we aimed to investigate the changes of CBF and the whole brain network organization in MCI by using a multimodal MRI approach. Resting state ASL MRI and BOLD MRI were used to evaluate disruptions of CBF and underlying functional connectivity in 27 patients with MCI and 35 cognitive normal controls …(NC). The eigenvector centrality mapping (ECM) was used to assess the whole brain network reorganization in MCI, and a seed-based ECM approach was proposed to reveal the contributions of the whole brain network on the ECM alterations. Significantly decreased perfusion in the posterior parietal cortex as well as its connectivity within the default mode network and occipital cortex were found in the MCI group compared to the NC group. The ECM analysis revealed decreased EC in the middle cingulate cortex, parahippocampal gyrus, medial frontal gyrus, and increased EC in the right calcarine sulcus, superior temporal gyrus, and supplementary motor area in the MCI group. The results of this study indicate that there are deficits in cerebral blood flow and functional connectivity in the default mode network, and that sensory-processing networks might play a compensatory role to make up for the decreased connections in MCI. Show more

Keywords: Cerebral blood flow, eigenvector centrality, functional connectivity, functional MRI, mild cognitive impairment

DOI: 10.3233/JAD-160201

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 397-409, 2016

Article Type: Other

DOI: 10.3233/JAD-160670

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 411-415, 2016