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