Journal of Alzheimer's Disease - Volume 59, issue 2

Authors: Vasquez, Jared B. | Simpson, James F. | Harpole, Ryan | Estus, Steven

Article Type: Research Article

Abstract: Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer’s disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro . Lastly, although the ABCA7 …isoform with an extended exon 41 is predicted to undergo nonsense mediated RNA decay, this was not supported by qPCR analyses, which showed relatively normal ABCA7 mRNA levels in the carrier of the rs200538373 minor C allele. In summary, rs200538373 is a functional polymorphism that alters ABCA7 exon 41 splicing without grossly altering the level of ABCA7 mRNA. Show more

Keywords: ABCA7, Alzheimer’s disease, genetics, SNP, splicing

DOI: 10.3233/JAD-170872

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 633-641, 2017

Authors: Bagattini, Chiara | Mazza, Veronica | Panizza, Laura | Ferrari, Clarissa | Bonomini, Cristina | Brignani, Debora

Article Type: Research Article

Abstract: The aim of this study was to investigate the behavioral and electrophysiological dynamics of multiple object processing (MOP) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and to test whether its neural signatures may represent reliable diagnostic biomarkers. Behavioral performance and event-related potentials [N2pc and contralateral delay activity (CDA)] were measured in AD, MCI, and healthy controls during a MOP task, which consisted in enumerating a variable number of targets presented among distractors. AD patients showed an overall decline in accuracy for both small and large target quantities, whereas in MCI patients, only enumeration of large quantities was impaired. …N2pc, a neural marker of attentive individuation, was spared in both AD and MCI patients. In contrast, CDA, which indexes visual short term memory abilities, was altered in both groups of patients, with a non-linear pattern of amplitude modulation along the continuum of the disease: a reduction in AD and an increase in MCI. These results indicate that AD pathology shows a progressive decline in MOP, which is associated to the decay of visual short-term memory mechanisms. Crucially, CDA may be considered as a useful neural signature both to distinguish between healthy and pathological aging and to characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology. Show more

Keywords: Alzheimer’s disease, attention, biomarkers, electroencephalography, event-related potentials, mild cognitive impairment, short-term memory

DOI: 10.3233/JAD-161274

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 643-654, 2017

Authors: Michalski, Dominik | Hofmann, Sarah | Pitsch, Roman | Grosche, Jens | Härtig, Wolfgang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most frequent type of dementia, is a prototypical neurodegenerative disease, but shares with stroke certain common risk factors. Consequently, how vascular pathology may modulate AD pathogenesis has gained scientific attention. Therefore, aside from typical features of AD (e.g., amyloid-β, tau hyperphosphorylation, and cholinergic dysfunction), changes within the ‘neurovascular unit’ (NVU) are of particular interest. This study focused on cholinergic, choline acetyltransferase (ChAT)-immunopositive, and tyrosine hydroxylase (TH)-containing neurons in association with the vasculature to explore the neurovascular complex of the AD brain affected by stroke. Wild-type and triple-transgenic (3xTg) mice of different ages underwent unilateral permanent focal …cerebral ischemia. Histochemical analyses comprised diverse neuronal and vascular NVU components, and markers of AD. Immunofluorescence labeling confirmed the existence of Aβ deposits and phospho-tau together with glial reactions and morphologically altered endothelia, visualized by Solanum tuberosum lectin. Twenty-four hours after ischemia induction, immunoreactivities for ChAT and TH declined in the ischemia-affected striatum and, at least in part, in the ischemic border zone and ipsilateral neocortex. Correlation analyses indicated simultaneous degeneration of neuronal and vascular components. A trend for more severe affection of ChAT was observed in younger as compared with older mice. The present findings suggest complex interactions within the NVU of the AD-like brain affected by ischemia, comprising alterations of the cholinergic system in conjunction with vascular pathology. Hence, it may be worthwhile to explore the impact of a cellular stabilization approach on vascular and glial elements in AD in terms of a potential disease-alleviating strategy. Show more

Keywords: Alzheimer’s disease, cerebral ischemia, choline acetyltransferase, neurovascular unit, stroke, tyrosine hydroxylase

DOI: 10.3233/JAD-170185

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 655-674, 2017

Authors: Darnai, Gergely | Nagy, Szilvia Anett | Horváth, Réka | Ács, Péter | Perlaki, Gábor | Orsi, Gergely | Kovács, Norbert | Altbäcker, Anna | Plózer, Enikő | Tényi, Dalma | Weintraut, Rita | Schwarcz, Attila | John, Flóra | Varga, Eszter | Bereczkei, Tamás | Clemens, Zsófia | Komoly, Sámuel | Janszky, József

Article Type: Research Article

Abstract: Abnormally high deposition of iron can contribute to neurodegenerative disorders with cognitive impairment. Since previous studies investigating cognition-brain iron accumulation relationships focused on elderly people, our aim was to explore the association between iron concentration in subcortical nuclei and two types of memory performances in a healthy young population. Gender difference was found only in the globus pallidus. Our results showed that iron load characterized by R2* value on the MRI in the caudate and putamen was related to visual memory, while verbal memory was unrelated to iron concentration.

Keywords: Alzheimer’s disease, caudate nucleus, magnetic resonance imaging, memory, putamen, thalamus

DOI: 10.3233/JAD-170118

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 675-681, 2017

Authors: Chen, Long | Huang, Zhilin | Du, Yehong | Fu, Min | Han, Huili | Wang, Yutian | Dong, Zhifang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of progressive cognitive impairment in the aged. The aggregation of the amyloid β-protein (Aβ) is a hallmark of AD and is linked to synapse loss and cognitive impairment. Capsaicin, a specific agonist of the transient receptor potential vanilloid 1 (TRPV1), has been proven to ameliorate stress-induced AD-like pathological and cognitive impairments, but it is unclear whether TRPV1 activation can affect cognitive and synaptic functions in Aβ-induced mouse model of AD. In this study, we investigated the effects of TRPV1 activation on spatial memory and synaptic plasticity in mice treated with Aβ. To …induce AD-like pathological and cognitive impairments, adult C57Bl/6 mice were microinjected with Aβ42 (100 μM, 2.5 μl/mouse, i.c.v.). Two weeks after Aβ42 microinjection, spatial learning and memory as well as hippocampal long-term potentiation (LTP) were examined. The results showed that Aβ42 microinjection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with controls. These behavioral changes were accompanied by synapse loss and impaired LTP in the CA1 area of hippocampus. More importantly, daily capsaicin (1 mg/kg, i.p.) treatment throughout the experiment dramatically improved spatial learning and memory and synaptic function, as reflected by enhanced hippocampal LTP and reduced synapse loss, whereas the TRPV1 antagonist capsazepine (1 mg/kg, i.p.) treatment had no effects on cognitive and synaptic function in Aβ42 -treated mice. These results indicate that TRPV1 activation by capsaicin rescues cognitive deficit in the Aβ42 -induced mouse model of AD both structurely and functionally. Show more

Keywords: Alzheimer’s disease, amyloid-β, capsaicin, learning and memory, long-term potentiation

DOI: 10.3233/JAD-170337

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 683-694, 2017

Authors: Stephen, Ruth | Liu, Yawu | Ngandu, Tiia | Rinne, Juha O. | Kemppainen, Nina | Parkkola, Riitta | Laatikainen, Tiina | Paajanen, Teemu | Hänninen, Tuomo | Strandberg, Timo | Antikainen, Riitta | Tuomilehto, Jaakko | Keinänen Kiukaanniemi, Sirkka | Vanninen, Ritva | Helisalmi, Seppo | Levälahti, Esko | Kivipelto, Miia | Soininen, Hilkka | Solomon, Alina

Article Type: Research Article

Abstract: Background: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. Objectives: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. Methods: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were …cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. Results: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05–1.43), lower total gray matter (β-coefficient –0.29, p  = 0.001) and hippocampal volume (β-coefficient –0.28, p  = 0.003), lower cortical thickness (β-coefficient –0.19, p  = 0.042), and poorer cognition (β-coefficients –0.31 for total NTB score, –0.25 for executive functioning, –0.33 for processing speed, and –0.20 for memory, all p  < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00–1.30). No associations were found with periventricular WML or amyloid accumulation. Conclusions: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes. Show more

Keywords: Aging, cognition, dementia, neuroimaging

DOI: 10.3233/JAD-170092

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 695-705, 2017

Authors: Montero-Odasso, Manuel | Pieruccini-Faria, Frederico | Bartha, Robert | Black, Sandra E. | Finger, Elizabeth | Freedman, Morris | Greenberg, Barry | Grimes, David A. | Hegele, Robert A. | Hudson, Christopher | Kleinstiver, Peter W. | Lang, Anthony E. | Masellis, Mario | McLaughlin, Paula M. | Munoz, Douglas P. | Strother, Stephen | Swartz, Richard H. | Symons, Sean | Tartaglia, Maria Carmela | Zinman, Lorne | Strong, Michael J. | ONDRI Investigators | McIlroy, William

Article Type: Research Article

Abstract: Background: The association of cognitive and motor impairments in Alzheimer’s disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual’s needs. Pathology in this “highest level” of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. Objective: …To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. Methods: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer’s disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson’s disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. Results: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. Conclusions: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, balance, dementia, dual-tasking, frontotemporal dementia, neurodegeneration, gait, Parkinson’s disease, vascular cognitive impairment

DOI: 10.3233/JAD-170149

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 707-721, 2017

Authors: Myrum, Craig | Nikolaienko, Oleksii | Bramham, Clive R. | Haavik, Jan | Zayats, Tetyana

Article Type: Research Article

Abstract: Background: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC ) plays an essential role. Objectives: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation. Methods: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). …As Alzheimer’s disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls). Results: The ARC complex revealed association with verbal and total IQ (empirical p  = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p  = 0.018), within the APP gene, was confirmed in the AD sample (p  = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2. Discussion: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD. Show more

Keywords: Alzheimer’s disease, APP, ARC, Avon Longitudinal Study of Parents and Children, dementia, intelligence, synaptic plasticity

DOI: 10.3233/JAD-170049

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 723-735, 2017

Authors: Lehrer, Steven | Rheinstein, Peter H. | Rosenzweig, Kenneth E.

Article Type: Research Article

Abstract: Background: Exposure of the brain to ionizing radiation might promote the development of Alzheimer’s disease (AD). Objective: Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states. Methods: Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer’s Association. Results: Radon background ionizing radiation was significantly correlated with …AD death rate in 50 states and the District of Columbia (r  = 0.467, p  = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r  = 0.452, p  = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (β= 0.169, p  < 0.001), age (β= 0.231, p  < 0.001), hypertension (β= 0.155, p  < 0.001), and diabetes (β= 0.353, p  < 0.001). Conclusion: Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor. Show more

Keywords: Alzheimer’s disease, brain, dementia, ionizing radiation

DOI: 10.3233/JAD-170308

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 737-741, 2017

Authors: Manassero, Giusi | Guglielmotto, Michela | Monteleone, Debora | Vasciaveo, Valeria | Butenko, Olena | Tamagno, Elena | Arancio, Ottavio | Tabaton, Massimo

Article Type: Research Article

Abstract: The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death.

Keywords: Alzheimer’s disease, hTau mice, paired helical filaments, tau protein

DOI: 10.3233/JAD-170298

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 743-751, 2017

Authors: Cacciamani, Federica | Tandetnik, Caroline | Gagliardi, Geoffroy | Bertin, Hugo | Habert, Marie-Odile | Hampel, Harald | Boukadida, Laurie | Révillon, Marie | Epelbaum, Stéphane | Dubois, Bruno | INSIGHT-PreAD study group

Collaborators: Audrain, C | Auffret, A | Bakardjian, H | Baldacci, F | Batrancourt, B | Benakki, I | Benali, H | Bertin, H | Bertrand, A | Boukadida, L | Cacciamani, F | Causse, V | Cavedo, E | Cherif Touil, S | Chiesa, P A | Colliot, O | Dalla Barba, G | Depaulis, M | Dos Santos, A | Dubois, B | Dubois, M | Epelbaum, S | Fontaine, B | Francisque, H | Gagliardi, G | Genin, A | Genthon, R | Glasman, P | Gombert, F | Habert, M O | Hampel, H | Hewa, H | Houot, M | Jungalee, N | Kas, A | Kilani, M | La Corte, V | Le Roy, F | Lehericy, S | Letondor, C | Levy, M | Lista, S | Lowrey, M | Ly, J | Makiese, O | Masetti, I | Mendes, A | Metzinger, C | Michon, A | Mochel, F | Nait Arab, R | Nyasse, F | Perrin, C | Poirier, F | Poisson, C | Potier, M C | Ratovohery, S | Revillon, M | Rojkova, K | Santos-Andrade, K | Schindler, R | Servera, M C | Seux, L | Simon, V | Skovronsky, D | Thiebaut, M | Uspenskaya, O | Vlaincu, M

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer’s disease (AD). Objective: In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. Methods: Cognitively normal older adults (N  = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants …with low versus high awareness were compared. Results: Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n  = 19) and high (n  = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the “low awareness” group showed greater amyloid burden and lower cortical metabolism, compared to the “high awareness” group. Conclusion: This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials. Show more

Keywords: Alzheimer’s disease, awareness, biomarkers, cognitive complaints, subjective cognitive decline

DOI: 10.3233/JAD-170399

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 753-762, 2017

Authors: Serrano-Pozo, Alberto | Aldridge, Georgina M. | Zhang, Qiang

Article Type: Research Article

Abstract: Background: Bibliometric and scientometric methods can be applied to the study of a research field. Objective: We hypothesized that a bibliometric and scientometric analysis of the Alzheimer’s disease (AD) research field could render trends that provide researchers and funding agencies valuable insight into the history of the field, current tendencies, and potential future directions. Methods: We performed searches in publicly available databases including PubMed, Scopus, Web of Science, and Alzheimer’s Funding Analyzer for the period 1975–2014, and conducted a curve fitting analysis with non-linear regression. Results: While the rate and impact of publications continue …to increase, the number of patents per year is currently declining after peaking in the late 2000s, and the funding budget has plateaued in the last 5–10 years analyzed. Genetics is the area growing at a fastest pace, whereas pathophysiology and therapy have not grown further in the last decade. Among the targets of pathophysiology research, amyloid-β continues to be the focus of greatest interest, with tau and apolipoprotein E stagnant after a surge in the 1990s. The role of inflammation, microglia, and the synapse are other research topics with growing interest. Regarding preventative strategies, education attainment, diet, and exercise are recently gaining some momentum, whereas NSAIDs and statins have lost the spotlight they once had. Conclusion: Our bibliometric and scientometric analysis provides distinct trends in AD research in the last four decades, including publication and patent output, funding, impact, and topics. Our findings could inform the decision-making of research funding agencies in the near future. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, bibliometrics, h-index, neurofibrillary tangle, scientometrics, tau proteins

DOI: 10.3233/JAD-170184

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 763-783, 2017