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

Authors: Nagai, Michiaki | Dote, Keigo | Kato, Masaya | Sasaki, Shota | Oda, Noboru | Kagawa, Eisuke | Nakano, Yoshinori | Yamane, Aya | Higashihara, Tasuku | Miyauchi, Shunsuke | Tsuchiya, Akane

Article Type: Review Article

Abstract: While hypertension has been shown to be a risk factor for vascular dementia, several studies have also demonstrated that hypertension also increases the risk of Alzheimer’s disease (AD). Although the relationship between visit-to-visit blood pressure variability (VVV) and cognitive impairment, including AD, have been provided, the mechanisms remain poorly understood. This review paper focuses on the relationship of VVV with AD and summarizes the pathophysiology underlying that relationship, which appears to be mediated by arterial stiffness.

Keywords: Alzheimer’s disease, amyloid beta, cognitive impairment, hypertension, visit-to-visit blood pressure variability

DOI: 10.3233/JAD-161172

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 515-526, 2017

Authors: Xie, Fang | Peng, Fangyu

Article Type: Review Article

Abstract: Aging is a risk factor for Alzheimer’s disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18 F]-fluoro-D-glucose (18 F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18 F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). …There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD. Show more

Keywords: Alzheimer’s disease, metabolism, glucose metabolism, lipid metabolism, amino acid transport, protein synthesis, biometal, copper, iron, zinc, manganese, positron emission tomography, radiopharmaceuticals

DOI: 10.3233/JAD-170280

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 527-536, 2017

Authors: Mandal, Pravat K. | Shukla, Deepika | Govind, Varan | Boulard, Yves | Ersland, Lars

Article Type: Research Article

Abstract: Glutathione (GSH) is a major antioxidant in humans that is involved in the detoxification of reactive radicals and peroxides. The molecular structural conformations of GSH depend on the surrounding micro-environment, and it has been experimentally evaluated using NMR and Raman spectroscopic techniques as well as by molecular dynamics simulation studies. The converging report indicates that GSH exists mainly in two major conformations, i.e., “extended” and “folded”. The NMR-derived information on the GSH conformers is essential to obtain optimal acquisition parameters in in vivo MRS experiments targeted for GSH detection. To further investigate the implications of GSH conformers in in …vivo MRS studies and their relative proportions in healthy and pathological conditions, a multi-center clinical research study is necessary with a common protocol for GSH detection and quantification. Show more

Keywords: Antioxidant, brain, conformation, glutathione, magnetic resonance spectroscopy, molecular dynamics, nuclear magnetic resonance

DOI: 10.3233/JAD-170350

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 537-541, 2017

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Liquid sheared amyloid-β (Aβ) initiates amyloid cascade reactions, producing unstable, potentially toxic oligomers. There is a need for new analytical tools with which to study these oligomers. A very small bore capillary flow system is proposed as a tool for studying the effects of liquid shear in amyloid research. This simple system consists of injecting a short cylindrical liquid sample plug containing dissolved amyloid into a liquid mobile phase flowing through an empty, very small internal diameter capillary tube. For liquid samples containing a single protein sample, under conditions in which there is laminar flow and limited sample protein molecular …diffusion, chromatograms monitoring the optical protein absorbance of capillary effluent contain either one or two peaks, depending on the mobile phase flow rate. By controlling the sample diffusion times through changes in flow rate and/or capillary diameter, this tool can be used to generate aliquot samples with precise, reproducible amounts of shear for exploring the effects of variable shear on amyloid systems. The tool can be used for producing in-capillary stopped flow spectra of shear-stressed Aβ monomers as well as for kinetic studies of Aβ dimer- and oligomer-forming reactions between shear stressed Aβ monomers. Many other experiments are suggested using this experimental tool for studying the effects of shear on different Aβ and other amyloid systems, including testing for potentially serious amyloid sampling errors in spinal tap quantitative analysis. The technique has potential as both a laboratory research and a clinical tool. Show more

Keywords: Aggregation, amyloid-β, amyloid cascade, amyloid dimer, amyloid oligomers, capillary analysis, limited diffusion, protein misfolding, spinal tap

DOI: 10.3233/JAD-170259

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 543-557, 2017

Authors: Stoccoro, Andrea | Siciliano, Gabriele | Migliore, Lucia | Coppedè, Fabio

Article Type: Short Communication

Abstract: Mitochondrial impairment is a feature of neurodegeneration and many investigators have suggested that epigenetic modifications of the mitochondrial DNA (mtDNA) might be involved in late-onset Alzheimer’s disease (LOAD), but evidence in humans is limited. We assessed the methylation levels of the mtDNA D-loop region in blood DNA from 133 LOAD patients and 130 controls, observing a significant 25% reduction of DNA methylation levels in the first group (2.3 versus 3.1%). Overall, the present data indicate that there is a decreased methylation of the D-loop region in LOAD peripheral blood DNA, suggesting that mtDNA epimutations deserve further investigations in AD pathogenesis.

Keywords: Alzheimer’s disease, D-loop region, DNA methylation, epigenetics, mitochondrial DNA, mtDNA

DOI: 10.3233/JAD-170139

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 559-564, 2017

Authors: Padala, Kalpana P. | Padala, Prasad R. | Lensing, Shelly Y. | Dennis, Richard A. | Bopp, Melinda M. | Roberson, Paula K. | Sullivan, Dennis H.

Article Type: Research Article

Abstract: Background/Objective: Balance problems are common in older adults with Alzheimer’s disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD. Methods: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73±6.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and …16 weeks (8-weeks post-intervention). Results: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3–6.2], p  < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0–5.0], p  < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6–9.4], p  < 0.001) and Falls Efficacy Scale (–4.8 [–7.6 to –2.0], p  = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p  = 0.445). Conclusion: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD. Show more

Keywords: Alzheimer’s disease, balance, fear of falling, older adults

DOI: 10.3233/JAD-170120

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 565-574, 2017

Authors: Adegoke, Oludotun O. | Qiao, Fangfang | Liu, Yanying | Longley, Kirsty | Feng, Shelley | Wang, Hongmin

Article Type: Research Article

Abstract: Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer’s disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo , we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the …AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40 ) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, amyloid-β, learning and memory, plaques, ubiquilin-1

DOI: 10.3233/JAD-170173

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 575-590, 2017

Authors: Zhang, Zhong-Hao | Wu, Qiu-Yan | Chen, Chen | Zheng, Rui | Chen, Yao | Liu, Qiong | Ni, Jia-Zuan | Song, Guo-Li

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and …the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aβ clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD. Show more

Keywords: Alzheimer’s disease, amyloid-β pathology, autophagy, clearance, selenomethionine

DOI: 10.3233/JAD-170216

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 591-602, 2017

Authors: Iaccarino, Leonardo | Chiotis, Konstantinos | Alongi, Pierpaolo | Almkvist, Ove | Wall, Anders | Cerami, Chiara | Bettinardi, Valentino | Gianolli, Luigi | Nordberg, Agneta | Perani, Daniela

Article Type: Research Article

Abstract: Assessments of brain glucose metabolism (18 F-FDG-PET) and cerebral amyloid burden (11 C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer’s disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18 F-FDG-PET and 11 C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18 F-FDG-PET and of standardized uptake value ratio semiquantification for 11 C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to …ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18 F-FDG-PET and 11 C-PiB-PET. 18 F-FDG-PET, compared to 11 C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p  = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18 F-FDG-PET and 11 C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings. Show more

Keywords: Alzheimer’s disease, 11C-PiB-PET, conversion prediction, dementia, early diagnosis, 18F-FDG-PET, mild cognitive impairment, prognosis

DOI: 10.3233/JAD-170158

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 603-614, 2017

Authors: Bellanti, Francesco | Iannelli, Giuseppina | Blonda, Maria | Tamborra, Rosanna | Villani, Rosanna | Romano, Adele | Calcagnini, Silvio | Mazzoccoli, Gianluigi | Vinciguerra, Manlio | Gaetani, Silvana | Giudetti, Anna Maria | Vendemiale, Gianluigi | Cassano, Tommaso | Serviddio, Gaetano

Article Type: Research Article

Abstract: A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer’s disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on …clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Ror α, Csnk1 ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis. Show more

Keywords: Aging, Alzheimer’s disease, clock genes, light exposure, suprachiasmatic nucleus

DOI: 10.3233/JAD-160942

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 615-631, 2017

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