Journal of Alzheimer's Disease - Volume 53, issue 3

Authors: Arendash, Gary W.

Article Type: Review Article

Abstract: We have demonstrated in multiple studies that daily, long-term electromagnetic field (EMF) treatment in the ultra-high frequency range not only protects Alzheimer’s disease (AD) transgenic mice from cognitive impairment, but also reverses such impairment in aged AD mice. Moreover, these beneficial cognitive effects appear to be through direct actions on the AD process. Based on a large array of pre-clinical data, we have initiated a pilot clinical trial to determine the safety and efficacy of EMF treatment to mild-moderate AD subjects. Since it is important to establish the safety of this new neuromodulatory approach, the main purpose of this review …is to provide a comprehensive assessment of evidence supporting the safety of EMFs, particularly through transcranial electromagnetic treatment (TEMT). In addition to our own pre-clinical studies, a rich variety of both animal and cell culture studies performed by others have underscored the anticipated safety of TEMT in clinical AD trials. Moreover, numerous clinical studies have determined that short- or long-term human exposure to EMFs similar to those to be provided clinically by TEMT do not have deleterious effects on general health, cognitive function, or a variety of physiologic measures—to the contrary, beneficial effects on brain function/activity have been reported. Importantly, such EMF exposure has not been shown to increase the risk of any type of cancer in human epidemiologic studies, as well as animal and cell culture studies. In view of all the above, clinical trials of safety/efficacy with TEMT to AD subjects are clearly warranted and now in progress. Show more

Keywords: Aβ oligomers, Alzheimer’s disease, cognition, electromagnetic treatment, memory, transcranial

DOI: 10.3233/JAD-160165

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 753-771, 2016

Authors: Allué, José Antonio | Sarasa, Leticia | Izco, María | Pérez-Grijalba, Virginia | Fandos, Noelia | Pascual-Lucas, María | Ogueta, Samuel | Pesini, Pedro | Sarasa, Manuel

Article Type: Research Article

Abstract: APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer’s disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, …whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD. Show more

Keywords: Alzheimer’s disease, amyloid peptide, immunoprecipitation, MALDI-TOF/TOF, Micro-LC-ESI-Q-TOF, transgenic mouse models

DOI: 10.3233/JAD-160280

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 773-785, 2016

Authors: Pickett, Eleanor K. | Koffie, Robert M. | Wegmann, Susanne | Henstridge, Christopher M. | Herrmann, Abigail G. | Colom-Cadena, Marti | Lleo, Alberto | Kay, Kevin R. | Vaught, Melissa | Soberman, Roy | Walsh, Dominic M. | Hyman, Bradley T. | Spires-Jones, Tara L.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron …microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue. Show more

Keywords: Alzheimer’s disease, amyloid-β, array tomography, synapses

DOI: 10.3233/JAD-160007

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 787-800, 2016

Authors: Dermody, Nadene | Wong, Stephanie | Ahmed, Rebekah | Piguet, Olivier | Hodges, John R. | Irish, Muireann

Article Type: Research Article

Abstract: Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer’s disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD …and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information. Show more

Keywords: Neurodegenerative diseases, orbitofrontal cortex, right hemisphere, social cognition, theory of mind

DOI: 10.3233/JAD-160175

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 801-816, 2016

Authors: Oboshi, Yumi | Kikuchi, Mitsuru | Terada, Tatsuhiro | Yoshikawa, Etsuji | Bunai, Tomoyasu | Ouchi, Yasuomi

Article Type: Research Article

Abstract: Background: Evidence shows that the cholinergic system plays an important role in regulating working memory and that working memory-related prefrontal activation decreases with age and neuronal degeneration, such as Alzheimer’s disease (AD). However, the relation between attention-related α 4β2 nicotinic cholinergic function and task-induced prefrontal activation especially time course-related activation remains to be explored. Objective: We aimed to elucidate the relationship between changes in task-induced oxy-hemoglobin concentration (cerebral blood flow, CBF) in the prefrontal cortex and the availability of α 4β2 nicotinic receptors in the brain of AD patients in light of their task performance. Methods: …Eleven mild-to-moderate AD patients and eleven normal elderly subjects underwent the near-infrared spectroscopy during easy and difficult working memory tasks for estimating prefrontal CBF changes and positron emission tomography with the α 4β2 tracer [18 F]2FA-85380 ([18 F]2FA) for measuring the α 4β2 nicotinic receptor binding. Results: Significant correlations between mean oxy-hemoglobin concentration in the channels with significant [group] main effects and prefrontal [18 F]2FA binding were observed during the early easy task period in the normal group and during the late difficult task in the AD group. In addition, those prefrontal CBF responses were significantly correlated with not correct performance but the execution time to spend. Conclusion: The α 4β2 nicotinic acetylcholine receptors in the prefrontal cortex play an important role in increasing prefrontal activation when attending to novel stimuli, irrespective of the accuracy of the outcome. A delay in the cholinergic-induced increase in prefrontal activation in AD patients might explain their delayed responses in the cognitive task. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, nicotinic acetylcholine receptor, prefrontal cortex, working memory

DOI: 10.3233/JAD-151165

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 817-830, 2016

Authors: Campanari, Maria-Letizia | Navarrete, Francisco | Ginsberg, Stephen D. | Manzanares, Jorge | Sáez-Valero, Javier | García-Ayllón, María-Salud

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (q RT-PCR). We found similar protein and mRNA …levels of the major cholinergic “tailed”-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic “readthrough” AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine. Show more

Keywords: Acetylcholinesterase, AChE splice variants, Alzheimer’s disease, human brain, readthrough AChE variants

DOI: 10.3233/JAD-160220

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 831-841, 2016

Authors: Zhou, Xiao | Huang, Jianou | Pan, Suyue | Xu, Miaojing | He, Rongni | Ji, Zhong | Hu, Yafang

Article Type: Research Article

Abstract: Background: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models. Objective: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9). Methods: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed. Results: GFP expression was detected by in …vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression. Conclusion: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo , as well as an alternative tool for development of drugs against neurotoxic of p25. Show more

Keywords: Adeno-associated virus 9, Alzheimer’s disease, cyclin-dependent kinase 5, disease models, magnetic resonance imaging, p25, transgenic mice

DOI: 10.3233/JAD-160191

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 843-855, 2016

Authors: Eugenín, Jaime | Vecchiola, Andrea | Murgas, Paola | Arroyo, Pablo | Cornejo, Francisca | von Bernhardi, Rommy

Article Type: Research Article

Abstract: The pathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques, neurofibrillary tangles, and glia activation. The pathology also includes vascular amyloidosis and cerebrovascular disease. Vascular compromise can result in hypoperfusion, local tissue hypoxia, and acidosis. Activated microglia and astrocytes can phagocytose Aβ through membrane receptors that include scavenger receptors. Changes in glial cells induced by extracellular acidosis could play a role in the development of AD. Here, we assess whether extracellular acidosis changes glial cell properties relevant for Aβ clearance capacity. Incubation of glial cells on acidified culture medium (pH 6.9 or 6.5) for 24–48 h resulted in decreased cell …diameter, with thinner branches in astrocytes, slight reduction in cell body size in microglia, a transient decrease in astrocyte adhesion to substrates, and a persistent decrease in microglia adhesion compared with control media (pH 7.4). Astrocyte Aβ phagocytosis decreased at pH 6.9 and 6.5, whereas microglia phagocytosis only transiently decreased in acidified media. Scavenger receptors class B member I (SR-BI) increased and scavenger receptors-macrophage receptors with collagenous structures (SR-MARCO) decreased in astrocytes cultured at pH 6.5. In contrast, in microglia exposed to pH 6.5, expression of SR-BI and SR-MARCO increased and fatty acid translocase (CD-36) decreased. In conclusion, the acidic environment changed the adhesiveness and morphology of both microglia and astrocytes, but only astrocytes showed a persistent decrease in Aβ clearance activity. Expression of scavenger receptors was affected differentially in microglia and astrocytes by acidosis. These changes in scavenger receptor patterns can affect the activation of glia and their contribution to neurodegeneration. Show more

Keywords: Acidosis, amyloid-β peptide, glial activation, phagocytosis, scavenger receptors

DOI: 10.3233/JAD-160083

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 857-873, 2016

Authors: Bamji-Mirza, Michelle | Li, Yan | Najem, Dema | Liu, Qing Yan | Walker, Douglas | Lue, Lih-Fen | Stupak, Jacek | Chan, Kenneth | Li, Jianjun | Ghani, Mahdi | Yang, Ze | Rogaeva, Ekaterina | Zhang, Wandong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe . Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection …experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of h ABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing h ABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of h ABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology. Show more

Keywords: ABC transporters, ABCA7 protein, Alzheimer’s disease, amyloid beta-peptides, BACE1 protein, genome-wide association study, myristoylation, SNPs

DOI: 10.3233/JAD-150965

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 875-892, 2016

Authors: Zhai, Yun | Yamashita, Toru | Nakano, Yumiko | Sun, Zhuoran | Shang, Jingwei | Feng, Tian | Morihara, Ryuta | Fukui, Yusuke | Ohta, Yasuyuki | Hishikawa, Nozomi | Abe, Koji

Article Type: Research Article

Abstract: Recently, aging societies have been showing an increasingly strong relationship between Alzheimer’s disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer’s disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP …mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action. Show more

Keywords: Alzheimer’s disease, APP23 mice, cerebral amyloid angiopathy, galantamine, hypoperfusion

DOI: 10.3233/JAD-160345

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 893-905, 2016

Authors: Wang, Jianhui | Ye, Fuqiang | Cheng, Xiaorui | Zhang, Xiaorui | Liu, Feng | Liu, Gang | Ni, Ming | Qiao, Shanyi | Zhou, Wenxia | Zhang, Yongxiang

Article Type: Research Article

Abstract: Microbes have deserved broader attention as causal factors in Alzheimer’s disease (AD), a neurodegenerative disorder. The senescence-accelerated mouse prone 8 (SAMP8) strain, a spontaneous mice of accelerated aging, are considered a robust model for sporadic AD. LW-AFC, an herbal medicine, was prepared from LiuweiDihuang decoction, which is a classical traditional Chinese medicine prescription. Here, we showed that the treatment of LW-AFC improved cognitive impairments of SAMP8 mice, including spatial learning and memory ability, active avoidance response, and object recognition memory capability. Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units (OTUs) in the gut …microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1 (SAMR1) strains, the control of SAMP8 mice. The treatment of LW-AFC altered 22 (16 increased and 6 decreased) OTUs in SAMP8 mice and among them, 15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice. We further showed that there were 7 (3 negative and 4 positive correlation) OTUs significantly correlated with all the three types of cognitive abilities, at the order level, including Bacteroidales , Clostridiales , Desulfovibrionales , CW040 , and two unclassified orders. LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice. Our results indicate that the effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent. Show more

Keywords: Alzheimer’s disease, LW-AFC, microbiome, senescence-accelerated mouse prone 8 strain, traditional Chinese medicine

DOI: 10.3233/JAD-160138

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 907-919, 2016

Authors: Chouraki, Vincent | Reitz, Christiane | Maury, Fleur | Bis, Joshua C. | Bellenguez, Celine | Yu, Lei | Jakobsdottir, Johanna | Mukherjee, Shubhabrata | Adams, Hieab H. | Choi, Seung Hoan | Larson, Eric B. | Fitzpatrick, Annette | Uitterlinden, Andre G. | de Jager, Philip L. | Hofman, Albert | Gudnason, Vilmundur | Vardarajan, Badri | Ibrahim-Verbaas, Carla | van der Lee, Sven J. | Lopez, Oscar | Dartigues, Jean-François | Berr, Claudine | Amouyel, Philippe | Bennett, David A. | van Duijn, Cornelia | DeStefano, Anita L. | Launer, Lenore J. | Ikram, M. Arfan | Crane, Paul K. | Lambert, Jean-Charles | Mayeux, Richard | Seshadri, Sudha | for the International Genomics of Alzheimer’s Project

Article Type: Research Article

Abstract: Effective prevention of Alzheimer’s disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ɛ 4. In eight prospective cohorts included in the International Genomics of Alzheimer’s Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of …incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ–C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13–1.21] per standard deviation increase in GRS; p -value =  2.86×10–16 ). This association was stronger among persons with at least one APOE ɛ 4 allele (HRGRS  = 1.24; 95% CI =   [1.15–1.34]) than in others (HRGRS  = 1.13; 95% CI =   [1.08–1.18]; pinteraction  = 3.45×10–2 ). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ɛ 4, and education (Δ–Cindex =  0.0043 [0.0019–0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ɛ 4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials. Show more

Keywords: Alzheimer’s disease, clinical utility, cohort studies, genetic risk score, IGAP, meta-analysis, risk prediction

DOI: 10.3233/JAD-150749

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 921-932, 2016

Authors: Mohseni, Hedieh K. | Cowan, David | Chettle, David R. | Milić, Ana Pejović | Priest, Nicholas | Matysiak, Witold | Atanackovic, Jovica | Byun, Soo Hyun | Prestwich, William V.

Article Type: Research Article

Abstract: Aluminum, being the most abundant metal in the earth’s crust, is widely distributed in the environment, and is routinely taken up by the human body through ingestion and inhalation. Aluminum is not considered an essential element and it can be toxic in high concentrations. Most of the body burden of aluminum is stored in the bones. Aluminum has been postulated to be involved in the causality of Alzheimer’s disease. A system for non-invasive measurement of bone aluminum using the in vivo neutron activation analysis technique has been developed and previously reported in the literature by our group. The results …are reported as ratio of Al to Ca in order to eliminate the variations in beam parameters and geometry as well as the physical variations among the subjects such as size of the hand and bone structure. This pilot study included 30 subjects, 15 diagnosed with Alzheimer’s disease in mild and moderate stages and 15 control subjects, all of whom were 60 years of age or older. The mean value of aluminum for the control group was 2.7±8.2μg Al/g Ca (inverse-variance weighted mean 3.5±0.9μg Al/g Ca) and for the Alzheimer’s disease subjects was 12.5±13.1μg Al/g Ca (inverse-variance weighted mean 7.6±0.6μg Al/g Ca). The difference between the mean of the Alzheimer’s disease group and the mean of the control group was 9.8±15.9μg Al/g Ca, with a p-value of 0.02. An age-dependent linear increase in bone aluminum concentration was observed for all subjects. The difference in serum aluminum levels between the two groups did not reach significance. Show more

Keywords: Aluminum, Alzheimer’s disease, bone, gamma spectroscopy, in vivo, neutron activation analysis

DOI: 10.3233/JAD-160194

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 933-942, 2016

Authors: Cavuoto, Marina G. | Ong, Ben | Pike, Kerryn E. | Nicholas, Christian L. | Bei, Bei | Kinsella, Glynda J.

Article Type: Research Article

Abstract: Background: Sleep disturbance is implicated in memory function across normal aging and neurodegenerative disease. Furthermore, there is mounting evidence to suggest that high levels of subjective memory decline (SMD) may signal very early neurodegenerative changes associated with Alzheimer’s disease (AD). This view prompts research examining the relationship between SMD and other risk factors for cognitive decline, including sleep disturbance. Objective: To determine whether objective and subjective indices of sleep predict SMD in older adults. Methods: 181 community-based older adults were divided into groups of high and low SMD based on their responses to the Memory …Assessment Complaint Questionnaire (MAC-Q). They undertook two weeks of objective sleep monitoring (actigraphy), and completed a subjective sleep quality assessment using the Pittsburgh Sleep Quality Index. Results: Hierarchical logistic regression indicated that after controlling for demographics and mood, objective sleep quality predicted high SMD group status (Δ Nagelkerke R2  = 0.07, χ 2  = 9.80 (3), p  = 0.020), while subjective sleep quality did not. Contrary to expectation, however, less sleep disruption predicted high SMD. Conclusion: These unexpected results may suggest a non-linear trajectory between sleep and memory decline in aging. The findings are discussed in relation to previous research, which taken together, may indicate compensatory sleep patterns of reduced sleep disruption in people with high levels of SMD. These preliminary findings suggest the utility of including analysis of sleep behavior in further longitudinal research of this at-risk group of older people. Show more

Keywords: Actigraphy, cognition, early diagnosis, memory, memory disorders, sleep

DOI: 10.3233/JAD-160187

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 943-953, 2016

Authors: González, Hector M. | Tarraf, Wassim | Gouskova, Natalia | Rodríguez, Carlos J. | Rundek, Tatjana | Grober, Ellen | Pirzada, Amber | González, Patricia | Lutsey, Pamela L. | Camacho, Alvaro | Daviglus, Martha L. | Wright, Clinton | Mosley, Thomas H.

Article Type: Research Article

Abstract: Background: Hispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed. Objective: We examined associations between neurocognition and cardiovascular health (CVH) metrics (Life’s Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance). Methods: We used baseline (2008–2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45–74 years) to examine neurocognition in relation to CVH LS7 scores. Results: In age and sex adjusted models, a one unit …LS7 score increase (range = 0–14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p  < 0.01]; range = 3–42), B-SEVLT recall (0.12 [p  < 0.01]; range = 0–15), Word Fluency (phonemic; 0.46 (p  < 0.01); range = 0–49), and Digit Symbol Substitution (0.49 (p  < 0.01); range = 0–83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations. Conclusions: We found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos. Show more

Keywords: Cardiovascular system, cognition, epidemiology, Hispanic Americans

DOI: 10.3233/JAD-151125

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 955-965, 2016

Authors: Hofrichter, Jacqueline | Krohn, Markus | Schumacher, Toni | Lange, Cathleen | Feistel, Bjöorn | Walbroel, Bernd | Pahnke, Jens

Article Type: Research Article

Abstract: Nowadays, Alzheimer’s disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard …to their effects on cognition in APP-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aβ deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in APP-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aβ42 load in APP-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α -secretase ADAM10. Moreover, the treatment was able to fully rescue neuronal loss of APP-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer’s disease by affecting its most prominent hallmarks: Aβ pathology and cognitive decline. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β , microglia, neuroprotection, Sideritis spp

DOI: 10.3233/JAD-160301

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 967-980, 2016

Authors: Skrobot, Olivia Anna | McKnight, Amy Jayne | Passmore, Peter Anthony | Seripa, Davide | Mecocci, Patrizia | Panza, Francesco | Kalaria, Rajesh | Wilcock, Gordon | Munafò, Marcus | Erkinjuntti, Timo | Karhunen, Pekka | Pessi, Tanja | Martiskainen, Mika | Love, Seth | the Genetic and Environmental Risk for Alzheimer’s disease Consortium (GERAD1) | Kehoe, Patrick Gavin

Article Type: Research Article

Abstract: Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ 4, ɛ 2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax  = 549) and elderly non-demented samples (nmax  = 552). Where available, genotype data derived …from Illumina’s 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16–1.58, p  = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42–0.90, p  = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17–2.16, p  = 0.003). Association was also observed with APOE epsilon alleles; ɛ 4 (OR = 1.85, 95% CI 1.35–2.52, p  = <0.0001) and ɛ 2 (OR = 0.67, 95% CI 0.46–0.98, p  = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ 4 allele. Show more

Keywords: Association, cognitive impairment, dementia, gene, meta-analysis, vascular

DOI: 10.3233/JAD-150862

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 981-989, 2016

Authors: Peter, Jessica | Lahr, Jacob | Minkova, Lora | Lauer, Eliza | Grothe, Michel J. | Teipel, Stefan | Köstering, Lena | Kaller, Christoph P. | Heimbach, Bernhard | Hüll, Michael | Normann, Claus | Nissen, Christoph | Reis, Janine | Klöppel, Stefan

Article Type: Research Article

Abstract: Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer’s disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate …regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage. Show more

Keywords: Basal forebrain cholinergic system, mediation, mild cognitive impairment, short afferent inhibition

DOI: 10.3233/JAD-160273

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 991-1001, 2016

Authors: Armstrong, Joshua J. | Godin, Judith | Launer, Lenore J. | White, Lon R. | Mitnitski, Arnold | Rockwood, Kenneth | Andrew, Melissa K.

Article Type: Research Article

Abstract: Background: As cognitive decline mostly occurs in late life, where typically it co-exists with many other ailments, it is important to consider frailty in understanding cognitive change. Objective: Here, we examined the association of change in frailty status with cognitive trajectories in a well-studied cohort of older Japanese-American men. Methods: Using the prospective Honolulu-Asia Aging Study (HAAS), 2,817 men of Japanese descent were followed (aged 71–93 at baseline). Starting in 1991 with follow-up health assessments every two to three years, cognition was measured using the Cognitive Abilities Screening Instrument (CASI). For this study, health data …was used to construct an accumulation of deficits frailty index (FI). Using six waves of data, multilevel growth curve analyses were constructed to examine simultaneous changes in cognition in relation to changes in FI, controlling for baseline frailty, age, education, and APOE-ɛ 4 status. Results: On average, CASI scores declined by 2.0 points per year (95% confidence interval 1.9–2.1). Across six waves, each 10% within-person increase in frailty from baseline was associated with a 5.0 point reduction in CASI scores (95% confidence interval 4.7–5.2). Baseline frailty and age were associated both with lower initial CASI scores and with greater decline across the five follow-up assessments (p  < 0.01). Discussion: Cognition is adversely affected by impaired health status in old age. Using a multidimensional measure of frailty, both baseline status and within-person changes in frailty were predictive of cognitive trajectories. Show more

Keywords: Aging, cognition, cohort studies, frail elderly, risk factors

DOI: 10.3233/JAD-151172

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1003-1013, 2016

Authors: Woody, Sarah K. | Zhou, Helen | Ibrahimi, Shaher | Dong, Yafeng | Zhao, Liqin

Article Type: Research Article

Abstract: Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ 2 (ApoE2), ApoE ɛ 3 (ApoE3), and ApoE ɛ 4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer’s disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and …synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H + -ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas—in which Atp6v may play a role—could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype. Show more

Keywords: Alzheimer’s disease, ApoE2, ApoE3, ApoE4, cellular bioenergetics, synaptic transmission, V-type H+-ATPase

DOI: 10.3233/JAD-160307

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1015-1031, 2016

Authors: Van Langenhove, Tim | Leyton, Cristian E. | Piguet, Olivier | Hodges, John R.

Article Type: Research Article

Abstract: Background: Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants. Objective: To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time. Methods: We measured behavioral changes in 73 prospectively recruited PPA (30 sv-PPA, 22 nfv-PPA, and 21 lv-PPA), as well as 33 behavioral variant frontotemporal dementia (bv-FTD) …and 31 Alzheimer’s disease (AD) patients, at baseline and after 1 year, using the Cambridge Behavioural Inventory Revised. All included patients had mild dementia severity at baseline. Results: Both at baseline and follow-up, sv-PPA exhibited significantly more behavioral disturbances of the type characteristic of bv-FTD compared with other PPA variants. 74% of sv-PPA patients with mild dementia severity exhibited at least one behavior disturbance at baseline, which increased to 84% during follow-up. Behavioral symptoms did not differ between nfv-PPA and lv-PPA groups at baseline. At follow-up, however, empathy loss was significantly more pronounced in nfv-PPA. The prevalence and course of behavioral symptoms in lv-PPA was similar to that found in AD. Conclusions: sv-PPA show more prominent FTD-like behavioral disturbances compared with other PPA variants which typically emerge already early in the disease course. Empathy loss may be an important factor that helps differentiating nfv-PPA from lv-PPA. Our results may allow improved prediction of likely progression in behavioral symptoms across the PPA variants. Show more

Keywords: Behavioral symptoms, empathy, frontotemporal dementia, longitudinal studies, primary progressive aphasia

DOI: 10.3233/JAD-160010

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1033-1042, 2016

Authors: Callisaya, Michele L. | Ayers, Emmeline | Barzilai, Nir | Ferrucci, Luigi | Guralnik, Jack M. | Lipton, Richard B. | Otahal, Petr | Srikanth, Velandai K. | Verghese, Joe

Article Type: Research Article

Abstract: Background: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints. Objectives: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people. Methods: Individual participant data (n  = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed …to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts. Results: The mean age of participants was 74.9 (SD 6.8) years and 44% (n  = 2728) were male. Overall 33.9% (n  = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51). Conclusion: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic. Show more

Keywords: Cognition, dementia, falls, gait

DOI: 10.3233/JAD-160230

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1043-1052, 2016

Authors: Lin, Chih-Yun | Cheng, Yu-Sung | Liao, Tai-Yan | Lin, Chen | Chen, Zih-ten | Twu, Woan-Ing | Chang, Chi-Wei | Tan, David Tat-Wei | Liu, Ren-Shyan | Tu, Pang-hsien | Chen, Rita P.-Y.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer’s disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10–40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10–40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 …in the mice’s hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice’s hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD. Show more

Keywords: Aggregate, Alzheimer’s disease, amyloid, amyloid-β, D-proline, fibril, peptide inhibitor, scavenger peptide, therapy

DOI: 10.3233/JAD-151024

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1053-1067, 2016

Authors: Marseglia, Anna | Fratiglioni, Laura | Laukka, Erika J. | Santoni, Giola | Pedersen, Nancy L. | Bäckman, Lars | Xu, Weili

Article Type: Research Article

Abstract: Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care–Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information …on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β – 1.10 [95% CI – 1.98, – 0.23]), category fluency (β – 1.27 [95% CI – 2.52, – 0.03]), and digit span forward (β – 0.35 [95% CI – 0.54, – 0.17]). Critically, these associations were present only among APOE ɛ 4 non–carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations. Show more

Keywords: Apolipoprotein E4, cognition, type 2 diabetes mellitus, vascular disorders

DOI: 10.3233/JAD-160266

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1069-1078, 2016

Authors: Vermeiren, Yannick | Janssens, Jana | Aerts, Tony | Martin, Jean-Jacques | Sieben, Anne | Van Dam, Debby | De Deyn, Peter P.

Article Type: Research Article

Abstract: Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer’s disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) …6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α 1/2 /β1 -blockers, seem to have a rationale and should be considered. Show more

Keywords: Alzheimer’s disease, brain tissue, frontotemporal dementia, monoamines, neurochemistry, neuropsychiatric symptoms, noradrenaline, prefrontal cortex, RP-HPLC-ECD, serotonin

DOI: 10.3233/JAD-160320

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1079-1096, 2016

Authors: Hsu, David C. | Mormino, Elizabeth C. | Schultz, Aaron P. | Amariglio, Rebecca E. | Donovan, Nancy J. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | Marshall, Gad A. | for the Harvard Aging Brain Study

Article Type: Research Article

Abstract: Background: Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer’s disease (AD) dementia. Objective: To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia. Methods: Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62–90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein …E ɛ 4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction. Results: In the primary analysis, greater PiB retention was associated with lower BMI (β  =  –0.14, p  = 0.02). In the secondary analyses, APOE4 carrier status (β= –0.27, p  = 0.02) and normal BMI (β= –0.25, p  = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= –0.14, p  = 0.04). Conclusions: This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, body mass index, clinically normal elderly, Pittsburgh compound B, positron emission tomography

DOI: 10.3233/JAD-150987

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1097-1105, 2016

Authors: Feeney, Joanne | Savva, George M. | O’Regan, Claire | King-Kallimanis, Bellinda | Cronin, Hilary | Kenny, Rose Anne

Article Type: Research Article

Abstract: Background: Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test. Objective: To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults. Methods: 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half …the group changed rater between assessments and half changed time of day. Results: Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation. Conclusion: An individual’s score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis. Show more

Keywords: Aging, cognition, measurement error, reliability

DOI: 10.3233/JAD-160248

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1107-1114, 2016

Authors: Lee, Chaeyoung

Article Type: Research Article

Abstract: Genetic factors of sporadic vascular dementia have been quite limitedly understood. Many underlying polygenes are suspected to contribute to susceptibility to sporadic vascular dementia as a typical complex disease although they have not been identified from genome-wide association studies. This study suggests a stochastic prediction of individual polygenetic susceptibility to sporadic vascular dementia using best linear unbiased prediction in a mixed model framework. The prediction shows a relative degree of individual genetic susceptibility to the disease that reflects its integrative polygenetic factors across the genome. The estimate should take into account heritability and the prevalence of sporadic vascular dementia to …cope with the disease. This offers a model for application of a genetic blueprint for a complex disease to personalized preventive medicine. Show more

Keywords: Complex trait, genetics, genome-wide association study, mixed model, vascular dementia

DOI: 10.3233/JAD-160391

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1115-1119, 2016

Authors: Vanderstichele, Hugo Marcel Johan | Janelidze, Shorena | Demeyer, Leentje | Coart, Els | Stoops, Erik | Herbst, Victor | Mauroo, Kimberley | Brix, Britta | Hansson, Oskar

Article Type: Research Article

Abstract: Background: Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42 ) reflects the presence of amyloidopathy in brains of subjects with Alzheimer’s disease (AD). Objective: To qualify the use of Aβ1-42 /Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis. Methods: Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF …analysis. Data were analyzed with linear repeated measures and mixed effects models. Results: Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42 /Aβ1-40 ratio, in contrast to Aβ1-42 , eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. ‘Low binding’ tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay. Conclusion: The ratio of Aβ1-42 /Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, ‘low binding’ recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42 /Aβ1-40 ratio and ‘low-binding tubes’ into guidance criteria may speed up worldwide standardization of CSF biomarker analysis. Show more

Keywords: Amyloid, cerebrospinal fluid, ELISA, improvement, standard operating procedure

DOI: 10.3233/JAD-160286

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1121-1132, 2016

Authors: Perales, Jaime | Turró-Garriga, Oriol | Gascón-Bayarri, Jordi | Reñé-Ramírez, Ramón | Conde-Sala, Josep Lluís

Article Type: Research Article

Abstract: Background: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver’s burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients’ health. Objective: To assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression. Methods: A convenience cohort of 221 consecutive dementia outpatient and caregiver …dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver’s socio-demographic and possible confounding factors. Results: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had < 5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient. Conclusion: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patient. Show more

Keywords: Anosognosia, bias, burden of illness, caregivers, dementia, depression, longitudinal studies

DOI: 10.3233/JAD-160065

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1133-1143, 2016

Authors: Zimmerer, Vitor C. | Wibrow, Mark | Varley, Rosemary A.

Article Type: Research Article

Abstract: Background: Language change can be a valuable biological marker of overall cognitive change in Alzheimer’s disease (AD) and other forms of dementia. Previous reports have described increased use of language formulas in AD, i.e., combinations likely processed in a holistic manner. Words that commonly occur together are more likely to become a formula. Objective: To determine if frequency of co-occurrence as one indicator for formulaic language can distinguish people with probable AD from controls and if variables are sensitive to time post-symptom onset. Methods: We developed the Frequency in Language Analysis Tool (FLAT), which indicates …degrees of formulaicity in an individual language sample. The FLAT accomplishes this by comparing individual language samples to co-occurrence data from the British National Corpus (BNC). Our analysis also contained more conventional language variables in order to assess novel contributions of the FLAT. We analyzed data from the Pitt Corpus, which is part of DementiaBank. Results: Both conventional and co-occurrence variables were able to distinguish AD and control groups. According to co-occurrence data, people with probable AD produced more formulaic language than controls. Only co-occurrence variables correlated with disease progression. Discussion: Frequency of word co-occurrences is one indicator for formulaicity and a valuable contribution to characterizing language change in AD. Show more

Keywords: Alzheimer’s disease, disease progression, language, verbal behavior

DOI: 10.3233/JAD-160099

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1145-1160, 2016

Authors: Hawkins, Kara M. | Sergio, Lauren E.

Article Type: Research Article

Abstract: Background: Many neuroimaging parameters have demonstrated utility as biomarkers in preclinical AD, including resting-state functional connectivity in the default mode network. However, neuroimaging is not a practical, cost effective screening instrument. Objective: Here we investigate the relationship between performance on a cognitive-motor integration assessment and alterations in resting-state functional connectivity in an at-risk population. Methods: Three groups of ten adults (young: mean age = 26.6 ± 2.7, low AD risk: mean age = 58.7 ± 5.6, and high AD risk: mean age = 58.5 ± 6.9) performed a simple cognitive-motor integration task using a dual-touchscreen laptop and also underwent functional magnetic …resonance imaging at rest. Results: We found poorer cognitive-motor integration performance in high AD risk participants, as well as an association with lower resting-state functional connectivity in this group. Conclusion: These findings provide novel insight into underlying AD-related brain alterations associated with a behavioral assessment that can be easily administered clinically. Show more

Keywords: Aging, ApoE4, dementia, functional magnetic resonance imaging, geriatric assessment, population at risk, psychomotor performance

DOI: 10.3233/JAD-151137

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1161-1172, 2016

Authors: Gao, Hui-ling | Li, Cheng | Nabeka, Hiroaki | Shimokawa, Tetsuya | Wang, Zhan-You | Cao, Ya-ming | Matsuda, Seiji

Article Type: Research Article

Abstract: The pathological hallmarks of Alzheimer’s disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1–42 peptide. Seven days after Aβ1–42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1–42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked …by Aβ1–42 . Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1–42 -induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1–42 -induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD. Show more

Keywords: Aβ1–42 peptide, Akt/GSK-3α/β, Alzheimer’s disease, apoptosis, neurogenesis, prosaposin

DOI: 10.3233/JAD-160093

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1173-1192, 2016

Authors: Biella, Gloria | Fusco, Federica | Nardo, Emanuele | Bernocchi, Ottavia | Colombo, Alessio | Lichtenthaler, Stefan F. | Forloni, Gianluigi | Albani, Diego

Article Type: Research Article

Abstract: The neuropathological hallmarks of Alzheimer’s disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of …SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy. Show more

Keywords: AK-7, Alzheimer’s disease, amyloid-β protein precursor processing, Sirtuin 2, tau

DOI: 10.3233/JAD-151135

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1193-1207, 2016

Authors: Salem, Haitham | Rocha, Natalia Pessoa | Colpo, Gabriela Delevati | Teixeira, Antonio Lucio

Article Type: Research Article

Abstract: To date, there is no definitive treatment for Alzheimer’s disease (AD). The realm of stem cells is very promising in regenerative medicine, particularly neurodegenerative disorders. Various types of stem cells have been used in multiple trials on AD models, trying to find an innovative management of this disease. In this systematic review, we trace the published preclinical and clinical data throughout the last decade, to show how much knowledge we gained so far in this field and the future perspectives of stem cells in AD treatment.

Keywords: Alzheimer’s disease, clinical trails, neurodegenerative diseases, preclinical trials, stem cells

DOI: 10.3233/JAD-160250

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1209-1230, 2016

Article Type: Other

DOI: 10.3233/JAD-160547

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1231-1235, 2016