Journal of Alzheimer's Disease - Volume 56, issue 3

Authors: Lin, Tian-Syuan | Tsai, Han-Jung | Lee, Chih-Han | Song, Yan-Qing | Huang, Rih-Sheng | Hsieh-Li, Hsiu-Mei | Liang, Mei-Chih | Lin, Yenshou

Article Type: Research Article

Abstract: The presence of amyloid-β (Aβ) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer’s disease (AD). At least some Aβ neurotoxicity is caused by the presence of excess glutamate that has been induced by Aβ accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate Aβ-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated …by Aβ; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this Aβ-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensi s and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound’s molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting Aβ-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate Aβ-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, baicalein, DiBAC4(3), glutamate receptors, memantine

DOI: 10.3233/JAD-160898

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 959-976, 2017

Authors: Gomez-Ramos, Alberto | Picher, Angel J. | García, Esther | Garrido, Patricia | Hernandez, Felix | Soriano, Eduardo | Avila, Jesús

Article Type: Research Article

Abstract: Next-generation sequencing techniques and genome-wide association study analyses have provided a huge amount of data, thereby enabling the identification of DNA variations and mutations related to disease pathogenesis. New techniques and software tools have been developed to improve the accuracy and reliability of this identification. Most of these tools have been designed to discover and validate single nucleotide variants (SNVs). However, in addition to germ-line mutations, human tissues bear genomic mosaicism, which implies that somatic events are present only in low percentages of cells within a given tissue, thereby hindering the validation of these variations using standard genetic tools. Here …we propose a new method to validate some of these somatic mutations. We combine a recently developed software with a method that cuts DNA by using restriction enzymes at the sites of the variation. The non-cleaved molecules, which bear the SNV, can then be amplified and sequenced using Sanger’s technique. This procedure, which allows the detection of alternative alleles present in as few as 10% of cells, could be of value for the identification and validation of low frequency somatic events in a variety of tissues and diseases. Show more

Keywords: Alzheimer’s disease, identification of nucleotide variations, Sanger sequencing, somatic mutations, Virmid software

DOI: 10.3233/JAD-161053

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 977-990, 2017

Authors: Salza, Romain | Lethias, Claire | Ricard-Blum, Sylvie

Article Type: Research Article

Abstract: The goals of this work were i) to identify the interactions of amyloid-β (Aβ)42 under monomeric, oligomeric, and fibrillar forms with the extracellular matrix (ECM) and receptors, ii) to determine the influence of Aβ42 supramolecular organization on these interactions, and iii) to identify the molecular functions, biological processes, and pathways targeted by Aβ42 in the ECM. The ECM and cell surface partners of Aβ42 and its supramolecular forms were identified with protein and glycosaminoglycan (GAG) arrays (81 molecules in triplicate) probed by surface plasmon resonance imaging. The number of partners of Aβ42 increased upon its …multimerization, ranging from 4 for the peptide up to 53 for the fibrillar aggregates. The peptide interacted only with ECM proteins but their percentage among Aβ42 partners decreased upon multimerization. Aβ42 and its supramolecular forms recognized different molecular features on their partners, and the partners of Aβ42 fibrillar forms were enriched in laminin IV-A, N-terminal, and EGF-like domains. Aβ42 oligomerization triggered interactions with receptors, whereas Aβ42 fibrillogenesis promoted binding to GAGs, proteoglycans, enzymes, and growth factors and the ability to interact with perineuronal nets. Fibril aggregation bind to further membrane proteins including tumor endothelial marker-8, syndecan-4, and discoidin-domain receptor-2. The partners of the Aβ42 supramolecular forms are enriched in proteins contributing to cell growth and/or maintenance, involved in integrin cell surface interactions and expressed in kidney cancer, preadipocytes, and dentin. In conclusion, the supramolecular assembly of Aβ42 governs its ability to interact in vitro with ECM proteins, remodeling and crosslinking ECM enzymes, proteoglycans, and receptors. Show more

Keywords: Aβ42, Aβ42 supramolecular assemblies, Alzheimer’s disease, biomolecular interactions, extracellular matrix

DOI: 10.3233/JAD-160751

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 991-1005, 2017

Authors: Kim, You Joung | An, Hoyoung | Kim, Binna | Park, Young Shin | Kim, Ki Woong

Article Type: Research Article

Abstract: Over 40% of people with dementia drive, with a two to five times greater accident risk than controls. This has fueled public concerns about the risk of traffic accidents by drivers with dementia (DWD). We compared driving regulations on seniors and DWD between ten European and Asia-Pacific countries to identify key implications for national strategies. Moderate to severe dementia was a reason for driver’s license revocation in all countries. However, regulations on mild dementia varied considerably, with most basing their decisions on severity, rather than simply the presence of dementia. Most used validated assessments, but responsibility for triggering the administrative …process fell on drivers in some countries and on physicians in others. Administrations should consider the following when developing driving policies: 1) ideal regulations on DWD should ensure that restrictions are implemented only when needed; 2) fitness to drive should be assessed using validated instruments; 3) the use of processes that automatically initiate driving competency examinations following a diagnosis of dementia should be explored; and 4) restrictions should be delicately tailored to a range of driving competence levels, and assistive incentives compensating for lost driving privileges should be provided. Show more

Keywords: Automobile driving, competence, dementia, elderly, policy, traffic accidents

DOI: 10.3233/JAD-160762

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1007-1014, 2017

Authors: Lee, Han-Kyu | Kwon, Bumsup | Lemere, Cynthia A. | de la Monte, Suzanne | Itamura, Kyohei | Ha, Austin Y. | Querfurth, Henry W.

Article Type: Research Article

Abstract: Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer’s disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were …also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42 , mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD. Show more

Keywords: Akt, Alzheimer’s disease, AMPK, autophagy, insulin resistance, mTOR, mTORC2, Rictor

DOI: 10.3233/JAD-161029

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1015-1036, 2017

Authors: Haddick, Patrick C.G. | Larson, Jessica L. | Rathore, Nisha | Bhangale, Tushar R. | Phung, Qui T. | Srinivasan, Karpagam | Hansen, David V. | Lill, Jennie R. | Alzheimer’s Disease Genetic Consortium (ADGC), Alzheimer’s Disease Neuroimaging Initiative (ADNI) | Pericak-Vance, Margaret A. | Haines, Jonathan | Farrer, Lindsay A. | Kauwe, John S. | Schellenberg, Gerard D. | Cruchaga, Carlos | Goate, Alison M. | Behrens, Timothy W. | Watts, Ryan J. | Graham, Robert R. | Kaminker, Joshua S. | van der Brug, Marcel

Article Type: Research Article

Abstract: The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer’s disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated …with the age of onset of Alzheimer’s disease in APOE ɛ 4 carriers. Across five datasets, p.D358A had a meta P  = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 –1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer’s disease in APOE ɛ 4 carriers. Show more

Keywords: Alzheimer’s disease, astrocytes, IL-6, metalloproteases, microglia

DOI: 10.3233/JAD-160524

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1037-1054, 2017

Authors: Squitti, Rosanna | Mendez, Armando J. | Simonelli, Ilaria | Ricordi, Camillo

Article Type: Research Article

Abstract: Background: Defective copper regulation, primarily referred to as chelatable redox active Cu(II), has been involved in the etiology of diabetes, and Alzheimer’s disease (AD). Objectives: However, no study has determined levels of labile copper non-bound to ceruloplasmin (non-Cp Cu, also known as ‘free’ copper) in the blood of subjects with diabetes compared with that of AD patients. Methods: To this aim, values of non-Cp Cu were measured in 25 Type 1 (T1D) and 31 Type 2 (T2D) subjects and in28 healthy controls, along with measurements of C-reactive protein, glycated hemoglobin A1c , cholesterol, and triglycerides. …Non-Cp Cu levels were compared with those of an AD group previously studied. Results: T2D subjects had significantly higher non-Cp Cu levels than Controls and T1D subjects (both p  < 0.001 after adjusting for age, sex, and body mass index). A multinomial logistic model revealed that a one unit standard deviation increase of non-Cp Cu increased the relative risk of having T2D by 9.64 with respect to Controls (95% CI: 2.86–32.47). The comparison of non-Cp Cu levels in T2D with those of an AD population previously studied shows rising blood non-Cp Cu copper levels from Controls to T2D and AD. Conclusion: These results suggest the involvement of catalytically-active Cu(II) and glucose dysregulation in oxidative stress reactions leading to tissue damage in both diseases. Show more

Keywords: Alzheimer’s disease, copper, diabetes, free copper, Type 1, Type 2

DOI: 10.3233/JAD-161033

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1055-1064, 2017

Authors: Tell-Marti, Gemma | Puig-Butille, Joan Anton | Potrony, Miriam | Plana, Estel | Badenas, Celia | Antonell, Anna | Sanchez-Valle, Raquel | Molinuevo, José L | Lleó, Alberto | Alcolea, Daniel | Fortea, Juan | Fernández-Santiago, Rubén | Clarimón, Jordi | Lladó, Albert | Puig, Susana

Article Type: Research Article

Abstract: Despite the recent identification of some novel risk genes for Alzheimer’s disease (AD), the genetic etiology of late-onset Alzheimer’s disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in …72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08–3.64, p  = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40–8.27, p  = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways. Show more

Keywords: Cerebrospinal fluid biomarkers, common variant, late-onset Alzheimer’s disease, melanocortin 1 receptor (MC1R) gene, p.V92M, risk

DOI: 10.3233/JAD-161113

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1065-1074, 2017

Authors: Fitz, Nicholas F. | Carter, Alexis Y. | Tapias, Victor | Castranio, Emilie L. | Kodali, Ravindra | Lefterov, Iliya | Koldamova, Radosveta

Article Type: Research Article

Abstract: ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoproteins and regulates the generation of high density lipoproteins. Previously, we have shown that lack of Abca1 significantly increases amyloid deposition and cognitive deficits in Alzheimer’s disease model mice expressing human amyloid-β protein precursor (APP). The goal of this study was to determine if ABCA1 plays a role in memory deficits caused by amyloid-β (Aβ) oligomers and examine neurite architecture of pyramidal hippocampal neurons. Our results confirm previous findings that Abca1 deficiency significantly impairs spatial memory acquisition and retention in the Morris water maze and long-term memory in …novel object recognition of APP transgenic mice at a stage of early amyloid pathology. Neither test demonstrated a significant difference between Abca1 ko and wild-type (WT) mice. We also examined the effect of intra-hippocampal infused Aβ oligomers on cognitive performance of Abca1 ko mice, compared to control infusion of scrambled Aβ peptide. Age-matched WT mice undergoing the same infusions were also used as controls. In this model system, we found a statistically significant difference between WT and Abca1 ko mice infused with scrambled Aβ, suggesting that Abca1 ko mice are vulnerable to the effect of mild stresses. Moreover, examination of neurite architecture in the hippocampi revealed a significant decrease in neurite length, number of neurite segments, and branches in Abca1 ko mice when compared to WT mice. We conclude that mice lacking ABCA1 have basal cognitive deficits that prevent them from coping with additional stressors, which is in part due to impairment of neurite morphology in the hippocampus. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, APP mice, ATP-binding cassette transporter A1 (Abca1), behavior, hippocampal infusion, neurite morphology, radial arm water maze

DOI: 10.3233/JAD-161056

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1075-1085, 2017

Authors: Mohamed, Loqman A. | Zhu, Haihao | Mousa, Youssef M. | Wang, Erming | Qiu, Wei Qiao | Kaddoumi, Amal

Article Type: Research Article

Abstract: Findings from Alzheimer’s disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by …siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aβ transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aβ efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aβ across the BBB. Collectively, our findings indicated that amylin induced Aβ brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β, blood-brain barrier, LRP1

DOI: 10.3233/JAD-160800

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1087-1099, 2017

Authors: Ferrari, Laura | Huang, Su-Chun | Magnani, Giuseppe | Ambrosi, Alessandro | Comi, Giancarlo | Leocani, Letizia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are leading causes of cognitive decline. Optical coherence tomography (OCT) allows the measurement of thickness of retinal neuroaxonal layers. While in AD and mild cognitive impairment (MCI), retinal nerve fiber layer (RNFL) thinning is frequently reported, less information is available on ganglion cell layer-inner plexiform layer (GCL-IPL). Data on FTD are lacking. Objective: To obtain cross-sectional information on RNFL and GCL-IPL thickness among MCI, AD, FTD, and healthy controls (HC), and their correlations with dementia severity. Methods: Peripapillary OCT scans were obtained in 27 MCI, 39 AD, …17 FTD, 49 HC using high-definition Heidelberg Spectral-domain OCT, with RNFL and GCL-IPL thickness measurement. Statistical analysis tested group effects and correlation with gender, disease duration and severity (Mini-Mental State Examination, MMSE). Results: RNFL showed a significant group effect [F(4,132) = 3.786, p  = 0.006], being reduced versus controls in MCI (p  = 0.033), moderate AD (p  = 0.025), and FTD (p  < 0.001), and versus mild AD in FTD (p  = 0.042). GCL-IPL showed a significant group effect as well [F(4,121) = 5.104, p  < 0.001], with reduction in moderate AD versus HC (p  < 0.001), MCI (p  = 0.037), and mild AD (p  = 0.009); in FTD versus HC (p  = 0.002) and mild AD (p  = 0.038). In AD, GCL-IPL correlated with MMSE (r  = 0.487, p  = 0.003), without significant effects of age, gender, or disease duration. Conclusion: Retinal neuroaxonal thinning occurs in MCI/AD consistently with previous reports, as well as in FTD. Correlation with disease severity in AD suggests that retinal and brain neurodegeneration may occur in parallel to some extent, and prompts larger studies aimed at providing surrogate endpoints for clinical trials in AD. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, ganglion cell layer, optical coherence tomography, retinal nerve fiber layer

DOI: 10.3233/JAD-160886

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1101-1107, 2017

Authors: Kaizik, Cassandra | Caga, Jashelle | Camino, Julieta | O’Connor, Claire M. | McKinnon, Colleen | Oyebode, Jan R. | Piguet, Olivier | Hodges, John R. | Mioshi, Eneida

Article Type: Research Article

Abstract: The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied …to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences. Show more

Keywords: Caregiver, carer burden, children, dementia severity, depression, frontotemporal dementia

DOI: 10.3233/JAD-160852

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1109-1117, 2017

Authors: Loewenstein, David A. | Curiel, Rosie E. | Wright, Clinton | Sun, Xiaoyan | Alperin, Noam | Crocco, Elzabeth | Czaja, Sara J. | Raffo, Arlene | Penate, Ailyn | Melo, Jose | Capp, Kimberly | Gamez, Monica | Duara, Ranjan

Article Type: Research Article

Abstract: Background: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer’s disease (AD). Objective: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults. Methods: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on …the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups. Results: Relative to traditional neuropsychological measures, MCI patients’ failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = –0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = –0.49), the failure to recover from PSI (rs = –0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = –0.48). Discussion: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation. Show more

Keywords: Alzheimer’s disease, LASSI-L, memory, mild cognitive impairment, MRI, proactive interference, semantic interference

DOI: 10.3233/JAD-160881

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1119-1126, 2017

Authors: Peters, Kirsten E. | Davis, Wendy A. | Taddei, Kevin | Martins, Ralph N. | Masters, Colin L. | Davis, Timothy M.E. | Bruce, David G.

Article Type: Research Article

Abstract: Background: Plasma amyloid-β (Aβ) levels have rarely been investigated in type 2 diabetes despite its known associations with Alzheimer’s disease. Objective: To compare blood plasma Aβ concentrations (Aβ40 and Aβ42 ) in cognitively normal individuals with and without type 2 diabetes. Methods: Plasma Aβ40 and Aβ42 were measured in 194 participants with diabetes recruited from the community-based Fremantle Diabetes Study Phase II cohort (mean age 71 years, 59% males) and 194 age-, sex-, and APOE ɛ 4 allele-matched, control subjects without diabetes from the Australian Imaging, Biomarkers and Lifestyle Study using …a multiplex microsphere-based immunoassay. Results: Plasma Aβ40 and Aβ42 were normally distributed in the controls but were bimodal in the participants with diabetes. Median Aβ40 and Aβ42 concentrations were significantly lower in those with type 2 diabetes (Aβ40 median [inter-quartile range]: 125.0 [52.6–148.3] versus 149.3 [134.0–165.6] pg/mL; Aβ42 : 26.9 [14.5–38.3] versus 33.6 [28.0–38.9] pg/mL, both p  < 0.001) while the ratio Aβ42 :Aβ40 was significantly higher (0.26 [0.23–0.32] versus 0.22 [0.19–0.25], p  < 0.001). After adjustment, participants with diabetes and plasma Aβ40 levels in the low peak of the bimodal distribution were significantly more likely to have normal to high estimated glomerular filtration rates (odds ratio (95% CI): 2.40 (1.20–4.80), p  = 0.013) although the group with diabetes had lower renal function overall. Conclusion: Type 2 diabetes is associated with altered plasma concentrations of Aβ peptides and is an important source of variation that needs to be taken into account when considering plasma Aβ peptides as biomarkers for Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, peptides, blood biomarkers, type 2 diabetes mellitus

DOI: 10.3233/JAD-161050

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1127-1133, 2017

Authors: Kunz, Lukas | Reuter, Martin | Axmacher, Nikolai | Montag, Christian

Article Type: Research Article

Abstract: The etiology of late onset Alzheimer’s disease (LOAD) depends on multiple factors, among which the APOE ɛ4 allele is the most adverse genetic determinant and conscientiousness represents an influential personality trait. A potential association of both factors with brain structure in young adulthood may constitute a constellation that sets the course toward or against the subtle disease progression of LOAD that starts decades before clinical manifestation. Hence, in the present study, we examined the modulating effects of APOE ɛ4 on the relation between personality dimensions, including conscientiousness, and total grey matter volume (GMV) in young healthy adults using …an a priori genotyping design. 105 participants completed an inventory assessing the Five Factor Model of Personality (NEO-FFI) and a structural MRI scan. Total GMV was estimated using both Freesurfer as well as VBM8. Across all participants, total GMV was positively associated with extraversion and negatively related to age. In APOE ɛ4-carriers— but not in APOE ɛ4-non-carriers— conscientiousness was negatively associated with total GMV. In line with the hypothesis of antagonistic pleiotropy of the APOE ɛ4 allele, this result suggests that young APOE ɛ4-carriers with increased total GMV may particularly benefit from cognitive advantages and thus have a lower need to engage in conscientious behavior. In this subset of young APOE ɛ4-carriers, the reduction in conscientiousness could then bring along adverse health behavior in the long run, potentiating the risk for LOAD. Hence, young APOE ɛ4-carriers with increased total GMV may be at a particularly high risk for LOAD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, big five, Freesurfer, NEO-FFI, personality, voxel-based morphometry

DOI: 10.3233/JAD-160854

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1135-1144, 2017

Authors: Zyśk, Marlena | Bielarczyk, Hanna | Gul-Hinc, Sylwia | Dyś, Aleksandra | Gapys, Beata | Ronowska, Anna | Sakowicz-Burkiewicz, Monika | Szutowicz, Andrzej

Article Type: Research Article

Abstract: Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis. Therefore, several neurotoxic signals, which inhibit pyruvate dehydrogenase, generate deeper shortages of acetyl-CoA and greater mortality of cholinergic neurons than noncholinergic ones. NAA is considered to be a marker of neuronal energy status in neuropathic brains. However, there is no data on putative differential fractional …distribution of the acetyl-CoA pool between energy producing and NAA or acetylcholine synthesizing pathways in noncholinergic and cholinergic neurons, respectively. Therefore, the aim of this study was to investigate whether zinc-excess, a common excitotoxic signal, may evoke differential effects on the NAA metabolism in neuronal cells with low and high expression of the cholinergic phenotype. Differentiated SN56 neuronal cells, displaying a high activity of choline acetyltransferase and rates of acetylcholine synthesis, contained lower levels of acetyl-CoA and NAA, being more susceptible to ZnCl2 exposition that the nondifferentiated SN56 or differentiated dopaminergic SHSY5Y neuronal and astroglial C6 cells. Differentiated SN56 accumulated greater amounts of Zn2 + from extracellular space than the other ones, and displayed a stronger suppression of pyruvate dehydrogenase complex activity and acetyl-CoA, NAA, ATP, acetylcholine levels, and loss of viability. These data indicate that the acetyl-CoA synthesizing system in neurons constitutes functional unity with energy generating and NAA or acetylcholine pathways of its utilization, which are uniformly affected by neurotoxic conditions. Show more

Keywords: N-acetyl-L-aspartate, acetyl-CoA, aspartate N-acetyltransferase, ATP, cholinergic neurons neurotoxicity, zinc

DOI: 10.3233/JAD-160693

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1145-1158, 2017

Authors: Khan, Wasim | Giampietro, Vincent | Banaschewski, Tobias | Barker, Gareth J. | Bokde, Arun L.W. | Büchel, Christian | Conrod, Patricia | Flor, Herta | Frouin, Vincent | Garavan, Hugh | Gowland, Penny | Heinz, Anreas | Ittermann, Bernd | Lemaître, Hervé | Nees, Frauke | Paus, Tomas | Pausova, Zdenka | Rietschel, Marcella | Smolka, Michael N. | Ströhle, Andreas | Gallinat, Jeurgen | Vellas, Bruno | Soininen, Hilkka | Kloszewska, Iwona | Tsolaki, Magda | Mecocci, Patrizia | Spenger, Christian | Villemagne, Victor L. | Masters, Colin L. | Muehlboeck, J-Sebastian | Bäckman, Lars | Fratiglioni, Laura | Kalpouzos, Grégoria | Wahlund, Lars-Olof | Schumann, Gunther | Lovestone, Simon | Williams, Steven C.R. | Westman, Eric | Simmons, Andrew | Alzheimer–s Disease Neuroimaging Initiative | AddNeuroMed Consortium, Australian, Imaging, Biomarkers, and Lifestyle Study Research Group | the IMAGEN consortium

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer’s disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n  = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n  = 1,387) was also used to compare hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging …dataset, hippocampal comparisons were performed in each APOE group and in ɛ 4 carriers with positron emission tomography (PET) Aβ who were dichotomized (Aβ+/Aβ–) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ 4 carriers possessing the smallest volumes, ɛ 3 carriers possessing intermediate volumes, and ɛ 2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ 4 carriers possessed the smallest hippocampal volumes and control ɛ 2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ 4 and Aβ positivity had the lowest hippocampal volumes when compared to Aβ- ɛ 4 carriers, suggesting a synergistic relationship between APOE ɛ 4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ 4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, hippocampus, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-161097

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1159-1174, 2017

Authors: Horváth, András | Szűcs, Anna | Barcs, Gábor | Kamondi, Anita

Article Type: Research Article

Abstract: Background: The reported prevalence of epilepsy in Alzheimer’s disease (AD) is variable, probably due to the different methodological approaches. Objective: We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients. Methods: We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated. Results: Significant high correlation was identified between the sensitivity of EEG and the …length of recordings (r  = 0.972, p  = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p  = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p  < 0.001). Conclusion: 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease. Show more

Keywords: Alzheimer’s disease, EEG sensitivity, epilepsy, epileptiform discharges, long-term EEG

DOI: 10.3233/JAD-160994

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1175-1183, 2017

Authors: Polcher, Alexandra | Frommann, Ingo | Koppara, Alexander | Wolfsgruber, Steffen | Jessen, Frank | Wagner, Michael

Article Type: Research Article

Abstract: Background: There is a need for more sensitive neuropsychological tests to detect subtle cognitive deficits emerging in the preclinical stage of Alzheimer’s disease (AD). Associative memory is a cognitive function supported by the hippocampus and affected early in the process of AD. Objective: We developed a short computerized face-name associative recognition test (FNART) and tested whether it would detect memory impairment in memory clinic patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Methods: We recruited 61 elderly patients with either SCD (n  = 32) or MCI (n  = 29) and 28 healthy controls (HC) …and compared performance on FNART, self-reported cognitive deterioration in different domains (ECog-39), and, in a reduced sample (n  = 46), performance on the visual Paired Associates Learning of the CANTAB battery. Results: A significant effect of group on FNART test performance in the total sample was found (p  < 0.001). Planned contrasts indicated a significantly lower associative memory performance in the SCD (p  = 0.001, d  = 0.82) and MCI group (p  < 0.001, d  = 1.54), as compared to HCs, respectively. The CANTAB-PAL discriminated only between HC and MCI, possibly because of reduced statistical power. Adjusted for depression, performance on FNART was significantly related to ECog-39 Memory in SCD patients (p  = 0.024) but not in MCI patients. Conclusions: Associative memory is substantially impaired in memory clinic patients with SCD and correlates specifically with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes. Show more

Keywords: Alzheimer’s disease, associative memory, cognition, early detection, hippocampus, mild cognitive impairment, neuropsychological tests, recognition, subjective cognitive decline

DOI: 10.3233/JAD-160637

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1185-1196, 2017

Authors: Ebel, Dalton L. | Torkilsen, Christopher G. | Ostrowski, Tim D.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is known for the progressive decline of cognition and memory. In addition to these disease-defining symptoms, impairment of respiratory function is frequently observed and often expressed by sleep-disordered breathing or reduced ability to adjust respiration when oxygen demand is elevated. The mechanisms for this are widely unknown. Postmortem analysis from the brainstem of AD patients reveals pathological alterations, including in nuclei responsible for respiratory control. In this study, we analyzed respiratory responses and morphological changes in brainstem nuclei following intracerebroventricular (ICV) injections of streptozotocin (STZ), a rat model commonly used to mimic sporadic AD. ICV-STZ induced significant …astrogliosis in the commissural part of the nucleus tractus solitarii, an area highly involved in respiration control. The astrogliosis was identified by a significant increase in S100B-immunofluorescence that is similar to the astrogliosis found in the CA1 region of the hippocampus. Using plethysmography, the control group displayed a typical age-dependent decrease of ventilation that was absent in the STZ rat group. This is indicative of elevated minute ventilation at rest after STZ treatment. Peripheral chemoreflex responses were significantly blunted in STZ rats as seen by a reduced respiratory rate and minute ventilation to hypoxia. Central chemoreflex responses to hypercapnia, on the other hand, only decreased in respiratory rate following STZ treatment. Overall, our results show that ICV-STZ induces respiratory dysfunction at rest and in response to hypoxia. This provides a new tool to study the underlying mechanisms of breathing disorders in clinical AD. Show more

Keywords: Astrocytosis, brainstem, chemoreflex, hypercapnia, hypoxia, nucleus tractus solitarii, ventilation

DOI: 10.3233/JAD-160974

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1197-1211, 2017

Article Type: Other

DOI: 10.3233/JAD-179002

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1213-1213, 2017