Journal of Alzheimer's Disease - Volume 44, issue 4

Authors: Elcombe, Emma L. | Lagopoulos, Jim | Duffy, Shantel L. | Lewis, Simon J.G. | Norrie, Louisa | Hickie, Ian B. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background and Objectives: Decreased hippocampal volume in older adults is associated with neurodegenerative and psychiatric diseases. Several modifiable risk factors have been associated with the size of this structure, however the relative contribution of these factors to hippocampal atrophy is unclear. This study aimed to examine the relationship between modifiable risk factors and hippocampal volume in older adults at risk of cognitive decline. Methods: Two hundred and eighteen participants (mean age = 67.3 years, MMSE = 28.6) with mood and/or memory complaints underwent clinical and neuropsychological assessment, and magnetic resonance imaging. Measures of depression, global cognitive functioning, exercise, …vascular health, cognitive reserve, sleep, and memory were collected. Hippocampal volumes were derived using image segmentation as implemented by FMRIB Software Library. Results: Smaller hippocampal volumes were strongly associated with poorer verbal learning and memory as well as diagnoses of either multiple or amnestic mild cognitive impairment. Based on univariate correlations, multivariable regressions were performed (controlling for age and total intracranial volume) to determine which modifiable risk factors were associated with hippocampal volume. For the left hippocampus, poor sleep efficiency and greater than five years untreated depressive illness remained significant predictors. For the right hippocampus, diabetes and low diastolic blood pressure significant predictors. Conclusions: Although their contribution is small, lower sleep efficiency, low blood pressure, diabetes, and untreated depression are associated with reduced hippocampal volumes. Studies exploring the impact of early intervention for these risk factors on hippocampal integrity are warranted. Show more

Keywords: Dementia, depression, diabetes, hippocampus, hypertension, magnetic resonance imaging, mild cognitive impairment, sleep

DOI: 10.3233/JAD-142016

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1279-1290, 2015

Authors: Hüttenrauch, Melanie | Baches, Sandra | Gerth, Janina | Bayer, Thomas A. | Weggen, Sascha | Wirths, Oliver

Article Type: Research Article

Abstract: The deposition of amyloid-β (Aβ) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aβ in production and clearance seems to be the reason for an enhanced Aβ accumulation. Besides a systematic clearance through the blood-brain barrier, Aβ is cleared from the brain by Aβ-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aβ-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust …behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP−/− ), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/− mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aβ42 as well as region-specific increases in extracellular Aβ deposition. Surprisingly, in young mice, a more abundant cortical Aβ plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/− mice. Additionally, young 5XFAD/NEP+/− as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aβ peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/− mice and might suggest a reciprocal effect between ECE and NEP activities in Aβ degradation. Show more

Keywords: AβPP, Alzheimer's disease, amyloid, endothelin-converting enzyme, intraneuronal Aβ, neprilysin, transgenic mice, working memory

DOI: 10.3233/JAD-142463

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1291-1302, 2015

Authors: Oláh, Zita | Kálmán, János | Tóth, Melinda E. | Zvara, Ágnes | Sántha, Miklós | Ivitz, Eszter | Janka, Zoltán | Pákáski, Magdolna

Article Type: Research Article

Abstract: Clinical diagnosis of Alzheimer's disease (AD) relying on symptomatic features has a low specificity, emphasizing the importance of the pragmatic use of neurochemical biomarkers. The most advanced and reliable markers are amyloid-β (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) with relatively high levels of sensitivity, specificity, and diagnostic accuracy. Recent advances within the field of proteomics offer the potential to search for novel biomarkers in CSF by using modern methods, such as microarrays. The purpose of this study was to identify pathognostic proteins in CSF obtained from patients whose clinical AD diagnosis was confirmed …by the “core” biomarkers. CSF samples were obtained from 25 AD patients and 25 control individuals. The levels of Aβ42 , t-tau, and p-tau were measured by ELISA. In the microarray experiments, ultrasensitive slides representing of 653 antigens were used. Apolipoprotein E genotyping was also determined. A decrease of seven CSF proteins in AD were found, four of them (POLG, MGMT, parkin, and ApoD) have a protective function against neuronal death, while the remaining three proteins (PAR-4, granzyme B, Cdk5) trigger multiple pathways facilitating neuronal cell death. Since these proteins from CSF samples could not be identified by western blot, their decreased levels in AD patients were not verified. Our results provide new information of pathognostic importance of POLG and granzyme B in AD. Although the function of MGMT, parkin, ApoD, PAR-4, and Cdk5 was previously known in AD, the findings presented here provide novel evidence of the significance of CSF analysis in the mapping of the AD pathomechanism. Show more

Keywords: Alzheimer's disease, antibody microarray, ApoD, apoptosis, Cdk5, cerebrospinal fluid, granzyme B, MGMT, PAR-4, parkin, POLG

DOI: 10.3233/JAD-140141

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1303-1312, 2015

Authors: Kettunen, Petronella | Larsson, Susanna | Holmgren, Sandra | Olsson, Sandra | Minthon, Lennart | Zetterberg, Henrik | Blennow, Kaj | Nilsson, Staffan | Sjölander, Annica

Article Type: Research Article

Abstract: Background: Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood. Objective: To evaluate possible associations between gene variants of GSK3B and risk of AD. Methods: Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and …cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau181 ), and amyloid-β (Aβ42 ). Results: After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (pc = 0.04). Next, rs1154597 showed association with reduced Aβ42 levels (pc = 0.007). Lastly, rs3107669 was associated with lower MMSE scores (pc = 0.03). In addition, one more SNP was nominally significantly associated with reduced Aβ42 levels and another was associated with reduced MMSE. Conclusion: We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and Aβ42 . To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (Aβ42 ). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, association, biomarker, cerebrospinal fluid, gene, glycogen synthase kinase 3 beta, Mini-Mental State Examination, single nucleotide polymorphism, tau

DOI: 10.3233/JAD-142025

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1313-1322, 2015

Authors: Persichilli, Silvia | Gervasoni, Jacopo | Di Napoli, Alessandra | Fuso, Andrea | Nicolia, Vincenzina | Giardina, Bruno | Scarpa, Sigfrido | Desiderio, Claudia | Cavallaro, Rosaria A.

Article Type: Research Article

Abstract: Widely confirmed reports were published on association between hyperhomocysteinemia, B vitamin deficiency, oxidative stress, and amyloid-β in Alzheimer's disease (AD). Homocysteine, cysteine, cysteinylglycine and glutathione are metabolically interrelated thiols that may be potential indicators of health status and disease risk; they all participate in the metabolic pathway of homocysteine. Previous data obtained in one of our laboratories showed that B vitamin deficiency induced exacerbation of AD-like features in TgCRND8 AD mice; these effects were counteracted by S-adenosylmethionine (SAM) supplementation, through the modulation of DNA methylation and antioxidant pathways. Since the cellular response to oxidative stress typically involves alteration in thiols …content, a rapid and sensitive HPLC method with fluorescence detection was here used to evaluate the effect of SAM and superoxide-dismutase (SOD) supplementation on thiols level in plasma, in TgCRND8 mice. The quantitative data obtained from HPLC analysis of mice plasma samples showed significant decrease of thiols level when the B vitamin deficient diet was supplemented with SAM + SOD and SOD alone, the latter showing the greatest effect. All these considerations point out the measurement of plasma thiols concentration as a powerful tool of relevance for all clinical purposes involving the evaluation of oxidative stress. The coupling of HPLC with fluorimetric detection, here used, provided a strong method sensitivity allowing thiols determination at very low levels. Show more

Keywords: Alzheimer's disease, homocysteine, HPLC, S-adenosylmethionine, superoxide-dismutase, thiols

DOI: 10.3233/JAD-142391

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1323-1331, 2015

Authors: Zygouris, Stelios | Giakoumis, Dimitrios | Votis, Konstantinos | Doumpoulakis, Stefanos | Ntovas, Konstantinos | Segkouli, Sofia | Karagiannidis, Charalampos | Tzovaras, Dimitrios | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Recent research advocates the potential of virtual reality (VR) applications in assessing cognitive functions highlighting the possibility of using a VR application for mild cognitive impairment (MCI) screening. Objective: The aim of this study is to investigate whether a VR cognitive training application, the virtual supermarket (VSM), can be used as a screening tool for MCI. Methods: Two groups, one of healthy older adults (n = 21) and one of MCI patients (n = 34), were recruited from day centers for cognitive disorders and administered the VSM and a neuropsychological test battery. The performance of …the two groups in the VSM was compared and correlated with performance in established neuropsychological tests. At the same time, the effectiveness of a combination of traditional neuropsychological tests and the VSM was examined. Results: VSM displayed a correct classification rate (CCR) of 87.30% when differentiating between MCI patients and healthy older adults, while it was unable to differentiate between MCI subtypes. At the same time, the VSM correlates with various established neuropsychological tests. A limited number of tests were able to improve the CCR of the VSM when combined with the VSM for screening purposes. Discussion: VSM appears to be a valid method of screening for MCI in an older adult population though it cannot be used for MCI subtype assessment. VSM's concurrent validity is supported by the large number of correlations between the VSM and established tests. It is considered a robust test on its own as the inclusion of other tests failed to improve its CCR significantly. Show more

Keywords: Aging, Alzheimer's disease, computers, dementia, diagnosis, memory disorders, mild cognitive impairment, user-computer interface

DOI: 10.3233/JAD-141260

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1333-1347, 2015

Authors: Zarrouk, Amira | Riedinger, Jean-Marc | Ahmed, Samia Hadj | Hammami, Sonia | Chaabane, Wafa | Debbabi, Meryam | Ben Ammou, Sofiene | Rouaud, Olivier | Frih, Mahbouba | Lizard, Gérard | Hammami, Mohamed

Article Type: Research Article

Abstract: Background: Several lipid metabolism alterations have been described in the brain and plasma of Alzheimer's disease (AD) patients, suggesting a relation between lipid metabolism alteration and dementia. Objective: We attempted to identify blood fatty acids as biomarkers of dementia. Methods: Fatty acid profiles were established using gas chromatography with or without mass spectrometry on matched plasma and red blood cells (RBCs) of demented patients diagnosed with AD, vascular dementia, or other dementia, and compared with a control group of elderly individuals. The severity of dementia was evaluated with the Mini-Mental State Examination test. Results: …Fatty acid analysis showed significant variations of fatty acid levels in demented patients including AD patients. The highest plasma and RBC accumulation was found with hexacosanoic acid (C26:0). Our data also support that alterations of desaturase and elongase activities may contribute to cognitive dysfunction. Conclusion: The variations of fatty acid levels and the accumulation of C26:0 in the plasma and RBCs highlight an alteration of fatty acid metabolism in demented patients and point toward possible peroxisomal dysfunction. It is suggested that C26:0 may constitute a convenient blood biomarker of dementia that could be useful in routine medical practice. Show more

Keywords: Dementia, fatty acid profiles, hexacosanoic acid (C26:0), lipid biomarkers, plasma, red blood cells

DOI: 10.3233/JAD-142046

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1349-1359, 2015

Authors: Jefferson, Angela L. | Hohman, Timothy J. | Liu, Dandan | Haj-Hassan, Shereen | Gifford, Katherine A. | Benson, Elleena M. | Skinner, Jeannine S. | Lu, Zengqi | Sparling, Jamie | Sumner, Emily C. | Bell, Susan | Ruberg, Frederick L.

Article Type: Research Article

Abstract: Background: Cardiovascular disease (CVD) and related risk factors are associated with Alzheimer's disease (AD). This association is less well-defined in normal cognition (NC) or prodromal AD (mild cognitive impairment, MCI). Objective: Cross-sectionally and longitudinally relate a vascular risk index to cognitive outcomes among elders free of clinical dementia. Methods: 3,117 MCI (74 ± 8 years, 56% female) and 6,603 NC participants (72 ± 8 years, 68% female) were drawn from the National Alzheimer's Coordinating Center. A composite measure of vascular risk was defined using the Framingham Stroke Risk Profile (FSRP) score (i.e., age, systolic blood pressure, …anti-hypertensive medication, diabetes, cigarette smoking, CVD history, atrial fibrillation). Ordinary linear regressions and generalized linear mixed models related baseline FSRP to cross-sectional and longitudinal cognitive outcomes, separately for NC and MCI, adjusting for age, gender, race, education, and follow-up time (in longitudinal models). Results: In NC participants, increasing FSRP was related to worse baseline global cognition, information processing speed, and sequencing abilities (p-values <0.0001) and a worse longitudinal trajectory on all cognitive measures (p-values <0.0001). In MCI, increasing FSRP correlated with worse longitudinal delayed memory (p = 0.004). In secondary models using an age-excluded FSRP score, associations persisted in NC participants for global cognition, naming, information processing speed, and sequencing abilities. Conclusions: An adverse vascular risk profile is associated with worse cognitive trajectory, especially global cognition, naming, and information processing speed, among NC elders. Future studies are needed to understand how effective management of CVD and related risk factors can modify cognitive decline to identify the ideal timeframe for primary prevention implementation. Show more

Keywords: Blood pressure, diabetes mellitus, Framingham Stroke Risk Profile, smoking, stroke

DOI: 10.3233/JAD-141812

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1361-1373, 2015

Article Type: Other

DOI: 10.3233/JAD-141813

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1375-1377, 2015

Article Type: Other

DOI: 10.3233/JAD-2015-44430

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1379-1393, 2015