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

Authors: Nolan, John M. | Loskutova, Ekaterina | Howard, Alan | Mulcahy, Riona | Moran, Rachel | Stack, Jim | Bolger, Maggie | Coen, Robert F. | Dennison, Jessica | Akuffo, Kwadwo Owusu | Owens, Niamh | Power, Rebecca | Thurnham, David | Beatty, Stephen

Article Type: Research Article

Abstract: Background: Patients with Alzheimer's disease (AD) exhibit significantly less macular pigment (MP) and poorer vision when compared to control subjects. Objective: To investigate supplementation with the macular carotenoids on MP, vision, and cognitive function in patients with AD versus controls. Methods: A randomized, double-blind clinical trial with placebo and active arms. 31 AD patients and 31 age-similar control subjects were supplemented for six months with either Macushield (10 mg meso-zeaxanthin [MZ]; 10 mg lutein [L]; 2 mg zeaxanthin [Z]) or placebo (sunflower oil). MP was measured using dual-wavelength autofluorescence (Heidelberg Spectralis® ). Serum L, Z, and …MZ were quantified by high performance liquid chromatography. Visual function was assessed by best corrected visual acuity and contrast sensitivity (CS). Cognitive function was assessed using a battery of cognition tests, including the Cambridge Neuropsychological Test Automated Battery (CANTAB)). Results: Subjects on the active supplement (for both AD and non-AD controls) exhibited statistically significant improvement in serum concentrations of L, Z, MZ, and MP (p < 0.001, for all) and also CS at (p = 0.039). Also, for subjects on the active supplement, paired samples t-tests exhibited four significant results (from five spatial frequencies tested) in the AD group, and two for the non-AD group, and all indicating improvements in CS. We found no significant changes in any of the cognitive function outcome variables measured (p > 0.05, for all). Conclusion: Supplementation with the macular carotenoids (MZ, Z, and L) benefits patients with AD, in terms of clinically meaningful improvements in visual function and in terms of MP augmentation. Show more

Keywords: Age-related macular degeneration, Alzheimer's disease, cognitive function, contrast sensitivity, lutein, meso-zeaxanthin, randomized clinical trial, visual function, zeaxanthin

DOI: 10.3233/JAD-142265

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1157-1169, 2015

Authors: Rist, Pamela M. | Marden, Jessica R. | Capistrant, Benjamin D. | Wu, Qiong | Glymour, M. Maria

Article Type: Research Article

Abstract: Background: Individual-level modifiers can delay onset of limitations in basic activities of daily living (ADLs) among cognitively impaired individuals. We assessed whether these modifiers also delayed onset of limitations in instrumental ADLs (IADLs) among individuals at elevated dementia risk. Objectives: To determine whether modifiable individual-level factors delay incident IADL limitations among adults stratified by dementia risk. Methods: Health and Retirement Study participants aged 65+ without activity limitations in 1998 or 2000 (n = 5,219) were interviewed biennially through 2010. Dementia probability, categorized in quartiles, was used to predict incident IADL limitations with Poisson regression. We estimated …relative (risk ratio) and absolute (number of limitations) effects from models including dementia, individual-level modifiers (physical inactivity, smoking, no alcohol consumption, and depression) and interaction terms between dementia and individual-level modifiers. Results: Dementia probability quartile predicted incident IADL limitations (relative risk for highest versus lowest quartile = 0.44; 95% CI: 0.28–0.70). Most modifiers did not significantly increase risk of IADL limitations among the cognitively impaired. Physical inactivity (RR = 1.60; 95% CI: 1.16, 2.19) increased the risk of IADL limitations among the cognitively impaired. The interaction between physical inactivity and low dementia probability was statistically significant (p = 0.009) indicating that physical inactivity had significantly larger effects on incident IADLs among cognitively normal than among those with high dementia probability. Conclusion: Physical activity may protect against IADL limitations while not smoking, alcohol consumption, and not being depressed do not afford substantial protection among the cognitively impaired. Results highlight the need for extra support for IADLs among individuals with cognitive losses. Show more

Keywords: Cognition, disability, epidemiology

DOI: 10.3233/JAD-141866

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1171-1180, 2015

Authors: Diamond, Keri | Mowszowski, Loren | Cockayne, Nicole | Norrie, Louisa | Paradise, Matthew | Hermens, Daniel F. | Lewis, Simon J.G. | Hickie, Ian B. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: With the rise in the ageing population and absence of a cure for dementia, cost-effective prevention strategies for those ‘at risk’ of dementia including those with depression and/or mild cognitive impairment are urgently required. Objective: This study evaluated the efficacy of a multifaceted Healthy Brain Ageing Cognitive Training (HBA-CT) program for older adults ‘at risk’ of dementia. Methods: Using a single-blinded design, 64 participants (mean age = 66.5 years, SD = 8.6) were randomized to an immediate treatment (HBA-CT) or treatment-as-usual control arm. The HBA-CT intervention was conducted twice-weekly for seven weeks and comprised group-based …psychoeducation about cognitive strategies and modifiable lifestyle factors pertaining to healthy brain ageing, and computerized cognitive training. Results: In comparison to the treatment-as-usual control arm, the HBA-CT program was associated with improvements in verbal memory (p = 0.03), self-reported memory (p = 0.03), mood (p = 0.01), and sleep (p = 0.01). While the improvements in memory (p = 0.03) and sleep (p = 0.02) remained after controlling for improvements in mood, only a trend in verbal memory improvement was apparent after controlling for sleep. Conclusion: The HBA-CT program improves cognitive, mood, and sleep functions in older adults ‘at risk’ of dementia, and therefore offers promise as a secondary prevention strategy. Show more

Keywords: Depression, memory, mild cognitive impairment, neuropsychology, sleep disorders

DOI: 10.3233/JAD-142061

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1181-1191, 2015

Authors: Koal, Therese | Klavins, Kristaps | Seppi, Daniele | Kemmler, Georg | Humpel, Christian

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a severe and chronic neurodegenerative disorder of the brain. The laboratory diagnosis is limited to the analysis of three biomarkers in cerebrospinal fluid (CSF): amyloid-β42 (Aβ42 ), total tau, and phospho-tau-181 (P-tau-181). However, there is a need to find more biomarkers in CSF that can improve the sensitivity and specificity. The aim of the present study was to analyze endogenous small metabolites (metabolome) in the CSF, which may provide potentially new insights into biochemical processes involved in AD. One hundred CSF samples were dichotomized by normal (n = 50) and pathological decreased Aβ42 and …increased tau and P-tau-181 levels (n = 50; correlating to an AD-like pathology). These CSF samples were analyzed using the AbsoluteIDQ® p180 Kit (BIOCRATES Life Sciences), which included 40 acylcarnitines, 21 amino acids, 19 biogenic amines, 15 sphingolipids, and 90 glycerophospholipids. Our data show that two sphingomyelins (SM (d18:1/18:0) and SM (d18:1/18:1)), 5 glycerophospholipids (PC aa C32:0, PC aa C34:1, PC aa C36:1, PC aa C38:4 and PC aa C38:6), and 1 acylcarnitine (C3-DC-M/C5-OH) were significantly altered in the CSF with pathological “AD-like pathology”. Sphingomyelin SM (d18:1/18:0) proved to be a specific (76%) and sensitive (66%) biomarker with a defined cut-off of 546 nM. Correct diagnoses for 21 out of 32 unknown samples could be achieved using this SM (d18:1/18:0) cut-off value. In conclusion, the sphingolipid SM (d18:1/18:0) is significantly increased in CSF of patients displaying pathological levels of Aβ42 , tau, and P-tau-181. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, diagnosis, liquor, metabolomics, sphingolipids, SM(d18:1/18:0)

DOI: 10.3233/JAD-142319

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1193-1201, 2015

Authors: Ramirez, Alfredo | Wolfsgruber, Steffen | Lange, Carolin | Kaduszkiewicz, Hanna | Weyerer, Siegfried | Werle, Jochen | Pentzek, Michael | Fuchs, Angela | Riedel-Heller, Steffi G. | Luck, Tobias | Mösch, Edelgard | Bickel, Horst | Wiese, Birgitt | Prokein, Jana | König, Hans-Helmut | Brettschneider, Christian | Breteler, Monique M. | Maier, Wolfgang | Jessen, Frank | Scherer, Martin | for the AgeCoDe Study Group

Article Type: Research Article

Abstract: Type 2 diabetes mellitus (T2DM) is a risk factor of dementia. The effect of T2DM treatment quality on dementia risk, however, is unclear. 1,342 elderly individuals recruited via general practitioner registries (AgeCoDe cohort) were analyzed. This study analyzed the association between HbA1c level and the incidence of all-cause dementia (ACD) and of Alzheimer's disease dementia (referred to here as AD). HbA1c levels ≥6.5% were associated with 2.8-fold increased risk of incident ACD (p = 0.027) and for AD (p = 0.047). HbA1c levels ≥7% were associated with a five-fold increased risk of incident ACD (p = 0.001) …and 4.7-fold increased risk of incident AD (p = 0.004). The T2DM diagnosis per se did not increase the risk of either ACD or AD. Higher levels of HbA1c are associated with increased risk of ACD and AD in an elderly population. T2DM diagnosis was not associated with increased risk if HbA1c levels were below 7%. Show more

Keywords: Alzheimer's disease, diabetes mellitus, epidemiology, glycosylated hemoglobin, incident dementia

DOI: 10.3233/JAD-141521

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1203-1212, 2015

Authors: Zhan, Xinhua | Jickling, Glen C. | Ander, Bradley P. | Stamova, Boryana | Liu, DaZhi | Kao, Patricia F. | Zelin, Mariko A. | Jin, Lee-Way | DeCarli, Charles | Sharp, Frank R.

Article Type: Research Article

Abstract: The goal of this study was to show that myelin and axons in cortical gray matter are damaged in Alzheimer's disease (AD) brain. Superior temporal gyrus gray matter of AD patients (9 male, 14 female) was compared to cognitively normal controls (8 male, 7 female). Myelin basic protein (MBP) and a degraded myelin basic protein complex (dMBP) were quantified by Western blot. Brain sections were immunostained for MBP, dMBP, axonal neurofilament protein (NF), autophagy marker microtubule-associated proteins 1A/B light chain 3B precursor (LC3B), amyloid-β protein precursor (AβPP), and amyloid markers amyloid β1-42 (Aβ1-42 ) and FSB. Co-immunoprecipitation and mass …spectroscopy evaluated interaction of AβPP/Aβ1-42 with MBP/dMBP. Evidence of axonal injury in AD cortex included appearance of AβPP in NF stained axons, and NF at margins of amyloid plaques. Evidence of myelin injury in AD cortex included (1) increased dMBP in AD gray matter compared to control (p < 0.001); (2) dMBP in AD neurons; and (3) increased LC3B that co-localized with MBP. Evidence of interaction of AβPP/Aβ1-42 with myelin or axonal components included (1) greater binding of dMBP with AβPP in AD brain; (2) MBP at the margins of amyloid plaques; (3) dMBP co-localized with Aβ1-42 in the core of amyloid plaques in AD brains; and (4) interactions between Aβ1-42 and MBP/dMBP by co-immunoprecipitation and mass spectrometry. We conclude that damaged axons may be a source of AβPP. dMBP, MBP, and NF associate with amyloid plaques and dMBP associates with AβPP and Aβ1-42 . These molecules could be involved in formation of amyloid plaques. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, autophagy, axon damage, degraded myelin basic protein, myelin basic protein

DOI: 10.3233/JAD-142013

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1213-1229, 2015

Authors: Littlejohns, Thomas J. | Kos, Katarina | Henley, William E. | Cherubini, Antonio | Ferrucci, Luigi | Lang, Iain A. | Langa, Kenneth M. | Melzer, David | Llewellyn, David J.

Article Type: Research Article

Abstract: Background: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. Objective: To investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. Methods: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests A and B were also incorporated, with cognitive decline defined as discontinued testing …or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. Results: The multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73–0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests A (RR = 0.85, 95% CI 0.71–1.02) and B (RR = 0.90, 0.79–1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. Conclusions: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians. Show more

Keywords: Adipokines, cognitive decline, cohort analysis, epidemiology, leptin

DOI: 10.3233/JAD-141836

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1231-1239, 2015

Authors: Bulati, Matteo | Buffa, Silvio | Martorana, Adriana | Gervasi, Francesco | Camarda, Cecilia | Azzarello, Delia Maria | Monastero, Roberto | Caruso, Calogero | Colonna-Romano, Giuseppina

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive, irreversible, and debilitating disease for which no effective preventive or disease modifying therapies or treatments have so far been detected. The crucial step in AD pathogenesis is the production of amyloid-β42 peptide, which causes chronic inflammation. Activated cells in the central nervous system (CNS) produce pro-inflammatory mediators that lead to the recruitment of myeloid or lymphocytic cells. As a consequence, the communication between the CNS and peripheral blood of AD subjects could influence the lymphocyte distribution and/or the expression of phenotypic markers. In the present paper, we show a significant decrease in total …CD19+ B lymphocytes and a remodeling of the B cell subpopulations in moderate-severe AD patients, compared with their coeval healthy controls and mild AD subjects. In particular, we report a significant reduction in naïve B cells (IgD+ CD27− ) and a simultaneous increase in double negative (DN, IgD− CD27− ) memory B lymphocytes. We have also evaluated the expression of the pro-inflammatory chemokine receptors CCR6 and CCR7 in total and naïve/memory B cells from mild and moderate-severe AD patients, with the aim to detect a possible relationship between the trafficking profile and the stage of the disease. Our results demonstrate that both the amount and the trafficking profile of B cells are related to the severity of AD. The results discussed in this paper suggest a well-selected antibody panel should be used as an additional test for the identification of early AD. Show more

Keywords: Aging, Alzheimer's disease, B cells, CCR6, CCR7, trafficking profile

DOI: 10.3233/JAD-142412

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1241-1251, 2015

Authors: Salza, Romain | Oudart, Jean-Baptiste | Ramont, Laurent | Maquart, François-Xavier | Bakchine, Serge | Thoannès, Henri | Ricard-Blum, Sylvie

Article Type: Research Article

Abstract: The aim of this study was to measure the level of endostatin, a fragment of collagen XVIII that accumulates in the brain of patients with Alzheimer's disease (AD), in the cerebrospinal fluids (CSF) of patients with neurodegenerative diseases. The concentrations of total protein, endostatin, amyloid-β1-42 peptide, tau, and hyperphosphorylated tau proteins were measured by enzyme-linked immunosorbent assay in CSF of patients with AD (n = 57), behavioral frontotemporal dementia (bvFTD, n = 22), non AD and non FTD dementia (nAD/nFTD, n = 84), and 45 subjects without neurodegenerative diseases. The statistical significance of the results was assessed by Mann-Whitney …and Kruskal and Wallis tests, and by ROC analysis. The concentration of endostatin in CSF was higher than the levels of the three markers of AD both in control subjects and in patients with neurodegenerative diseases. The endostatin/amyloid-β1-42 ratio was significantly increased in patients with AD (257%, p < 0.0001) and nAD/nFTD (140%, p < 0.0001) compared to controls. The endostatin/tau protein ratio was significantly decreased in patients with AD (−49%, p < 0.0001) but was increased in bvFTD patients (89%, p < 0.0001) compared to controls. In the same way, the endostatin/hyperphosphorylated tau protein ratio was decreased in patients with AD (−21%, p = 0.0002) but increased in patients with bvFTD (81%, p = 0.0026), compared to controls. The measurement of endostatin in CSF and the calculation of its ratio relative to well-established AD markers improve the diagnosis of bvFTD patients and the discrimination of patients with AD from those with bvFTD and nAD/nFTD. Show more

Keywords: Alzheimer's disease, amyloid-β1-42 peptide, biomarkers, cerebrospinal fluid, endostatin, hyperphosphorylated tau, neurodegenerative diseases, tau

DOI: 10.3233/JAD-142544

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1253-1261, 2015

Authors: Puig, Kendra L. | Lutz, Brianna M. | Urquhart, Siri A. | Rebel, Andrew A. | Zhou, Xudong | Manocha, Gunjan D. | Sens, MaryAnn | Tuteja, Ashok K. | Foster, Norman L. | Combs, Colin K.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder histologically characterized by amyloid-β (Aβ) protein accumulation and activation of associated microglia. Although these features are well described in the central nervous system, the process and consequences of Aβ accumulation in the enteric nervous system have not been extensively studied. We hypothesized that Aβ also may accumulate in the enteric nervous system and lead to immune cell activation and neuronal dysfunction in the digestive tract not unlike that observed in diseased brain. To test this hypothesis, ileums of the small intestine of thirteen month old AβPP/PS1 and C57BL/6 (wild type) mice were collected …and analyzed using immunohistochemistry, western blot analysis, cytokine arrays, and ELISA. AβPP/PS1 mice demonstrated no differences in intestinal motility or water absorption but elevated luminal IgA levels compared to wild type mice. They also had increased protein levels of AβPP and the proteolytic enzyme, BACE, corresponding to an increase in Aβ1–40 in the intestinal lysate as well as an increase in both Aβ1–40 and Aβ1–42 in the stool. This correlated with increased protein markers of proinflammatory and immune cell activation. Histologic analysis localized AβPP within enteric neurons but also intestinal epithelial cells with elevated Aβ immunoreactivity in the AβPP/PS1 mice. The presence of AβPP, Aβ, and CD68 immunoreactivity in the intestines of some patients with neuropathologically-confirmed AD are consistent with the findings in this mouse model. These data support the hypothesis that in AD the intestine, much like the brain, may develop proinflammatory and immune changes related to AβPP and Aβ. Show more

Keywords: Amyloid-β, cytokines, inflammation, intestine

DOI: 10.3233/JAD-142259

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1263-1278, 2015

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