Journal of Alzheimer's Disease - Volume 40, issue 3

Authors: Del Campo, Marta | Teunissen, Charlotte E.

Article Type: Review Article

Abstract: Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 …is a potential regulator of AβPP processing, and it can inhibit the production and fibrillation of Aβ. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, familial British dementia (FBD), familial Danish dementia (FDD), integral membrane protein 2B (ITM2B/BRI2)

DOI: 10.3233/JAD-131364

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 481-494, 2014

Authors: Abisambra, Jose F. | Scheff, Stephen

Article Type: Review Article

Abstract: Traumatic brain injury (TBI) is the most common form of head injury and is a leading cause of death worldwide. Due to the vast variability in the types and severity of trauma, the cellular consequences of head injury are not completely understood. The development of reliable models of TBI will aid in understanding the molecular consequences of head trauma, and they will assist in identifying biological surrogate markers of the degree of damage and prognosis. In doing so, effective therapeutic strategies can be applied. Current in vivo experimental models yield important information, but they too have a significant amount of …variation. The goal of this review is to re-evaluate the use of these in vivo models of TBI and assess whether they correlate with the consequence of TBI in humans from the perspective of tau, an axonal microtubule-stabilizing protein. We present and discuss the current models of traumatic head injury, and we focus on those that assess changes in tau. We evaluate reports of TBI in humans that measured changes in tau and that were detectable in serum and cerebrospinal fluid, and as a pathological consequence in brain tissue. Show more

Keywords: Alzheimer's disease, chronic traumatic encephalopathy, tau, tau post-translational modification, traumatic brain injury

DOI: 10.3233/JAD-131019

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 495-518, 2014

Authors: Saharan, Sumiti | Mandal, Pravat K.

Article Type: Review Article

Abstract: With millions of older individuals presently suffering from Alzheimer's disease (AD) worldwide, AD is an unduly common form of dementia that exacts a heavy toll on affected individuals and their families. One of the emerging causative factors associated with AD pathology is oxidative stress. This AD-related increase in oxidative stress has been attributed to decreased levels of the brain antioxidant, glutathione (GSH). In this article, we review the role of GSH in AD from a pathological as well as a diagnostic point of view. We recapitulate the literature that has assessed the role of GSH in AD onset and progression. …We discuss the various methodologies through which alterations in GSH levels might be monitored, and highlight the yet uncharted potential of assaying GSH levels in vivo with magnetic resonance spectroscopy in AD therapeutics and prognostics. Finally, the present manuscript integrates findings from various studies to elucidate the possible molecular mechanisms through which disruptions in GSH homeostasis may contribute to AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarker, glutathione, oxidative stress

DOI: 10.3233/JAD-132483

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 519-529, 2014

Authors: Pertl, Marie-Theres | Benke, Thomas | Zamarian, Laura | Martini, Caroline | Bodner, Thomas | Karner, Elfriede | Delazer, Margarete

Article Type: Research Article

Abstract: Patients with mild cognitive impairment (MCI) are by definition still autonomous in daily life and therefore make their own decisions, for example, concerning their own or their partners' health care. Health care information typically contains complex mathematical constructs like proportions, probabilities, and survival rates. The purpose of this study was to investigate whether patients with MCI have difficulties with understanding health numeracy questions and to explore the impact of declining cognitive functions. The performance of 25 patients with MCI in a health numeracy questionnaire was compared with the performance of a control sample including 164 healthy older adults, matched in …age and educational level. Participants were asked to convert percentages, assess different probabilities, or understand the dosage of a short patient information leaflet. Additionally, neuropsychological background tests were administered. Patients with MCI answered fewer items correctly than controls in the health numeracy questionnaire. A correlation analysis showed statistically significant associations between performance in the health numeracy task and mental arithmetic, executive functions (psychomotor speed, conceptualization), and global cognitive status, respectively. Patients with MCI show problems in understanding numerical information concerning health care. Since patients with MCI are confronted with several health care decisions, special attention has to be paid to presenting information in an easily understandable way, to make additional sources of information available, and to provide adequate support. Show more

Keywords: Advanced age, cognition, decision making, health numeracy, mental arithmetic, mild cognitive impairment

DOI: 10.3233/JAD-131895

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 531-540, 2014

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: Neuritic plaque (NP) formation can be dated in vivo. This analysis attempts to “date” the progression of neurofibrillary tangles (NFT) using the spatial distribution of NP as a reference. Autopsy data from 471 participants in the Honolulu-Asia Aging Study (HAAS) were combined into latent factor measures of NFT and NP counts. The variance in “early” and “late” NP pathology was used to estimate the spatial distribution of “early” and “late” NFT formation. A third latent factor representing “non-NP-related NFT” was also constructed. “Early” NP and “late” NP correlated significantly with objectively early and later cognitive performance, respectively. In contrast to …our expectations, neocortical NFT correlated best with “early” NP pathology, while NFT in allocortical structures correlated best with “late” NP pathology. Therefore, the NP-related fraction of NFT appears to be co-localized spatially with NP. However, since the latter evolve corticofugally in time, this suggests that NP-related NFT do so as well. Corticotropic NFT formation must therefore be either unrelated to NP formation, a temporally distinct process, or both. Show more

Keywords: Alzheimer's disease, dementia, mild cognitive impairment, neuropathology

DOI: 10.3233/JAD-131733

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 541-549, 2014

Authors: Buckley, Rachel F. | Saling, Michael M. | Irish, Muireann | Ames, David | Rowe, Christopher C. | Lautenschlager, Nicola T. | Maruff, Paul | Macaulay, S. Lance | Martins, Ralph N. | Masters, Colin L. | Rainey-Smith, Stephanie R. | Rembach, Alan | Savage, Greg | Szoeke, Cassandra | Ellis, Kathryn A. | the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) Research Group

Article Type: Research Article

Abstract: Background: Autobiographical memory (ABM) refers to the recollection of individual experiences, while personal semantic memory (PSM) refers to personally relevant, but shared, facts. Mild cognitive impairment (MCI) is routinely diagnosed with the aid of neuropsychological tests, which do not tap the ABM and PSM domains. Objective: We aimed to characterize the nature of ABM and PSM retrieval in cognitively healthy (HC) memory complainers, non-memory complainers, and MCI participants, and to investigate the relationship between neuropsychological tests and personal memory. Methods: Gender- and education-matched participants (HC = 80 and MCI = 43) completed the Episodic ABM Interview …(EAMI) and a battery of neuropsychological tests. Results: ABM and PSM did not differ between complainers and non-complainers, but were poorer in MCI participants, after accounting for age and depressive symptomatology. There were significant associations between personal memory and objective memory measures were found in MCI participants, but standard cognitive measures were more sensitive to MCI. Conclusion: Personal memory was compromised in MCI, reflected by lower scores on the EAMI. Memory complaining, assessed by current approaches, did not have an impact on personal memory. Standard subjective questionnaires might not reflect the sorts of concerns that bring individuals to clinical attention. Understanding personal memory function in the elderly may aid in the development of a more sensitive measure of subjective memory concerns. Show more

Keywords: Aging, Alzheimer dementia, autobiographical memory, cognitive function, episodic memory, mild cognitive impairment, subjective cognitive decline, subjective memory complaint

DOI: 10.3233/JAD-131820

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 551-561, 2014

Authors: Cunningham, Rebecca L. | Singh, Meharvan | O'Bryant, Sid E. | Hall, James R. | Barber, Robert C.

Article Type: Research Article

Abstract: Background: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal. Objective: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone’s neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load. Methods: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer’s Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = …116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone. Results: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 µmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans. Conclusion: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST. Show more

Keywords: Androgens, antioxidants, homocysteine, luteinizing hormone, Mexican American

DOI: 10.3233/JAD-131994

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 563-573, 2014

Authors: Sui, Xiaojing | Ren, Xiaohu | Huang, Peiwu | Li, Shuiming | Ma, Quan | Ying, Ming | Ni, Jiazuan | Liu, Jianjun | Yang, Xifei

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common fatal neurodegenerative disease affecting the elderly worldwide. There is an urgent need to identify novel biomarkers of early AD. This study aims to search for potential early protein biomarkers in serum from a triple transgenic (PS1M146V /APPSwe /TauP301L ) mouse model. Proteomic analysis via two-dimensional fluorescence difference gel electrophoresis was performed on serum samples from wild-type (WT) and triple transgenic mice that were treated with or without coenzyme Q10 (CoQ10) (800 mg/kg body weight/day), a powerful endogenous antioxidant displaying therapeutic benefits against AD pathology and cognitive impairment in multiple AD mouse models, for …a period of three months beginning at two months of age. A total of 15 differentially expressed serum proteins were identified between the WT and AD transgenic mice. The administration of CoQ10 was found to alter the changes in the differentially expressed serum proteins by upregulating 10 proteins and down-regulating 10 proteins. Among the proteins modulated by CoQ10, clusterin and α-2-macroglobulin were validated via ELISA assay. These findings revealed significant changes in serum proteins in the AD mouse model at an early pathological stage and demonstrated that administration of CoQ10 could modulate these changes in serum proteins. Our study suggested that these differentially expressed serum proteins could serve as potential protein biomarkers of early AD and that screening for potential candidate AD therapeutic drugs and monitoring of therapeutic effects could be performed via measurement of the changes in these differentially expressed serum proteins. Show more

Keywords: Alzheimer's disease, coenzyme Q10, serum, triple transgenic (PS1M146V/APPSwe/TauP301L) mice, two-dimensional fluorescence difference gel electrophoresis

DOI: 10.3233/JAD-131823

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 575-586, 2014

Authors: Steenland, Kyle | Zhao, Liping | Goldstein, Felicia | Cellar, Janet | Lah, James | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Most studies evaluating Alzheimer's disease (AD) biomarkers longitudinally have studied patients with mild cognitive impairment (MCI) who progress to AD; data on normal subjects are scarce. We studied which biomarkers best predict cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) among those with normal cognition at baseline, and derived cut points to predict decline. We studied 191 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had normal cognition at baseline, 2 + visits (mean follow-up 3.1 years), and data on neuropsychological tests, cerebrospinal fluid (CSF) biomarkers, and structural MRI. We used repeated measures linear regression of log …ADAS-Cog on age, race, gender, education, APOE4 status, baseline biomarker values, and follow-up time; an interaction between biomarker and time assessed predictive power. Neuropsychological tests did not significantly predict ADAS-Cog decline, while both MRI variables and CSF biomarkers did; CSF markers were the strongest predictors. Optimal cut points for baseline CSF markers to distinguish decliners were < 220 pg/ml (Aβ42 ), ≥61 pg/ml (t-tau), ≥21 pg/ml (p-tau), ≥0.31 (t-tau/Aβ42 ), and ≥0.10 (p-tau/Aβ42 ). For progression to MCI/AD (n = 28), the best markers were t-tau, t-tau/Aβ42 , and p-tau/Aβ42 , with optimal cut points of 58, 0.31, and 0.08, respectively. The optimal cut points across all markers and cut points predicted decline in ADAS-Cog, as well as transition to MCI, with a 65% accuracy. Our findings support current models of AD progression and suggest it is feasible to establish biomarker criteria to predict cognitive decline in individuals with normal cognition. Larger studies will be needed to more accurately characterize optimal cut points. Show more

Keywords: biomarkers, cerebrospinal fluid, cognition, mild cognitive impairment

DOI: 10.3233/JAD-2014-131343

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 587-594, 2014

Authors: O'Caoimh, Rónán | Healy, Liam | Gao, Yang | Svendrovski, Anton | Kerins, David M. | Eustace, Joseph | Kehoe, Patrick Gavin | Guyatt, Gordon | Molloy, D. William

Article Type: Research Article

Abstract: Background: Centrally acting angiotensin converting enzyme inhibitors (CACE-Is) are associated with reduced rates of cognitive decline in patients with dementia. CACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition, suggesting that CACE-Is may positively influence activities of daily living (ADL) in dementia. Objective: To compare rates of decline in patients with mild to moderate Alzheimer’s disease (AD) receiving CACE-Is to those not currently treated with CACE-Is (NoCACE-I), included in the Doxycycline and Rifampicin for Alzheimer’s Disease study (n = 406). Methods: Patients were included if baseline and end-point (twelve months apart) …scores were available for measures including the Standardized Alzheimer’s Disease Assessment Scale – Cognitive Subscale; Quick Mild Cognitive Impairment screen; Clinical Dementia Rating Scale (CDR-SB), and Lawton-Brody ADL Scale. Results: There was a significant, 25% difference (median one-point) in the 12-month rate of decline in ADL scores in patients taking CACE-Is (n = 91), compared to the NoCACE-I group (n = 274), p = 0.024. This remained significant after adjusting for age, gender, education, and blood pressure, p = 0.034. When individual CACE-Is were compared to the NoCACE-I group, a significant reduction in the rate of decline in ADLs (median one versus four points), were only observed for perindopril, p = 0.01. The CDR-SB was also reduced (median one-point) for the perindopril compared to the NoCACE-I group, p = 0.04. Conclusion: This observational study suggests that CACE-Is, and potentially perindopril in particular, are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior. This suggests that CACE-Is may slow disease progression in AD. Show more

Keywords: ACE inhibitors, Alzheimer's disease, cognitive, dementia, function, psychological decline

DOI: 10.3233/JAD-131694

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 595-603, 2014

Authors: Zhang, Qiang | Descamps, Olivier | Hart, Matthew J. | Poksay, Karen S. | Spilman, Patricia | Kane, Darci J. | Gorostiza, Olivia | John, Varghese | Bredesen, Dale E.

Article Type: Research Article

Abstract: An unbiased screen for compounds that block amyloid-β protein precursor (AβPP) caspase cleavage identified ADDN-1351, which reduced AβPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AβPP-C31 and cell death. TrkA was shown to interact with AβPP and suppress AβPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAβPPα and the sAβPPα to Aβ ratio. These results suggest TrkA inhibition—rather than NGF activation—as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from …the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that one component of an optimal therapy for Alzheimer's disease may be a TrkA inhibitor. Show more

Keywords: AβPPneo, Alzheimer's disease, amyloid-β protein precursor, GW441756, nerve growth factor, transcriptional activation, TrkA receptor

DOI: 10.3233/JAD-130017

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 605-617, 2014

Authors: Grammas, Paula | Martinez, Joseph | Sanchez, Alma | Yin, Xiangling | Riley, Jarred | Gay, Dylan | Desobry, Katherine | Tripathy, Debjani | Luo, Jinhua | Evola, Marianne | Young, Alice

Article Type: Research Article

Abstract: No disease-modifying therapies are currently available for Alzheimer's disease (AD), a neurodegenerative disorder that affects more than 36 million people worldwide. Although cardiovascular risk factors such as hypertension and diabetes are increasingly implicated as contributing to the development of AD, the mechanisms whereby these factors influence pathological processes in the AD brain have not been defined. Here we propose, for the first time, vascular activation as a relevant mechanism in AD pathogenesis. We explore this hypothesis in two transgenic AD animal models: AD2576APPSwe (AD2576) and LaFerla 3xTg (3xTgAD) mice using the vascular activation inhibitor sunitinib. Our data show that in …both AD animal models, the cerebrovasculature is activated and overexpresses amyloid beta, thrombin, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and matrix metalloproteinase 9. Oral administration of sunitinib significantly reduces vascular expression of these proteins. Furthermore, sunitinib improves cognitive function, as assessed by several behavioral paradigms, in both AD animal models. Finally, oxidant injury of brain endothelial cells in culture, resulting in expression of inflammatory proteins, is mitigated by sunitinib. The current data, as well as published studies showing cerebrovascular activation in human AD, support further exploration of vascular-based mechanisms in AD pathogenesis. New thinking about AD pathogenesis and novel, effective treatments are urgently needed. Identification of “vascular activation” as a heretofore unexplored target could stimulate translational investigations in this newly defined area, leading to innovative therapeutic approaches for the treatment of this devastating disease. Show more

Keywords: Alzheimer's disease, angiogenesis, behavior, cognitive decline, sunitinib

DOI: 10.3233/JAD-2014-132057

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 619-630, 2014

Authors: Kraijo, Henk | Brouwer, Werner | de Leeuw, Rob | Schrijvers, Guus | van Exel, Job

Article Type: Research Article

Abstract: Background: Health care systems aim to involve as much informal care as possible and dementia patients prefer to stay home as long as they can. In this context, perseverance time (Pt)—the period that the informal carer indicates to be able to maintain current care if the situation remains stable—is an important concept. Objective: The aim of this study was to introduce the concept Pt and validate it in a sample of informal carers of dementia patients living at home. Methods: Data were collected from 223 informal carers of dementia patients. Convergent validity was assessed by looking …at associations of Pt with validated instruments for measuring subjective burden (CSI, CarerQol-7D, and SRB) and happiness (CarerQol-VAS). Content validity was evaluated by performing multivariate correlations between Pt and characteristics of dementia patients, informal carers, and care situations. The Medical Ethics Committee of Utrecht MC advised positively about the study protocol. Results: Correlation coefficients between Pt and the measures of burden CSI, SRB, and CarerQol-VAS were −0.46, −0.63, and 0.23 (p < 0.01), respectively. Health of dementia patient, informal carer living apart from the patient, and male gender of caregiver were positively associated with Pt; need for supervision, intensity of informal care provision, and reductions in working hours and hobbies in order to be able to provide care were negatively associated. Conclusions: Pt is helpful in monitoring need for support and planning the transition of care from home to nursing home. This study provides a first indication of its validity, but replication is necessary. Show more

Keywords: Burden, dementia, informal care, perseverance time, validity

DOI: 10.3233/JAD-132420

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 631-642, 2014

Authors: Ramos-Fernández, Eva | Tajes, Marta | Palomer, Ernest | ILL-Raga, Gerard | Bosch-Morató, Mònica | Guivernau, Biuse | Román-Dégano, Irene | Eraso-Pichot, Abel | Alcolea, Daniel | Fortea, Juan | Nuñez, Laura | Paez, Antonio | Alameda, Francesc | Fernández-Busquets, Xavier | Lleó, Alberto | Elosúa, Roberto | Boada, Mercé | Valverde, Miguel A. | Muñoz, Francisco J.

Article Type: Research Article

Abstract: Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimer's disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated …albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD. Show more

Keywords: Albumin, Alzheimer's disease, amyloid, glycation, nitrotyrosination, oxidative stress

DOI: 10.3233/JAD-130914

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 643-657, 2014

Authors: Yang, Hongqian | Lyutvinskiy, Yaroslav | Herukka, Sanna-Kaisa | Soininen, Hilkka | Rutishauser, Dorothea | Zubarev, Roman A.

Article Type: Research Article

Abstract: Background: Patients with mild cognitive impairment (MCI) have varying risks of progression to Alzheimer’s disease (AD). Objective: To test the utility of the relative abundances of blood plasma polypeptides for predicting the risk of AD progression. Methods: 119 blood plasma samples of patients with MCI with different outcomes (stable MCI and progressive MCI) were analyzed by untargeted, label-free shotgun proteomics. Predictive biomarkers of progressive MCI were selected by multivariate analysis, followed by cross-validation of the predictive model. Results: The best model demonstrated the accuracy of ca. 79% in predicting progressive MCI. Sex differences of …the predictive biomarkers were also assessed. We have identified some sex-specific protein biomarkers, e.g., alpha-2-macrogloblin (A2M), which strongly correlates with female AD progression but not with males. Conclusion: Significant sex bias in AD-specific biomarkers underscores the necessity of selecting sex-balanced cohort in AD biomarker studies, or using sex-specific models. Blood protein biomarkers are found to be promising for predicting AD progression in clinical settings. Show more

Keywords: Biomarkers, human blood plasma, label-free quantification, mass spectrometry

DOI: 10.3233/JAD-132102

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 659-666, 2014

Authors: Hanzel, Cecilia E. | Iulita, M. Florencia | Eyjolfsdottir, Helga | Hjorth, Erik | Schultzberg, Marianne | Eriksdotter, Maria | Cuello, A. Claudio

Article Type: Research Article

Abstract: The expression of matrix metallo-proteases (MMP-2, MMP-3, MMP-7, and MMP-9), plasminogen and their regulators (TIMP-1, tissue plasminogen activator and neuroserpin) was investigated in cerebrospinal fluid (CSF) from subjective cognitive impairment (SCI) subjects, mild cognitive impairment (MCI), and Alzheimer's disease (AD) cases. ELISA analysis revealed a significant increase in MMP-3 protein levels in CSF from AD subjects, compared to age-matched SCI and MCI cases. No significant differences in MMP-2 and MMP-9 protein levels were detected between the three groups. MMP-7 was undetectable in all three groups. MCI individuals exhibited increased levels of the metallo-protease inhibitor TIMP-1 in CSF as well as …higher plasminogen and neuroserpin expression, compared to SCI subjects. Levels of tissue plasminogen activator (tPA) were significantly reduced in AD CSF. Correlation analysis revealed a significant positive association between MMP-3, p-tau, and total-tau levels. Conversely, there was a significant negative correlation between this protease and Mini-Mental State Examination (MMSE) scores. tPA positively correlated with amyloid-β levels in CSF and with MMSE scores. Our results suggest that MMP-3 and tPA, in combination with current amyloid-β and tau biomarkers, may have potential as surrogate indicators of an ongoing AD pathology. Show more

Keywords: Alzheimer's disease, biomarkers, metallo-proteases, neuroserpin, plasminogen

DOI: 10.3233/JAD-132282

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 667-678, 2014

Authors: Piaceri, Irene | Pradella, Silvia | Cupidi, Chiara | Nannucci, Serena | Polito, Cristina | Bagnoli, Silvia | Tedde, Andrea | Smirne, Nicoletta | Anfossi, Maria | Gallo, Maura | Bernardi, Livia | Colao, Rosanna | Maletta, Raffaele | Bruni, Amalia Cecilia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer’s disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. Objective: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. …Methods: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. Results: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. Conclusion: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD. Show more

Keywords: Cys139Arg, frontotemporal dementia, mutation, plasma, progranulin

DOI: 10.3233/JAD-132126

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 679-685, 2014

Authors: Kilimann, Ingo | Grothe, Michel | Heinsen, Helmut | Alho, Eduardo Joaquim Lopez | Grinberg, Lea | Amaro Jr., Edson | dos Santos, Gláucia Aparecida Bento | da Silva, Rafael Emídio | Mitchell, Alex J. | Frisoni, Giovanni B. | Bokde, Arun L.W. | Fellgiebel, Andreas | Filippi, Massimo | Hampel, Harald | Klöppel, Stefan | Teipel, Stefan J.

Article Type: Research Article

Abstract: Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which …were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD. Show more

Keywords: Atrophy, biomarker, cholinergic system, dementia, European DTI Study on Dementia

DOI: 10.3233/JAD-132345

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 687-700, 2014

Authors: Bedse, Gaurav | Romano, Adele | Cianci, Silvia | Lavecchia, Angelo M. | Lorenzo, Pace | Elphick, Maurice R. | LaFerla, Frank M. | Vendemiale, Gianluigi | Grillo, Caterina | Altieri, Fabio | Cassano, Tommaso | Gaetani, Silvana

Article Type: Research Article

Abstract: The endocannabinoid system has gained much attention as a new potential pharmacotherapeutic target in various neurodegenerative diseases, including Alzheimer's disease (AD). However, the association between CB1 alterations and the development of AD neuropathology is unclear and often contradictory. In this study, brain CB1 mRNA and CB1 protein levels were analyzed in 3 × Tg-AD mice and compared to wild-type littermates at 2, 6 and 12 months of age, using in-situ hybridization and immunohistochemistry, respectively. Semiquantitative analysis of CB1 expression focused on the prefrontal cortex (PFC), prelimbic cortex, dorsal hippocampus (DH), basolateral amygdala complex (BLA), and ventral hippocampus (VH), all areas …with high CB1 densities that are strongly affected by neuropathology in 3 × Tg-AD mice. At 2 months of age, there was no change in CB1 mRNA and protein levels in 3 × Tg-AD mice compared to Non-Tg mice in all brain areas analyzed. However, at 6 and 12 months of age, CB1 mRNA levels were significantly higher in PFC, DH, and BLA, and lower in VH in 3 × Tg-AD mice compared to wild-type littermates. CB1 immunohistochemistry revealed that CB1 protein expression was unchanged in 3 × Tg-AD at 2 and 6 months of age, while a significant decrease in CB1 receptor immunoreactivity was detected in the BLA and DH of 12-month-old 3 × Tg-AD mice, with no sign of alteration in other brain areas. The altered CB1 levels appear, rather, to be age-and/or pathology-dependent, indicating an involvement of the endocannabinoid system in AD pathology and supporting the ECS as a potential novel therapeutic target for treatment of AD. Show more

Keywords: 3 × Tg-AD mice, Alzheimer's disease, basolateral amygdala complex, CB1 mRNA, CB1 receptor, endocannabinoid system, hippocampus, prefrontal cortex

DOI: 10.3233/JAD-131910

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 701-712, 2014

Authors: Suszyńska-Zajczyk, Joanna | Łuczak, Magdalena | Marczak, Łukasz | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLMH) participates in Hcy metabolism and is also linked to AD. The inactivation of the Blmh gene in mice causes accumulation of Hcy-thiolactone in the brain and increases susceptibility to Hcy-thiolactone-induced seizures. To gain insight into brain-related Blmh function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to examine brain proteomes of Blmh−/− mice and their Blmh+/+ littermates fed with a hyperhomocysteinemic high-Met or a control diet. We found that: 1) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1, Stmn2), antioxidant defenses (Aop1), cell …cycle (RhoGDI1, Ran), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Blmh-null mice; 2) hyperhomocysteinemia amplified effects of the Blmh−/− genotype on brain protein expression; 3) proteins involved in brain-specific function (Pebp1), antioxidant defenses (Sod1, Prdx2, DJ-1), energy metabolism (Atp5d, Ak1, Pgam-B), and iron metabolism (Fth) showed differential expression in Blmh-null brains only in hyperhomocysteinemic animals; 4) most proteins regulated by the Blmh−/− genotype were also regulated by high-Met diet, albeit in the opposite direction; and 5) the differentially expressed proteins play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Blmh interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in AD. Show more

Keywords: Alzheimer's disease, bleomycin hydrolase, Blmh-null mouse, brain proteome, dietary hyperhomocysteinemia, homocysteine, neurodegenerative diseases

DOI: 10.3233/JAD-132033

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 713-726, 2014

Authors: Miners, James Scott | Jones, Ruth | Love, Seth

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ), the cerebral accumulation of which is thought to cause Alzheimer's disease (AD), is produced throughout life. The level of insoluble Aβ rises with age and is further increased in AD. In contrast, we showed previously that in mid-frontal cortex in a cohort without neurological disease, soluble Aβ declined progressively between 16 and 95 y. We speculated that the divergent changes in the levels of soluble and insoluble Aβ with age might reflect an increasing tendency to favor the production or retention within the brain of Aβ42 over Aβ40 , leading to elevation of Aβ42 : 40 …even as total soluble Aβ decreased. We have now measured Aβ40 and Aβ42 in soluble and insoluble (guanidine-extractable) fractions of human postmortem brain tissue from the same cohort studied previously. Although in normal brains the absolute level of Aβ40 in both soluble and insoluble fractions and that of Aβ42 in the soluble fraction declined with age, those declines were predominantly before about 50 y, after which Aβ42 : 40 tended to increase in both the soluble and insoluble fractions. Insoluble Aβ42 increased progressively with age. Differential production or retention of Aβ40 and Aβ42 in the over-50 s is likely to contribute to the influence of age on the risk of sporadic AD. Show more

Keywords: Aβ40, Aβ42, aging, amyloid

DOI: 10.3233/JAD-132339

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 727-735, 2014

Authors: Bracco, Laura | Bessi, Valentina | Padiglioni, Sonia | Marini, Sandro | Pepeu, Giancarlo

Article Type: Research Article

Abstract: Attention is the first non-memory domain affected in Alzheimer's disease (AD), before deficits in language and visuo-spatial function, and it is claimed that attention deficits are responsible for the difficulties with daily living in early demented patients. The aim of this longitudinal study in a group of 121 Caucasian, community-dwelling, mild-to-moderate AD patients (Mini-Mental State Examination (MMSE) score >17) was to detect which cognitive domains were most affected by the disease and whether one year treatment with cholinesterase inhibitors was more effective in preserving attention than memory. All subjects were evaluated by a neuropsychological battery including global measurements (MMSE, Information-Memory-Concentration …Test) and tasks exploring verbal long-term memory, language, attention, and executive functions. The comparison between two evaluations, made 12 months apart, shows statistically significant differences, indicating deterioration compared to baseline, in the following tests: MMSE (with no gender differences), Composite Memory Score, Short Story Delayed Recall, Trail-Making Test A, Semantic Fluency Test, and Token Test. Conversely, there were no differences in the two evaluations of the Digit Span, Corsi Tapping Test, Short Story Immediate Recall, and Phonemic Fluency Tests. It appears that the treatment specifically attenuated the decline in tests assessing attention and executive functions. A stabilization of the ability to pay attention, with the ensuing positive effects on executive functions, recent memory, and information acquisition which depend on attention, appears to be the main neuropsychological mechanism through which the activation of the cholinergic system, resulting from cholinesterase inhibition, exerts its effect on cognition. Show more

Keywords: Acetylcholine, attention, cholinergic system, donepezil, galantamine, rivastigmine

DOI: 10.3233/JAD-131154

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 737-742, 2014

Authors: van der Steen, Jenny T. | van Soest-Poortvliet, Mirjam C. | Hallie-Heierman, Meertje | Onwuteaka-Philipsen, Bregje D. | Deliens, Luc | de Boer, Marike E. | Van den Block, Lieve | van Uden, Nicole | Hertogh, Cees M.P.M. | de Vet, Henrica C.W.

Article Type: Research Article

Abstract: Background: Planning ahead may be particularly relevant in dementia considering patients’ cognitive decline and difficulty to predict the course of the dementia. Objective: To identify factors associated with initiation of advance care planning (ACP) regarding end-of-life issues in dementia. Methods: Systematic review of the PubMed, Embase, Cinahl, Psychinfo, and Cochrane databases until January 2013. We included articles reporting on empirical research, identifying factors related to initiation of ACP defined as starting a discussion, starting the decision making, or having a documented patient-written advance directive. Results: Of 4,647 unique articles, we assessed 178 as full-texts, …and included 33. Most designs (64%) were qualitative; 42% limited to moderate to severe, and 6% to mild to moderate stages. Perspectives varied: family (33%), professional caregivers (24%), patient (15%), or multiple (27%). A variety of factors with complex interplay was involved in initiating ACP. Family factors dominated, with family’s initiative or lack of it, and willingness or reluctance to engage in initiating ACP identified in a series of studies. Further, professional caregivers’ initiative or lack of it and patient’s health status were important factors that facilitated or hindered initiating ACP. Ethnic minority status of those involved and family distance may be barriers. Continuity of care and health care system factors also affected initiating of ACP. Conclusion: Professional caregivers may initiate ACP early if strategies carefully consider timing and family and patient receptiveness or reluctance, and are family and patient-centered. Interventions should address the complexity of interrelated system and personal factors affecting initiation of ACP. Show more

Keywords: advance care planning, decision making, dementia, end of life care, hospice care, long-term care, palliative care, professional-family relations, professional-patient relations

DOI: 10.3233/JAD-131967

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 743-757, 2014

Article Type: Other

DOI: 10.3233/JAD-131968

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 759-761, 2014

Article Type: Other

DOI: 10.3233/JAD-149002

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 763-763, 2014