Journal of Alzheimer's Disease - Volume 43, issue 4

Authors: Jung, Cha-Gyun | Uhm, Kyung-Ok | Horike, Hirofumi | Kim, Mi-Jeong | Misumi, Sachiyo | Ishida, Akimasa | Ueda, Yoshimoto | Choi, Eun-Kyoung | Kim, Yong-Sun | Michikawa, Makoto | Hida, Hideki

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by β- and γ-secretase-mediated proteolytic processing of amyloid-β protein precursor (AβPP). In the present study, we investigated the effect of 118 natural compounds on Aβ production in the medium of HEK293 cells stably expressing human AβPP695 (HEK293-AβPP) using Aβ42 sandwich ELISA to find natural compounds that can modulate Aβ production. We found that a coumarin derivative of citrus fruits, auraptene, increased Aβ production. Treatment of HEK293-AβPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Aβ40 , Aβ42 …, and the Aβ42/40 ratio. However, auraptene did not change the protein levels of the AβPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, α-secretase), β-site AβPP cleaving enzyme-1 (BACE-1, β-secretase), and presenilin 1 (PS1, γ-secretase component). Auraptene increased the activity of γ-secretase but not that of α- and β-secretase. Furthermore, auraptene enhanced γ-secretase-mediated production of Aβ from AβPP or AβPP-C99, but not through α- and β-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced γ-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of Aβ by promoting γ-secretase activity. Show more

Keywords: Alzheimer's disease, amyloid-β production, auraptene, c-Jun N-terminal kinase, γ-secretase

DOI: 10.3233/JAD-141692

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1215-1228, 2015

Authors: Schmidt, Christian | Gerlach, Nicole | Peter, Christoph | Gherib, Kerim | Lange, Katharina | Friede, Tim | Zerr, Inga

Article Type: Research Article

Abstract: Background/Objective: Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a potential biomarker, which would be predictive of cognitive, functional, or motor decline, we analyzed CSF apolipoprotein E (ApoE) levels of AD patients in this regard. Methods: Subjects with newly diagnosed AD enrolled into an observational study were followed up longitudinally. Neuropsychological testing and physical examination were performed annually. In a sub-cohort of patients, where baseline CSF ApoE concentration values were available, multiple regression analyses were used to determine …possible associations of CSF ApoE concentration and speed of decline on different cognitive, functional, and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusting for possible confounders. Results: No association of CSF ApoE levels and speed of decline on the various scales could be established (p = 0.09 to 0.88). Nevertheless, the use of neuroleptic drugs could be linked to higher velocity of global and extrapyramidal deterioration (p = 0.04 and 0.05 for GDS and UPDRSIII, respectively), but not to other outcomes (MMSE, bADL, and iADL). Conclusion: Herein, CSF ApoE at time of AD diagnosis could not be shown to be a viable biomarker for future cognitive, functional, or motor decline. Expectedly, the use of neuroleptic drugs was associated with detrimental effects. Show more

Keywords: Alzheimer's disease, apolipoprotein E, biomarker, cerebrospinal fluid, cognition

DOI: 10.3233/JAD-141581

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1229-1236, 2015

Authors: Zhu, Mingqin | Wang, Xiuzhe | Schultzberg, Marianne | Hjorth, Erik

Article Type: Research Article

Abstract: Resolution of inflammation terminates the inflammatory response in physiological conditions and promotes restoration and healing of the tissue; however, failure in resolution results in chronic inflammation that may lead to disease. Chronic inflammation mediated by microglia is a feature of Alzheimer's disease (AD) and can be a pathogenic factor in which both treatment targets and diagnostic markers may be found. In addition, there is evidence that the resolution pathway is altered in AD. It is therefore relevant to investigate whether amyloid-β (Aβ) peptide, the major component of senile plaque in AD brain, may have a negative influence on components of …the resolution cascade. In this pursuit, we exposed microglia to Aβ42 , and with bacterial lipopolysaccharides (LPS) for comparison with a general infectious stimulus. Differential effects were observed: LPS upregulated components of the resolution pathway including the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and phosphorylated 5-lipoxygenase (p-5-LOX), as well as cholinergic alpha 7 nicotinic receptor (α7nAChR) and peroxisome proliferator-activated receptor (PPAR)-δ whereas Aβ42 had an opposite or insignificant effect. Our results indicate that LPS-induced changes in the microglia were conducive for resolution of inflammation, whereas these responses were absent or suppressed in microglia treated with Aβ42 . Further studies may prove if Aβ42 -induced dysfunction of resolution in microglia contributes to the impaired resolution in the AD brain, and if stimulation of microglial resolution constitutes a treatment strategy for AD. Show more

Keywords: α7nAChR, ALX/FPR2, Alzheimer's disease, amyloid, lipopolysaccharide, microglia, specialized pro-resolving mediators

DOI: 10.3233/JAD-141233

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1237-1250, 2015

Authors: Bajic, Vladan | Mandusic, Vesna | Stefanova, Elka | Bozovic, Ana | Davidovic, Radoslav | Zivkovic, Lada | Cabarkapa, Andrea | Spremo-Potparevic, Biljana

Article Type: Research Article

Abstract: X-chromosome instability has been a long established feature in Alzheimer's disease (AD). Premature centromere division and aneuploidy of the X-chromosome has been found in peripheral blood lymphocytes and neuronal tissue in female AD patients. Interestingly, only one chromosome of the X pair has been affected. These results raised a question, “Is the X-chromosome inactivation pattern altered in peripheral blood lymphocytes of women affected by AD?” To address this question, we analyzed the methylation status of androgen receptor promoter which may show us any deviation from the 50 : 50% X inactivation status in peripheral blood lymphocytes of women with AD. …Our results showed skewed inactivation patterns (>90%). These findings suggest that an epigenetic alteration on the inactivation centers of the X-chromosome (or skewing) relates not only to aging, by might be a novel property that could account for the higher incidence of AD in women. Show more

Keywords: Alzheimer's disease, aneuploidy, methylation specific qPCR, X-chromosome, X-chromosome skewing

DOI: 10.3233/JAD-141674

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1251-1259, 2015

Authors: Haghighi, Mona | Smith, Amanda | Morgan, Dave | Small, Brent | Huang, Shuai | for the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Background: Detecting participants who are positive for amyloid-β (Aβ) pathology is germane in designing prevention trials by enriching for those cases that are more likely to be amyloid positive. Existing brain amyloid measurement techniques, such as the Pittsburgh Compound B-positron emission tomography and cerebrospinal fluid, are not reasonable first-line approaches limited by either feasibility or cost. Objective: We aimed to identify simple and cost-effective rules that can predict brain Aβ level by integrating both neuropsychological measurements and blood-based markers. Method: Several decision tree models were built for extracting the predictive rules based on the Alzheimer's Disease …Neuroimaging Initiative cohort. Results: We successfully extracted predictive rules of Aβ level. For cognitive function variables, cases above the 45th percentile in total cognitive score (TOTALMOD), above the 52nd percentile of delayed word recall, and above the 70th percentile in orientation resulted in a group that was highly enriched for amyloid negative cases. Conversely scoring below the 15th percentile of TOTALMOD resulted in a group highly enriched for amyloid positive cases. For blood protein markers, scoring below the 57th percentile for apolipoprotein E (ApoE) levels (irrespective of genotype) enriched two fold for the risk of being amyloid positive. In the high ApoE cases, scoring above the 60th percentile for transthyretin resulted in a group that was >90% amyloid negative. A third decision tree using both cognitive and blood-marker data slightly improved the classification of cases. Conclusion: Our study demonstrated that the integration of the neuropsychological measurements and blood-based markers significantly improved prediction accuracy. The prediction model has led to several simple rules, which have a great potential of being naturally translated into clinical settings such as enrichment screening for AD prevention trials of anti-amyloid treatments. Show more

Keywords: Amyloid, decision rules, neuropsychological tests, plasma markers, prediction

DOI: 10.3233/JAD-140705

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1261-1270, 2015

Authors: Takizawa, Claire | Thompson, Paula L. | van Walsem, Anneloes | Faure, Céline | Maier, William C.

Article Type: Research Article

Abstract: Background: Alzheimer's disease (AD) weighs heavily on health expenditure and is strongly associated with increasing age. Due to population aging, increasing global prevalence of AD will pose huge challenges to public health and elderly care systems in all countries across the world. Objectives: This study aimed to better understand the burden of AD from a healthcare perspective. Methods: A systematic literature review of journal articles published between January 2002 and December 2012 was performed for studies conducted in France, Germany, Italy, The Netherlands, Spain, the United Kingdom (UK), and the United States of America (USA), using …Medline, Embase, and the NHS Economic Evaluation Database. Results: 3,288 references were initially retrieved, and 39 epidemiological and 66 economic publications were selected for data extraction. AD incidence rates greatly varied between countries; however, prevalence was more consistent across all included countries, ranging between 3–7%. Overall, medical costs were lower in France compared to other included countries and increased with AD severity, e.g., direct medical costs per year for mild AD ranged from 5,476 int$ in France to 27,380 int$ in Spain. Limitations, such as heterogeneous methodology and missing data, prevented the comparison of results across studies between countries or the conclusion of any trend over time. Conclusion: This review corroborates previous understanding that AD burden is high for both society and healthcare providers. Limitations regarding study heterogeneity restricted conclusions; further research is required. Stakeholders could benefit from new healthcare strategies addressing both epidemiological and economic aspects of AD. Show more

Keywords: Alzheimer's disease, direct costs, economic, epidemiology, incidence, indirect costs, medical costs, mortality, non-medical costs, prevalence

DOI: 10.3233/JAD-141134

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1271-1284, 2015

Authors: Bonoti, Fotini | Tzouvaleka, Evanthia | Bonotis, Konstantinos | Vlachos, Filippos

Article Type: Research Article

Abstract: Background: Previous studies have shown that AD patients present a stepwise regression to their cognitive functioning from a mature adult to that of an infant. Objectives: The present study aimed to compare Alzheimer's disease (AD) patients' and 4–10 year old children's drawing performance, taking into account that drawing is currently considered as a cognitive process and that AD manifests a severe cognitive impairment. Methods: The sample consisted of 10 AD patients and 10 adult controls, as well as of 40 children, divided into 4 age groups (4-, 6-, 8-, and 10-years old). Participants were asked to …draw from memory (a) six simple objects, (b) a man, and (c) a tree behind a house. Results: Analysis showed an improvement with age in children's drawing performance, while controls' drawing scores were similar to those obtained by older children. On the contrary, drawing performance of AD patients significantly decreased into levels under that of the 4-year old children in drawing errors, or under that of the 8-year old children in drawing a man task and partial occlusion task. Conclusions: The observed regression in AD patients' drawing performance is discussed in relation to the cognitive deficits accompanying the disease. Show more

Keywords: Alzheimer's disease, children, drawing, drawing development, impairment

DOI: 10.3233/JAD-140528

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1285-1292, 2015

Authors: Peña-Longobardo, Luz María | Oliva-Moreno, Juan

Article Type: Research Article

Abstract: Background: Alzheimer's disease constitutes one of the leading causes of burden of disease, and it is the third leading disease in terms of economic and social costs. Objective: To analyze the burden and problems borne by informal caregivers of patients who suffer from Alzheimer's disease in Spain. Data and Methods: We used the Survey on Disabilities, Autonomy and Dependency to obtain information on the characteristics of disabled people with Alzheimer's disease and the individuals who provide them with personal care. Additionally, statistical multivariate analyses using probit models were performed to analyze the burden placed on caregivers …in terms of health, professional, and leisure/social aspects. Results: 46% of informal caregivers suffered from health-related problems as a result of providing care, 90% had leisure-related problems, and 75% of caregivers under 65 years old admitted to suffering from problems related to their professional lives. The probability of a problem arising for an informal caregiver was positively associated with the degree of dependency of the person cared for. In the case of caring for a greatly dependent person, the probability of suffering from health-related problems was 22% higher, the probability of professional problems was 18% higher, and there was a 10% greater probability of suffering from leisure-related problems compared to non-dependents. Conclusions: The results show a part of the large hidden cost for society in terms of problems related to the burden lessened by the caregivers. This information should be a useful tool for designing policies focused toward supporting caregivers and improving their welfare. Show more

Keywords: Alzheimer's disease, burden, caregivers, informal care, social costs

DOI: 10.3233/JAD-141374

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1293-1302, 2015

Authors: Eichler, Tilly | Wucherer, Diana | Thyrian, Jochen René | Kilimann, Ingo | Hertel, Johannes | Michalowsky, Bernhard | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: The present study is the first to analyze primary data about the use of antipsychotic drugs among community dwelling people with dementia in German primary care. Objectives: To determine (1) prevalence of antipsychotic drug treatment in German primary care patients who screened positive for dementia and (2) factors associated with antipsychotic drug treatment. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is an ongoing general practitioner-based, randomized, controlled intervention trial. A total of 4,064 community dwelling patients (≥70 years) recruited from 108 participating practices were screened for dementia (DemTect <9). Of 692 eligible …patients (17%), a total of 406 patients provided informed consent (59%). Present analyses are based on data of 243 patients who completed baseline assessment before January 2014 (preliminary data). Results: Of the 243 patients who screened positive for dementia, a total of 25 patients (10%) received at least one antipsychotic drug. Atypical antipsychotic drugs (64%) were prescribed more often than typical antipsychotic drugs (36%). The results of the multivariate analysis showed that treatment by a specialist (neurologist/psychiatrist) was the only factor significantly associated with antipsychotic drug treatment (odds ratio, 12.86; p < 0.05; 95% confidence interval, 1.04–158.71). Conclusions: Compared to the antipsychotic drug treatment rate among people with dementia living in nursing homes (>50%), the rate we found for community dwelling primary care patients who screened positive for dementia was low. Further research is needed to evaluate if these patients are adequately treated or if the antipsychotic drug treatment should and could be further reduced. Show more

Keywords: Ambulatory care, antipsychotic drugs, dementia, general practitioner, primary health care

DOI: 10.3233/JAD-141554

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1303-1311, 2015

Authors: Salvadori, Emilia | Poggesi, Anna | Pracucci, Giovanni | Inzitari, Domenico | Pantoni, Leonardo | on behalf of the VMCI-Tuscany Study Group

Article Type: Research Article

Abstract: Background and Objective: Vascular cognitive impairment may have a selective neuropsychological profile. We developed a battery for assessing mild cognitive impairment (MCI) in patients with small vessel disease (SVD), its applicability, and psychometric properties. Methods: Among those proposed by the 2006 NINDS-CSN Consensus Conference, we selected tests for which norms based on healthy Italians and equivalent scores methodology were available. Confirmatory factor analysis was applied to ascertain the fit of the theoretically assumed dimensions to empirical data and to derive each cognitive dimension compound measures. Results: The entire battery was applied to 146 out of a …cohort of 201 patients with MCI and SVD. Most tests showed good applicability. Fifty-five patients, who were older and cognitively more impaired, proved unable to complete the Trail Making Test part B, the Rey-Osterrieth Complex Figure, and the Stroop test, and were excluded from the analysis. Among the remaining patients, Mini-Mental State Examination proved largely normal, while Rey-Osterrieth Complex Figure, Symbol digit modalities test, and Trail Making Test part B were most frequently abnormal. Confirmatory factor analysis showed a good fit of the 4-factor theoretical model to empirical data. Praxis domain resulted in the highest percentage of abnormal performance (65%), followed by Memory and Attention/EF domains (19% and 15%), and Language (8%). Conclusions: Our battery proved to be comprehensive, robust, and applicable. Attention-executive dysfunction and impaired memory and visuo-constructional abilities, were the prominent features. The assessment of the Consensus Conference, that included Trial Making Test, looks poorly applicable to older and cognitively impaired patients. Show more

Keywords: Cognitive assessment, confirmatory factor analysis, psychometric properties, small vessel disease, neuropsychology, subcortical ischemic vascular disease

DOI: 10.3233/JAD-141449

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1313-1323, 2015

Authors: Ni, Jun | Auriel, Eithan | Martinez-Ramirez, Sergi | Keil, Boris | Reed, Anne K. | Fotiadis, Panagiotis | Gurol, Edip Mahmut | Greenberg, Steven M. | Viswanathan, Anand

Article Type: Research Article

Abstract: The extent of cortical involvement of cerebral amyloid angiopathy (CAA)-related microbleeds (CMBs) remains unclear. We examined five consecutive patients with probable CAA and three non-demented elderly subjects with ultra-high field 7T MRI, to identify the precise location of CAA-related CMBs. In five CAA patients, 169 of a total of 170 lobar CMBs were located in cortical areas on 7T MRI, while a precise cortical versus juxtacortical localization was unable to be determined for 50/76 CMBs observed by conventional MRI. 7T MRI demonstrates that nearly all lobar CMBs are located in cortex in CAA.

Keywords: Cerebral amyloid angiopathy, cerebral microbleed, cortex, magnetic resonance imaging, ultra-high field

DOI: 10.3233/JAD-140864

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1325-1330, 2015

Authors: Henriksen, Kim | Byrjalsen, Inger | Christiansen, Claus | Karsdal, Morten Asser

Article Type: Research Article

Abstract: Enzyme-generated fragments of tau have been linked to neuronal death and may serve as serum biomarkers of cognitive loss. Two competitive ELISAs detecting an ADAM10-generated fragment (Tau-A) or a caspase-3-generated fragment (Tau-C) were measured in baseline serum samples from patients with mild to moderate Alzheimer's disease (AD) from a Phase III clinical trial, and correlated to change in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Dementia Rating–Sum of Boxes (CDR-SB) over a 64-week period using an MMRM-analysis. Relationship between the biomarkers and changes in ADAS-Cog11 score as a function of time were observed for Tau-C and change in …ADAS-Cog11 (p = 0.06), and for Tau-A and change in CDR-SB (p = 0.04). The correlation of Tau-A/Tau-C ratio with cognitive change assessed by ADAS-Cog11 was even more significant (p < 0.006). These data indicate that measuring the balance between tau fragments in serum may provide a marker of the rate of progression of AD and warrant studies in larger cohorts. Show more

Keywords: Alzheimer's disease, biomarkers, prediction, serum, tau

DOI: 10.3233/JAD-140984

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1331-1341, 2015

Authors: Castellano, Christian-Alexandre | Nugent, Scott | Paquet, Nancy | Tremblay, Sébastien | Bocti, Christian | Lacombe, Guy | Imbeault, Hélène | Turcotte, Éric | Fulop, Tamas | Cunnane, Stephen C.

Article Type: Research Article

Abstract: Background: The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimer's disease (AD). The ketones, acetoacetate and β-hydroxybutyrate, are the brain's main alternative energy substrates to glucose. Objective: To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). Methods: Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults …(Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. Results: ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 ± 5.0 versus 38.3 ± 4.7 μmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p ≤ 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p ≥ 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p ≤ 0.005) but with no difference in CMRa. Conclusion: Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones. Show more

Keywords: Acetoacetate, Alzheimer's disease, β-hydroxybutyrate, cerebral metabolic rate, energy metabolism, glucose, ketones

DOI: 10.3233/JAD-141074

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1343-1353, 2015

Authors: Muenchhoff, Julia | Poljak, Anne | Song, Fei | Raftery, Mark | Brodaty, Henry | Duncan, Mark | McEvoy, Mark | Attia, John | Schofield, Peter W. | Sachdev, Perminder S.

Article Type: Research Article

Abstract: To unlock the full potential of disease modifying treatments, it is essential to develop early biomarkers for Alzheimer's disease (AD). For practical reasons, blood-based markers that could provide a signal at the stage of mild cognitive impairment (MCI) or even earlier would be ideal. Using the proteomic approach of isobaric tagging for relative and absolute quantitation (iTRAQ), we compared the plasma protein profiles of MCI, AD, and cognitively normal control subjects from two independent cohorts: the Sydney Memory and Ageing Study (261 MCI subjects, 24 AD subjects, 411 controls) and the Hunter Community Study (180 MCI subjects, 153 controls). The …objective was to identify any proteins that are differentially abundant in MCI and AD plasma in both cohorts, since they might be of interest as potential biomarkers, or could help direct future mechanistic studies. Proteins representative of biological processes relevant to AD pathology, such as the complement system, the coagulation cascade, lipid metabolism, and metal and vitamin D and E transport, were found to differ in abundance in MCI. In particular, levels of complement regulators C1 inhibitor and factor H, fibronectin, ceruloplasmin, and vitamin D-binding protein were significantly decreased in MCI participants from both cohorts. Several apolipoproteins, including apolipoprotein AIV, B-100, and H were also significantly decreased in MCI. Most of these proteins have previously been reported as potential biomarkers for AD; however, we show for the first time that a significant decrease in plasma levels of two potential biomarkers (fibronectin and C1 inhibitor) is evident at the MCI stage. Show more

Keywords: Alzheimer's disease, apolipoproteins, biomarkers, complement system proteins, fibrinogen, fibronectin, mild cognitive impairment, plasma, proteomics, vitamin D-binding protein

DOI: 10.3233/JAD-141266

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1355-1373, 2015

Authors: Monteiro-Cardoso, Vera F. | Oliveira, M. Manuel | Melo, Tânia | Domingues, Maria R.M. | Moreira, Paula I. | Ferreiro, Elisabete | Peixoto, Francisco | Videira, Romeu A.

Article Type: Research Article

Abstract: Brain mitochondria are fundamental to maintaining healthy functional brains, and their dysfunction is involved in age-related neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we conducted a research on how both non-synaptic and synaptic mitochondrial functions are compromised at an early stage of AD-like pathologies and their correlation with putative changes on membranes lipid profile, using 3 month-old nontransgenic and 3xTg-AD mice, a murine model of experimental AD. Bioenergetic dysfunction in 3xTg-AD brains is evidenced by a decrease of brain ATP levels resulting, essentially, from synaptic mitochondria functionality disruption as indicated by declined respiratory control ratio associated with …a 50% decreased complex I activity. Lipidomics studies revealed that synaptic bioenergetic deficit of 3xTg-AD brains is accompanied by alterations in the phospholipid composition of synaptic mitochondrial membranes, detected either in phospholipid class distribution or in the phospholipids molecular profile. Globally, diacyl- and lyso-phosphatidylcholine lipids increase while ethanolamine plasmalogens and cardiolipins content drops in relation to nontransgenic background. However, the main lipidomic mark of 3xTg-AD brains is that cardiolipin cluster-organized profile is lost in synaptic mitochondria due to a decline of the most representative molecular species. In contrast to synaptic mitochondria, results support the idea that non-synaptic mitochondria function is preserved at the age of 3 months. Although the genetically construed 3xTg-AD mouse model does not represent the most prevalent form of AD in humans, the present study provides insights into the earliest biochemical events in AD brain, connecting specific lipidomic changes with synaptic bioenergetic deficit that may contribute to the progressive synapses loss and the neurodegenerative process that characterizes AD. Show more

Keywords: Alzheimer's disease, brain bioenergetics, cardiolipin, mitochondrial lipidomics

DOI: 10.3233/JAD-141002

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1375-1392, 2015

Authors: Thordardottir, Steinunn | Ståhlbom, Anne Kinhult | Ferreira, Daniel | Almkvist, Ove | Westman, Eric | Zetterberg, Henrik | Eriksdotter, Maria | Blennow, Kaj | Graff, Caroline

Article Type: Research Article

Abstract: Background: It is currently believed that therapeutic interventions will be most effective when introduced at the preclinical stage of Alzheimer's disease (AD). This underlines the importance of biomarkers to detect AD pathology in vivo before clinical disease onset. Objective: To examine the evolution of cerebrospinal fluid (CSF) biomarker and brain structure changes in the preclinical phase of familial AD. Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y, or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 mutation carriers (MC) and 20 non-carriers …(NC) and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC from familial AD families and analyzed for Aβ42 , total tau (T-tau) and phospho-tau (P-tau). Results: The MC had significantly lower levels of CSF Aβ42 and higher levels T-tau and P-tau than the NC. There was a trend for a decrease in Aβ42 15–20 years before expected onset of clinical symptoms, while increasing T-tau and P-tau was not found until close to the expected clinical onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus, and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical familial AD, several years before the expected onset of clinical symptoms. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, genetics, magnetic resonance imaging, natural history studies, preclinical

DOI: 10.3233/JAD-140339

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1393-1402, 2015

Authors: Tan, Ji-ping | Li, Nan | Gao, Jing | Wang, Lu-ning | Zhao, Yi-ming | Yu, Bao-cheng | Du, Wei | Zhang, Wen-jun | Cui, Lian-qi | Wang, Qing-song | Li, Jian-jun | Yang, Jin-sheng | Yu, Jian-min | Xia, Xiang-nan | Zhou, Pei-yi

Article Type: Research Article

Abstract: Background: All versions of the Montreal Cognitive Assessment (MoCA) lack population-based data of 80-plus individuals. The norms and cut-off scores for mild cognitive impairment (MCI) and dementia of the MoCA are different among five Chinese versions. Objective: To provide the cut-off scores in detecting MCI and dementia of the Peking Medical Union College Hospital version of the MoCA (MoCA-P). Methods: In a cross-sectional survey, Chinese veterans aged ≥60 years completed the MoCA-P and the Mini-Mental State Examination (MMSE). Results: Among 7,445 elderly veterans, 5,085 (68.30%) were aged ≥80 years old, 2,621 (35.20%) had 6 …years of education or less, 6,847 (91.97%) were male, and 2,311 (31.04%) and 984 (13.22%) veterans were diagnosed as having MCI and dementia, respectively. Adding two points and one point to the MoCA scores for the primary and middle school groups, respectively, can fully adjust for the notable impact of education but cannot compensate for the effect of age. In the three age groups (60–79, 80–89, and ≥90 years old), the optimal MoCA-P cut-off scores for detecting MCI were ≤25, ≤24, and ≤23, respectively, and for detecting dementia were ≤24, ≤21, and ≤19, respectively, which demonstrated relatively high sensitivities and specificities. The areas under the curves for the MoCA-P for detecting MCI and dementia (0.937 and 0.908, respectively) were greater than those for the MMSE (0.848 and 0.892, respectively). Conclusion: Compared with the MMSE, the MoCA-P is significantly better for detecting MCI in the elderly, particularly in the oldest old population, and it also displays more effectiveness in detecting dementia. Show more

Keywords: Dementia, elderly, mild cognitive impairment, Mini-Mental State Examination, Montreal Cognitive Assessment, oldest old

DOI: 10.3233/JAD-141278

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1403-1412, 2015

Authors: Ma, Quan | Ying, Ming | Sui, Xiaojing | Zhang, Huimin | Huang, Haiyan | Yang, Linqing | Huang, Xinfeng | Zhuang, Zhixiong | Liu, Jianjun | Yang, Xifei

Article Type: Research Article

Abstract: Copper is an essential element for human growth and development; however, excessive intake of copper could contribute to neurotoxicity. Here we show that chronic exposure to copper in drinking water impaired spatial memory with simultaneous selective loss of hippocampal pre-synaptic protein synapsin 1, and post-synaptic density protein (PSD)-93/95 in mice. Copper exposure was shown to elevate the levels of nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG) in hippocampus, two markers of oxidative stress. Concurrently, we also found that copper exposure activated double stranded RNA-dependent protein kinase (PKR) as evidenced by increased ratio of phosphorylated PKR at Thr451 and total PKR and increased the …phosphorylation of its downstream signaling molecule eukaryotic initiation factor 2α (eIF2α) at Ser51 in hippocampus. Consistent with activation of PKR/eIF2α signaling pathway which was shown to mediate synaptic deficit and cognitive impairment, the levels of activating transcription factor 4 (ATF-4), a downstream signaling molecule of eIF2α and a repressor of CREB-mediated gene expression, were significantly increased, while the activity of cAMP response elements binding protein (CREB) was inactivated as suggested by decreased phosphorylation of CREB at Ser133 by copper exposure. In addition, the expression of the pro-apoptotic target molecule C/EBP homology protein (CHOP) of ATF-4 was upregulated and hippocampal neuronal apoptosis was induced by copper exposure. Taken together, we propose that chronic copper exposure might cause spatial memory impairment, selective loss of synaptic proteins, and neuronal apoptosis through the mechanisms involving activation of PKR/eIF2α signaling pathway. Show more

Keywords: Copper, double stranded RNA-dependent protein kinase (PKR), eukaryotic initiation factor 2α (eIF2α), spatial learning and memory, synaptic proteins

DOI: 10.3233/JAD-140216

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1413-1427, 2015

Authors: Santangelo, Roberto | Coppi, Elisabetta | Ferrari, Laura | Bernasconi, Maria Paola | Pinto, Patrizia | Passerini, Gabriella | Comi, Giancarlo | Magnani, Giuseppe

Article Type: Research Article

Abstract: Background: Three variants of primary progressive aphasia (PPA) have been currently characterized: non fluent/agrammatic (nfv-PPA), semantic (sv-PPA), and logopenic variant (lv-PPA). lv-PPA is most commonly associated with Alzheimer's disease (AD), while nfv-PPA and sv-PPA are related to frontotemporal lobar degeneration. Objective: We aimed to determine whether cerebrospinal fluid (CSF) amyloid-β42 (Aβ42 ), total tau protein (t-tau), and phosphorylated tau (p-tau), frequently abnormal in AD, could constitute a useful tool in the PPA diagnostic work up, in order to identify subjects with an underlying AD pathology. Methods: We measured CSF biomarker levels in a group of twenty-eight …patients, fourteen lv-PPA, nine nfv-PPA, and five sv-PPA. Results: Since there were no significant differences in any of the parameters investigated between nfv-PPA and sv-PPA, the two groups were considered as one (nfv/sv-PPA). At diagnosis, lv-PPA were older than nfv/sv-PPA patients (mean values: 70.7 versus 64.6 years, p = 0.02). CSF biomarker mean concentrations were significantly different in lv-PPA versus nfv/sv-PPA patients (p = 0.000): Aβ42 350.64 versus 661.64 ng/L; tau 631.21 versus 232.71 ng/L; p-tau 101 versus 38.21 ng/L. According to the recent AD diagnostic criteria, (Cummings et al., 2013) eleven lv-PPA and only one nfv/sv-PPA showed a liquoral pattern typical for AD. Finally lv-PPA had CSF biomarker levels very similar to a sample of 72 AD patients from our Department. Conclusions: Our data showed that CSF biomarkers can easily and reliably detect those patients with language disorders due to an underlying AD pathology, thus offering the possibility of targeted therapeutic interventions. However, because of the small sample size, such analyses should be reproduced in larger populations of patients to confirm our data. Show more

Keywords: CSF biomarkers, logopenic variant, non fluent-agrammatic variant, primary progressive aphasia, semantic variant

DOI: 10.3233/JAD-141122

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1429-1440, 2015

Authors: Ma, Fei | Wu, Tianfeng | Miao, Rujuan | Xiao, Yan yu | Zhang, Wenwen | Huang, Guowei

Article Type: Research Article

Abstract: Type 2 diabetes mellitus (T2DM) is associated with dementia. Mild cognitive impairment (MCI) is a key determinant in this association. It is not clear whether T2DM increases the risk of conversion from MCI to dementia. We plan to explore the relationship between T2DM-MCI and dementia and identify its potential risk factors. A prospective community-based cohort study was conducted from March 2010 to March 2014, including 634 participants with T2DM-MCI, 261 T2DM participants who were cognitively intact, and 585 MCI participants without diabetes. All cohort members received detailed annual evaluations to detect dementia onset during the 5 years of follow-up. The …three cohorts were compared to assess differences in dementia onset. Furthermore, Cox proportional hazards regression was used to identify risk factors for dementia onset in the T2DM-MCI cohort. During follow-up, 152 and 49 subjects developed dementia in the MCI and cognitively-intact cohorts, amounting to an adjusted hazard ratio (HR) of 1.66 (95% CI 1.07–2.26). In a survival analysis of the cohorts, MCI accelerated the median progression to dementia by 2.74 years. In a multivariable analysis of the T2DM-MCI cohort, major risk factors for dementia were age >75 years and longer durations of diabetes, while significantly reduced risks of dementia were associated with oral hypoglycemic agents and HMG-CoA reductase inhibitors. Insulin was not associated with significantly changed risk. T2DM-MCI may aggravate the clinical picture as a concomitant factor. To minimize progression to dementia, it may be worthwhile to target several modifiable diabetes-specific features, such as the duration of disease, glycemic control, and antidiabetic agents. Show more

Keywords: Alzheimer's disease, cohort study, mild cognitive impairment, risk factors, type 2 diabetes mellitus

DOI: 10.3233/JAD-141566

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1441-1449, 2015

Article Type: Other

DOI: 10.3233/JAD-141567

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1451-1453, 2015

Article Type: Other

DOI: 10.3233/JAD-2015-43432

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1455-1469, 2015