Journal of Alzheimer's Disease - Volume 46, issue 4

Authors: Wang, Hui | Tan, Lan | Wang, Hui-Fu | Liu, Ying | Yin, Rui-Hua | Wang, Wen-Ying | Chang, Xiao-Long | Jiang, Teng | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The application of non-invasive proton magnetic resonance spectroscopy (1 H-MRS) could potentially identify changes in cerebral metabolites in the patients with Alzheimer’s disease (AD). However, whether these metabolites can serve as biomarkers for the diagnosis of AD remains unclear. Objective: Using meta-analysis, we aimed to investigate the patterns of cerebral metabolite changes in several cerebral regions that are strongly associated with cognitive decline in AD patients. Methods: Using Hedges’ g effect size, a systematic search was performed in PubMed, Cochrane Library, Ovid, Embase, and EBSCO, and 38 studies were integrated into the final meta-analysis. …Results: According to the observational studies, N-acetyl aspartate (NAA) in AD patients was significantly reduced in the posterior cingulate (PC) (effect size (ES) =−0.924, p  <  0.005) and bilateral hippocampus (left hippocampus: ES =−1.329, p  <  0.005; right hippocampus: ES =−1.287, p  <  0.005). NAA/Cr (creatine) ratio decreased markedly in the PC (ES =−1.052, p  <  0.005). Simultaneously, significant elevated myo-inositol (mI)/Cr ratio was found not only in the PC but also in the parietal gray matter. For lack of sufficient data, we failed to elucidate the efficacy of pharmacological interventions with the metabolites changes. Conclusion: The available data indicates that NAA, mI, and the NAA/Cr ratio might be potential biomarkers of brain dysfunction in AD subjects. Choline (Cho)/Cr and mI/NAA changes might also contribute toward the diagnostic process. Thus, large, well-designed studies correlated with cerebral metabolism are needed to better estimate the cerebral extent of alterations in brain metabolite levels in AD patients. Show more

Keywords: Alzheimer’s disease, choline, creatine, glutamate and glutamine, magnetic resonance spectroscopy, meta-analysis, myo-inositol, N-acetyl aspartate

DOI: 10.3233/JAD-143225

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1049-1070, 2015

Authors: DiFrancesco, Jacopo C. | Touat, Mehdi | Caulo, Massimo | Gallucci, Massimo | Garcin, Béatrice | Levy, Richard | Uncini, Antonino | Piazza, Fabrizio

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) represents the most readily responsive form of CAA, if diagnosed and treated early. Although CAA-ri typically presents with a monophasic pattern, recurrences have been occasionally reported. Objectives: To describe the evolution of the clinical and neuroradiological features of CAA-ri recurrence. Methods: From the 60 CAA-ri cases recruited through the i CAβ International Network, we identified those patients who experienced a CAA-ri recurrence at more than 12 months after the first inflammatory event. Neuroradiological evidence of cerebral inflammation (vasogenic edema) and sulcal superficial siderosis or multiple areas of cortical/subcortical microhemorrhages …(MHs) were evaluated based upon fluid-attenuated inversion recovery and T2 * -weighted gradient echo or susceptibility weighted imaging, respectively. In one patient, the deposition of amyloid-β was evaluated using 11 C-Pittsburgh Compound B-positron emission tomography (PiB-PET). Results : Of the 60 cases, two were identified as having experienced a late CAA-ri recurrence, at two and seven years after the first presentation, respectively. At recurrence, the inflammatory lesions colocalized with the appearance of new MHs and were observed in brain areas different from those where the first onset occurred. PiB-PET four months after remission showed particularly low amyloid-β deposition in the left frontal lobe, while no change was observed in the area of the inflammatory relapse. Conclusions: Our observations highlight the importance of not underestimating any new neurological symptoms in patients who have already experienced an episode of CAA-ri. Although the frequency of CAA-ri recurrences is rare, in cases of suspected relapse, a prompt clinical and radiological follow-up should be considered in order to obtain a timely diagnosis and treatment, having a potential strong impact on patients’ clinical outcome. Show more

Keywords: Alzheimer’s disease, amyloid-PET, amyloid-related imaging abnormalities, cerebral amyloid angiopathy related inflammation, immunotherapy trials, iCAβ International Network, inflammatory relapse, microhemorrhages, steroid treatment, vasogenic edema

DOI: 10.3233/JAD-150070

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1071-1077, 2015

Authors: Burnham, Samantha C. | Raghavan, Nandini | Wilson, William | Baker, David | Ropacki, Michael T. | Novak, Gerald | Ames, David | Ellis, Kathryn | Martins, Ralph N. | Maruff, Paul | Masters, Colin L. | Romano, Gary | Rowe, Christopher C. | Savage, Greg | Macaulay, S. Lance | Narayan, Vaibhav A. | for the Alzheimer’s Disease Neuroimaging Initiative | the AIBL Research Group

Article Type: Research Article

Abstract: Background: There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer’s disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. Objective: To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. Methods: An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, …as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the study. Results: The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites. Conclusion: A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial. Show more

Keywords: Alzheimer’s disease, clinical marker, clinical trial, mild cognitive impairment, prodromal stage

DOI: 10.3233/JAD-143015

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1079-1089, 2015

Authors: Bogstedt, Anna | Groves, Maria | Tan, Keith | Narwal, Rajesh | McFarlane, Mary | Höglund, Kina

Article Type: Research Article

Abstract: Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aβ42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free …Aβ42 concentration (unbound) in CSF, and Aβ40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aβ protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aβ42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aβ42 in plasma, a 4-fold and 8-fold increase in total Aβ42 in CSF together with a 95% and 96% reduction of free Aβ42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aβ40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aβ42 . Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cerebrospinal fluid, immunotherapy, plasma, pre-clinical

DOI: 10.3233/JAD-142988

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1091-1101, 2015

Authors: Jongbloed, Wesley | van Dijk, Karin D. | Mulder, Sandra D. | van de Berg, Wilma D.J. | Blankenstein, Marinus A. | van der Flier, Wiesje | Veerhuis, Robert

Article Type: Research Article

Abstract: Background: Increased clusterin levels have been reported in brain, cerebrospinal fluid (CSF), and plasma of Alzheimer’s disease (AD) patients. Because changes are also observed in mild cognitive impairment (MCI), a possible relationship between clusterin levels and early neurodegenerative changes in AD was suggested. Objectives: To determine whether clusterin concentrations could 1) serve as a diagnostic marker for AD, 2) predict disease progression in MCI, and 3) correlate with AD-biomarkers. Methods: Clusterin levels in CSF and plasma, as well as AD biomarker levels of Aβ 42 , Tau, and pTau in CSF and Mini-Mental State …Examination scores (MMSE) were determined in 67 controls, 50 MCI, and 107 AD patients. Repeated MMSE was obtained for 44 MCI and 72 AD patients after, on average, 2.7 years. Results: Elevated clusterin concentrations in plasma, but not in CSF, were a risk factor for AD (HR 18.6; 95% CI 2.8–122), and related to cognitive decline in MCI (r  =−0.38; p  <  0.01). An inverse relation between plasma clusterin levels and cognitive decline was observed in AD patients (r  = 0.23; p ≤0.05). In CSF, but not in plasma, clusterin levels correlated with Tau and pTau in all groups. Conclusion: Elevated plasma clusterin levels in MCI confer an increased risk for progression to AD, and more rapid cognitive decline. We speculate that clusterin levels in CSF may reflect its involvement in the earliest neurodegenerative processes associated with AD pathology. Whereas neither clusterin levels in CSF nor in plasma had diagnostic value, plasma clusterin levels may serve as a prognostic marker for AD. Show more

Keywords: Alzheimer’s disease, apolipoprotein J, biomarker, cerebrospinal fluid, clusterin, disease progression, mild cognitive impairment, plasma

DOI: 10.3233/JAD-150036

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1103-1110, 2015

Authors: Gustafson, Deborah R. | Clare Morris, Martha | Scarmeas, Nikolaos | Shah, Raj C. | Sijben, John | Yaffe, Kristine | Zhu, Xiongwei

Article Type: Meeting Report

Abstract: Accumulating evidence shows nutritional factors influence the risk of developing Alzheimer’s disease (AD) and its rate of clinical progression. Dietary and lifestyle guidelines to help adults reduce their risk have been developed. However, the clinical dementia picture remains complex, and further evidence is required to demonstrate that modifying nutritional status can protect the brain and prevent, delay, or reduce pathophysiological consequences of AD. Moreover, there is a pressing need for further research because of the global epidemic of overweight and obesity combined with longer life expectancy of the general population and generally observed decreases in body weight with aging and …AD. A new research approach is needed, incorporating more sophisticated models to account for complex scenarios influencing the relationship between nutritional status and AD. Systematic research should identify and address evidence gaps. Integrating longitudinal epidemiological data with biomarkers of disease, including brain imaging technology, and randomized controlled interventions may provide greater insights into progressive and subtle neurological changes associated with dietary factors in individuals at risk for or living with AD. In addition, greater understanding of mechanisms involved in nutritional influences on AD risk and progression, such as oxidative stress and loss of neuronal membrane integrity, will better inform possible interventional strategies. There is consensus among the authors that nutritional deficits, and even states of excess, are associated with AD, but more work is needed to determine cause and effect. Appropriately designed diets or nutritional interventions may play a role, but additional research is needed on their clinical–cognitive effectiveness. Show more

Keywords: Alzheimer’s disease, cognition disorders, diet therapy, neuronal membrane, nutrition

DOI: 10.3233/JAD-150084

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1111-1127, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150337

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1129-1133, 2015

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1135-1146, 2015