Journal of Alzheimer's Disease - Volume 43, issue 2

Authors: Tucker, Stina | Möller, Christer | Tegerstedt, Karin | Lord, Anna | Laudon, Hanna | Sjödahl, Johan | Söderberg, Linda | Spens, Erika | Sahlin, Charlotte | Waara, Erik Rollman | Satlin, Andrew | Gellerfors, Pär | Osswald, Gunilla | Lannfelt, Lars

Article Type: Research Article

Abstract: Amyloid-β (Aβ) immunotherapy for Alzheimer's disease (AD) has good preclinical support from transgenic mouse models and clinical data suggesting that a long-term treatment effect is possible. Soluble Aβ protofibrils have been shown to exhibit neurotoxicity in vitro and in vivo, and constitute an attractive target for immunotherapy. Here, we demonstrate that the humanized antibody BAN2401 and its murine version mAb158 exhibit a strong binding preference for Aβ protofibrils over Aβ monomers. Further, we confirm the presence of the target by showing that both antibodies efficiently immunoprecipitate soluble Aβ aggregates in human AD brain extracts. mAb158 reached the brain and reduced …the brain protofibril levels by 42% in an exposure-dependent manner both after long-term and short-term treatment in tg-ArcSwe mice. Notably, a 53% reduction of protofibrils/oligomers in cerebrospinal fluid (CSF) that correlated with reduced brain protofibril levels was observed after long-term treatment, suggesting that CSF protofibrils/oligomers could be used as a potential biomarker. No change in native monomeric Aβ42 could be observed in brain TBS extracts after mAb158-treatment in tg-ArcSwe mice. By confirming the specific ability of mAb158 to selectively bind and reduce soluble Aβ protofibrils, with minimal binding to Aβ monomers, we provide further support in favor of its position as an attractive new candidate for AD immunotherapy. BAN2401 has undergone full phase 1 development, and available data indicate a favorable safety profile in AD patients. Show more

Keywords: Alzheimer's disease, amyloid-β, antibody, BAN2401, biomarker, cerebrospinal fluid, immunotherapy, mAb158, oligomer, protofibrils

DOI: 10.3233/JAD-140741

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 575-588, 2015

Authors: Tan, Meng-Shan | Yu, Jin-Tai | Tan, Chen-Chen | Wang, Hui-Fu | Meng, Xiang-Fei | Wang, Chong | Jiang, Teng | Zhu, Xi-Chen | Tan, Lan

Article Type: Research Article

Abstract: Background: Research into Ginkgo biloba has been ongoing for many years, while the benefit and adverse effects of Ginkgo biloba extract EGb761 for cognitive impairment and dementia has been discussed controversially. Objective: To discuss new evidence on the clinical and adverse effects of standardized Ginkgo biloba extract EGb761 for cognitive impairment and dementia. Methods: MEDLINE, EMBASE, Cochrane, and other relevant databases were searched in March 2014 for eligible randomized controlled trials of Ginkgo biloba EGb761 therapy in patients with cognitive impairment and dementia. Results: Nine trials met our inclusion criteria. Trials were of 22–26 …weeks duration and included 2,561 patients in total. In the meta-analysis, the weighted mean differences in change scores for cognition were in favor of EGb761 compared to placebo (−2.86, 95%CI −3.18; −2.54); the standardized mean differences in change scores for activities in daily living (ADLs) were also in favor of EGb761 compared to placebo (−0.36, 95%CI −0.44; −0.28); Peto OR showed a statistically significant difference from placebo for Clinicians' Global Impression of Change (CGIC) scale (1.88, 95%CI 1.54; 2.29). All these benefits are mainly associated with EGb761 at a dose of 240 mg/day. For subgroup analysis in patients with neuropsychiatric symptoms, 240 mg/day EGb761 improved cognitive function, ADLs, CGIC, and also neuropsychiatric symptoms with statistical superiority than for the whole group. For the Alzheimer's disease subgroup, the main outcomes were almost the same as the whole group of patients with no statistical superiority. Finally, safety data revealed no important safety concerns with EGb761. Conclusions: EGb761 at 240 mg/day is able to stabilize or slow decline in cognition, function, behavior, and global change at 22–26 weeks in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms. Show more

Keywords: Adverse effects, cognitive impairment, dementia, efficacy, Ginkgo biloba, meta-analysis, systematic review

DOI: 10.3233/JAD-140837

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 589-603, 2015

Authors: Solfrizzi, Vincenzo | Panza, Francesco

Article Type: Research Article

Abstract: Among nutraceuticals and nutritional bioactive compounds, the standardized Ginkgo biloba extract EGb 761 is the most extensively clinically tested herbal-based substance for cognitive impairment, dementia, and Alzheimer's disease (AD). In the last three years, notwithstanding negative meta-analytic findings and the discouraging results of preventive trials against AD, some randomized controlled trials focusing particularly on dementia, AD, and mild cognitive impairment (MCI) subgroups with neuropsychiatric symptoms (NPS) and some recent meta-analyses have suggested a renowned role for EGb 761 for cognitive impairment and dementia. Meta-analytic findings suggested overall benefits of EGb 761 for stabilizing or slowing decline in cognition of subjects …with cognitive impairment and dementia. The safety and tolerability of EGb 761 appeared to be excellent at different doses. Subgroup analyses showed that these clinical benefits of EGb 761 were mainly associated with the 240 mg/day dose, and also confirmed in the AD subgroup. More importantly, one of these meta-analyses showed clinical benefits in cognition, behavior, functional status, and global clinical change of EGb 761 at a dose of 240 mg/day in the treatment of patients with dementia, AD, and MCI with NPS. The inclusion of the recent randomized controlled trials focusing on dementia, AD, and MCI subgroups with NPS may partly explain the conflicting results of these recent meta-analyses and previous pooled findings. Show more

Keywords: Alzheimer's disease, cognitive impairment, dementia, EGb 761, Gingko biloba extract, meta-analysis, mild cognitive impairment, nutraceuticals, systematic review

DOI: 10.3233/JAD-141887

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 605-611, 2015

Authors: Pisa, Diana | Alonso, Ruth | Juarranz, Angeles | Rábano, Alberto | Carrasco, Luis

Article Type: Research Article

Abstract: Recently, we have reported the presence of fungal infections in patients with Alzheimer's disease (AD). Accordingly, fungal proteins and DNA were found in brain samples, demonstrating the existence of infection in the central nervous system. In the present work, we raised antibodies to specific fungal species and performed immunohistochemistry to directly visualize fungal components inside neurons from AD patients. Mice infected with Candida glabrata were initially used to assess whether yeast can be internalized in mammalian tissues. Using polyclonal rabbit antibodies against C. glabrata, rounded immunopositive cells could be detected in the cytoplasm of cells from liver, spleen, and brain …samples in infected, but not uninfected, mice. Immunohistochemical analyses of tissue from the frontal cortex of AD patients revealed the presence of fungal material in a small percentage (~10%) of cells, suggesting the presence of infection. Importantly, this immunopositive material was absent in control samples. Confocal microscopy indicated that this fungal material had an intracellular localization. The specific morphology of this material varied between patients; in some instances, disseminated material was localized to the cytoplasm, whereas small punctate bodies were detected in other patients. Interestingly, fungal material could be revealed using different anti-fungal antibodies, suggesting multiple infections. In summary, fungal infection can only be observed using specific anti-fungal antibodies and only a small percentage of cells contain fungi. Our findings provide an explanation for the hitherto elusive detection of fungi in AD brains, and are consistent with the idea that fungal cells are internalized inside neurons. Show more

Keywords: Candida, fungal infection, intracellular infection, neurodegenerative disease

DOI: 10.3233/JAD-141386

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 613-624, 2015

Authors: Boutoleau-Bretonnière, Claire | Camuzat, Agnès | Le Ber, Isabelle | Bouya-Ahmed, Kawtar | Guerreiro, Rita | Deruet, Anne-Laure | Evrard, Christelle | Bras, José | Lamy, Estelle | Auffray-Calvier, Elisabeth | Pallardy, Amandine | Hardy, John | Brice, Alexis | Derkinderen, Pascal | Vercelletto, Martine

Article Type: Research Article

Abstract: SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

Keywords: Amyotrophic lateral sclerosis, apraxia of speech, behavioral variant of FTD, frontotemporal lobar degeneration, non fluent variant of primary progressive aphasia, p62, Paget disease of bone, progressive non-fluent aphasia, progressive supranuclear palsy, SQSTM1

DOI: 10.3233/JAD-141512

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 625-630, 2015

Authors: Cespón, Jesús | Galdo-Álvarez, Santiago | Pereiro, Arturo X. | Díaz, Fernando

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) may represent a prodromal stage of Alzheimer's disease (AD), although the clinical manifestations of MCI are heterogeneous. Consequently, MCI subtypes are differentiated since amnestic decline (particularly when combined with decline on multiple cognitive domains) increases the probability of progression to AD. In the present study, event-related potential (ERP) correlates of stimulus evaluation (N2), visuospatial attention (negativity posterior-contralateral, N2pc), stimulus categorization (P3b), executive control (pre-response positivity, PP, and medial frontal negativity), and motor (lateralized readiness potential, LRP) processes were studied in 53 participants while they performed a Simon task. Participants were divided into control group (CG), multiple-domain …non-amnestic MCI (mdnaMCI), single-domain amnestic MCI (sdaMCI), and multiple-domain amnesic MCI (mdaMCI). Although there were no differences in reaction times and percentage of errors in the performed Simon-type task, a differential pattern of electrophysiological correlates was observed in MCI compared to CG. Concretely, amnestic MCI (sdaMCI and mdaMCI) showed reduced motor activity (LRP amplitude; AUC: 0.84); impairment in executive control (PP amplitude; AUC: 0.80) was observed in multiple-domain MCI (mdaMCI and mdnaMCI); finally, stimulus evaluation (N2 latency; AUC: 0.86) and visuospatial attention (N2pc amplitude; AUC: 0.78) was affected in mdaMCI. Overall, results linked the poorer prognosis of the mdaMCI subtype with a greater number of differences in ERP correlates regarding CG. Therefore, the present results enable us to suggest possible ERP biomarkers for specific MCI subtypes. Show more

Keywords: Central nervous system diseases, mental processes, neurodegenerative diseases, psychophysiology

DOI: 10.3233/JAD-132774

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 631-647, 2015

Authors: Wang, Xingbin | Lopez, Oscar L. | Sweet, Robert A. | Becker, James T. | DeKosky, Steven T. | Barmada, Mahmud M. | Demirci, F. Yesim | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as “rapid progressors” if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and “slow progressors” if the …MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p = 0.94) or APOE*2 (p = 0.33) with AD progression, we found multiple nominally significant associations (p < 0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. Show more

Keywords: Alzheimer's disease progression, genome-wide association studies, late-onset Alzheimer's disease, Mini-Mental State Examination

DOI: 10.3233/JAD-140729

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 649-655, 2015

Authors: Chen, Jiu | Shu, Hao | Wang, Zan | Liu, Duan | Shi, Yongmei | Zhang, Xiangrong | Zhang, Zhijun

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) gene has been confirmed as the major genetic risk factor for the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). The present study was to assess whether there was a specific interaction of APOE by the aging process on brain morphology in aMCI. The analysis of gray matter (GM) voxel-based morphometry was performed in 85 aMCI and 100 healthy controls (HC). A significant interaction of APOE genotype by age on GM volume was found in the left calcarine, the left insula, and the left medial frontal gyrus in aMCI. GM volume in aMCI …decreased significantly with ε 2-carriers < ε3/ε3 < ε4-carriers in above brain regions (except the left insula) while there was only a reduced tendency in HC. The multivariate regression analysis showed the well-known negative relationship for ε4-carriers and the positive relationship for ε2-carriers (except the left insula), while no correlations were found for ε3/ε3 between age and GM volumes on above brain regions. Moreover, the reduced GM volumes in the left calcarine and insula correlated with the impairment of visuo-spatial cognition and episodic memory in ε4- and ε2-carriers but not ε3/ε3, respectively. These results suggest that the APOE ε4 and ε2 alleles have the opposing effects on brain morphology across the spectrum of cognitive aging. Moreover, the interaction of APOE by age on brain morphology may accelerate the pathological progression of late-life cognitive decline in aMCI with ε4-carriers and delay the possible conversion from aMCI with ε2-carriers to AD. Show more

Keywords: Age, amnestic mild cognitive impairment, apolipoprotein E, episodic memory, voxel-based morphometry

DOI: 10.3233/JAD-141677

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 657-668, 2015

Authors: Xu, Xin | Xiao, Shifu | Rahardjo, Tri Budi | Hogervorst, Eef

Article Type: Research Article

Abstract: Tofu is a soy product which is commonly consumed in Asian countries, such as China and Indonesia. Several studies found negative associations of high tofu consumption with cognitive function in older Asian populations. However, the effect of tofu on cognitive function remains disputed as it was not found in Western populations. In the present study, the effect of weekly tofu intake on cognitive performance was investigated in an observational cross sectional study of 517 Chinese elderly from Shanghai. Similar to earlier studies, results showed that a higher weekly intake of tofu was associated with worse memory performance using the Hopkins …Verbal Learning Test (β = −0.10, p = 0.01) after controlling for age, gender, education, being vegetarian, and weekly intake of fruit/juice, green vegetables, and orange/red vegetables. Furthermore, among older elderly (≥68 years of age), high tofu intake increased the risk of cognitive impairment indicative of dementia (OR = 1.27, 95% CI = 0.99–1.64, p = 0.04), after adjusting for all covariates. Consumption of meat and green vegetables independently also reduced risk of dementia. To conclude, high intake of tofu was negatively related to cognitive performance among community-dwelling elderly in China. Similar findings were reported in Indonesia and in Japanese Americans in the US. These findings suggest that the effect of tofu on cognition in elderly should be further investigated. Show more

Keywords: China, cognition, dementia, memory, tofu

DOI: 10.3233/JAD-141593

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 669-675, 2015

Authors: Hollands, Simone | Lim, Yen Ying | Buckley, Rachel | Pietrzak, Robert H. | Snyder, Peter J. | Ames, David | Ellis, Kathryn A. | Harrington, Karra | Lautenschlager, Nicola | Martins, Ralph N. | Masters, Colin L. | Villemagne, Victor L. | Rowe, Christopher C. | Maruff, Paul | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: The detection of early Alzheimer's disease (AD) can rely on subjective and informant reports of cognitive impairment. However, relationships between subjective cognitive impairment, objectively measured cognitive function, and amyloid-β (Aβ) biomarkers remain unclear. Objective: To determine the extent to which impairment or decline in subjective and informant rated cognitive impairment was associated with memory in healthy older adults with high Aβ. Methods: Healthy older adults (n = 289) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were studied at baseline. Pittsburgh Compound B was used to determine Aβ status at baseline. At baseline …and 18 months assessments, subjective memory impairment was assessed using the Memory Complaint Questionnaire and the Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly. Cognition was measured using the Cogstate Brief Battery. Results: At baseline, there were no differences between low and high Aβ groups in subjective or informant-rated cognitive impairment, depressive and anxiety symptoms, or cognitive function. Longitudinal analyses showed moderate decline in learning and working memory over the 18 months in the high Aβ group. However there was no change over time in subjective or informant-rated cognitive impairment, depressive and anxiety symptoms, or cognition in either Aβ group. Conclusions: Although healthy older adults with high Aβ levels show decline in learning and working memory over 18 months, subjective or informant ratings of cognitive impairment do not change over the same period suggesting subjective cognitive impairment may have limited utility for the very early identification of AD. Show more

Keywords: Amyloid, cognitive, depression, subjective memory impairment

DOI: 10.3233/JAD-140678

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 677-686, 2015