Journal of Alzheimer's Disease - Volume 52, issue 1

Authors: Spilman, Patricia R. | Corset, Veronique | Gorostiza, Olivia | Poksay, Karen S. | Galvan, Veronica | Zhang, Junli | Rao, Rammohan | Peters-Libeu, Clare | Vincelette, Jon | McGeehan, Andrew | Dvorak-Ewell, Melita | Beyer, Janine | Campagna, Jesus | Bankiewicz, Krystof | Mehlen, Patrick | John, Varghese | Bredesen, Dale E.

Article Type: Research Article

Abstract: Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ1- 40 resulted in increased de novo human Aβ1-42 production and exposure …of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ1- 40 -induced Aβ1-42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro . In vivo , induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ1-42 and Aβ1- 40 , and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1’s potential as a therapeutic for Alzheimer’s disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ1-42 in vitro . Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it. Show more

Keywords: Aβ1-42, AβPP, amplification, CED, inducible, mimetic, netrin-1, sAβPPα

DOI: 10.3233/JAD-151046

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 223-242, 2016

Authors: Ontiveros-Torres, Miguel Ángel | Labra-Barrios, María Luisa | Díaz-Cintra, Sofía | Aguilar-Vázquez, Azucena Ruth | Moreno-Campuzano, Samadhi | Flores-Rodríguez, Paola | Luna-Herrera, Claudia | Mena, Raúl | Perry, George | Florán-Garduño, Benjamín | Luna-Muñoz, José | Luna-Arias, Juan Pedro

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding …APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide. Show more

Keywords: Amyloid-β, hippocampus, inflammation, TauP301L, 3×Tg-AD transgenic mouse

DOI: 10.3233/JAD-150837

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 243-269, 2016

Authors: Fernández-Blázquez, Miguel A. | Ávila-Villanueva, Marina | Maestú, Fernando | Medina, Miguel

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a silent disorder that needs the earliest possible intervention in order to reduce its high economic and social impact. It has been recently suggested that subjective cognitive decline (SCD) appears at preclinical stages many years before the onset of AD. Therefore, SCD could become an ideal target for early therapeutic intervention. Objective: The goal of this study was to evaluate the clinical significance of SCD on the conversion from a cognitively healthy stage to a mild cognitive impairment (MCI) in one-year follow-up. Methods: A total of 608 cognitively intact individuals …from the Vallecas Project’s cohort, a community-based prospective study to identify early markers of AD, were enrolled in this study. Participants were classified in three groups: i) No Complaints (NCg), ii) Subjects with complaints in one or more cognitive domains (SCDg), and iii) Subjects who, besides complaints, fulfilled the features of SCD Plus proposed by the International Working Group of SCD (SCD-Pg). Results: Individuals were followed up for a mean of 13.1 months (range 10.7–22.4). During this time, 41 volunteers developed MCI (6.7% of total sample). The conversion rate for SCD-Pg (18.9%) was significantly higher than SCDg (5.6%) and NCg (4.9%). Conclusion: Specific features associated with SCD may help to identify individuals at high risk of fast conversion to MCI. These results highlight the importance of a close follow-up of subjects with SCD-P and include them in early intervention programs because of their increased risk for the development of MCI. Show more

Keywords: Aging, Alzheimer’s disease, cognitive symptoms, dementia, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-150956

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 271-281, 2016

Authors: Gramunt, Nina | Sánchez-Benavides, Gonzalo | Buschke, Herman | Diéguez-Vide, Faustino | Peña-Casanova, Jordi | Masramon, Xavier | Fauria, Karine | Gispert, Juan D. | Molinuevo, José L.

Article Type: Research Article

Abstract: Background: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer’s disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required. Objectives: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence. Method: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A …crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations. Results: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82. Conclusion: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests. Show more

Keywords: Alzheimer–s disease, cognition, episodic memory, neuropsychological assessment, preclinical, psycholinguistics

DOI: 10.3233/JAD-151175

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 283-293, 2016

Authors: Teich, Andrew F. | Sakurai, Mikako | Patel, Mitesh | Holman, Cameron | Saeed, Faisal | Fiorito, Jole | Arancio, Ottavio

Article Type: Research Article

Abstract: Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human …brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease. Show more

Keywords: Alzheimer’s disease, memory, PDE5 inhibitors, phosphodiesterase 5

DOI: 10.3233/JAD-151104

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 295-302, 2016

Authors: Sánchez, Alba | Maseda, Ana | Marante-Moar, M. Pilar | de Labra, Carmen | Lorenzo-López, Laura | Millán-Calenti, José Carlos

Article Type: Research Article

Abstract: The objective of this study was to compare the effects of a multisensory stimulation environment (MSSE) and individualized music sessions on agitation, emotional and cognitive status, and dementia severity in a sample of institutionalized patients with severe dementia. Twenty-two participants with a diagnosis of severe or very severe dementia were randomly assigned to two groups: MSSE and individualized music sessions. Both groups participated in two 30-min weekly sessions over 16 weeks. Outcomes were agitation (Cohen-Mansfield Agitation Inventory, CMAI), mood (Cornell Scale for Depression in Dementia, CSDD), anxiety (Rating Anxiety in Dementia, RAID), cognitive function (Severe Mini-Mental State Examination, SMMSE), and …the overall severity of dementia (Bedford Alzheimer Nursing Severity Scale, BANS-S). They were assessed at baseline (pre-trial), in the middle (mid-trial), at the end of the intervention (post-trial), and 8 weeks after the intervention (follow-up). Patients in the MSSE group showed significant improvement in their RAID and BANS-S scores compared with the individualized music group post- versus pre-trial. With regard to agitation, there was improvement during the intervention in both the MSSE and individualized music groups in the CMAI total score after 16 weeks of intervention, with no significant differences between the groups. The results suggest that MSSE could have better effects on anxiety symptoms and dementia severity in comparison with individualized music sessions in elderly patients with severe dementia. Show more

Keywords: Dementia, elderly, individualized music, multisensory environments, multisensory stimulation, randomized controlled trial, Snoezelen

DOI: 10.3233/JAD-151150

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 303-315, 2016

Authors: Matura, Silke | Prvulovic, David | Hartmann, Daniel | Scheibe, Monika | Sepanski, Beate | Butz, Marius | Oertel-Knöchel, Viola | Knöchel, Christian | Karakaya, Tarik | Fußer, Fabian | Hattingen, Elke | Pantel, Johannes

Article Type: Research Article

Abstract: The apolipoprotein E (ApoE) ɛ 4 allele is a well-established genetic risk factor for sporadic Alzheimer’s disease. Some evidence suggests a negative role of the ApoE ɛ 4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n  = 50; age 26.4±4.6 years, 25 ɛ 4 carriers) and old (n  = 40; age 66.1±7.0 years, 20 ɛ 4 carriers) participants. A cross-sectional …factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ 4 carriers. The increased BOLD response in old ɛ 4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ 4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ 4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age. Show more

Keywords: Apolipoprotein 4, brain, functional MRI, memory

DOI: 10.3233/JAD-150990

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 317-331, 2016

Authors: Isla, Arturo G. | Vázquez-Cuevas, Francisco Gabriel | Peña-Ortega, Fernando

Article Type: Research Article

Abstract: Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer’s disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-β (Aβ) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aβ-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aβ, which has been associated to glycogen synthase kinase-3β (GSK3β) activation. We found that the …hippocampal population activity recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and faster frequency composition than slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aβ-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aβ to activate GSK3β, is mimicked by GSK3β inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aβ by avoiding GSK3β activation. Show more

Keywords: Amyloid-β, GSK3β, hippocampus, PI3K, spontaneous population activity, voluntary-exercise

DOI: 10.3233/JAD-150352

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 333-343, 2016

Authors: Homma, Akira | Atarashi, Hirotsugu | Kubota, Naoki | Nakai, Kenya | Takase, Takao

Article Type: Research Article

Abstract: Background: Donepezil is an established treatment for mild, moderate, and severe Alzheimer’s disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD. Objective: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD). Methods: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery …(SIB), Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety. Results: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: –1.7, 1.8; p  = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p  = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil. Conclusion: SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, donepezil, double-blind study, Japan

DOI: 10.3233/JAD-151149

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 345-357, 2016

Authors: Tramutola, Antonella | Pupo, Gilda | Di Domenico, Fabio | Barone, Eugenio | Arena, Andrea | Lanzillotta, Chiara | Broekaart, Diede | Blarzino, Carla | Head, Elizabeth | Butterfield, D. Allan | Perluigi, Marzia

Article Type: Research Article

Abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer’s disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower …levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α ) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS. Show more

Keywords: Apoptosis, caspase, p53, sirtuins, Ts65Dn mouse model, trisomy 21

DOI: 10.3233/JAD-151105

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 359-371, 2016

Authors: Nho, Kwangsik | Saykin, Andrew J. | Alzheimer’s Disease Neuroimaging Initiative | Nelson, Peter T.

Article Type: Research Article

Abstract: Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer’s disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n  = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN , TMEM106B , ABCC9 , and KCNMB2 (minor allele frequency for each is >30%). …A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer’s disease contribution to atrophy outside of the hippocampus in older adults. Show more

Keywords: Arteriolosclerosis, dementia, KATP, progranulin, rs5848, rs704180, rs1990622, rs9637454, SUR2, TDP-43

DOI: 10.3233/JAD-160077

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 373-383, 2016

Article Type: Other

DOI: 10.3233/JAD-160202

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 385-389, 2016