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

Authors: Shang, Jingwei | Yamashita, Toru | Zhai, Yun | Nakano, Yumiko | Morihara, Ryuta | Fukui, Yusuke | Hishikawa, Nozomi | Ohta, Yasuyuki | Abe, Koji

Article Type: Research Article

Abstract: Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer’s disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer’s disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α 7 subunit of nicotinic acetylcholine receptors (α 7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and …blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities. Show more

Keywords: Alzheimer’s disease, APP23 mice, cerebrovascular remodeling, chronic cerebral hypoperfusion, galantamine, neurovascular unit, neurovascular trophic coupling

DOI: 10.3233/JAD-151126

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 113-126, 2016

Authors: Tiihonen, Miia | Taipale, Heidi | Tanskanen, Antti | Tiihonen, Jari | Hartikainen, Sirpa

Article Type: Research Article

Abstract: We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer’s disease (AD). The MEDALZ-2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002–2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD …(n  = 3121, 12.3%) than among persons with AD (n  = 2,920, 11.2%) (p  = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p  = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p  <  0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD. Show more

Keywords: Alzheimer’s disease, bisphosphonates, community dwelling, osteoporosis

DOI: 10.3233/JAD-151181

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 127-132, 2016

Authors: López, María Eugenia | Turrero, Agustín | Cuesta, Pablo | López-Sanz, David | Bruña, Ricardo | Marcos, Alberto | Gil, Pedro | Yus, Miguel | Barabash, Ana | Cabranes, José Antonio | Maestú, Fernando | Fernández, Alberto

Article Type: Research Article

Abstract: Recent proposals of diagnostic criteria within the healthy aging-Alzheimer’s disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to …predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The “stable” MCI group (sMCI, 21 subjects) and the “progressive” MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as “first order” predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role. Show more

Keywords: Alzheimer’s disease, APOE, cognitive reserve, hippocampal volume, magnetoencephalography; mild cognitive impairment, neuropsychological tests, predictive model

DOI: 10.3233/JAD-151034

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 133-143, 2016

Authors: Jahng, Geon-Ho | Oh, Janghoon | Lee, Do-Wan | Kim, Hyug-Gi | Rhee, Hak Young | Shin, Wonchul | Paik, Jong-Woo | Lee, Kyung Mi | Park, Soonchan | Choe, Bo-Young | Ryu, Chang-Woo

Article Type: Research Article

Abstract: Background: The metabolite response during a memory task in Alzheimer’s disease (AD) patients is unknown. Objective: To investigate the metabolite changes in subjects with AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) elderly during a memory task using functional magnetic resonance spectroscopy (fMRS). Methods: This study involved 23 young normal controls (YC), 24 CN elderly, 24 aMCI, and 24 mild and probable AD individuals. fMRS data were acquired at the precuneus and posterior cingulate brain regions during a face-name association task. Statistical analyses of quantified metabolites were performed to evaluate differences of the …metabolite values between the stimulation conditions and among the four subject groups. Receiver operating curve analysis was performed to evaluate whether the metabolic changes after functional activations can differentiate the subject groups. Result: Glutamine and glutamate complex (Glx) was statistically significantly different between the fixation and repeat conditions in aMCI (p  = 0.0492) as well as between the fixation and the novel conditions in the AD (p  = 0.0412) group. The total N-acetylaspartate (tNAA) was statistically significantly different among the four subject groups in the fixation condition (DF = 3, F = 7.673, p  <  0.001), the novel condition (DF = 3, F = 6.945, p  <  0.001), and the repeat condition (DF = 3, F = 7.127, p  <  0.001). tNAA, tCr, and mIns could be used to differentiate CN from aMCI. Furthermore, tNAA, tCr, Glx, and Glu could also differentiate CN from AD, and aMCI from AD. Conclusion: Glx was altered during a stimulation that may be used to evaluate neuronal dysfunction in a demented patient. tNAA and tCr were reduced in patients with AD. Show more

Keywords: Alzheimer–s disease, functional magnetic resonance spectroscopy, glutamine and glutamate complex (Glx), mild cognitive impairment, total N-acetylaspartate (tNAA)

DOI: 10.3233/JAD-150877

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 145-159, 2016

Authors: Roeben, Benjamin | Maetzler, Walter | Vanmechelen, Eugeen | Schulte, Claudia | Heinzel, Sebastian | Stellos, Konstantinos | Godau, Jana | Huber, Heiko | Brockmann, Kathrin | Wurster, Isabel | Gaenslen, Alexandra | Grüner, Eva | Niebler, Raphael | Eschweiler, Gerhard W. | Berg, Daniela | the TREND study team

Article Type: Research Article

Abstract: Background/Objective: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals. Methods: Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire …and/or medical records. Results: Plasma Aβ1 - 40 levels were significantly higher in individuals with CAD (p  = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p  = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOE ɛ 4 carriers (p  = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype. Discussion: Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-beta, APOE genotype, coronary artery disease, diabetes mellitus, vascular

DOI: 10.3233/JAD-150575

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 161-169, 2016

Authors: Xiong, Li | Davidsdottir, Sigurros | Reijmer, Yael D. | Shoamanesh, Ashkan | Roongpiboonsopit, Duangnapa | Thanprasertsuk, Sekh | Martinez-Ramirez, Sergi | Charidimou, Andreas | Ayres, Alison M. | Fotiadis, Panagiotis | Gurol, Edip | Blacker, Deborah L. | Greenberg, Steven M. | Viswanathan, Anand

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized. Objective: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA. Methods: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis …in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed. Results: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of –1.92±1.56 (mean±SD), then followed by executive function (–0.93±1.01), episodic memory (–0.87±1.29), semantic fluency (–0.73±1.06), and attention (–0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p  = 0.03) and executive function (β= 0.394, p  = 0.01). Conclusions: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function. Show more

Keywords: Brain atrophy, cerebral amyloid angiopathy, cerebral microbleeds, clinical neuropsychology, cognitive impairment, hippocampal atrophy, intracranial hemorrhage, white matter hyperintensities

DOI: 10.3233/JAD-150890

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 171-178, 2016

Authors: Wang, Hui-Fu | Wan, Yu | Hao, Xiao-Ke | Cao, Lei | Zhu, Xi-Chen | Jiang, Teng | Tan, Meng-Shan | Tan, Lin | Zhang, Dao-Qiang | Tan, Lan | Yu, Jin-Tai | Disease Neuroimaging Initiative Alzheimer’s

Article Type: Research Article

Abstract: Background: Bridging integrator 1 (BIN1 ) has been identified as one of the most associated loci for Alzheimer’s disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro . However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed. Objective: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis. Methods: We calculated the associations of BIN1 loci with these markers …at baseline and follow-up in multiple linear models in 812 ADNI subjects. Results: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc  = 0.047, rs13031703: pc  = 0.042) and P-tau (rs744373: pc  = 0.044, rs13031703: pc  = 0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc  = 0.011), CA1 (rs1469980: pc  = 0.029) and parahippocampus (rs72838284, pc  = 0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals. Conclusion: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology. Show more

Keywords: Aβ deposition, Alzheimer’s disease, BIN1, brain structure, cerebrospinal fluid, glucose metabolism

DOI: 10.3233/JAD-150972

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 179-190, 2016

Authors: Downer, Brian | Veeranki, Sreenivas P. | Wong, Rebeca

Article Type: Research Article

Abstract: Background: Several dementia risk indices have been developed for older adults in high-income countries. However, no index has been developed for populations in low- or middle-income countries. Objective: To create a risk index for predicting severe cognitive impairment among adults aged ≥60 in Mexico and to compare the accuracy of this index to the Dementia Screening Indicator (DSI). Methods: This study included 3,002 participants from the Mexican Health and Aging Study (MHAS) interviewed in 2001 and 2012. The MHAS risk index included sociodemographic, health, and functional characteristics collected in 2001. A point value based on …the beta coefficients from a multivariable logistic regression model was assigned to each risk factor and the total score was calculated. Results: The MHAS risk index (AUC = 0.74 95% CI = 0.70–0.77) and DSI (AUC = 0.72 95% CI = 0.69–0.77) had similar accuracy for discriminating between participants who developed severe cognitive impairment from those who did not. A score of ≥16 on the MHAS risk index had a sensitivity of 0.69 (95% CI = 0.64–0.70) and specificity of 0.67 (95% CI = 0.66–0.69). A score of ≥23 on the DSI had a sensitivity of 0.56 (95% CI = 0.50–0.63) and specificity of 0.78 (95% CI = 0.76–0.79). Discussion: The MHAS risk index and DSI have moderate accuracy for predicting severe cognitive impairment among older adults in Mexico. This provides evidence that existing dementia risk indices may be applicable in low- and middle-income countries such as Mexico. Future research should seek to identify additional risk factors that can improve the accuracy of the MHAS risk index. Show more

Keywords: Aging, dementia, diagnosis, Mexico

DOI: 10.3233/JAD-150702

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 191-203, 2016

Authors: Takemoto, Mami | Sato, Kota | Hatanaka, Noriko | Yamashita, Toru | Ohta, Yasuyuki | Hishikawa, Nozomi | Abe, Koji

Article Type: Research Article

Abstract: Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n  = 52) and DLB (n  = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p  = 0.013 and 8.6±4.7, p  = 0.039, respectively). DLB patients performed worse than PDD patients in “orientation to …place” tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99m Tc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients’ lower average scores for “repetition” (MMSE), “recent memory” (HDS-R), and “lexical fluency” (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients’ poorer average subscale scores of “orientation to place” (MMSE) and “similarities”, “conflicting instructions”, and “go-no go” (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD. Show more

Keywords: Affective function, cognitive function, dementia with Lewybodies, Parkinson’s disease with dementia, 99mTc-ECD images

DOI: 10.3233/JAD-150952

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 205-211, 2016

Authors: Pimouguet, Clément | Rizzuto, Debora | Fastbom, Johan | Lagergren, Mårten | Fratiglioni, Laura | Xu, Weili

Article Type: Research Article

Abstract: Background: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs). Objective: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization. Methods: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged ≥78 years were followed for 3 years, and those aged 60–72 years, for 6 years. Number of hospitalizations was retrieved from …the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis. Results: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR = 2.3, 95% CI 1.3–3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than in those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia. Conclusion: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization. Show more

Keywords: Dementia, hospitalization longitudinal follow-up, population based study

DOI: 10.3233/JAD-150853

Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 213-222, 2016

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