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