Journal of Alzheimer's Disease - Volume 51, issue 2

Authors: Abdin, Edimansyah | Subramaniam, Mythily | Achilla, Evanthia | Chong, Siow Ann | Vaingankar, Janhavi Ajit | Picco, Louisa | Sambasivam, Rajeswari | Pang, Shirlene | Chua, Boon Yiang | Ng, Li Ling | Chua, Hong Choon | Heng, Derrick | Prince, Martin | McCrone, Paul

Article Type: Research Article

Abstract: Background: There is currently limited evidence on the economic burden that dementia exerts on multi-ethnic Asian populations. Objective: The present study aimed to estimate the economic cost of dementia in Singapore. Methods: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above. Generalized linear modeling was used to estimate factors associated with costs. Results: The total cost of dementia in 2013 was estimated at S$532 million (95% CI, S$361 million to S$701 million) while the annual cost per …person was estimated at S$10,245 per year (95% CI, S$6,954 to S$12,495). Apart from dementia, higher total societal cost were also significantly associated with older age, Indian ethnicity, and those who were diagnosed with heart problems, stroke, diabetes or depression, whereas being divorced/separated, lower education, and those who were diagnosed with hypertension were significantly associated with lower total societal cost. Conclusion: The study provides a rich body of information on healthcare utilization and cost of dementia, which is essential for future planning of services for the elderly population. Show more

Keywords: Cost of illness, dementia, elderly, health services, societal cost

DOI: 10.3233/JAD-150930

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 439-449, 2016

Authors: Karakis, Ioannis | Pase, Matthew P. | Beiser, Alexa | Booth, Sarah L. | Jacques, Paul F. | Rogers, Gail | DeCarli, Charles | Vasan, Ramachandran S. | Wang, Thomas J. | Himali, Jayandra J. | Annweiler, Cedric | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts. Objective: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer’s disease (AD), MRI markers of brain aging, and neuropsychological function. Methods: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of …incident dementia (n  = 1663), multiple neuropsychological tests (n  = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n  = 1139). Results: In adjusted models, participants with vitamin D deficiency (n  = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= –0.03 to –0.05±0.02) and the Hooper Visual Organization Test (β= –0.09 to –0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= –0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. Conclusions: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function. Show more

Keywords: Alzheimer’s disease, brain, dementia, diet, lifestyle, magnetic resonance imaging, neuropsychology, nutritional status, risk factors, vitamin D

DOI: 10.3233/JAD-150991

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 451-461, 2016

Authors: White, Matthew T. | Shaw, Leslie M. | Xie, Sharon X. | for the Alzheimer’s Disease Neuroimaging Initiative | and the National Alzheimer’s Coordinating Center

Article Type: Research Article

Abstract: Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer’s disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer’s Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF …biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnostic testing, maximum likelihood, measurement error, replicate data

DOI: 10.3233/JAD-151045

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 463-470, 2016

Authors: Xu, He | Perreau, Victoria M. | Dent, Krista A. | Bush, Ashley I. | Finkelstein, David I. | Adlard, Paul A.

Article Type: Research Article

Abstract: Background: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer’s disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored. Objective: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes. Methods: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE. …Results: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to Aβ PP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1. Conclusion: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD. Show more

Keywords: Apolipoprotein E, iron, lipoprotein receptor-related protein, low-density lipoprotein receptor

DOI: 10.3233/JAD-150797

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 471-487, 2016

Authors: Aso, Ester | Andrés-Benito, Pol | Carmona, Margarita | Maldonado, Rafael | Ferrer, Isidre

Article Type: Research Article

Abstract: The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer’s disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9 -tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases …the levels of soluble Aβ40 . However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing. Show more

Keywords: AβPP/PS1 mice, Alzheimer’s disease, amyloid, cannabinoid receptor 2, cognitive impairment, Δ9-tetrahidrocannabinol and cannabidiol, tau, therapy

DOI: 10.3233/JAD-150913

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 489-500, 2016

Authors: Luchsinger, José A. | Perez, Thania | Chang, Helena | Mehta, Pankaj | Steffener, Jason | Pradabhan, Gnanavalli | Ichise, Masanori | Manly, Jennifer | Devanand, Davangere P. | Bagiella, Emilia

Article Type: Research Article

Abstract: Diabetes and hyperinsulinemia may be risk factors for Alzheimer’s disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective …Reminding Test (SRT) and the score of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p  = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD. Show more

Keywords: Amnestic mild cognitive impairment, insulin, memory, metformin, randomized clinical trial

DOI: 10.3233/JAD-150493

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 501-514, 2016

Authors: Chen, Huei-Yang | Panegyres, Peter K.

Article Type: Research Article

Abstract: Background: Ethnic minorities seem to be at an increased risk of Alzheimer’s disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD). Objective: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression. Methods: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities— including Native …Alaskans, Americans, and Hawaiians. Results: Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ 2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p  <  0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1–2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2–3.5) were significantly higher, compared with Caucasians. Conclusions: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age. Show more

Keywords: Alzheimer’s disease, ApoE, early onset Alzheimer’s disease, early onset dementia, ethnicity

DOI: 10.3233/JAD-151089

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 515-523, 2016

Authors: Chu, Shuguang | Xu, Feijia | Su, Ya | Chen, Hong | Cheng, Xin

Article Type: Research Article

Abstract: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ɛ 4/ɛ 4. More clinical markers for diagnosis of CAA-ri warrant …further researches. Show more

Keywords: Amyloid-β-related angiitis, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, inflammatory cerebral amyloid angiopathy

DOI: 10.3233/JAD-151036

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 525-532, 2016

Authors: Benito-León, Julián | Contador, Israel | Mitchell, Alex J. | Domingo-Santos, Ángela | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox’s proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01–10.7), after which the death …certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01–10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p  = 0.03); 1.22 (semantic fluency, p  = 0.04), 1.32 (delayed free recall, p  = 0.003), and 1.23 (delayed logical memory, p  = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality. Show more

Keywords: Cause specific-mortality, cognitive aging, epidemiology, neuropsychology, prospective cohort, population-based study

DOI: 10.3233/JAD-150875

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 533-544, 2016

Authors: Heßmann, Philipp | Seeberg, Greta | Reese, Jens Peter | Dams, Judith | Baum, Erika | Müller, Matthias J. | Dodel, Richard | Balzer-Geldsetzer, Monika

Article Type: Research Article

Abstract: The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer’s disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer’s Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients’ HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer’s …Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p  <  0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3±5.7 in the group with the highest MMSE scores to 27.1±5.5 in patients with the lowest MMSE scores (p  <  0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7±4.6 versus 26.0±7.1, p  <  0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients’ HrQoL. Multivariate models explained between 22% and 54% of the variance in patients’ HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted. Show more

Keywords: Alzheimer’s disease, BPSD, care, dementia, depression, quality of life

DOI: 10.3233/JAD-150835

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 545-561, 2016