Journal of Alzheimer's Disease - Volume 52, issue 4

Authors: Wang, Min Jeong | Yi, SangHak | Han, Jee-young | Park, So Young | Jang, Jae-Won | Chun, In Kook | Giau, Vo Van | Bagyinszky, Eva | Lim, Kun Taek | Kang, Sung Min | An, Seong Soo A. | Park, Young Ho | Youn, Young Chul | Kim, SangYun

Article Type: Research Article

Abstract: Background: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer’s Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers. Objective: Here, we analyzed fluid and imaging biomarkers of Alzheimer’s disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD. Methods: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD = 26, NC = 29) following the Korea consensus …protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed. Results: The cutoff values of CSF amyloid beta 1-42 (Aβ42 ), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ = 0.849, CI 0.71–0.99) than CSF Aβ42 alone (κ = 0.703, CI 0.51–0.89). Conclusions: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, diagnosis, Pittsburgh compound B, protocol

DOI: 10.3233/JAD-160143

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1403-1413, 2016

Authors: Beydoun, May A. | Canas, Jose-Atilio | Dore, Gregory A. | Beydoun, Hind A. | Rostant, Ola S. | Fanelli-Kuczmarski, Marie T. | Evans, Michele K. | Zonderman, Alan B.

Article Type: Research Article

Abstract: Uric acid, a waste metabolite among humans, was linked to various cognitive outcomes. We describe sex and age-group specific associations of baseline serum uric acid (SUAbase ) and significant change in SUA (ΔSUA: 1 versus 0 = decrease versus no change; 2 versus 0 = increase versus no change) with longitudinal annual rate of cognitive change among a large sample of urban adults. Data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2004–2009 (visit 1) and 2009–2013 (visit 2) were used. Of 3,720 adults selected at baseline (age range: 30–64 y), complete data were available for N  = 1,487–1,602 with …a mean repeat of 1.5–1.7 visits/participant. Cognitive test domains spanned attention, processing speed, learning/memory, executive function, visuo-spatial/visuo-construction ability, language/verbal, and global cognitive function. SUA was measured at both visits. Multiple mixed-effects regression analyses were conducted. In the total population, a higher SUAbase was associated with a faster annual rate of decline on a measure of visual memory/visuo-construction ability (the Benton Visual Retention Test) by γ = 0.07 with a standard error of 0.02, p  < 0.001. Among older men, a significant increase in SUA was associated with slower decline on a test of attention/processing speed, namely Trailmaking test, Part A, measured in seconds to completion (γ = –6.91 ± 1.73, p  < 0.001). In sum, a higher SUAbase was associated with faster cognitive decline over-time in a visual memory/visuo-construction ability test. ΔSUA had particular beneficial effects of an increasing ΔSUA on the domain of attention/processing speed among older men. More longitudinal studies are needed to examine cognitive domain-specific effects of over-time change in SUA within sex and age groups. Show more

Keywords: Aging, cognition, serum uric acid, sex differences

DOI: 10.3233/JAD-160028

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1415-1430, 2016

Authors: Shindler-Itskovitch, Tali | Ravona-Springer, Ramit | Leibovitz, Arthur | Muhsen, Khitam

Article Type: Research Article

Abstract: Background: A positive association between Helicobacter pylori infection and dementia has been reported, yet findings are inconsistent. Objective: To examine the association between H. pylori infection and dementia. Methods: A literature search was performed using the databases OVID-Medline, Institute of Scientific Information Web of Science, and EMBASE. The meta-analysis was conducted using the random effects model. The primary analysis included studies in which the exposure variable was presence of H. pylori infection (yes versus no) and the outcome was incident dementia (yes versus no), which was pre-selected as the end-result of gradual …cognitive decline overtime. Publication bias was explored using funnel plot and the Egger regression intercept. Results: A total of 260 records were identified; 13 addressed cognition and/or dementia in relation to H. pylori infection, of which only seven were included in the meta-analysis. The primary analysis showed a significant positive association between H. pylori infection and dementia; pooled odds ratio 1.71 (95% CI 1.17–2.49) (pv  = 0.01). No significant evidence of publication bias was found. Conclusions: H. pylori may play a role in the etiology of dementia. Identification of the biological mechanisms of such association is needed, as well as assessment of the impact of H. pylori therapy on the risk and progression of dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, Helicobacter pylori infection, meta-analysis

DOI: 10.3233/JAD-160132

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1431-1442, 2016

Authors: Teipel, Stefan | Grothe, Michel J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Smoking has been found associated with decreased cerebral volumes in healthy adults and in various neuropsychiatric disorders. Objective: We aimed to determine whether chronic nicotine exposure through smoking is associated with reduced volume of cortically projecting cholinergic basal forebrain nuclei in healthy aging, mild cognitive impairment (MCI), and dementia stages of Alzheimer’s disease (AD). Methods: We retrieved cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database including 179 cognitively normal elderly subjects, 270 subjects with early stage MCI, 136 subjects in later, more advanced, stage of MCI, and 86 subjects in dementia stages …of AD. We determined the association between past or current smoking versus lifetime non-smoker status on the volumes of the basal forebrain determined from volumetric MRI scans. Hippocampus volume was used as a control region. Significant effects were controlled for mediating or moderating effects of respiratory and cardiovascular morbidity. Results: In cognitively healthy individuals and early MCI, past or current smoking was significantly associated with smaller basal forebrain volume. This effect was independent from age, sex, or cardiovascular or respiratory morbidity. Hippocampus volume was not associated with smoking. In late MCI and AD dementia, smoking was not associated with basal forebrain or hippocampus volumes. Conclusions: Our findings suggest that chronic nicotine exposure through smoking may lead to atrophy of cholinergic input areas of the basal forebrain. This effect may account for an increased risk of AD dementia onset with smoking by exhausting the cholinergic system reserve capacity. Show more

Keywords: Aging, cholinergic system, hippocampus, magnetic resonance imaging, nicotine

DOI: 10.3233/JAD-151100

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1443-1451, 2016

Authors: Waragai, Masaaki | Adame, Anthony | Trinh, Ivy | Sekiyama, Kazunari | Takamatsu, Yoshiki | Une, Kaori | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Research Article

Abstract: Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it …was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD. Show more

Keywords: Adiponectin, Alzheimer’s disease, cerebrospinal fluid, neurofibrillary tangles, sequestration, serum, tau

DOI: 10.3233/JAD-151116

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1453-1459, 2016

Authors: Han, Pengcheng | Shi, Jiong

Article Type: Research Article

Abstract: Amyloid plaques and Tau protein neurofibrillary tangles are considered the two most important pathogenic factors in Alzheimer’s disease. The prevailing amyloid cascade hypothesis suggests that amyloid-β (Aβ) elevation induces downstream Tau hyperphosphorylation and aggregation, synaptic dysfunction, and neuronal loss that ultimately results in cognitive impairment. Alternatively, the dual-pathway hypothesis suggests that Aβ and abnormal Tau are two independent factors that exert synergistic effects on synaptic dysfunction and neuronal loss. We hypothesize that the intrinsic interaction of Aβ and Tau would better predict cognitive impairment. Herein, we propose an Aβ-Tau interactive model based on a review of the medical literature, mathematic …modeling, and analysis of our clinicopathological data. Show more

Keywords: Alzheimer’s disease, amyloid plaque, neurofibrillary tangle, Tau

DOI: 10.3233/JAD-151206

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1461-1470, 2016

Authors: Fernandez, Ana M. | Hervas, Ruben | Dominguez-Fraile, Manuel | Garrido, Victoria Navarro | Gomez-Gutierrez, Patricia | Vega, Miguel | Vitorica, Javier | Perez, Juan J. | Torres Aleman, Ignacio

Article Type: Research Article

Abstract: Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer’s disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set …of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted. Show more

Keywords: Alzheimer’s disease, astrocytes, calcineurin, decoy compounds, FOXO

DOI: 10.3233/JAD-160149

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1471-1478, 2016

Authors: Cestari, José Augusto Ferrari | Fabri, Gisele Maria Campos | Kalil, Jorge | Nitrini, Ricardo | Jacob-Filho, Wilson | de Siqueira, José Tadeu Tesseroli | Siqueira, Silvia Regina D.T.

Article Type: Research Article

Abstract: Background: Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer’s disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. Objective: The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α , and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. Methods: Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, …periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. Results: Patients with AD had high serum IL-6 levels (p  = 0.029), and patients with periodontitis had high serum TNF-α levels (p  = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p  = 0.023). Conclusion: The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation. Show more

Keywords: Alzheimer’s disease, IL-6, inflammation, mild cognitive impairment, oral infection, periodontitis, TNF-α

DOI: 10.3233/JAD-160212

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1479-1485, 2016

Authors: Ramos-Goicoa, Marta | Galdo-Álvarez, Santiago | Díaz, Fernando | Zurrón, Montserrat

Article Type: Research Article

Abstract: Event-related potentials (ERPs) were recorded from 84 adults (51 to 87 years old) with the aim of exploring the effects of aging (middle-aged and older groups) and cognitive status (healthy or with amnestic mild cognitive impairment, aMCI) on the neural functioning associated with stimulus and response processing in a Stroop color-word task. An interference (or Stroop) effect was observed in the Reaction Time (RT), and the RT and number of errors results were consistent with the age-related decline in performance. Cognitive status did not affect the behavioral performance of the task, but age and cognitive status affected several ERP parameters. …Aging was associated with a) slowing of the neural processing of the stimuli (P150, N2, and P3b latencies were longer), b) greater activation of the motor cortex for response preparation (LRP-R amplitude was larger), and c) use of more neural resources for cognitive control of stimuli (N2 amplitude was larger to the congruent and incongruent stimuli than to the colored X-strings, in the older group). Independent of age, aMCI dedicated more neural resources to processing the irrelevant dimension of the stimulus (they showed a greater difference than the control participants between the P3b amplitude to the colored X-strings and to the congruent/incongruent stimuli) and showed a deficit in the selection and preparation of the motor response (with smaller LRP-S and LRP-R amplitudes). Furthermore, the middle-aged aMCI participants evaluated and classified both congruent and incongruent stimuli more slowly (they showed longer P3b latencies) relative to middle-aged controls. Show more

Keywords: Aging, event-related potentials, mild cognitive impairment, Stroop task

DOI: 10.3233/JAD-151031

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1487-1501, 2016

Authors: Barry, Heather E. | Cooper, Janine A. | Ryan, Cristín | Passmore, A. Peter | Robinson, A. Louise | Molloy, Gerard J. | Darcy, Carmel M. | Buchanan, Hilary | Hughes, Carmel M.

Article Type: Research Article

Abstract: Background: Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD). Objective: To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender. Methods: A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013–31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons …Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender. Results: The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n  = 5564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2– 65.5; n  = 4393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2–26.2; n  = 1718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6–8.7) and 1.3 (95% CI 1.2–1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy. Conclusion: This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, polypharmacy, primary health care

DOI: 10.3233/JAD-151177

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1503-1513, 2016