Journal of Alzheimer's Disease - Volume 42, issue 3

Authors: Freund-Levi, Yvonne | Vedin, Inger | Hjorth, Erik | Basun, Hans | Faxén Irving, Gerd | Schultzberg, Marianne | Eriksdotter, Maria | Palmblad, Jan | Vessby, Bengt | Wahlund, Lars-Olof | Cederholm, Tommy | Basu, Samar

Article Type: Research Article

Abstract: Background: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. Objective: TThe objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. Methods: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for …6 months. Urinary samples were collected before and after supplementation. The levels of the major F2 -isoprostane, 8-iso-PGF2α , a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α , a major metabolite of PGF2α and biomarker of inflammatory response, were measured. Results: F2 -isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2 -isoprostanes and 15-keto-dihydro-PGF2α . At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. Conclusion: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2 -isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α . The correlative relationships to FAs indicate a potential role of FAs in immunoregulation. Show more

Keywords: Alzheimer's disease, eicosanoids, F2-isoprostane, inflammation, lipids, omega-3 fatty acids, oxidative stress, prostaglandin F2α

DOI: 10.3233/JAD-132042

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 823-831, 2014

Authors: Appleby, Brian S. | Rincon-Beardsley, Tonya D. | Appleby, Kristin K. | Crain, Barbara J. | Wallin, Mitchell T.

Article Type: Research Article

Abstract: Background: Prion diseases are rapidly progressive neurodegenerative diseases that frequently mimic other forms of dementia making them difficult to diagnose. Objective: To explore factors associated with the initial diagnoses of cases later determined to be caused by prion disease in an attempt to recognize key clinical variables that impact the timely diagnosis of prion disease. Methods: A retrospective chart review performed at Johns Hopkins Medicine and the Department of Veterans Affairs Health Care System (1995–2008) was conducted. Ninety-two subjects with definite or probable prion disease were included in the analyses. Demographic, clinical, diagnostic test results, neuropathologic, …molecular, and genetic data were collected using a standardized instrument and compared between initial diagnosis groups. Results: Cases were separated into five broad categories pertaining to their initial diagnoses: prion disease, non-prion-related dementia, psychiatric disorder, stroke, and other. The majority of cases did not receive an initial diagnosis of prion disease (n = 76, 83%). The plurality of subjects received an initial diagnosis of a non-prion disease related dementia (n = 33, 36%). Mean survival times varied between initial diagnosis groups (p = 0.042). Times to cerebrospinal fluid 14-3-3 analysis and electroencephalogram also differed between initial diagnosis groups. Conclusions: Most patients with prion disease are initially diagnosed with a non-prion disease related dementia. Several clinical features were associated with initial diagnoses including survival time, onset of specific symptoms, and times to 14-3-3 analyses and electroencephalogram. Expanding our knowledge of the various clinical presentations of prion disease, especially dementia, may aid in the earlier diagnoses of these rapidly progressive diseases. Show more

Keywords: Creutzfeldt-Jakob disease, Creutzfeldt-Jakob syndrome, dementia, diagnosis, diagnostic errors, fatal familial insomnia, Gerstmann-Straussler-Scheinker Disease, mean survival time, phenotype, prion diseases, sporadic

DOI: 10.3233/JAD-132465

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 833-839, 2014

Authors: Chen, Yaojing | Wang, Jun | Zhang, Junying | Zhang, Ting | Chen, Kewei | Fleisher, Adam | Wang, Yongyan | Zhang, Zhanjun

Article Type: Research Article

Abstract: Silent or asymptomatic lacunar infarcts (LACI) are common in elderly individuals, but it remains largely unclear how these often neglected silent brain infarcts lead to multiple domain cognitive deficits and even Alzheimer's disease (AD). In this study, we investigated the difference between patients with silent LACI in basal ganglia region and healthy controls for the structural and functional changes in the aspects of alterations of gray matter (GM) volume and intra-/inter-default mode network (DMN) and salience network (SN) connectivity. Thirty patients with silent LACI in the basal ganglia region and thirty healthy controls participated in the study. Voxel-based morphometry analysis …was employed to measure the GM volume. We further investigated the intra/inter-network connectivity of DMN and SN using resting-state functional magnetic resonance imaging. Compared with healthy controls, patients performed worse in cognitive function in the aspects of general mental status, attention, and memory. The LACIs showed more severe GM atrophy in insula, anterior cingulate cortex, caudate, and superior temporal pole than controls. The connectivity within and between two networks was also reduced in patients. Importantly, the disrupted connectivity correlated with the patients' cognitive performance. Our findings support the hypothesis that silent lacunar infarcts result in cognitive decline, GM, and functional connectivity loss. Show more

Keywords: Cognition, functional connectivity, gray matter, network, silent stroke

DOI: 10.3233/JAD-140948

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 841-850, 2014

Authors: Polito, Letizia | Chierchia, Armando | Tunesi, Marta | Bouybayoune, Ihssane | Kehoe, Patrick Gavin | Albani, Diego | Forloni, Gianluigi

Article Type: Research Article

Abstract: Environmental enrichment (EE) is a non-pharmacological intervention reported to counteract pathological signs in models of Alzheimer's disease (AD). We developed EE protocols in APP23 mice and evaluated how they influenced cognitive decline and brain amyloid-β (Aβ) burden. We also investigated the involvement of sirtuins (SIRTs) as a possible molecular mediator of EE, by assessing hippocampal and cortical mRNA and protein levels of the SIRT family members (SIRT1 to SIRT7). APP23 transgenic mice were moved to EE cages (TG-EEs) starting from 3 months of age. TG-EEs were compared to transgenic mice housed in standard cages (TG-SHs) and to wild-type littermates in …the two housing conditions (WT-EEs and WT-SHs). At 7 months of age, all mice were tested for behavioral performance with Morris Water Maze (MWM) and visual novel Object Recognition Test (vORT). After a month, a group underwent biochemical analyses, while another group continued in the EE environment till 18 months of age, when Aβ plaque load was assessed. At 7 months, TG-SHs had impaired behavioral performance in MWM and vORT. In contrast, TG-EE mice had restored behavioral performance. At 8 months, EE did not affect AβPP expression or processing, Aβ40/42 , pGlu-Aβ3-40 /3-42 , or Aβ oligomer level. The expression of two Aβ degrading enzymes (insulin degrading enzyme and neprilysin) was not modulated by EE. Brain sirtuin mRNA and protein levels were unchanged, while brain-derived neurotrophic factor expression increased after EE. Aβ deposition was attenuated in 18-month-old TG-EE mice, without apparent reduction of neuroinflammatory signs. We suggest that EE had a beneficial effect on cognitive performance and lessened long-term Aβ accumulation, but brain sirtuin expression was not modulated when cognitive impairment was restored. Show more

Keywords: Alzheimer's disease, APP23 mice, cognitive impairment, environmental enrichment, sirtuin

DOI: 10.3233/JAD-131430

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 851-864, 2014

Authors: Tong, Yawei | Yang, Huan | Tian, Xiaosheng | Wang, Hecheng | Zhou, Ting | Zhang, Shouzi | Yu, Jia | Zhang, Tao | Fan, Dongshen | Guo, Xiangyang | Tabira, Takeshi | Kong, Fanjun | Chen, Zheng | Xiao, Weizhong | Chui, Dehua

Article Type: Research Article

Abstract: Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer's disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-β (Aβ) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aβ peptides increased with elevated …Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aβ by Mn treatment, which was probably caused by disrupted Aβ degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor. Show more

Keywords: High manganese (Mn), cognitive impairment, amyloid-beta (Abeta), Alzheimer's disease (AD), Aβ degradation

DOI: 10.3233/JAD-140534

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 865-878, 2014

Authors: Lanza, Claudia | Knörzer, Oliver | Weber, Michael | Riepe, Matthias W.

Article Type: Research Article

Abstract: Background/Objective: Spatial orientation declines early in patients with Alzheimer’s disease (AD) and is a major cause for institutionalization of patients. Methods: Use of either an aerial map or an assistive device to get from start to goal zone, both located on the campus of the hospital (distance between start and goal zone 300 m to 500 m). Use of the assistive device was trained for 15 minutes prior to the task. Results: We assessed 14 patients with mild to moderate AD (DSM-IV and NINCDS-ADRDA criteria; 9 female patients, 5 male patients; age 71.9 ± 7.4 years; …MMSE 21.7 ± 2.9 (mean ± SD), range 16–26). Each patient had to find the way for three different routes with different start and goal zones. None of the patients found their way to the goal zone for any of the routes when using an aerial map in which the way was highlighted. With use of the assistive device, patients found their way from start to goal zones autonomously for 20 of 42 routes (3 routes each for 14 patients). For 22 of 42 routes intermediate re-assurance was necessary, but herewith routes were completed. Conclusion: This study lays ground for the use of mobile technical devices in patients with mild to moderate AD. Mobile assistive devices may enable patients with mild to moderate AD to maintain autonomous spatial orientation in unfamiliar environments. Improvement of the familiarization of patients with the device and further sophistication of assistive cues is likely to further improve autonomous use of navigational devices in patients with mild to moderate AD. Show more

Keywords: Alzheimer's disease, assistive devices, spatial orientation

DOI: 10.3233/JAD-140063

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 879-884, 2014

Authors: Elias, Alby | Woodward, Michael | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) may assist the diagnosis of dementia but it is an expensive investigation. Objective: To obtain management impact data for FDG-PET in dementia. Methods: This was a prospective study of 194 consecutive patients referred from a memory clinic for FDG-PET at the discretion of the dementia specialists. Diagnosis and management plans formulated at a multidisciplinary patient review meeting were compared before and after the release of PET findings. Results: FDG-PET had moderate to high impact on the diagnosis and management in 85 (44%) participants. Diagnosis changed from probable …neurodegenerative disease in 27 patients to a non-degenerative diagnosis and vice versa in 12 patients. PET changed the type of dementia in another 29 (15%) participants and prescription of cholinesterase inhibitors in 33 patients (17%). Number of uncertain diagnoses reduced from 58 to 35 (p < 0.001, χ2 = 15.12), differential diagnoses reduced from 127 to 55 (p = 0.003) and very probable diagnoses increased from 5 to 42 (p ≤ 0.001, χ2 = 1.01). Mini-Mental State Examination score was higher in those where PET had high diagnostic impact (26.3 ± 3.1 versus 23.9 ± 5.1, p ≤ 0.05). The degree of impact correlated with the pre-scan level of diagnostic uncertainty (ρ = −0.258, p < 0.001). Discussion: The management impact was higher in those with greater diagnostic uncertainty and in those with less severe cognitive impairment. The findings suggest that FDG-PET is a useful adjunct for the management of suspected dementing disorders in appropriately selected patients. Show more

Keywords: Alzheimer's disease, diagnostic impact, FDG-PET, memory clinic

DOI: 10.3233/JAD-132729

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 885-892, 2014

Authors: Shen, Xiao-Li | Yu, Jian-Han | Zhang, Dong-Feng | Xie, Jun-Xia | Jiang, Hong

Article Type: Research Article

Abstract: An imbalance of metal ions is implicated in the development of Alzheimer's disease (AD). We investigated the relationship between the annual mortality of AD and ionic concentration (iron, zinc, copper, and aluminum) in the soil in mainland China. The AD annual mortality data were from 26 provinces and 3 municipal districts within mainland China between the years 1991 and 2000 and provided by the National Death Cause Surveillance Database of China. The ionic concentration in soil was provided by the China State Environmental Protection Bureau, which was published in 1990. The results showed that the relative risk of mortality in …the regions with the highest copper concentrations (60–80 mg/kg) reached 2.634 (95% CI: 2.626–2.642) compared with the regions that had the lowest copper concentrations. The relative risk was 1.292 (95% CI: 1.290–1.294) and 1.248 (95% CI: 1.245–1.251) when the soil iron concentrations exceeded 3 mg/kg and 4 mg/kg, respectively. When the soil zinc concentration was over 100 mg/kg and 200 mg/kg, the relative risk was 1.870 (95% CI: 1.859–1.881) and 2.289 (95% CI: 2.276–2.304), respectively. However, the relative risk was 0.560 (95% CI: 0.559–0.561), 0.604 (95% CI: 0.603–0.605), and 0.267 (95% CI: 0.265–0.268) when the soil aluminum concentration was over 6 mg/kg, 7 mg/kg, and 8 mg/kg, respectively. This study suggests that high concentrations of iron and copper in the soil might be associated with the high AD annual mortality in this region in China, while aluminum had no association with AD mortality. Show more

Keywords: Alzheimer's disease, annual mortality, metals, soil

DOI: 10.3233/JAD-140153

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 893-900, 2014

Authors: Antonell, Anna | Mansilla, Alicia | Rami, Lorena | Lladó, Albert | Iranzo, Alex | Olives, Jaume | Balasa, Mircea | Sánchez-Valle, Raquel | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: An increase in YKL-40 levels seems to correlate with disease severity and poor prognosis in many diseases, including several neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease (AD). Specifically, YKL-40 protein is increased in mild AD with respect to controls, both in cerebrospinal fluid (CSF) and plasma. Objective: We hypothesize that subjects in the preclinical (Pre-AD) and prodromal (Prod-AD) stage of AD could already present an increase in CSF YKL-40 levels with respect to healthy controls and idiopathic REM sleep behavior disorder (iRBD) subjects, included as a control group of a distinct neurological …disease. Methods: We measured CSF YKL-40 levels using a commercial ELISA kit in a cohort of 95 subjects, consisting of controls (n = 43), Pre-AD (n = 18), Prod-AD (n = 22), and iRBD (n = 12) subjects. We explored for possible correlations of YKL-40 levels with demographic characteristics, a wide battery of neuropsychological tests, and the AD CSF biomarkers: amyloid-β42 (Aβ42 ), total-tau protein (t-tau), and phosphorylated-tau protein (p-tau). Results: We detected statistically significant differences between Prod-AD patients and controls. YKL-40 levels showed a significant correlation with t-tau and p-tau levels in the predementia AD continuum and the Pre-AD group. We also observed significant correlations with the MMSE, FCSRT, and M@T tests within the AD continuum, but not in iRBD subjects. Conclusion: Our data suggest that CSF YKL-40 levels, although not useful as a diagnostic marker for Prod-AD, may be a valuable marker to detect early physiopathological changes potentially linked with the neurodegenerative process. Show more

Keywords: Alzheimer's disease, amyloid-β42, cerebrospinal fluid, correlation, neuropsychological tests, preclinical, tau protein, YKL-40

DOI: 10.3233/JAD-140624

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 901-908, 2014

Authors: Williams, Michael A. | Silvestri, Vittorio | Craig, David | Passmore, A. Peter | Silvestri, Giuliana

Article Type: Research Article

Abstract: Background: Age-related macular degeneration (AMD) and Alzheimer’s disease (AD) share several features, including the presence of extracellular abnormal deposits associated with neuronal degeneration, drusen, and plaques, respectively. Investigation of any association of AMD and specifically AD is worthwhile but has rarely been done. Objectives: The aim of this study was to determine the prevalence of AMD in subjects with AD in comparison with an age-matched cognitively normal cohort. Methods: Cases were defined as those diagnosed with AD using standardized criteria as part of their clinical care, while controls were cognitively intact individuals aged 65 years or …more. Dilated retinal photographs were taken, and a range of potentially confounding factors measured including APOE genotype. AMD features were recorded and AMD grades given. Results: Data was collected on 322 controls and 258 cases. While AMD was associated with AD, and the proportion of cases of advanced AMD in AD cases was twice that of controls, when corrected the association was lost. AD was associated with age, the presence of an APOE allele, and smoking, while being ‘generally unwell recently’ was associated with a reduced risk of AD. Conclusion: AD and AMD are both associated with age, but our study does not find evidence they are associated with each other. However the retina offers an opportunity to non-invasively image neuronal tissue, and more sophisticated imaging techniques may shed light on ocular biomarkers of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, macular degeneration, retinal drusen

DOI: 10.3233/JAD-140243

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 909-914, 2014