Journal of Alzheimer's Disease - Volume 63, issue 4

Authors: Arnoldussen, Ilse A.C. | Sundh, Valter | Bäckman, Kristoffer | Kern, Silke | Östling, Svante | Blennow, Kaj | Zetterberg, Henrik | Skoog, Ingmar | Kiliaan, Amanda J. | Gustafson, Deborah R.

Article Type: Research Article

Abstract: Background: Adiposity measured in mid- or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures. Objective: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence. Methods: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based …in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000–2005, 2005–2010, and 2000–2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used. Results: Within 5 years of baseline, low BMI (<20 kg/m2 ) was associated with higher odds of dementia compared to those in the healthy BMI category (≥ 20–24.9 kg/m2 ). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p  < 0.05). Conclusion: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age ≥70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity. Show more

Keywords: Adiponectin, body mass index, dementia, elderly, leptin, waist hip ratio

DOI: 10.3233/JAD-180099

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1325-1335, 2018

Authors: Zhuang, Zhen-Qian | Shen, Lin-Lin | Li, Wei-Wei | Fu, Xue | Zeng, Fan | Gui, Li | Lü, Yang | Cai, Min | Zhu, Chi | Tan, Yin-Ling | Zheng, Peng | Li, Hui-Yun | Zhu, Jie | Zhou, Hua-Dong | Bu, Xian-Le | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer’s disease (AD) remains largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, …such as Bacteroides , Actinobacteria , Ruminococcus , Lachnospiraceae , and Selenomonadales . Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, gut microbiota, 16S ribosomal RNA sequencing

DOI: 10.3233/JAD-180176

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1337-1346, 2018

Authors: Alosco, Michael L. | Sugarman, Michael A. | Besser, Lilah M. | Tripodis, Yorghos | Martin, Brett | Palmisano, Joseph N. | Kowall, Neil W. | Au, Rhoda | Mez, Jesse | DeCarli, Charles | Stein, Thor D. | McKee, Ann C. | Killiany, Ronald J. | Stern, Robert A.

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer’s disease. Clinicopathological studies are needed to elucidate and confirm this possibility. Objective: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer’s disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. Methods: The sample included 82 participants from the National Alzheimer’s Coordinating Center’s Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. …The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Results: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p  = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p  = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (p s < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP–participants (p s < 0.04). Conclusions: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer’s disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuropathology, cerebrovascular disease, dementia, magnetic resonance imaging, white matter hyperintensities

DOI: 10.3233/JAD-180017

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1347-1360, 2018

Authors: Lu, Lingling | Jia, Huanzhen | Gao, Ge | Duan, Chunli | Ren, Jing | Li, Yi | Yang, Hui

Article Type: Research Article

Abstract: PTEN induced putative kinase 1 (PINK1), also known as PARK6, is causally linked to familial Parkinsonism, and heterozygous loss of PINK1 is a risk factor for sporadic Parkinson’s disease. However, little is known about its physiological function. Its deficiency was shown to decrease dopamine without significant loss of dopaminergic neurons. We investigated the mechanistic basis for this observation in the present study using dopaminergic MN9D cells. We found that PINK1 knockdown resulted in dopamine content to decrease with suppressed tyrosine hydroxylase expression in cells. Conversely, PINK1 overexpression increased tyrosine hydroxylase protein level. We also found that PINK1 deficiency blocked the …nuclear translocation and activity of nuclear receptor-related 1, a transcription factor regulating tyrosine hydroxylase gene expression. These data suggest that PINK1 regulates tyrosine hydroxylase gene expression and dopamine content by modulating the transcriptional activity of nuclear receptor-related 1. Taken together, our results reveal a novel function of PINK1 in dopamine homeostasis. Show more

Keywords: MN9D cells, Nurr1, PINK1, RNA interference, tyrosine hydroxylase

DOI: 10.3233/JAD-170832

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1361-1371, 2018

Authors: Allali, Gilles | Kern, Ilse | Laidet, Magali | Armand, Stéphane | Assal, Frédéric

Article Type: Research Article

Abstract: Background: Central neurological gait abnormalities (CNGA) are frequently associated with parkinsonism in older adults. However, the neuropathological substrates and the clinical impact of parkinsonism have been not described in CNGA. Objective: This cross-sectional study aims to compare the CSF total tau, Aβ1-42 , and phosphorylated tau levels in non-Parkinson’s disease (PD) patients with CNGA with and without parkinsonism and to study the clinical impact of parkinsonism on gait and cognition. Methods: CSF biomarkers were measured by ELISA in 49 non-PD patients with CNGA (77.7±6.6 years; 32.7% women). Gait was quantified with an optoelectronic system and cognition …with a comprehensive neuropsychological assessment. Parkinsonism was defined by presence of bradykinesia and at least one of the following signs among muscular rigidity, rest tremor, or postural instability. Results: Parkinsonism was identified in 14 CNGA patients (28.6% ). CSF Aβ1-42 level was decreased in CNGA patients with parkinsonism (β: – 189.4; 95% CI [– 352.3; – 26.6]; p  = 0.024) even after adjusting for age, gender, comorbidities, and total white matter burden; while CSF total tau and phosphorylated tau levels were similar between CNGA patients with and without parkinsonism. CNGA patients with parkinsonism presented decreased attentional and executive performances but similar gait parameters than those without parkinsonism. Conclusion: Parkinsonism represents a phenotype related with amyloidopathy—decreased CSF Aβ1-42 level—in non-PD patients with CNGA. This phenotype is clinically associated with impaired cognition, but similar quantitative gait parameters in comparison to CNGA patients without parkinsonism. Show more

Keywords: Amyloidopathy, biomarkers, dementia, gait disorders, parkinsonism

DOI: 10.3233/JAD-171055

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1373-1381, 2018

Authors: Steenland, Kyle | Zhao, Liping | John, Samantha E. | Goldstein, Felicia C. | Levey, Allan | Alvaro, Alonso | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: There are no agreed-upon variables for predicting progression from unimpaired cognition to amnestic mild cognitive impairment (aMCI), or from aMCI to Alzheimer’s disease (AD). Objective: Use ADNI data to develop a ‘Framingham-like’ prediction model for a 4-year period. Methods: We developed models using the strongest baseline predictors from six domains (demographics, neuroimaging, CSF biomarkers, genetics, cognitive tests, and functional ability). We chose the best predictor from each domain, which was dichotomized into more versus less harmful. Results: There were 224 unimpaired individuals and 424 aMCI subjects with baseline data on all predictors, of …whom 37 (17% ) and 150 (35% ) converted to aMCI and AD, respectively, during 4 years of follow-up. For the unimpaired, CSF tau/Aβ ratio, hippocampal volume, and a memory score predicted progression. For those aMCI at baseline, the same predictors plus APOE4 status and functional ability predicted progression. Demographics and family history were not important predictors for progression for either group. The fit statistic was good for the unimpaired-aMCI model (C-statistic 0.80) and very good for the aMCI-AD model (C-statistic 0.91). Among the unimpaired, those with no harmful risk factors had a 4-year predicted 2% risk of progression, while those with the most harmful risk factors had a predicted 35% risk. The aMCI subjects with no harmful risk factors had a predicted 1% risk of progression those with all six harmful risk factors had a predicted 90% risk. Conclusion: Our parsimonious model accurately predicted progression from unimpaired to aMCI with three variables, and from aMCI to AD with five variables. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, imaging, mild cognitive impairment

DOI: 10.3233/JAD-170769

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1383-1393, 2018

Authors: Costa, Montserrat | Horrillo, Raquel | Ortiz, Ana María | Pérez, Alba | Mestre, Anna | Ruiz, Agustín | Boada, Mercè | Grancha, Salvador

Article Type: Research Article

Abstract: Background: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer’s disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. Objective: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. Methods: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed …by mass spectrometry. Results: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p  < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p  < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p  < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p  < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. Conclusion: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation. Show more

Keywords: Albumin, Alzheimer’s disease, cerebrospinal fluid, oxidation status, plasma

DOI: 10.3233/JAD-180243

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1395-1404, 2018

Authors: Fattoretti, Patrizia | Malavolta, Marco | Fabbietti, Paolo | Papa, Roberta | Giacconi, Robertina | Costarelli, Laura | Galeazzi, Roberta | Paoloni, Cristina | Postacchini, Demetrio | Lattanzio, Fabrizia | Giuli, Cinzia

Article Type: Research Article

Abstract: Background: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objective: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training (“My Mind Project”). Methods: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive …performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable. Results: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM. Conclusions: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias. Show more

Keywords: Aging, Alzheimer’s disease, cognitive dysfunction, oxidative stress

DOI: 10.3233/JAD-171117

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1405-1414, 2018

Authors: Maseda, Ana | Cibeira, Nuria | Lorenzo-López, Laura | González-Abraldes, Isabel | Buján, Ana | de Labra, Carmen | Millán-Calenti, José Carlos

Article Type: Research Article

Abstract: Background: Multisensory stimulation and individualized music have shown to be good in handling the psychological and behavioral symptoms in people with severe dementia. Objective: Explore the effects of two nonpharmacological interventions, multisensory stimulation environment (MSSE) in a Snoezelen room and individualized music sessions, on mood, behavior, and biomedical parameters of institutionalized elderly patients with severe dementia. Methods: Randomized trial of 21 patients aged ≥65 years randomly assigned to two groups (MSSE and individualized music). Interventions administered in two-weekly sessions lasted 30 minutes for a period of 12 weeks. Main outcomes were recorded before, during, and at …the end of the intervention. Results: Both groups had immediate positive effects on mood and behavior. Participants were more happy/more content (p  < 0.001), talked more spontaneously (p  = 0.009), related to people better (p  = 0.002), were more attentive to/focused on their environment (p  < 0.001), enjoyed themselves (p  = 0.003), were less bored/inactive (p  = 0.004), and more relaxed/content (p  = 0.003). The MSSE group performed a better visual follow-up of the stimuli (p  = 0.044), and the music group were more relaxed and happy (p  = 0.003). A decrease in heart rate (p  = 0.013) and an increase in oxygen saturation (p  = 0.011) were observed from before to after interventions in both groups, with no significant differences between them. Conclusions: Both interventions seem to be effective at managing mood and behavioral disturbances in the short term and at improving physiological rates, highlighting the efficacy of nonpharmacological treatments in patients with severe dementia. Show more

Keywords: Dementia, elderly, individualized music, randomized trial, Snoezelen

DOI: 10.3233/JAD-180109

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1415-1425, 2018

Authors: Squitti, Rosanna | Fostinelli, Silvia | Siotto, Mariacristina | Ferrari, Clarissa | Binetti, Giuliano | Benussi, Luisa | Rongioletti, Mauro | Ghidoni, Roberta

Article Type: Research Article

Abstract: Meta-analyses show copper dyshomeostasis in Alzheimer’s disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

Keywords: Ceruloplasmin, copper, frontotemporal dementia, non-ceruloplasmin copper, serum

DOI: 10.3233/JAD-171074

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1427-1432, 2018