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

Authors: Li, Sinian | Shao, Yiming | Li, Kanglan | HuangFu, Changmei | Wang, Wenjie | Liu, Zhou | Cai, Zhiyou | Zhao, Bin

Article Type: Review Article

Abstract: Vascular cognitive impairment (VCI), the second most common cause of dementia in elderly people, is a term that refers to all forms of cognitive disorders that can be attributed to cerebrovascular disease such as manifestations of discrete infarctions, brain hemorrhages, and white matter lesions. The gut microbiota (GM) has emerged recently as an essential player in the development of VCI. The GM may affect the brain’s physiological, behavioral, and cognitive functions through the brain-gut axis via neural, immune, endocrine, and metabolic pathways. Therefore, microbiota dysbiosis may mediate or affect atherosclerosis, cerebrovascular disease, and endothelial dysfunction, which are the predominant risk …factors for VCI. Moreover, the composition of the GM includes the bacterial component lipopolysaccharides and their metabolic products including trimethylamine-N -oxide and short-chain fatty acids. These products may increase the permeability of the intestinal epithelium, leading to systemic immune responses, low-grade inflammation, and altered signaling pathways that are associated with the pathogenesis of VCI. In this review, we discuss the proposed mechanisms of the GM in the maintenance of VCI and how it is implicated in acquired metabolic diseases, particularly in VCI regulation. Show more

Keywords: Atherosclerosis, cerebrovascular disease, endothelial dysfunction, gut microbiota, lipopolysaccharides, short-chain fatty acids, trimethylamine-N-oxide, vascular cognitive impairment

DOI: 10.3233/JAD-171103

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1209-1222, 2018

Authors: Cai, Zhiyou | Qiao, Pei-Feng | Wan, Cheng-Qun | Cai, Min | Zhou, Nan-Kai | Li, Qin

Article Type: Review Article

Abstract: The blood-brain barrier (BBB) is involved in the pathogenesis of Alzheimer’s disease (AD). BBB is a highly selective semipermeable structural and chemical barrier which ensures a stable internal environment of the brain and prevents foreign objects invading the brain tissue. BBB dysfunction induces the failure of Aβ transport from brain to the peripheral circulation across the BBB. Especially, decreased levels of LRP-1 (low density lipoprotein receptor-related protein 1) and increased levels of RAGE (receptor for advanced glycation endproducts) at the BBB can cause the failure of Aβ transport. The pathogenesis of AD is related to the BBB structural components, including …pericytes, astrocytes, vascular endothelial cells, and tight junctions. BBB dysfunction will trigger neuroinflammation and oxidative stress, then enhance the activity of β-secretase and γ-secretase, and finally promote Aβ generation. A progressive accumulation of Aβ in brain and BBB dysfunction may become a feedback loop that gives rise to cognitive impairment and the onset of dementia. The correlation between BBB dysfunction and tau pathology has been well-reported. Therefore, regulating BBB function may be a new therapeutic target for treating AD. Show more

Keywords: Alzheimer’s disease, astrocyte, blood-brain barrier, endothelial cell, pericyte

DOI: 10.3233/JAD-180098

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1223-1234, 2018

Authors: Akingbade, Oluwatomi E.S. | Gibson, Claire | Kalaria, Raj N. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Review Article

Abstract: Dementia continues to be the most burdening neurocognitive disorder, having a negative impact on the lives of millions. The search for biomarkers to improve the clinical diagnosis of dementia is ongoing, with the focus on effective use of readily accessible peripheral markers. In this review, we concentrate on platelets as biomarkers of dementia and analyze their potential as easily-accessible clinical biomarkers for various subtypes of dementia. Current platelet protein biomarkers that have been investigated for their clinical utility in the diagnosis of dementia, in particular Alzheimer’s disease, include amyloid-β protein precursor (AβPP), the AβPP secretases (BACE1 and ADAM10), α-synuclein, tau …protein, serotonin, cholesterol, phospholipases, clusterin, IgG, surface receptors, MAO-B, and coated platelets. Few of them, i.e., platelet tau, AβPP (particularly with regards to coated platelets) and secreted ADAM10 and BACE1 show the most promise to be taken forward into clinical setting to diagnose dementia. Aside from protein biomarkers, changes in factors such as mean platelet volume have the potential to play a very specific role in both the dementia diagnosis and prognosis. This review raises a number of research questions for consideration before application of the above biomarkers to routine clinical setting. It is without doubt that there is a need for more clarification on the effects of dementia on platelet morphology and protein content before these changes can be clinically applied as dementia biomarkers and explored further in differentiating distinct dementia subtypes. Show more

Keywords: Amyloid, biomarkers, blood platelets, dementia, tau protein

DOI: 10.3233/JAD-180181

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1235-1259, 2018

Authors: Ma, Fang-Chen | Wang, Hui-Fu | Cao, Xi-Peng | Tan, Chen-Chen | Tan, Lan | Yu, Jin-Tai

Article Type: Short Communication

Abstract: The ATP-binding cassette transporter A7 (ABCA7) was identified as a known risk factor for Alzheimer’s disease (AD). However, the relation between ABCA7 and AD was still inconsistent across these studies. Here, our meta-analysis aimed at confirming the association of ABCA7 with AD. Finally, 16 case-control studies (63747 versus 85833) were retrieved from PubMed and other databases. Three common loci were confirmed to increase the risk of AD (rs3764650: OR = 1.20, 95% CI = 1.16–1.24; rs3752246: OR = 1.13,95% CI = 1.08–1.19; rs4147929: OR = 1.17, 95% CI = 1.10–1.24), but the associations varied among the different races. Furthermore, ABCA7 loss-of-function (LOF) mutations conferred a higher risk for AD than did the …above variants (LOF: OR = 1.78, 95%  = 1.43–2.22). In conclusion, ABCA7 genetic variants, especially the LOF mutations, were significantly associated with the risk of AD. Show more

Keywords: ABCA7, Alzheimer’s disease, loss-of-function, meta-analysis

DOI: 10.3233/JAD-180107

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1261-1267, 2018

Authors: Smith, Mark A. | Bowen, Richard L. | Nguyen, Richard Q. | Perry, George | Atwood, Craig S. | Rimm, Alfred A.

Article Type: Research Article

Abstract: Background: Estrogen and hormone replacement therapies to reduce Alzheimer’s disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population. Objective: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management. Methods: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n  = 115,789) were compared to three control groups: men of the …same demographics undergoing a cholecystectomy (n  = 97,267), herniorrhaphy (n  = 68,778), or transurethral prostatectomy (n  = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group. Results: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83. Conclusion: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins. Show more

Keywords: Alzheimer’s disease, cancer, castration, epidemiology, gonadotropin receptors, hormone replacement therapy, leuprolide, Medicare Part A, testosterone

DOI: 10.3233/JAD-170847

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1269-1277, 2018

Authors: Moustafa, Ahmed A. | El Haj, Mohamad

Article Type: Research Article

Abstract: This study investigates phenomenological reliving of future thinking in Alzheimer’s disease (AD) patients and matched controls. All participants were asked to imagine in detail a future event, and afterward, were asked to rate phenomenological characteristics of their future thinking. As compared to controls, AD participants showed poor rating for reliving, travel in time, visual imagery, auditory imagery, language, and spatiotemporal specificity. However, no significant differences were observed between both groups in emotion and importance of future thinking. Results also showed lower rating for visual imagery relative to remaining phenomenological features in AD participants compared to controls; conversely, these participants showed …higher ratings for emotion and importance of future thinking. AD seems to compromise some phenomenological characteristics of future thinking, especially, visual imagery; however, other phenomenological characteristics, such as emotion, seem to be relatively preserved in these populations. By highlighting the phenomenological experience of future thinking in AD, our paper opens a unique window into the conscious experience of the future in AD patients. Show more

Keywords: Alzheimer’s disease, emotion, future thinking, phenomenological reliving, visual imagery

DOI: 10.3233/JAD-180182

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1279-1287, 2018

Authors: Noguchi-Shinohara, Moeko | Abe, Chiemi | Yuki-Nozaki, Sohshi | Dohmoto, Chiaki | Mori, Ayaka | Hayashi, Koji | Shibata, Syutaro | Ikeda, Yoshihisa | Sakai, Kenji | Iwasa, Kazuo | Yokogawa, Masami | Ishimiya, Mai | Nakamura, Hiroyuki | Yokoji, Hidehiro | Komai, Kiyonobu | Nakamura, Hiroyuki | Yamada, Masahito

Article Type: Research Article

Abstract: Background: Antioxidants like vitamins C and E may minimize the risk for Alzheimer’s disease. Objective: We examined whether vitamins C and E modify the apolipoprotein E (APOE) E4-related risks for developing cognitive decline. Methods: We conducted a population-based prospective study including Japanese residents aged 65 years from Nakajima, Japan. The participants received an evaluation of cognitive function and underwent blood tests including tests for vitamins C and E levels and APOE phenotypes. The APOE E4-by-gender-by-vitamin C or E interactions on developing cognitive decline were analyzed. Results: Of 606 participants with normal cognitive function determined …using a baseline survey (2007–2008), 349 completed the follow up survey between 2014 and 2016. In women with APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin C concentration tertile [multivariate OR 0.10 (95% CI 0.01–0.93)] compared with the lowest tertile. In men without APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin E concentration tertile [multivariate OR 0.19 (0.05–0.74)] as compared with the lowest tertile. Conclusion: Our results demonstrate significant beneficial effects of vitamins C and E in reducing the risk of cognitive decline in women with APOE E4 and men without APOE E4, respectively. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, vitamin C, vitamin E

DOI: 10.3233/JAD-170971

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1289-1297, 2018

Authors: Brown, Belinda M. | Rainey-Smith, Stephanie R. | Dore, Vincent | Peiffer, Jeremiah J. | Burnham, Samantha C. | Laws, Simon M. | Taddei, Kevin | Ames, David | Masters, Colin L. | Rowe, Christopher C. | Martins, Ralph N. | Villemagne, Victor L.

Article Type: Research Article

Abstract: Numerous animal studies have reported exercise reduces the accumulation of Alzheimer’s disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into …low-moderate PA (LMPA; n  = 16) or high PA (HPA; n  = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: – 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA. Show more

Keywords: Alzheimer’s disease, physical activity, positron emission tomography, tau

DOI: 10.3233/JAD-170998

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1299-1305, 2018

Authors: Kennedy, Greg | Meyer, Denny | Hardman, Roy J. | Macpherson, Helen | Scholey, Andrew B. | Pipingas, Andrew

Article Type: Research Article

Abstract: Background: Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. Objective: To investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition. Methods: Residents of independent living …facilities, aged 60–90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. Results: Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation. Conclusions: Greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline. Show more

Keywords: Aging, aortic stiffness, arterial stiffness, cognition, fitness, working memory

DOI: 10.3233/JAD-171107

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1307-1316, 2018

Authors: Roudil, Jennifer | Deramecourt, Vincent | Dufournet, Boris | Dubois, Bruno | Ceccaldi, Mathieu | Duyckaerts, Charles | Pasquier, Florence | Lebouvier, Thibaud | and the Brainbank Neuro-CEB Neuropathology Network

Article Type: Research Article

Abstract: Background: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer’s Disease (AD). Objective: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD. Methods: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological …data. Results: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with ‘classical’ (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p  < 0.01). There was no significant difference in cognitive profiles. Conclusion: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease with amygdala Lewy bodies, braak stages, dementia with Lewy bodies, Lewy bodies, Lewy body variant of Alzheimer’s disease, neurofibrillary tangles

DOI: 10.3233/JAD-170914

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1317-1323, 2018

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

Authors: Adams, Stephanie L. | Benayoun, Laurent | Tilton, Kathy | Mellott, Tiffany J. | Seshadri, Sudha | Blusztajn, Jan Krzysztof | Delalle, Ivana

Article Type: Research Article

Abstract: The pathophysiology of Alzheimer’s disease (AD) includes signaling defects mediated by the transforming growth factor β—bone morphogenetic protein—growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was …similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD. Show more

Keywords: ACVRL1, ALK1, CA1, CA3, GAD67, hippocampus, immunohistochemistry

DOI: 10.3233/JAD-171065

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1433-1443, 2018

Authors: Bourgin, Jessica | Guyader, Nathalie | Chauvin, Alan | Juphard, Alexandra | Sauvée, Mathilde | Moreaud, Olivier | Silvert, Laetitia | Hot, Pascal

Article Type: Research Article

Abstract: Emotional deficits have been repetitively reported in Alzheimer’s disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more …AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning. Show more

Keywords: Alzheimer’s disease, attention, emotion, eye movements, inhibition

DOI: 10.3233/JAD-180170

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1445-1458, 2018

Authors: Smith, Glenn E. | Chandler, Melanie | Fields, Julie A. | Aakre, Jeremiah | Locke, Dona E.C.

Article Type: Research Article

Abstract: Background: The patient-centered movement in health care is increasing efforts to design studies and interventions that address the outcomes that matter most to patients and their families. Research has not adequately addressed Alzheimer’s disease patient and caregiver preferences. Objective: To survey the outcome and treatment preferences of patients and caregivers who had completed a multicomponent behavioral intervention for mild cognitive impairment (MCI). Methods: Extending prior work, we conducted an online survey regarding outcome and intervention preferences. Participants were patients with MCI and partners who completed the HABIT Healthy Action to Benefit Independence & Thinking ® program. …Results: Both patient and partner respondents ranked patient quality of life as the highest priority, followed by patient self-efficacy, functional status, patient mood, and patient memory performance. Distressing behaviors and caregiver outcomes (burden, mood, and self-efficacy) had low rankings. Regarding the importance of HABIT ® program components, memory compensation training was ranked highest and wellness education lowest by all groups. Conclusion: Additional research should compare patient preference for patient reported outcomes, traditional neuropsychological and clinician outcomes, and modern biomarker outcomes. Show more

Keywords: Behavioral intervention, caregiver, daily function, mild cognitive impairment, patient preference, quality of life

DOI: 10.3233/JAD-171161

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1459-1468, 2018

Authors: Falck, Ryan S. | Best, John R. | Davis, Jennifer C. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Current evidence suggests physical activity (PA) and sleep are important for cognitive health; however, few studies examining the role of PA and sleep for cognitive health have measured these behaviors objectively. Objective: We cross-sectionally examined whether 1) higher PA is associated with better cognitive performance independently of sleep quality; 2) higher sleep quality is associated with better cognitive performance independently of PA; and 3) whether higher PA is associated with better sleep quality. Methods: We measured PA, subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep quality (i.e., fragmentation, efficiency, duration, …and latency) using the MotionWatch8© in community-dwelling adults (N = 137; aged 55+). Cognitive function was indexed using the Alzheimer’s Disease Assessment Scale-Plus. Correlation analyses were performed to determine relationships between PA, sleep quality, and cognitive function. We then used latent variable modelling to examine the relationships of PA with cognitive function independently of sleep quality, sleep quality with cognitive function independently of PA, and PA with sleep quality. Results: We found greater PA was associated with better cognitive performance independently of 1) PSQI (β = –0.03; p  < 0.01); 2) sleep fragmentation (β = –0.02; p  < 0.01); 3) sleep duration (β = –0.02; p  < 0.01); and 4) sleep latency (β = –0.02; p  < 0.01). In addition, better sleep efficiency was associated with better cognitive performance independently of PA (β = –0.01; p  = 0.04). We did not find any associations between PA and sleep quality. Conclusions: PA is associated with better cognitive performance independently of sleep quality, and sleep efficiency is associated with better cognitive performance independently of PA. However, PA is not associated with sleep quality and thus PA and sleep quality may be related to cognitive performance through independent mechanisms. Show more

Keywords: Cognitive function, older adults, physical activity, sleep

DOI: 10.3233/JAD-170936

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1469-1484, 2018

Authors: Banerjee, Gargi | Jang, Hyemin | Kim, Hee Jin | Kim, Sung Tae | Kim, Jae Seung | Lee, Jae Hong | Im, Kiho | Kwon, Hunki | Lee, Jong Min | Na, Duk L. | Seo, Sang Won | Werring, David John

Article Type: Research Article

Abstract: Background: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. Objective: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. Methods: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer’s disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11 C] PiB-PET scanning …and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. Results: Total SVD score was associated with the performance of frontal (β – 4.31, SE 2.09, p  = 0.040) and visuospatial (β – 0.95, SE 0.44, p  = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. Conclusion: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption. Show more

Keywords: Alzheimer’s disease, cerebral small vessel diseases, cognitive dysfunction, magnetic resonance imaging, positron-emission tomography, vascular dementia

DOI: 10.3233/JAD-170943

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1485-1497, 2018

Authors: Paire-Ficout, Laurence | Lafont, Sylviane | Conte, Fanny | Coquillat, Amandine | Fabrigoule, Colette | Ankri, Joël | Blanc, Frédéric | Gabel, Cécilia | Novella, Jean-Luc | Morrone, Isabella | Mahmoudi, Rachid

Article Type: Research Article

Abstract: Background: Because cognitive processes decline in the earliest stages of Alzheimer’s disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants. Objective: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior. Methods: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in …the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events. Results: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more “unaware” critical events. Conclusion: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components. Show more

Keywords: Alzheimer’s disease, critical events, dementia, naturalistic driving, self-awareness

DOI: 10.3233/JAD-171031

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1499-1508, 2018

Authors: Niemantsverdriet, Ellis | Ribbens, Annemie | Bastin, Christine | Benoit, Florence | Bergmans, Bruno | Bier, Jean-Christophe | Bladt, Roxanne | Claes, Lene | De Deyn, Peter Paul | Deryck, Olivier | Hanseeuw, Bernard | Ivanoiu, Adrian | Lemper, Jean-Claude | Mormont, Eric | Picard, Gaëtane | Salmon, Eric | Segers, Kurt | Sieben, Anne | Smeets, Dirk | Struyfs, Hanne | Thiery, Evert | Tournoy, Jos | Triau, Eric | Vanbinst, Anne-Marie | Versijpt, Jan | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer’s disease (AD). Objective: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. Methods: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n  = 887) and follow-up (FU, n  = 95) T1-weighted …brain MRIs and time-linked neuropsychological data were available. Results: The cohort consisted of cognitively healthy controls (HC, n  = 93), subjective cognitive decline (n  = 102), mild cognitive impairment (MCI, n  = 379), and AD dementia (n  = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n  = 95) compared to HC (FU>24months, p  = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. Conclusion: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials. Show more

Keywords: Alzheimer’s disease, biomarkers, magnetic resonance image, MSmetrix, volumetry

DOI: 10.3233/JAD-171140

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1509-1522, 2018

Authors: Bessi, Valentina | Mazzeo, Salvatore | Padiglioni, Sonia | Piccini, Carolina | Nacmias, Benedetta | Sorbi, Sandro | Bracco, Laura

Article Type: Research Article

Abstract: The aim of this study was to evaluate the accuracy of neuropsychological assessment in predicting conversion from subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and the effect of personality traits and cognitive reserve in progression from SCD to MCI. As part of a longitudinal, clinical-neuropsychological-genetic survey on SCD and MCI, 284 patients referred to our hospital between 1990 and 2017 were included. All patients underwent clinical-extensive neuropsychological evaluation and Apolipoprotein E genotyping; personality traits were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up. Subjects with a follow-up shorter than two years were excluded. …A total of 212 subjects were, after exclusions, considered: 26 out of 109 SCD subjects progressed to MCI (SCD-p), 15 converted to AD (SCD-c), and 68 remained stable (SCD-s). Of 103 MCI subjects, 39 converted to AD (MCI-c) and 64 remained stable (MCI-s). At baseline, SCD-c performed significantly worse than SCD-s in tests assessing long-term verbal memory. MCI-c showed worse performance on neuropsychological tests for short- and long-term verbal memory and for ecological evaluation of memory (RBMT). These tests provided good accuracy in distinguishing MCI-c and MCI-s. Emotional stability was significantly lower in SCD-s than in SCD-p while higher intellectual activities were associated with a lower risk of conversion to MCI. Our results suggest that memory neuropsychological tests may represent a reliable tool to estimate the risk of progression to AD. Personality and lifestyle factors could provide useful information to identify SCD subjects who may develop an objective cognitive impairment. Show more

Keywords: Alzheimer’s disease, APOE, cognitive reserve, dementia, mild cognitive impairment, neuropsychology, personality traits, prediction, subjective cognitive decline

DOI: 10.3233/JAD-171180

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1523-1535, 2018

Authors: Chai, Gao-Shang | Feng, Qiong | Ma, Rong-Hong | Qian, Xiao-Hang | Luo, Dan-Ju | Wang, Zhi-Hao | Hu, Yu | Sun, Dong-Sheng | Zhang, Jun-Fei | Li, Xiao | Li, Xiao-Guang | Ke, Dan | Wang, Jian-Zhi | Yang, Xi-Fei | Liu, Gong-Ping

Article Type: Research Article

Abstract: There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice …and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, ANP32A, cognition, histone acetylation, synaptic-related protein

DOI: 10.3233/JAD-180090

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1537-1546, 2018

Authors: Miron, Justin | Picard, Cynthia | Frappier, Josée | Dea, Doris | Théroux, Louise | Poirier, Judes

Article Type: Research Article

Abstract: One important aspect in Alzheimer’s disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer’s disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF …genes (p  = 0.001 and p  = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p  = 0.0367 and p  = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p  = 0.0055 and p  = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process. Show more

Keywords: Alzheimer’s disease, cytokines, inflammation, TLR4

DOI: 10.3233/JAD-171160

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1547-1556, 2018

Article Type: Correction

DOI: 10.3233/JAD-189003

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1557-1557, 2018