Journal of Alzheimer's Disease - Volume 61, issue 3

Authors: Liu, Guiyou | Zhang, Yan | Wang, Longcai | Xu, Jianyong | Chen, Xiaoyun | Bao, Yunjuan | Hu, Yang | Jin, Shuilin | Tian, Rui | Bai, Weiyang | Zhou, Wenyang | Wang, Tao | Han, Zhifa | Zong, Jian | Jiang, Qinghua

Article Type: Research Article

Abstract: Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer’s disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale …eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk. Show more

Keywords: Alzheimer’s disease, EPHA1, eQTLs, genome-wide association study

DOI: 10.3233/JAD-170468

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1077-1088, 2018

Authors: Siddarth, Prabha | Rahi, Berna | Emerson, Natacha D. | Burggren, Alison C. | Miller, Karen J. | Bookheimer, Susan | Lavretsky, Helen | Dobkin, Bruce | Small, Gary | Merrill, David A.

Article Type: Research Article

Abstract: Background: Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited. Objective: To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints. Methods: Twenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day …determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups. Results: Twenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n  = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p  = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p  = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p  = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p  = 0.05). Memory recall was not significantly different between the two groups. Conclusion: Older non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy. Show more

Keywords: Cortical thickness, memory complaints, older adults, physical activity

DOI: 10.3233/JAD-170586

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1089-1096, 2018

Authors: Gabriel, António José | Almeida, Maria Rosário | Ribeiro, Maria Helena | Carneiro, Diogo | Valério, Daniela | Pinheiro, Ana Cristina | Pascoal, Rui | Santana, Isabel | Baldeiras, Inês

Article Type: Research Article

Abstract: Background: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. Objective: To investigate the influence of the BuChE-K variant in MCI progression to AD. Methods: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels …of AD biomarkers amyloid-β 42 (Aβ42 ), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. Results: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ 4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ 4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. Conclusion: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ 4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients. Show more

Keywords: Alzheimer’s disease, butyrylcholinesterase, disease progression, mildcognitive impairment

DOI: 10.3233/JAD-170695

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1097-1105, 2018

Authors: Renard, Dimitri | Collombier, Laurent | Demattei, Christophe | Wacongne, Anne | Charif, Mahmoud | Ayrignac, Xavier | Azakri, Souhayla | Gaillard, Nicolas | Boudousq, Vincent | Lehmann, Sylvain | Menjot de Champfleur, Nicolas | Thouvenot, Eric

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11 C-Pittsburgh compound B and 18 F-florbetapir, but not 18 F-florbetaben). Objective: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18 F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients. Methods: CSF levels of total tau, phosphorylated tau, Aβ1-42 , and Aβ1-40 , MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET …(using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients. Results: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = –0.83, p  = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p  = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = –0.63, p  = 0.076; phosphorylated tau, rho = –0.68, p  = 0.05; Aβ1-42 , rho = –0.59, p  = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = –0.50, p  = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers. Conclusion: In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri. Show more

Keywords: Amyloid, florbetaben, imaging

DOI: 10.3233/JAD-170843

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1107-1117, 2018

Authors: Subic, Ana | Cermakova, Pavla | Religa, Dorota | Han, Shuang | von Euler, Mia | Kåreholt, Ingemar | Johnell, Kristina | Fastbom, Johan | Bognandi, Liselia | Winblad, Bengt | Kramberger, Milica G. | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF). Objective: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF. Methods: Of 49,792 patients registered in the Swedish Dementia Registry 2007–2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death. Results: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 …(37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p  < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59–0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01–1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03–1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment. Conclusions: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible. Show more

Keywords: Atrial fibrillation, dementia, hemorrhage, ischemic stroke, warfarin

DOI: 10.3233/JAD-170575

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1119-1128, 2018

Authors: Pastori, Daniele | Miyazawa, Kazuo | Lip, Gregory Y.H.

Article Type: Article Commentary

Abstract: The risk of developing dementia is increased in patients with atrial fibrillation (AF), with the incidence of both conditions increasing with aging. Patients with dementia frequently do not receiving adequate thrombo-prophylaxis, because of the inability to monitor INR and/or to achieve and maintain good compliance with anticoagulant treatment. Under-treatment is therefore an important contributor to the increased risk of ischemic stroke and mortality in this subgroup of AF patients. In newly-diagnosed patients with AF starting oral anticoagulation, the presence of cognitive impairment should be considered in addition to the calculation of the SAMe-TT2 R2 score, as part of an …integrated decision management pathway to choose the most appropriate oral anticoagulant [i.e., vitamin K antagonists (VKAs) or non-vitamin K oral anticoagulants (NOACs)]. Moreover, in patients with low or worsening time in therapeutic range during VKAs therapy, the assessment of cognitive impairment may help identify those patients who may benefit from switching to NOACs. In conclusion, patients with AF and dementia benefit from anticoagulation and should not be denied receiving adequate stroke prevention. Cognitive function assessment and social support are pivotal elements in the management of these AF patients. Show more

Keywords: Anticoagulation, atrial fibrillation, dementia, ischemic stroke, mortality

DOI: 10.3233/JAD-170955

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1129-1132, 2018

Authors: Heinrich, Juliette | Vidal, Jean-Sébastien | Simon, Axelle | Rigaud, Anne-Sophie | Hanon, Olivier | Epelbaum, Jacques | Viollet, Cecile | Duron, Emmanuelle

Article Type: Research Article

Abstract: Background: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML. Objective: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI. Methods: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. …Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens’ scale and WML according to Fazekas criteria. Results: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p  = 0.007), lower BMI (p  = 0.08), lower MMSE score (p  = 0.05), lower FCRST (p  = 0.008), hippocampal atrophy (p  = 0.04), periventricular WML (p  = 0.007), and deep WML burden (p  = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4–35.13), p  = 0.02) remained associated with low BSIT score independently from hippocampal atrophy. Conclusion: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing. Show more

Keywords: Brain white matter lesions, magnetic resonance imaging, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-170378

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1133-1141, 2018

Authors: Raha-Chowdhury, Ruma | Henderson, James W. | Raha, Animesh Alexander | Stott, Simon R.W. | Vuono, Romina | Foscarin, Simona | Wilson, Liam | Annus, Tiina | Fincham, Robert | Allinson, Kieren | Devalia, Vinod | Friedland, Robert P. | Holland, Anthony | Zaman, Shahid H.

Article Type: Research Article

Abstract: Background: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer’s disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. Objective: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. Methods: We analyzed …peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. Results: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. Conclusion: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets. Show more

Keywords: Alzheimer’s disease, dementia, Down syndrome, innate immunity, immunomodulation, inflammation, myelination, myeloid hypothesis, neurodegeneration, soluble TREM2

DOI: 10.3233/JAD-170814

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1143-1162, 2018

Authors: Sundermann, Erin E. | Edmonds, Emily C. | Delano-Wood, Lisa | Galasko, Douglas R. | Salmon, David P. | Rubin, Leah H. | Bondi, Mark W. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer’s disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer’s Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into “overestimates,” “comparable estimates”, and “underestimates” of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC …and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of “overestimates” in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to “comparable estimates,” “underestimates” of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC. Show more

Keywords: Alzheimer’s disease, amyloid, awareness, cognitive reserve, mild cognitive impairment, sex differences memory

DOI: 10.3233/JAD-170425

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1163-1178, 2018

Authors: Maletta, Raffaele | Smirne, Nicoletta | Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Conidi, Maria Elena | Colao, Rosanna | Puccio, Gianfranco | Curcio, Sabrina A.M. | Laganà, Valentina | Frangipane, Francesca | Cupidi, Chiara | Mirabelli, Maria | Vasso, Franca | Torchia, Giusi | Muraca, Maria G. | Di Lorenzo, Raffaele | Rose, Giuseppina | Montesanto, Alberto | Passarino, Giuseppe | Bruni, Amalia C.

Article Type: Research Article

Abstract: Background: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. Objectives: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. Methods: The …genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. Results: Carriers of at least one APOE ɛ 4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477–5.011)] and VaD [OR(95% CI) = 6.205(2.356–16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364–4.319)] and VaD [OR(95% CI) = 3.649(1.455–9.152)] compared to subjects with the II-VV genotypes. Conclusion: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOE ɛ 4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia. Show more

Keywords: Alzheimer’s disease, APOE, cerebrovascular, CETP I405V, dementia, genetic, risk factors, vascular dementia

DOI: 10.3233/JAD-170687

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1179-1187, 2018