Journal of Alzheimer's Disease - Volume 60, issue 3

Authors: Hilal, Saima | Akoudad, Saloua | van Duijn, Cornelia M. | Niessen, Wiro J. | Verbeek, Marcel M. | Vanderstichele, Hugo | Stoops, Erik | Ikram, M. Arfan | Vernooij, Meike W.

Article Type: Research Article

Abstract: Background: Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ1-42 have been linked with risk of Alzheimer’s disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementia Objective: To examine the association of plasma Aβ levels (i.e., Aβ1-38 , Aβ1-40 , and Aβ1-42 ) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. Methods: We …analyzed plasma Aβ1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects. Results: Higher levels of plasma Aβ1-38 , Aβ1-40 , Aβ1-42 , and Aβ1-40 / Aβ1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Aβ1-40 and Aβ1-40 / Aβ1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Aβ1-38 Aβ1-40 and Aβ1-40 / Aβ1-42 was related to worse performance on cognitive test specifically in memory domain. Conclusion: Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology. Show more

Keywords: Cerebral small vessel disease, cognition, magnetic resonance imaging, plasma amyloid-β levels, population-based

DOI: 10.3233/JAD-170458

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 977-987, 2017

Authors: Licher, Silvan | de Bruijn, Renée F.A.G. | Wolters, Frank J. | Zillikens, M. Carola | Ikram, M. Arfan | Ikram, M. Kamran

Article Type: Research Article

Abstract: Background: Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results. Objective: To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population. Methods: Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models …to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer’s disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOE ɛ 4 carriership. Results: At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24). Conclusion: Lower serum vitamin D concentrations are associated with a higher incidence of dementia. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, vitamin D

DOI: 10.3233/JAD-170407

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 989-997, 2017

Authors: Rane, Jitendra Subhash | Bhaumik, Prasenjit | Panda, Dulal

Article Type: Research Article

Abstract: The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson’s disease, and Alzheimer’s disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic …light scattering, thioflavin S fluorescence, 90° light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90° light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments. Show more

Keywords: Alzheimer’s disease, curcumin, microtubule-associated proteins, neurodegeneration, tau

DOI: 10.3233/JAD-170351

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 999-1014, 2017

Authors: Serra, Laura | Gabrielli, Giulia Bechi | Tuzzi, Elisa | Spanò, Barbara | Giulietti, Giovanni | Failoni, Virginia | Marra, Camillo | Caltagirone, Carlo | Koch, Giacomo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: The frontal aslant tract (FAT) has been described as a bundle connecting the Broca’s area to the supplementary motor area (SMA) and the pre-SMA in both hemispheres. The functional properties of this tract and its role in degenerative dementia, such as Alzheimer’s disease (AD), still need to be fully clarified. The aim of this study was to explore the microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning. Twenty-three patients with AD and 25 healthy subjects (HS) were enrolled. All subjects underwent cognitive and MRI examination. MRI, including diffusion sequences, was used for …probabilistic tractography analysis. We reconstructed individual FATs bilaterally and assessed their microstructural integrity using fractional anisotropy (FA), computed as both mean tract value and voxel-wise using SPM-8. Mean FA values were then used to test for correlations with cognitive measures. Mean tract FA and voxel-wise analyses revealed that patients with AD, compared to HS, had decreased FA in the FAT bilaterally. In addition, positive associations were found between FA in the FATs and patients’ performance at tests for constructional praxis and visuospatial logical reasoning. The present results reveal a bilateral damage of FAT in AD patients. The association between FATs’ microscopic abnormalities and constructive abilities fits well with the knowledge of a functional involvement of SMA and pre-SMA in movement sequences when executing constructive praxis tasks. The FAT is an associative bundle critically involved in the network sub-serving constructional praxis in patients with AD. Show more

Keywords: Alzheimer’s disease, disconnection, frontal aslant tract, tractography, visuo-spatial abilities

DOI: 10.3233/JAD-170638

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1015-1024, 2017

Authors: Reijs, Babette L.R. | Ramakers, Inez H.G.B. | Elias-Sonnenschein, Lyzel | Teunissen, Charlotte E. | Koel-Simmelink, Marleen | Tsolaki, Magda | Wahlund, Lars-Olof | Waldemar, Gunhild | Hausner, Lucrezia | Johannsen, Peter | Vanderstichele, Hugo | Verhey, Frans | Devanand, D.P. | Visser, Pieter Jelle

Article Type: Research Article

Abstract: Background: Impaired olfactory function is an early characteristic of Alzheimer’s disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF). Objective: To investigate the association between odor identification and amyloid-β 1–42 (Aβ42 ) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF Aβ42 and t-tau and apolipoprotein E (APOE) genotype. Methods: We included 160 individuals (40 with normal cognition, 45 with mild …cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF Aβ42 and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline. Results: Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE ɛ 4 carriers and in individuals with abnormal Aβ42 . Conclusion: Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β (1–42), cerebrospinal fluid, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-170564

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1025-1034, 2017

Authors: dos Santos Matioli, Maria Niures Pimentel | Suemoto, Claudia Kimie | Rodriguez, Roberta Diehl | Farias, Daniela Souza | da Silva, Magnólia Moreira | Leite, Renata Elaine Paraizo | Ferretti-Rebustini, Renata Eloah Lucena | Farfel, José Marcelo | Pasqualucci, Carlos Augusto | Jacob Filho, Wilson | Arvanitakis, Zoe | Naslavsky, Michel Satya | Zatz, Mayana | Grinberg, Lea Tenenholz | Nitrini, Ricardo

Article Type: Research Article

Abstract: Background: Previous evidence linking diabetes to Alzheimer’s disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries. Objective: To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults. Methods: In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. A standardized neuropathological examination was performed using immunohistochemistry. The associations of diabetes with Consortium to Establish and Registry for Alzheimer Disease (CERAD) scores for neuritic plaques and Braak-Braak (BB) scores for neurofibrillary tangles were investigated using multivariable ordinal logistic …regression. We investigated effect modification of education, race, and APOE on these associations. Results: Among 1,037 subjects (mean age = 74.4±11.5 y; mean education = 4.0±3.7 y; 48% male, 61% White), diabetes was present in 279 subjects. Diabetes was not associated with BB (OR = 1.12, 95% CI = 0.81–1.54, p  = 0.48) or with CERAD (OR = 0.97, 95% CI = 0.68–1.38, p  = 0.86) scores on analyses adjusted for sociodemographic and clinical variables. We observed effect modification by the APOE allele ɛ 4 on the association between diabetes mellitus and BB scores. Conclusion: No evidence of an association between diabetes and AD neuropathology was found in a large sample of Brazilians; however, certain subgroups, such as APOE allele ɛ 4 carriers, had higher odds of accumulation of neurofibrillary tangles. Show more

Keywords: Alzheimer’s disease, autopsy study, dementia, diabetes mellitus, neuropathology

DOI: 10.3233/JAD-170179

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1035-1043, 2017

Authors: Chen, Yaohua | Sillaire, Adeline Rollin | Dallongeville, Jean | Skrobala, Emilie | Wallon, David | Dubois, Bruno | Hannequin, Didier | Pasquier, Florence | Lille YOD study group

Collaborators: Bombois, Stéphanie | Boutantin, Justine | Cassagnaud, Pascaline | Chen, Yaohua | Delbeuck, Xavier | Delmaire, Christine | Deramecourt, Vincent | Gele, Patrick | Houssein-Foucher, Claude | Jacquemont, Charlotte | Lebert, Florence | Lebouvier, Thibaud | Lopez, Renaud | Mackowiak, Marie-Anne | Maureille, Aurélien | Pasquier, Florence | Petyt, Grégory | Pollet, Marianne | Rollin-Sillaire, Adeline | Schraen, Susanna | Semah, Franck | Vanhoutte, Matthieu

Article Type: Research Article

Abstract: Background: Determinants of early-onset Alzheimer’s disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. Objective: The objective of this study was to assess the putative association between VRFs and EOAD. Methods: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in …multivariable logistic regression analyses. Results: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p  < 0.0001), were less likely to be regular alcohol consumers (p  < 0.0001), had a lower body mass index (–2 kg/m2 ; p  < 0.0004), and a lower mean systolic blood pressure (–6.2 mmHg; p  = 0.0036). The prevalence of APOE ɛ 4 allele was higher in participants with dementia than in controls (50% versus 29.4%; p  = 0.0002), as was the prevalence of depression (48% versus 32%; p  < 0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; p  = 0.03). Conclusion: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD. Show more

Keywords: APOE, early onset Alzheimer disease, late onset Alzheimer disease, vascular risk factors

DOI: 10.3233/JAD-170367

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1045-1054, 2017

Authors: Costa, Andrea Saul | Agostini, Simone | Guerini, Franca Rosa | Mancuso, Roberta | Zanzottera, Milena | Ripamonti, Enrico | Racca, Vittorio | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer’s disease (AD), the most common form of dementia. IFN-lambda (IFN-λ ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 …rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p  = 0.014; MCI versus HC: p  = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p  = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p  = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, gene polymorphisms, HSV-1, IRF7, MED23, Interferon lambda, mild cognitive impairment, SNP

DOI: 10.3233/JAD-170520

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1055-1063, 2017

Authors: Noble, James M. | Schupf, Nicole | Manly, Jennifer J. | Andrews, Howard | Tang, Ming-Xin | Mayeux, Richard

Article Type: Research Article

Abstract: Background: Determination of secular trends in cognitive aging is important for prioritization of resources, services, and research in aging populations. Prior studies have identified declining dementia incidence associated with changes in cardiovascular risk factors and increased educational attainment. However, few studies have examined these factors in multi-ethnic cohorts. Objective: To identify secular trends in the incidence rate of dementia in an elderly population. Methods: Participants in this study were drawn from the Washington Heights-Inwood Columbia Aging Project, a multi-ethnic cohort study of northern Manhattan residents aged 65 years and older. Cox proportional hazards models were used …to examine differences in the incidence of dementia in cohorts recruited in 1992 and 1999, with age at dementia or age at last follow-up visit as the “time-to-event” variable. Results: Overall, there was a 41% reduction in the hazard ratio for dementia among participants in the 1999 cohort compared with those in the 1992 cohort, adjusting for age, sex, race, and baseline memory complaints (HR = 0.59). The reduction in incidence was greatest among non-Hispanic Whites and African-Americans and lowest among Hispanic participants (HRs = 0.60, 0.52 and 0.64, respectively), and was associated with increases in level of educational attainment, especially among African-Americans. Reduction in incidence of dementia was also greater among persons 75 years or older than among younger participants (HR = 0.52 versus HR = 0.69). Conclusions: Our results support previous findings that secular trends in dementia incidence are changing, including in aging minority populations. Show more

Keywords: Cohorts, dementia, incidence, race/ethnicity, secular trends

DOI: 10.3233/JAD-170300

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1065-1075, 2017

Authors: Huovinen, Joel | Helisalmi, Seppo | Paananen, Jussi | Laiterä, Tiina | Kojoukhova, Maria | Sutela, Anna | Vanninen, Ritva | Laitinen, Marjo | Rauramaa, Tuomas | Koivisto, Anne M. | Remes, Anne M. | Soininen, Hilkka | Kurki, Mitja | Haapasalo, Annakaisa | Jääskeläinen, Juha E. | Hiltunen, Mikko | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer’s disease (AD) seems to be frequent in iNPH. Objective: We aim to evaluate the role of AD-related polymorphisms in iNPH. Methods: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8 ) adjusted …to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. Results: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p  = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p  = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. Conclusions: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study. Show more

Keywords: Alzheimer’s disease, genetics, idiopathic normal pressure hydrocephalus, pathology, radiology

DOI: 10.3233/JAD-170583

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1077-1085, 2017