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

Authors: de Jager, Celeste A. | Msemburi, William | Pepper, Katy | Combrinck, Marc I.

Article Type: Research Article

Abstract: Background: Dementia is a growing concern for low- and middle-income countries where longevity is increasing and service provision is poor. Global prevalence estimates vary from 2% to 8.5% for those aged 60 years and older. There have been few dementia studies in sub-Saharan Africa, and prevalence data are lacking for South Africa. Objective: To conduct a large dementia prevalence study in a low income rural population in South Africa. Methods: 1,394 Xhosa-speaking community dwellers, aged ≥60 y (mean age±sd 71.3±8.3 y), in three clinic catchment areas, were screened at home. Trained community health workers administered the brief Community …Screening Instrument for Dementia (CSID) to participants and informants to assess cognitive and functional capacity. Depressive symptoms were assessed with three questions from the EURO-D. Results: The prevalence estimate using published CSID sensitivity/specificity values was 0.8 (95% CI: 0.06–0.09). Using CSID cut-off scores the estimated prevalence was 0.12 (95% CI: 0.10–0.13), with 161 screen-positives. Both methods gave a rate of 0.11 (95% CI: 0.09–0.13) for those over 65 years (n  = 1051). 68.6% of participants were female and 69.8% had less than 7 years of education. Dementia risk was associated with older age and symptoms of depression, but not with sex. The association with education was not significant when controlled for by age. Conclusions: Dementia prevalence estimates were higher than expected for this low-income rural community. There is a need for increased dementia awareness and feasible support interventions. We also need further studies of regional prevalences, dementia subtypes, and modifiable risk factors in South Africa. Show more

Keywords: Community Screening Instrument for Dementia, dementia screening, epidemiology, low- and middle-income country, older people, population

DOI: 10.3233/JAD-170325

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1087-1096, 2017

Authors: Palmieri, Gianna | Cocca, Ennio | Gogliettino, Marta | Valentino, Roberta | Ruvo, Menotti | Cristofano, Gloria | Angiolillo, Antonella | Balestrieri, Marco | Rossi, Mosè | Di Costanzo, Alfonso

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia. To date, there are no definitive diagnostic tests that can predict or assess onset and progression of the disease. Blood biomarkers for AD are being sought for many years but their identification remains a challenging task. In this study, we investigated the potential relationship between AD and levels of acyl-peptide hydrolase (APEH) and proteasome in erythrocyte samples of 52 participants (26 AD and 26 cognitively healthy controls). A statistically significant decrease in proteasome and exopeptidase/endopeptidase APEH activities was found in AD samples compared to …those of healthy controls. Moreover, in contrast to what was observed for proteasome transcripts, APEH activities reduction in AD patients was unrelated to its gene expression levels, suggesting the occurrence of posttranslational modifications or the expression of endogenous inhibitors that might impair enzyme activity. These preliminary data further support a relationship between the APEH-proteasome system and AD molecular players, providing the first evidence of its potential use as a novel blood-based indicator for the routine detection of AD. Show more

Keywords: Alzheimer’s disease, APEH, blood-based indicator system, oxidized peptide hydrolase activity, proteasome, protein quality control

DOI: 10.3233/JAD-170389

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1097-1106, 2017

Authors: Mise, Ayano | Yoshino, Yuta | Yamazaki, Kiyohiro | Ozaki, Yuki | Sao, Tomoko | Yoshida, Taku | Mori, Takaaki | Mori, Yoko | Ochi, Shinichiro | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE ), andis reported in several genome-wide association studies to be associated with Alzheimer’s disease (AD). Objective: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. Methods: We examined TOMM40 , PTEN-induced putative kinase 1 (PINK1 ), Parkin RBR E3 ubiquitin protein ligase (PARK2 ), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40 exon 1 in peripheral leukocytes and TOMM40 523 …polyT genotypes in 60 AD and age- and sex-matched control subjects. Results: TOMM40 mRNA expression was significantly lower in AD subjects (0.87±0.18 versus 1.0±0.23, p  = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5±0.61 versus 1.0±0.52, p  < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r  = 0.290, p  = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p  = 0.32). Methylation rates in the upstream region of TOMM40 exon 1 were not different between AD and control subjects (average rate: 1.37±0.99 versus 1.39±1.20, p  = 0.885), and TOMM40 523 polyT genotypes were also not different between AD and control subjects (p  = 0.67). Conclusion: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction. Show more

Keywords: Alzheimer’s disease, apolipoprotein E (ApoE), methylation, mitochondria, mRNA expression, Parkin RBR E3 ubiquitin protein ligase (PARK2), PTEN-induced putative kinase 1 (PINK1), translocase of outer mitochondrial membrane 40 (TOMM40)

DOI: 10.3233/JAD-170361

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1107-1117, 2017

Authors: Reijs, Babette L.R. | Ramakers, Inez H.G.B. | Köhler, Sebastian | Teunissen, Charlotte E. | Koel-Simmelink, Marleen | Nathan, Pradeep J. | Tsolaki, Magda | Wahlund, Lars-Olof | Waldemar, Gunhild | Hausner, Lucrezia | Vandenberghe, Rik | Johannsen, Peter | Blackwell, Andrew | Vanderstichele, Hugo | Verhey, Frans | Visser, Pieter Jelle

Article Type: Research Article

Abstract: Background: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer’s disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression. Objective: To examine the association between amyloid-β 1-42 (Aβ42 ) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline. Methods: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR …study. Assessment included CSF Aβ42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline. Results: At baseline, decreased CSF Aβ42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aβ42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis. Conclusion: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cerebrospinal fluid, episodic memory, spatial memory, working memory

DOI: 10.3233/JAD-160766

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1119-1128, 2017

Authors: Garrido, Sandra | Dunne, Laura | Chang, Esther | Perz, Janette | Stevens, Catherine J. | Haertsch, Maggie

Article Type: Research Article

Abstract: The use of pre-recorded music to ease behavioral and psychological symptoms associated with dementia is popular in health-care contexts in both formal music therapy settings and in non-therapist led interventions. However, further understanding of how non-therapist led interventions compare to therapist led interventions is needed. This paper reviews 28 studies that used pre-recorded music with people with dementia using a critical interpretive synthesis model. Results revealed that pre-recorded music can be effective in reducing a variety of affective and behavioral symptoms, in particular agitation, even where a trained music therapist is not present. However, the results are not universally positive, …suggesting the need for further clarification of protocols for music use and closer investigation of variables that influence individual responseto music. Show more

Keywords: Alzheimer’s disease, critical synthesis, dementia, music, music interventions, music therapy, review

DOI: 10.3233/JAD-170612

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1129-1142, 2017

Authors: Ahmed, Mohammad Ejaz | Iyer, Shankar | Thangavel, Ramasamy | Kempuraj, Duraisamy | Selvakumar, Govindhasamy Pushpavathi | Raikwar, Sudhanshu P. | Zaheer, Smita | Zaheer, Asgar

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid-β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory, has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 …inflammasome and autophagy- lysosomal markers in relation to Aβ, p-tau and GMF in human postmortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human postmortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the APs and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, Aβ and hyperphosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the auto-phagosomal pathway. Show more

Keywords: Alzheimer’s disease, amyloid plaques, autophagy, glia maturation factor, inflammasome, neurofibrillary tangles, pro-inflammatory cytokine

DOI: 10.3233/JAD-170634

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1143-1160, 2017

Authors: Finger, Elizabeth | Zhang, Jing | Dickerson, Bradford | Bureau, Yves | Masellis, Mario | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Neuropsychiatric symptoms in Alzheimer’s disease are among the most disabling and difficult aspects for caregivers and treating health professionals to manage. Despite the high prevalence of these behaviors, little is known about the factors which lead some patients to develop florid behavioral symptoms while others may progress to severe dementia without such phenomenon. We examined whether regional brain volumes as measured by cortical thickness would predict the presence or absence of disinhibition in patients with Alzheimer’s disease. Using data from the ADNI, we identified 758 patients with caregiver ratings on the Neuropsychiatric Inventory and a volumetric MRI scan with cortical …thickness measurements completed in FreeSurfer by the UCSF core. Of these, 177 patients were found to have disinhibition. Logistic regression models demonstrated that reduced cortical thickness in the right frontal pole was associated with the presence of disinhibition even when controlling for age, disease severity, total intracranial volume, gender, and APOE genotype. The results are considered in the context of leading models of the functions of frontopolar cortex. Show more

Keywords: Alzheimer’s disease, disinhibition, frontopolar cortex

DOI: 10.3233/JAD-170348

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1161-1170, 2017

Authors: Dutzi, Ilona | Schwenk, Michael | Kirchner, Marietta | Bauer, Jürgen M. | Hauer, Klaus

Article Type: Research Article

Abstract: Background: Dementia is a frequent diagnosis in geriatric rehabilitation. Studies in patients with dementia on the development of their cognitive status during rehabilitation and its relation to functional outcomes have been scarce. Objectives: To describe the changes in cognitive status in patients with dementia during inpatient rehabilitation and to determine its association with patient characteristics and rehabilitation outcome. Methods: Cohort study in a geriatric rehabilitation center with data collection at admission and discharge. Outcome measures were change in global and domain-related cognitive functioning and its association with activities of daily living (ADL) and discharge home. …Results: 154 patients (mean age 83.7 years) diagnosed with mild to moderate dementia were included. Cognitive performance significantly improved from admission to discharge for all cognitive variables tested (p  < 0.001 to 0.03). Change in global cognitive functioning, executive functions, and episodic memory were positively associated with ADL recovery. Change in global cognitive functioning predicted ADL improvements (β= 0.32; p  = 0.006). Only 7.8% of patients, characterized by worse ADL and motor abilities as well as higher frailty scores at admission, deteriorated in global cognitive scores. In comparison to patients with stable or improved cognition, these patients showed least improvements in ADL-scores (4.1 versus 12.5) and a trend for higher institutionalization (50% versus 26.5%). Conclusions: The findings highlight the potential of patients with dementia to recover cognitive functioning during rehabilitation. Cognitive change represents an independent rehabilitation outcome and a prognostic factor for successful rehabilitation suggesting that specific interventions are indicated to maintain and enhance cognitive functioning in these highly vulnerable patients. Show more

Keywords: Cognitive development, cognitive impairment, dementia, geriatrics, rehabilitation, rehabilitation outcomes

DOI: 10.3233/JAD-170401

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1171-1182, 2017

Authors: Sánchez, Stella M. | Abulafia, Carolina | Duarte-Abritta, Barbara | de Guevara, M. Soledad Ladrón | Castro, Mariana N. | Drucaroff, Lucas | Sevlever, Gustavo | Nemeroff, Charles B. | Vigo, Daniel E. | Loewenstein, David A. | Villarreal, Mirta F. | Guinjoan, Salvador M.

Article Type: Research Article

Abstract: Background: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer’s disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. Objective: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. Methods: We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on …traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. Results: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. Conclusion: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations. Show more

Keywords: Entorhinal cortex, functional connectivity, late-onset Alzheimer’s disease, limbic, proactive semantic interference, thalamus

DOI: 10.3233/JAD-170491

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1183-1193, 2017

Authors: Buratti, Laura | Viticchi, Giovanna | Baldinelli, Sara | Falsetti, Lorenzo | Luzzi, Simona | Pulcini, Alessandra | Petrelli, Cristina | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Background: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. Objective: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. Methods: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. Results: At baseline, some cognitive performances involved in …executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p  < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p  < 0.001) and in short-term (p  = 0.02) and long-term Rey Auditory Verbal Learning Test (p  < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. Conclusions: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk. Show more

Keywords: Cerebral hemodynamics, cognitive performances, obstructive sleep apnea

DOI: 10.3233/JAD-170445

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1195-1203, 2017

Authors: Khalsa, Dharma Singh

Article Type: Book Review

DOI: 10.3233/JAD-170827

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1205-1207, 2017