Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Zuo, Li-jun | Guo, Peng | Liu, Li | Yu, Shu-yang | Lian, Teng-hong | Yu, Qiu-jin | Hu, Yang | Jin, Zhao | Wang, Rui-dan | Piao, Ying-shan | Li, Li-xia | Wang, Ya-iie | Wang, Xiao-min | Zhang, Wei

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is common in patients with Alzheimer’s disease (AD). However, the relationship between olfactory dysfunction (OD) and clinical symptoms and the potential mechanisms of OD of AD are still unknown. Objective: To explore the relationship between olfactory dysfunction and clinical symptoms and the potential mechanisms of olfactory dysfunction of AD. Methods: We evaluated OD using the Hyposmia Rating Scale (HRS), classified patients into AD with OD (AD-OD) and AD with no OD (AD-NOD) groups, and detected the levels of free radicals and inflammatory factors, including hydroxyl radical (•OH), hydrogen peroxide (H2 O2 ), nitric …oxide, interleukin-1β , interleukin-6, tumor necrosis factor-α , and prostaglandin E2 in serum from AD patients. Results: It was shown that the scores on the Mini-Mental State Examination, Animal Fluency Test, Boston Naming Test (BNT), and Auditory Verbal Learning Test-delayed recall were all significantly lower and the score of overall activity of daily living (ADL) and instrumental ADL were significantly higher in AD-OD group than those in AD-NOD group. Compared with AD-NOD group, •OH level in serum was prominently elevated, and H2 O2 level was dramatically declined in AD-OD group. In the correlation analysis, HRS score was significantly and positively correlated with the score of BNT, and negatively correlated with •OH level in serum. Conclusions: AD-OD patients suffered from severe cognitive impairment in the domain of language. Oxidative stress might be correlated with AD-OD featured by the drastically increased •OH level in serum. Show more

Keywords: Alzheimer’s disease, language, •OH, olfactory dysfunction, oxidative stress

DOI: 10.3233/JAD-180425

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: C.M. Stephan, Blossom | Birdi, Ratika | Yee Hing Tang, Eugene | Cosco, Theodore D. | Donini, Lorenzo M. | Licher, Silvan | Ikram, M. Arfan | Siervo, Mario | Robinson, Louise

Article Type: Research Article

Abstract: Background: Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline. Objective: To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time. Methods: Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained. Results: Overall, prevalence rates are largely increasing …(evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria. Conclusions: The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies. Show more

Keywords: Dementia, incidence, prevalence, secular trends, systematic review

DOI: 10.3233/JAD-180375

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-28, 2018

Authors: Chen, Mei | Song, Hailong | Cui, Jiankun | Johnson, Catherine E. | Hubler, Graham K. | DePalma, Ralph G. | Gu, Zezong | Xia, Weiming

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ )-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using …Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development. Show more

DOI: 10.3233/JAD-180726

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2018

Authors: Ryan, Margaret M. | Guévremont, Diane | Mockett, Bruce G. | Abraham, Wickliffe C. | Williams, Joanna M.

Article Type: Research Article

Abstract: Pathological changes underlying Alzheimer’s disease (AD) begin decades before the classical symptoms of memory loss become evident. As microRNAs are released from neurons and enter the bloodstream, circulating microRNAs may be reflective of AD progression and ideal candidates as biomarkers for early-stage disease detection. Here, we provide a novel, in-depth analysis of how plasma microRNAs alter with aging, the most prominent risk factor for AD, and with development of amyloid-β (Aβ ) plaque deposition. We assessed the circulating microRNAs in APPswe/PSEN1dE9 transgenic mice and wild-type controls at 4, 8, and 15 m (n = 8–10) using custom designed …Taqman arrays representing 185 neuropathology-related microRNAs. We performed a linear mixed-effects model to investigate the effects of age and genotype on plasma microRNAs expression. Following this analysis, we found 8 microRNAs were significantly affected by age alone in wild-type animals and 12 microRNAs altered in APPswe/PSEN1dE9 mice, either prior to Aβ plaque deposition (4 m) or during the development of AD-like pathogenesis (8 m or 15 m). Importantly, we found that differing sets of microRNAs were identified at each time point. Functional analysis of these data revealed that while common biological pathways, such as Inflammatory Response , were enriched throughout the disease process, Free Radical Scavenging, Immunological Disease , and Apoptosis Signaling were specifically enriched later in the disease process. Overall, this study reinforces that distinct biological processes underpin the early versus late stages of AD-like pathogenesis and highlights potential pre-symptomatic microRNAs biomarkers of neurodegeneration. Show more

Keywords: Aging, Alzheimer’s disease, circulating microRNAs, real-time polymerase chain reaction, transgenic mice

DOI: 10.3233/JAD-180385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2018

Authors: Innes, Kim E. | Selfe, Terry Kit | Brundage, Kathleen | Montgomery, Caitlin | Wen, Sijin | Kandati, Sahiti | Bowles, Hannah | Khalsa, Dharma Singh | Huysmans, Zenzi

Article Type: Research Article

Abstract: Background: Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ ) levels have emerged as possible predictors of cognitive decline and dementia. Objective: To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL). Methods: Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ (38/40/42) and peripheral …blood mononuclear cell TL and TA were measured at baseline and 3 months; cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months. Results: Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ 40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (p s-interaction <0.006). Both groups improved in cognitive and psychosocial status (p s ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures. Conclusion: Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships. Show more

Keywords: Alzheimer’s disease, cognition, memory complaints, mind-body therapy, mood, plasma amyloid-β, quality of life, sleep, subjective cognitive impairment, telomerase, telomeres

DOI: 10.3233/JAD-180164

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2018

Authors: de Matos, Mafalda Ramos | Ferreira, Catarina | Herukka, Sanna-Kaisa | Soininen, Hilkka | Janeiro, André | Santana, Isabel | Baldeiras, Inês | Almeida, Maria Rosário | Lleó, Alberto | Dols-Icardo, Oriol | Alcolea, Daniel | Benussi, Luisa | Binetti, Giuliano | Paterlini, Anna | Ghidoni, Roberta | Nacmias, Benedetta | Meulenbroek, Olga | van Waalwijk van Doorn, Linda J.C. | Kuiperij, H. Bea | Hausner, Lucrezia | Waldemar, Gunhild | Simonsen, Anja Hviid | Tsolaki, Magda | Gkatzima, Olymbia | de Oliveira, Catarina Resende | Verbeek, Marcel M. | Clarimon, Jordi | Hiltunen, Mikko | de Mendonça, Alexandre | Martins, Madalena

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer’s disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ 1–42 ), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ 1–42 is decreased due to the accumulation of Aβ 1–42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating …the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ 1 - 42 , t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within ten European consortium centers. Our results highlighted five genes, APOE , LOC100129500 , PVRL2 , SNAR-I , and TOMM40 , previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D , CD2AP , and CASS4 , showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, endophenotypes, European multicenter study, quantitative trait loci

DOI: 10.3233/JAD-180512

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Weng, Yi-Ching | Hsiao, Ing-Tsung | Huang, Chu-Yun | Huang, Kuo-Lun | Liu, Chi-Hung | Chang, Ting-Yu | Yen, Tzu-Chen | Lin, Kun-Ju | Huang, Chin-Chang

Article Type: Research Article

Abstract: Background: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer’s disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown. Objective: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis. Methods: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18 F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in …serial brain 18 F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients. Results: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from –2.62% to –16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively. Conclusions: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage. Show more

Keywords: Amyloid, angiopathy, annual change rate, brain AV-45 PET, familial Alzheimer’s disease, Taiwan D678H APP mutation

DOI: 10.3233/JAD-180824

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Elias, Alby | Cummins, Tia | Tyrrell, Regan | Lamb, Fiona | Dore, Vincent | Williams, Robert | Rosenfeld, Jeffrey | Hopwood, Malcolm | Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: An association between obstructive sleep apnea (OSA) and Alzheimer’s disease has been suggested but little is known about amyloid-β and tau deposition in this syndrome. Objective: To determine amyloid and tau burden and cognitive function in OSA in comparison to those without a diagnosis of OSA. Methods: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio …(SUVR) of 18 F-florbetaben and 18 F-AV1451, to quantify amyloid and tau burden. Results: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18 F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p  = 0.04). There were more apolipoprotein E ɛ 4 allele (APOE ɛ 4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18 F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ 4 was adjusted. The reported use of CPAP (n  = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18 F-AV1451 uptake between the two groups. Conclusions: Obstructive sleep apnea is associated with Alzheimer’s disease pathology, but this relationship is moderated by APOE ɛ 4 and BMI. Show more

Keywords: Alzheimer’s disease, amyloid PET, dementia, obstructive sleep apnea, tau PET

DOI: 10.3233/JAD-180640

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Katisko, Kasper | Kokkonen, Nina | Krüger, Johanna | Hartikainen, Päivi | Koivisto, Anne M. | Helisalmi, Seppo | Korhonen, Ville E. | Kokki, Merja | Tuusa, Jussi | Herukka, Sanna-Kaisa | Solje, Eino | Haapasalo, Annakaisa | Tasanen, Kaisa | Remes, Anne M.

Article Type: Research Article

Abstract: Recent studies have shown an epidemiological and immunological association between bullous pemphigoid (BP) and several neurological or psychiatric diseases. Here, our aim was for the first time to specify whether an association exists between BP and frontotemporal lobar degeneration (FTLD). Medical histories of FTLD patients (N = 196) were screened for clinical comorbidity, and BP180 and BP230 autoantibodies were analyzed in the sera of FTLD patients (N = 70, including 24 C9orf72 repeat expansion carriers) by BP180-NC16A-ELISA and BP230-ELISA. One FTLD patient (C9orf72 repeat expansion carrier) had a comorbid diagnosis of BP. Increased levels of serum BP180 autoantibodies …(cutoff value >9 U/ml) were detected more often in FTLD patients (10.0%) than in controls (4.9%). Moreover, elevated levels of both BP180 and BP230 autoantibodies were found more often in C9orf72 repeat expansion-carrying FTLD than non-carrying patients or controls. However, none of these differences reached a statistical significance likely due to our limited cohort size. In conclusion, our findings suggest that subset of FTLD patients especially with the C9orf72 repeat expansion may have an immunological association with BP. Show more

Keywords: Autoantibody, bullous pemphigoid, C9orf72, comorbidity, dementia, frontotemporal dementia, immunology

DOI: 10.3233/JAD-180624

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Hadjichrysanthou, Christoforos | McRae-McKee, Kevin | Evans, Stephanie | de Wolf, Frank | Anderson, Roy M.

Article Type: Research Article

Abstract: Despite the progressive nature of Alzheimer’s disease and other dementias, it is observed that many individuals that are diagnosed with mild cognitive impairment (MCI) in one clinical assessment, may return back to normal cognition (CN) in a subsequent assessment. Less frequently, such ‘back-transitions’ are also observed in people that had already been diagnosed with later stages of dementia. In this study, an analysis was performed on two longitudinal cohort datasets provided by 1) the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 2) the National Alzheimer’s Coordinating Centre (NACC). The focus is on the observed improvement of individuals’ clinical condition recorded in …these datasets to explore potential associations with different factors. It is shown that, in both datasets, transitions from MCI to CN are significantly associated with younger age, better cognitive function, and the absence of ApoE ɛ 4 alleles. Better cognitive function and in some cases the absence of ApoE ɛ 4 alleles are also significantly associated with transitions from types of dementia to less severe clinical states. The effect of gender and education is not clear-cut in these datasets, although highly educated people who reach MCI tend to be more likely to show an improvement in their clinical state. The potential effect of other factors such as changes in symptoms of depression is also discussed. Although improved clinical outcomes can be associated with many factors, better diagnostic tools are required to provide insight into whether such improvements are a result of misdiagnosis, and if they are not, whether they are linked to improvements in the underlying neuropathological condition. Show more

Keywords: Alzheimer’s disease, back-transitions, clinical states, dementia, longitudinal studies, mild cognitive impairment, misdiagnosis

DOI: 10.3233/JAD-180101

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018