Journal of Alzheimer's Disease - Volume 63, issue 1

Authors: Xie, Long | Shinohara, Russell T. | Ittyerah, Ranjit | Kuijf, Hugo J. | Pluta, John B. | Blom, Kim | Kooistra, Minke | Reijmer, Yael D. | Koek, Huiberdina L. | Zwanenburg, Jaco J.M. | Wang, Hongzhi | Luijten, Peter R. | Geerlings, Mirjam I. | Das, Sandhitsu R. | Biessels, Geert Jan | Wolk, David A. | Yushkevich, Paul A. | Wisse, Laura E.M.

Article Type: Research Article

Abstract: Background: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images (“atlases”) to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer’s disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy. Objective: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD …at 3T and 7T. Methods: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T. Results: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set. Conclusion: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions. Show more

Keywords: Alzheimer’s disease, ASHS, high-field magnetic resonance imaging, mild cognitive impairment, multi-atlas label fusion

DOI: 10.3233/JAD-170932

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 217-225, 2018

Authors: Marešová, Petra | Dolejš, Josef | Kuca, Kamil

Article Type: Research Article

Abstract: Background: There is now a general attempt in developed countries to implement strategic plans to fight against Alzheimer’s disease and other dementia disorders. Among others, attention is paid to the issues of registers and calculations of economic burden. Currently available calculations of costs are difficult to compare. The problem is a different breakdown of cost categories and non-unified monitoring of cost types. Objective: The aim of this paper is to note the problem of poor availability and inconsistencies in cost monitoring. Furthermore, the intersection of cost items that are comparable and consistently monitored in expert studies are specified. …Methods: The Web of Science, Elsevier Science Direct, PubMed, and Scopus databases are used in a systematic review. Two independent reviewers screened the identified records and selected relevant articles published in the period from 2010 to 2016. A meta-analysis of costs is performed in four categories related to patients suffering from Alzheimer’s disease. Results: The resulting estimation of total costs per patient per month through meta-analysis is € 3,896, with 95% CI [2078, 5713]. The highest costs arise from informal care following non-medical and medical care. Conclusion: The results confirm assumption that inconsistencies in cost monitoring of the treatment and care of people with dementia exists in Europe. Homogeneity could be assumed only in the medical costs of severe patients. Heterogeneity is assumed in non-medical costs, informal costs. Cost items should be defined and collected more precisely for future more precise monitoring of the economic burden. Show more

Keywords: Alzheimer’s disease, data collection uniformity, developed countries, meta-analysis

DOI: 10.3233/JAD-171028

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 227-238, 2018

Authors: Krämer, Julia | Lueg, Gero | Schiffler, Patrick | Vrachimis, Alexis | Weckesser, Matthias | Wenning, Christian | Pawlowski, Matthias | Johnen, Andreas | Teuber, Anja | Wersching, Heike | Meuth, Sven G. | Duning, Thomas

Article Type: Research Article

Abstract: Background: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging. Objective: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI. Methods: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a …“typical” pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a “non-typical”/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses. Results: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET. Conclusion: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary. Show more

Keywords: Behavioral symptoms, diffusion tensor imaging, frontotemporal dementia, frontotemporal lobar degeneration, magnetic resonance imaging, positron-emission tomography, sensitivity, specificity

DOI: 10.3233/JAD-170224

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 239-253, 2018

Authors: Jin, He | Wang, Rong | Liu, Zhaohui | Jia, Qiang | Wu, Yanchuan | Zhao, Zhiwei | Wang, Yulan | Zhang, Xu

Article Type: Research Article

Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer’s disease (AD). Objective: To investigate the effects of urine collected time, different preservatives addition, and storage condition on the measurement of urine AD7c-NTP by enzyme-linked immunosorbent assay (ELISA). Methods: Three hundred urine samples were collected from 20 participants at three time points on five consecutive days. These samples were immediately placed at 4°C and detected within 2 h. The single spot samples of the first day morning were split into eleven duplicate aliquots (a-k) of 1 ml each, (a) without any preservative …(untreated), (b) containing boric acid (2 g/L), (c) containing NaHCO3 (5 g/L), (a-c) were detected at six different time points. For the other eight preservative-free samples, (d-g) were stored at –20°C and (h-k) were stored at –70°C, respectively, detected at different time points. All of the results were compared with the baseline urine. Results: The urine AD7c-NTP levels at different time points behaved stably (p  > 0.05). Urine samples without any preservative increased over time, and compared with the NaHCO3 addition group, boric acid addition group behaved stably. Samples stored at –20°C and –70°C led to an obviously false positive. Conclusions: AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4°C, freezing is not recommended. Show more

Keywords: Alzheimer-associated neuronal thread protein, biomarker, enzyme-linked immunosorbent assay, urine

DOI: 10.3233/JAD-171109

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 255-262, 2018

Authors: Kero, Mia | Raunio, Anna | Polvikoski, Tuomo | Tienari, Pentti J. | Paetau, Anders | Myllykangas, Liisa

Article Type: Research Article

Abstract: Background: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. Objective: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. Methods: The population-based Vantaa 85+ study includes all inhabitants of the city of Vantaa, who were >85 years in 1991 (n  = 601). Neuropathological assessment was possible …in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE- staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. Results: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p  < 0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p  < 0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. Conclusion: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination. Show more

Keywords: Dementia, hippocampal sclerosis, hippocampal sclerosis without any comorbid neurodegenerative pathology, laterality, population-based, TDP-43, very old

DOI: 10.3233/JAD-171068

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 263-272, 2018

Authors: Masoud, Anwar M. | Bihaqi, Syed W. | Alansi, Bothaina | Dash, Miriam | Subaiea, Gehad M. | Renehan, William E. | Zawia, Nasser H.

Article Type: Research Article

Abstract: Amyloid deposits originating from the amyloid-β protein precursor (AβPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer’s disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AβPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and protein levels of AβPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid …and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl– CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AβPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AβPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation. Show more

Keywords: Alzheimer’s disease, AβPP, DNMT3a, lead, MAPT, miRNA, SP1

DOI: 10.3233/JAD-170824

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 273-282, 2018

Authors: Dong, Yang-Ting | Cao, Kun | Tan, Long-Chun | Wang, Xiao-Ling | Qi, Xiao-Lan | Xiao, Yan | Guan, Zhi-Zhong

Article Type: Research Article

Abstract: In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein …and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2 O2 , O2 ·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective. Show more

Keywords: AβOs, APP/PS1 mice, oxidative stress, primary neurons, resveratrol, SIRT1, suramin

DOI: 10.3233/JAD-171020

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 283-301, 2018

Authors: Zhao, Ming-Liang | Chen, Shi-Jin | Li, Xiao-Hong | Wang, Li-Na | Chen, Feng | Zhong, Shi-Jiang | Yang, Cheng | Sun, Sheng-Kai | Li, Jian-Jun | Dong, Hua-Jiang | Dong, Yue-Qing | Wang, Yi | Chen, Chong

Article Type: Research Article

Abstract: Electrical excitability by membrane depolarization is crucial for survival and maturation of newborn cells in the dentate gyrus of the hippocampus. However, traditional technology for membrane depolarization lacks temporal and spatial precision. Optogenetics can be used to activate channelrhodopsin-2 (ChR2), allowing cationic current to depolarize genetically targeted cells. In this study, we used ChR2-EGFP driven by doublecortin (DCX) to promote survival and maturation of newborn cells in the dentate gyrus after traumatic brain injury (TBI). C57BL/6 mice underwent lateral fluid percussion TBI. TBI mice were transfected with a lentivirus carrying the DCX-ChR2-EGFP gene. We observed that not only immature neurons …but also type-2b intermediate progenitor (IPs) and neuroblasts expressed DCX-EGFP, indicating that DCX-expressing newborn cells could provide a long time window for electrical activity regulation. Quantitative results showed that the number of EGFP-expressing cells began to rise at 3 days after TBI and peaked at 9 days after TBI. By optical depolarization of DCX-EGFP-expressing cells between 3 and 12 days, we observed significantly improved cognitive deficits after TBI with enhanced survival and maturation of newborn cells in the dentate gyrus. We also investigated the role of optical depolarization in neural stem cells transfected with a lentivirus carrying the ChR2-DCX-EGFP gene in vitro . By administrating verapamil to block L-type calcium channels, we verified that the up-regulation of MAP2, NeuN, Neurog2, NeuroD1 and GluR2 in newborn cells was mediated by ChR2-elicted depolarization. By using β-catenin inhibitor Dkk1, we demonstrated that optical depolarization of DCX-EGFP-expressing cells facilitated survival and maturation probably through the Wnt/β-catenin signaling cascade. Show more

Keywords: Adult neurogenesis, cognition, depolarization, optical, traumatic brain injury

DOI: 10.3233/JAD-180002

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 303-318, 2018

Authors: Tebrügge, Sarah | Winkler, Angela | Gerards, Diana | Weimar, Christian | Moebus, Susanne | Jöckel, Karl-Heinz | Erbel, Raimund | Jokisch, Martha | on behalf of the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: Background: There is strong evidence for an association of olfactory dysfunction and neurodegenerative diseases. Studies on the association of olfaction and cognition in the general population are rare. Objective: To evaluate gender- and age-specific associations of olfactory function and cognitive performance in a well characterized population-based study sample. Methods: At the third examination of the Heinz Nixdorf Recall study (n  = 3,087), 2,640 participants (48% men; 68.2±7.2 years) underwent Sniffin’ Sticks Screening Test measuring olfactory function on a scale of 0–12 points. Olfactory function was rated as anosmic, hyposmic, or normosmic (≤6, 7–10 or ≥11 points, respectively). …All participants performed eight validated cognitive subtests. Age- (55–64 years, 65–74 years, 75–86 years) and gender-stratified multivariate analysis of covariance was used to evaluate group differences in cognitive performance. Results: Women showed better olfactory function than men (p  < 0.001). For middle-aged participants, olfactory groups differed in almost all cognitive subtests. The analyses revealed no gender effects, although associations were slightly greater for women than for men. Anosmics showed the worst cognitive performance and normosmics showed the best cognitive performance. In the young- and old-aged groups, a quantitative association was found for anosmics in all subtests and for normosmics and hyposmics in almost all subtests. Conclusion: This is the first study reporting on age-specific associations of olfactory function and cognitive performance in the general population. The association found in middle-aged participants (65–74 years) may serve as a marker to improve identification of persons at high risk for cognitive decline and dementia. Show more

Keywords: Adults, Alzheimer’s disease, cognition, olfaction, population-based

DOI: 10.3233/JAD-170863

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 319-329, 2018

Authors: Mc Ardle, Ríona | Morris, Rosie | Hickey, Aodhán | Del Din, Silvia | Koychev, Ivan | Gunn, Roger N. | Lawson, Jennifer | Zamboni, Giovanna | Ridha, Basil | Sahakian, Barbara J. | Rowe, James B. | Thomas, Alan | Zetterberg, Henrik | MacKay, Clare | Lovestone, Simon | Rochester, Lynn

Article Type: Research Article

Abstract: Gait is emerging as a potential diagnostic tool for cognitive decline. The ‘Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study’ (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer’s disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health …Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD. Show more

Keywords: Alzheimer’s disease, cognition, free-living, gait, phenotyping, wearables

DOI: 10.3233/JAD-171116

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 331-341, 2018