Journal of Alzheimer's Disease - Volume 75, issue 1

Authors: Yamoah, Alfred | Tripathi, Priyanka | Sechi, Antonio | Köhler, Christoph | Guo, Haihong | Chandrasekar, Akila | Nolte, Kay Wilhelm | Wruck, Christoph Jan | Katona, Istvan | Anink, Jasper | Troost, Dirk | Aronica, Eleonora | Steinbusch, Harry | Weis, Joachim | Goswami, Anand

Article Type: Research Article

Abstract: Granulovacuolar degeneration (GVD) occurs in Alzheimer’s disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones Glucose – regulated protein, 78 KDa (GRP78/BiP), Sigma receptor 1 (SigR1), and Vesicle-associated membrane protein associated protein B (VAPB) were elevated in many AD patients’ subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau …aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-β in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis. Show more

Keywords: Endoplasmic reticulum chaperones, exosomes, FUS, granulovacuolar degeneration, Matrin 3, Sigma receptor 1 (SigR1), stress granules

DOI: 10.3233/JAD-190722

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 139-156, 2020

Authors: Beydoun, May A. | Beydoun, Hind A. | Hossain, Sharmin | El-Hajj, Ziad W. | Weiss, Jordan | Zonderman, Alan B.

Article Type: Research Article

Abstract: Microbial agents including periodontal pathogens have recently appeared as important actors in Alzheimer’s disease (AD) pathology. We examined associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality among US middle-aged and older adults. Clinical [Attachment Loss (AL); probing pocket depth (PPD)] and bacterial [pathogen immunoglobulin G (IgG)] periodontal markers were investigated in relation to AD and all-cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988–1994) linked longitudinally with National Death Index and Medicare data through January 1, 2014, with …up to 26 years of follow-up. Sex- and age-specific multivariable-adjusted Cox proportional hazards models were conducted. Among those ≥65 years, AD incidence and mortality were consistently associated with PPD, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P. gingivalis ), Prevotella melaninogenica (P. melaninogenica ) and Campylobacter rectus (C. rectus ) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (per SD, aHR = 1.22; 95% CI, 1.04–1.43, p  = 0.012), while AD mortality risk was increased with another composite (per SD, aHR = 1.46; 95% CI, 1.09–1.96, p  = 0.017) loading highly on IgG for P. gingivalis , Prevotella intermedia , Prevotella nigrescens , Fusobacterium nucleatum , C. rectus , Streptococcus intermedius , Capnocylophaga Ochracea , and P. melaninogenica . This study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials. Show more

Keywords: Aging, Alzheimer’s disease, dementia, periodontal pathogens, periodontitis

DOI: 10.3233/JAD-200064

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 157-172, 2020

Authors: Miyamoto, Masakazu | Kuzuya, Akira | Noda, Yasuha | Ueda, Sakiho | Asada-Utsugi, Megumi | Ito, Shinji | Fukusumi, Yoshiyasu | Kawachi, Hiroshi | Takahashi, Ryosuke | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer’s disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear. Objective: This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse. Methods: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain …synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. Results: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP. Conclusion: SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses. Show more

Keywords: Alzheimer’s disease, amyloid-β , BACE1, SV2B, synapse

DOI: 10.3233/JAD-200071

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 173-185, 2020

Authors: Racine, Annie M. | Touroutoglou, Alexandra | Abrantes, Tatiana | Wong, Bonnie | Fong, Tamara G. | Cavallari, Michele | Travison, Thomas G. | Gou, Yun | Marcantonio, Edward R. | Alsop, David C. | Jones, Richard N. | Inouye, Sharon K. | Dickerson, Bradford C. | for the SAGES study group

Article Type: Research Article

Abstract: Background: Older surgical patients with Alzheimer’s disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. Objective: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. Methods: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in ‘AD-Signature’ regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months …1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2–36. Results: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, β = –0.030, 95% confidence interval [–0.060, –0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (β = –0.100 [–0.192, –0.007]). Conclusion: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery. Show more

Keywords: aging signature, Alzheimer’s disease signature, cognitive decline, cortical thickness, delirium, preclinical Alzheimer’s disease, post-operative, surgery

DOI: 10.3233/JAD-190380

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 187-199, 2020

Authors: Garnier-Crussard, Antoine | Vernaudon, Julien | Auguste, Nicolas | Dauphinot, Virginie | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Neurocognitive disorders (NCD) are a growing health issue and the importance of diagnosis is still debated despite the benefits of making a diagnosis appearing to be greater than the risks. Objective: The aim of the present study was to explore the perception of the main benefits and risks to perform a diagnosis workup of NCD in a population of general practitioners (GPs), specialized physicians (SPs), other healthcare professionals (OHPs), and informal caregivers (ICs), and to identify the lowest perceived benefits and the highest perceived risks that could be levers to promote a diagnosis of NCD. …Methods: A standardized questionnaire was submitted to GPs, SPs, OHPs, and ICs aiming to evaluate the importance of eight benefits and eight risks related to NCD diagnosis (selected from the literature) for four prototypical clinical cases at different stages of the disease: subjective cognitive impairment/mild NCD, major NCD at mild/moderate stage, moderate stage with behavioral and psychotic symptoms, and severe stage. Results: The lowest perceived benefits of making an NCD diagnosis were “access to medical research”, “patient’s right to know”, and “initiation of symptomatic drug treatment”. The highest perceived risks of making an NCD diagnosis were “negative psychological impact for the patient”, “absence of disease-modifying treatment”, and “absence of suitable institution”. Conclusion: This study highlights the lowest perceived benefits and the highest perceived risks of making an NCD diagnosis. These benefits and risks could be modified to become levers to promote a personalized diagnosis of NCD. Show more

Keywords: Benefits and risks, ethical issues, neurocognitive disorders, personalized diagnosis, timely diagnosis

DOI: 10.3233/JAD-191253

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 201-210, 2020

Authors: Qiao, Yuan | Xie, Xin-Yi | Lin, Guo-Zhen | Zou, Yang | Chen, Sheng-Di | Ren, Ru-Jing | Wang, Gang

Article Type: Research Article

Abstract: Background: Language dysfunction is a frequently reported symptom in Alzheimer’s disease (AD). However, computer-assisted analysis of spontaneous speech in AD and mild cognitive impairment (MCI) is rarely used to date. Objective: To characterize the language impairment in AD and amnestic MCI (aMCI) with computer-based automatic analysis via the “Automatic Speech Recognition (ASR) software for cognitive impairment V1.3”. Methods: A total of 64 subjects, including 20 AD patients, 20 aMCI patients, and 24 healthy controls were recruited. All subjects underwent neuropsychological tests, and spontaneous speech samples were recorded through the description of the “Cookie-Theft Picture” and then …analyzed by the computerized software. Subsequently, we compared the speech parameters between the subjects and the controls. Results: We identified seven spontaneous speech parameters (percentage of silence duration, average duration of phrasal segments, average duration of silence segments, number of speech segments, number of long pauses, ratio of hesitation/speech counts and ratio of short pause/speech counts) demonstrating significant differences between the three groups (p  < 0.05). All seven speech parameters significantly correlated with cognitive performance, with average duration of silence segments demonstrating the best correlation to cognitive performance on stepwise multiple linear regression analysis. Conclusion: Computer-assisted automated analysis of speech/silence segments demonstrated the potential to reflect the intrinsic linguistic impairment associated with MCI and AD. It has a promising prospect in the early detection of AD and assessment of disease severity. Show more

Keywords: Alzheimer’s disease, computer-assisted speech analysis, language impairment, mild cognitive impairment, spontaneous speech

DOI: 10.3233/JAD-191056

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 211-221, 2020

Authors: de Sousa, Angelica Vieira Cavalcanti | Grittner, Ulrike | Rujescu, Dan | Külzow, Nadine | Flöel, Agnes

Article Type: Research Article

Abstract: Background: Associative object-location memory (OLM) is known to decline even in normal aging, and this process is accelerated in patients with mild cognitive impairment (MCI). Given the lack of curative treatment for Alzheimer’s disease, activating cognitive resources during its preclinical phase might prevent progression to dementia. Objective: To evaluate the effects of anodal transcranial direct current stimulation (atDCS) combined with an associative episodic memory training on OLM in MCI patients and in healthy elderly (HE). Methods: In a single-blind cross-over design, 16 MCI patients and 32 HE underwent a 3-day visuospatial OLM training paired with either …20 min or 30 s (sham) atDCS (1 mA, right temporoparietal cortex). Effects on immediate (training success) and long-term memory (1-month) were investigated by conducting Mixed Model analyses. In addition, the impact of combined intervention on within-session (online) and on between-session (offline) performance were explored. Results: OLM training+atDCS enhanced training success only in MCI patients, but not HE (difference n.s.). Relative performance gain was similar in MCI patients compared to HE under atDCS. No beneficial effect was found after 1-month. Exploratory analyses suggested a positive impact on online, but a negative effect on offline performance in MCI patients. In both groups, exploratory post-hoc analyses indicated an association between initially low-performers and greater benefit from atDCS. Conclusion: Cognitive training in MCI may be enhanced by atDCS, but further delineation of the impact of current brain state, as well as temporal characteristics of multi-session atDCS-training application, may be needed to induce longer-lasting effects. Show more

Keywords: Association learning, cognition, dementia, episodic memory, transcranial direct current stimulation

DOI: 10.3233/JAD-191234

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 223-244, 2020

Authors: Lu, Mei-Hong | Zhao, Xiu-Yun | Xu, De-En | Chen, Ji-Bo | Ji, Wen-Li | Huang, Ze-Ping | Pan, Ting-Ting | Xue, Lu-Lu | Wang, Fen | Li, Qi-Fa | Zhang, Yue | Wang, Ting-Hua | Yanagawa, Yuchio | Liu, Chun-Feng | Xu, Ru-Xiang | Xia, Yi-Yuan | Li, Shao | Ma, Quan-Hong

Article Type: Research Article

Abstract: Excitatory (E) and inhibitory (I) balance of neural network activity is essential for normal brain function and of particular importance to memory. Disturbance of E/I balance contributes to various neurological disorders. The appearance of neural hyperexcitability in Alzheimer’s disease (AD) is even suggested as one of predictors of accelerated cognitive decline. In this study, we found that GAD67+ , Parvalbumin+ , Calretinin+ , and Neuropeptide Y+ interneurons were progressively lost in the brain of APP/PS1 mice. Transplanted embryonic medial ganglionic eminence derived interneuron progenitors (IPs) survived, migrated, and differentiated into GABAergic interneuron subtypes successfully at 2 months after transplantation. Transplantation …of IPs hippocampally rescued impaired synaptic plasticity and cognitive deficits of APP/PS1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-β accumulation, neuroinflammation, and synaptic loss of APP/PS1 transgenic mice. These observations indicate that transplantation of IPs improves learning and memory of APP/PS1 transgenic mice via suppressing neural hyperexcitability. This study highlights a causal contribution of GABAergic dysfunction to AD pathogenesis and the potentiality of IP transplantation in AD therapy. Show more

Keywords: Alzheimer’s disease, cell transplantation, GABA, hyperexcitability, interneuron, interneuron progenitor

DOI: 10.3233/JAD-200010

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 245-260, 2020

Authors: Pereira, Marta Luísa Gonçalves de Freitas | Camargo, Marina von Zuben de Arruda | Bellan, Ariella Fornachari Ribeiro | Tahira, Ana Carolina | dos Santos, Bernardo | dos Santos, Jéssica | Machado-Lima, Ariane | Nunes, Fátima L.S. | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: Visual search abilities are essential to everyday life activities and are known to be affected in Alzheimer’s disease (AD). However, little is known about visual search efficiency in mild cognitive impairment (MCI), a transitive state between normal aging and dementia. Eye movement studies and machine learning methods have been recently used to detect oculomotor impairments in individuals with dementia. Objective: The aim of the present study is to investigate the association between eye movement metrics and visual search impairment in MCI and AD. Methods: 127 participants were tested: 43 healthy controls, 51 with MCI, and …33 with AD. They completed an eyetracking visual search task where they had to find a previously seen target stimulus among distractors. Results: Both patient groups made more fixations on the screen when searching for a target, with longer duration than controls. MCI and AD fixated the distractors more often and for a longer period of time than the target. Healthy controls were quicker and made less fixations when scanning the stimuli for the first time. Machine-learning methods were able to distinguish between controls and AD subjects and to identify MCI subjects with a similar oculomotor profile to AD with a good accuracy. Conclusion: Results showed that eye movement metrics are useful for identifying visual search impairments in MCI and AD, with possible implications in the early identification of individuals with high-risk of developing AD. Show more

Keywords: Alzheimer’s disease, eye movements, eyetracking, machine learning, mild cognitive impairment, visual attention, visual impairments, visual search

DOI: 10.3233/JAD-190690

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 261-275, 2020

Authors: Gill, Sascha | Mouches, Pauline | Hu, Sophie | Rajashekar, Deepthi | MacMaster, Frank P. | Smith, Eric E. | Forkert, Nils D. | Ismail, Zahinoor | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy of ML models but have barely been used for this purpose. Objectives: To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI. Method: Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer’s Disease Neuroimaging …Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis. Results: In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve [ROC-AUC] = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73). Conclusion: Baseline NPS, categorized for MBI domain and duration, have prognostic utility in addition to brain morphology measures for predicting diagnosis change using ML. MBI total score, followed by impulse dyscontrol and affective dysregulation were most predictive of future diagnosis. Show more

Keywords: Alzheimer’s disease, artificial intelligence, magnetic resonance imaging, mild behavioral impairment, mild cognitive impairment

DOI: 10.3233/JAD-191169

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 277-288, 2020