Journal of Alzheimer's Disease - Volume 65, issue 2

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

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have …made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality. Show more

Keywords: AAV, Alzheimer’s disease, CRISPR, gene editing, gene therapy, regenerative medicine, stem cells

DOI: 10.3233/JAD-180422

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 321-344, 2018

Authors: Filley, Christopher M. | Kelly, James P.

Article Type: Review Article

Abstract: Traumatic brain injury (TBI) is a leading cause of disability and produces a wide range of cognitive, emotional, and physical consequences. The impact of TBI on cognition is among the most important questions in this field but remains incompletely understood. The immediate cognitive effects of concussion, while usually short-lived, may be profound and lasting in some individuals, and long-term sequelae of TBI may include dementia of several varieties including post-traumatic leukoencephalopathy, chronic traumatic encephalopathy, and Alzheimer’s disease. Whereas the etiopathogenesis of cognitive dysfunction after TBI remains uncertain, a reasonable point to begin is a focus on the white matter of …the brain, where the neuropathological lesion known as diffuse axonal injury (DAI) is routinely identified. White matter is not typically accorded the significance granted to cortical gray matter in discussions of cognitive dysfunction and dementia, but increasing evidence is accumulating to suggest that cognitive decline after TBI is a direct result of white matter injury, and that lesions in this brain component are crucial in the sequence of events leading ultimately to dementia of several types. In this review, we consider the topic of white matter and cognition in TBI, beginning with DAI and proceeding to the role of inflammation in the pathogenesis of cognitive dysfunction and dementia that can follow. A brief review of possible therapeutic options will also be offered, including the use of anti-inflammatory agents and the exploitation of white matter plasticity, to treat acute and post-acute injuries, and lower the incidence of dementia resulting from TBI. Show more

Keywords: Alzheimer’s disease, chronic traumatic encephalopathy, cognition, diffuse axonal injury, traumatic brain injury, white matter

DOI: 10.3233/JAD-180287

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 345-362, 2018

Authors: McDermott, Barry | Porter, Emily | Hughes, Diarmaid | McGinley, Brian | Lang, Mark | O’Halloran, Martin | Jones, Marggie

Article Type: Review Article

Abstract: Existing treatments for Alzheimer’s disease (AD) have questionable efficacy with a need for research into new and more effective therapies to both treat and possibly prevent the condition. This review examines a novel therapeutic modality that shows promise for treating AD based on modulating neuronal activity in the gamma frequency band through external brain stimulation. The gamma frequency band is roughly defined as being between 30 Hz-100 Hz, with the 40 Hz point being of particular significance. The epidemiology, diagnostics, existing pathological models, and related current treatment targets are initially briefly reviewed. Next, the concept of external simulation triggering brain …activity in the gamma band with potential demonstration of benefit in AD is introduced with reference to a recent important study using a mouse model of the disease. The review then presents a selection of relevant studies that describe the neurophysiology involved in brain stimulation by external sources, followed by studies involving application of the modality to clinical scenarios. A table summarizing the results of clinical studies applied to AD patients is also reported and may aid future development of the modality. The use of a therapy based on modulation of gamma neuronal activity represents a novel non-invasive, non-pharmacological approach to AD. Although use in clinical scenarios is still a relatively recent area of research, the technique shows good signs of efficacy and may represent an important option for treating AD in the future. Show more

Keywords: 40 Hz, Alzheimer’s disease, gamma, neural stimulation

DOI: 10.3233/JAD-180391

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 363-392, 2018

Authors: Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Little is known about the impact of prior mild cognitive impairment (MCI, ICD-10: F06.7) diagnosis on the time to dementia diagnosis, anti-dementia drug therapy, and treatment persistence in patients with dementia (PWD). Patients with dementia diagnoses who started anti-dementia therapy between January 2010 and December 2016 were selected from 203 neurological/psychiatric practices in the Disease Analyzer databank (IQVIA). Patients with a history of MCI were compared to non-MCI controls in terms of demographic characteristics, anti-dementia therapy, and the rate of persistence with anti-dementia drugs. For persistence analyses, a 1:1 matching procedure was used based on age, gender, type of residence, …and depression and dementia diagnosis. Persistence was represented using Kaplan-Meier curves. A Cox regression analysis was used to determine the influence of MCI diagnosis on persistence with anti-dementia drugs. 339 PWD with MCI diagnoses and 339 controls were available for analysis. PWD with MCI were younger (78.9 versus 80.4 years), less likely to live in a nursing home (8.5% versus 22.5%), more frequently received donepezil (40.1% versus 33.7%), and more likely to exhibit comorbid depression (29.6% versus 16.9%). There was no association between the risk of treatment discontinuation and prior MCI diagnosis. After 24 months, 40% versus 41.1% of patients had discontinued treatment. The prior MCI diagnosis presumably led to an earlier diagnosis of dementia and earlier anti-dementia treatment. Treatment continuity did not differ, which would suggest that it does not depend on prior MCI diagnosis but on the behavior of patients and their caregiving relatives. Show more

Keywords: Alzheimer’s disease, anti-dementia drugs, Germany, mild cognitive impairment, preclinical dementia, real-world-data

DOI: 10.3233/JAD-180567

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 393-399, 2018

Authors: Kostev, Karel | Hadji, Peyman | Jacob, Louis

Article Type: Research Article

Abstract: Background: There has been in recent decades a growing interest in the relationship between osteoporosis and cognitive decline. Objective: The goal of this study was to analyze the impact of osteoporosis on the risk of dementia in patients followed for up to 20 years in general practices in Germany. Methods: This study included patients who received an initial diagnosis of osteoporosis and were followed by 1,215 general practitioners in Germany between January 1993 and December 2012 (index date). Controls were matched (1:1) to osteoporosis patients using propensity scores based on age, gender, index year, comorbidities, and …co-therapies. Kaplan-Meier curves were performed to study the development of dementia separately in men and women with or without osteoporosis within 20 years of the index date. Cox proportional regression models were used to estimate the relationship between osteoporosis and dementia in men and women. Results: The present study included 29,983 cases and 29,983 controls. After 20 years of follow-up, 20.5% of women with osteoporosis and 16.4% of controls had been diagnosed with dementia (log-rank p -value <0.001). At the end of the follow-up period, dementia was found in 22.0% of men previously diagnosed with osteoporosis and 14.9% of men without this chronic condition (log-rank p -value <0.001). Osteoporosis was associated with a 1.2-fold increase in the risk of being diagnosed with dementia in women and a 1.3-fold increase in the risk of being diagnosed with dementia in men. Conclusions: There was a positive association between osteoporosis and dementia in patients followed in general practices in Germany. Show more

Keywords: Dementia, general practices, Germany, osteoporosis, risk factor

DOI: 10.3233/JAD-180569

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 401-407, 2018

Authors: Si, Zizhen | Wang, Xidi | Zhang, Zhujun | Wang, Jinxin | Li, Jihong | Li, Jing | Li, Ling | Li, Yuanxin | Peng, Yahui | Sun, Chongran | Hui, Yang | Gao, Xu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by behavioral changes and cognitive decline. Recent evidence suggests that it is the soluble forms of tau oligomers (Tau-O) and Aβ oligomers (oAβ) rather than the well-studied insoluble protein aggregates that possess the neurotoxicity, infectivity, and amplification underlying disease progression. Heme oxygenase 1 (HO-1), an inducible enzyme upregulated in the cortex and hippocampus of AD brains, was reported to damage neural structures and disrupt brain function, suggesting possible contributions to Tau-O-mediated neurodegeneration. In this study, we focused on the effects of HO-1 on Tau-O formation. In hippocampus of HO-1-overexpressing transgenic mice …and neural 2a (N2a) cells, Tau-O was co-localized with HO-1 as visualized by immunofluorescence staining. Furthermore, primary cultured hippocampal neurons from HO-1 transgenic mice showed elevated Tau-O and concomitant reductions in spine density and length as well as dendritic length, diameter, and arborization. Blocking Tau-O formation by isoprenaline reversed these HO-1-induced morphological changes. These results indicated that HO-1 contributes to Tau-O formation and ensuing synaptic damage. Thus, HO-1 is a promising target for AD drug development. Show more

Keywords: Alzheimer’s disease, dendritic spine, heme oxygenase 1, synaptic plasticity, tau oligomer

DOI: 10.3233/JAD-180451

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 409-419, 2018

Authors: Yao, Fang | Hong, Xiaoyu | Li, Shuiming | Zhang, Yan | Zhao, Qing | Du, Wei | Wang, Yong | Ni, Jiazuan

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder contributing to nearly 70% of dementia cases. However, no diagnostic protein biomarkers are available in urine. In this study, we combined computational and experimental methods to identify urinary biomarkers for AD. First, by analyzing brain tissue-based gene expression data of AD, 2,754 differentially expressed genes were identified, 559 of which were predicted to encode urine-excretory proteins that might act as candidate protein biomarkers of AD. GO enrichment analyses implied that they were mainly involved in microtubule-based process, myelin sheath, and calcium ion binding, suggesting that they might be associated with AD pathogenesis. …In order to verify these proteins in urine, an iTRAQ experiment was carried out to analyze urine samples from AD patients and healthy controls, and 15 proteins were detected. Based on the expression changes of these proteins, 4 proteins were chosen for further validation by ELISA experiment, and SPP1, GSN, and IGFBP7 were found to be differentially expressed in the urine of AD patients. After a literature survey, we found that they were involved in AD pathophysiology and might serve as new urine biomarkers for AD. To our knowledge, this is the first time that urine biomarkers for AD were identified by combining computational and experimental methods. Furthermore, this is the first time SPP1, GSN, and IGFBP7 have been reported as potential urine protein biomarkers for AD. Therefore, our findings might provide significant guidance for finding early biomarkers of AD in urine. Show more

Keywords: Alzheimer’s disease, biomarkers, protein, urine

DOI: 10.3233/JAD-180261

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 421-431, 2018

Authors: Jin, He | Guan, Shaochen | Wang, Rong | Fang, Xianghua | Liu, Hongjun | Wu, Yanchuan | Zhang, Yanlei | Liu, Chunxiao

Article Type: Research Article

Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a biomarker for Alzheimer’s disease (AD). Objective: The aim of the present study was to investigate the distribution of Alzheimer-associated neuronal thread protein and its relationship to common chronic diseases in the general population. Methods: Urine samples of 1,805 participants were collected from four districts (Xi Cheng, Fang Shan, Tong Zhou, and Yan Qing) in Beijing. The assessment in this study included a questionnaire that captured participants’ demographic information, use of medication and histories of disease, neurological examinations, psychometric evaluations, physical and clinical examinations, and …laboratory tests. Results: Urine AD7c-NTP level was increased among the population over 60 years old and females exhibited higher levels than males. These results controlled for other demographic factors such as education levels, employment status, body mass index and current residence. The urine AD7c-NTP levels exhibited no association with non-neurological diseases (0.3346±0.4482 ng/ml), such as hypertension (0.3445±0.4187), stroke (0.3652±0.4010), diabetes (0.3319±0.4371), dyslipidemia (0.3440±0.4314), renal insufficiency (0.3223±0.3909), cancer (0.5055±1.0006), chronic lung disease (0.2911±0.2852), chronic liver disease (0.5579±0.6726), severe depression symptoms (0.5186±0.7040), and mild depression symptoms (0.3669±0.3811). Conclusions: Cut-off values for urine AD7c-NTP levels for different age groups and genders should be established. AD7c-NTP levels proved relatively stable in the body and were not impacted by demographic factors or common chronic diseases. Show more

Keywords: Alzheimer’s disease, Alzheimer-associated neuronal thread protein, biomarker, urine

DOI: 10.3233/JAD-180441

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 433-442, 2018

Authors: Guerrier, Laura | Le Men, Johanne | Gane, Anaıs | Planton, Mélanie | Salabert, Anne-Sophie | Payoux, Pierre | Dumas, Hervé | Bonneville, Fabrice | Péran, Patrice | Pariente, Jérémie

Article Type: Research Article

Abstract: Background: Anosognosia is a frequent symptom of Alzheimer’s disease (AD), but its neural substrates remain in question. Objective: In this study, we combined neuroimaging with a neuropsychological evaluation to assess neural substrates of anosognosia. Methods: We prospectively recruited 30 patients with probable early-stage AD and matched healthy controls. Participants underwent MRI, FDG-PET, and a neuropsychological evaluation that includes an assessment of anosognosia. In the AD group, correlations between the anosognosia score, neuroimaging modalities, and neuropsychological performance were performed. Results: Atrophy and hypometabolism were correlated with the anosognosia score in the left dorsal anterior cingulate …cortex. The anosognosia score was also correlated with atrophy of the cerebellar vermis, the left postcentral gyrus, and the right fusiform gyrus. No relation was found between anosognosia and the neuropsychological assessment. Discussion: Structural and metabolic alteration in the dorsal anterior cingulate cortex seems to be associated with a diminution of awareness in patients with early-stage AD. Show more

Keywords: Alzheimer’s disease, anosognosia, FDG-positron emission tomography, magnetic resonance imaging, neuropsychological assessment

DOI: 10.3233/JAD-180324

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 443-453, 2018

Authors: Piscopo, Paola | Grasso, Margherita | Puopolo, Maria | D’Acunto, Emanuela | Talarico, Giuseppina | Crestini, Alessio | Gasparini, Marina | Campopiano, Rosa | Gambardella, Stefano | Castellano, Anna Elisa | Bruno, Giuseppe | Denti, Michela A. | Confaloni, Annamaria

Article Type: Research Article

Abstract: Given the heterogeneous nature of frontotemporal dementia (FTD), sensitive biomarkers are greatly needed for the accurate diagnosis of this neurodegenerative disorder. Circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system, especially in aging. The objective of the study was to evaluate if some circulating miRNAs linked with apoptosis (miR-29b-3p, miR-34a-5p, miR-16-5p, miR-17-5p, miR-107, miR-19b-3p, let-7b-5p, miR-26b-5p, and 127-3p) were able to distinguish between FTD patients and healthy controls. For this study, we enrolled 127 subjects, including 54 patients with FTD, 20 patients with Alzheimer’s disease (AD), and 53 healthy controls. The …qRT-PCR analysis showed a downregulation of miR-127-3p in FTD compared to controls, while the levels of other miRNAs remained unchanged. Then, miR-127-3p expression was also analyzed in AD patients, finding a different expression between two patient groups. A receiver operating characteristic curve was then created for miR-127-3p to discriminate FTD versus AD (AUC: 0.8986), and versus healthy controls (AUC: 0.8057). In conclusion, miR-127-3p could help to diagnose FTD and to distinguish it from AD. Show more

Keywords: Biomarker, differential diagnosis, frontotemporal dementia, miR-127-3p, miRNA

DOI: 10.3233/JAD-180364

Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 455-464, 2018