Journal of Alzheimer's Disease - Volume 78, issue 4

Authors: Si, Zizhen | Wang, Xidi

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by complex pathological and biological features. Notably, extracellular amyloid-β deposits as senile plaques and intracellular aggregation of hyperphosphorylated tau as neurofibrillary tangles remain the primary premortem criterion for the diagnosis of AD. Currently, there exist no disease-modifying therapies for AD, and many clinical trials have failed to show its benefits for patients. Heme oxygenase 1 (HO-1) is a 32 kDa enzyme, which catalyzes the degradation of cellular heme to free ferrous iron, biliverdin, and carbon monoxide under stressful conditions. Several studies highlight the crucial pathological roles of HO-1 in the molecular processes of …AD. The beneficial roles of HO-1 overexpression in AD brains are widely accepted due to its ability to convert pro-oxidant heme to biliverdin and bilirubin (antioxidants), which promote restoration of a suitable tissue redox microenvironment. However, the intracellular oxidative stress might be amplified by metabolites of HO-1 and exacerbate the progression of AD under certain circumstances. Several lines of evidence have demonstrated that upregulated HO-1 is linked to tauopathies, neuronal damage, and synapse aberrations in AD. Here, we review the aspects of the molecular mechanisms by which HO-1 regulates AD and the latest information on the pathobiology of AD. We further highlight the neuroprotective and neurodystrophic actions of HO-1 and the feasibility of HO-1 as a therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, heme oxygenase 1, neurodystrophic effects, neuroprotective effects

DOI: 10.3233/JAD-200720

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1259-1272, 2020

Authors: Jayatunga, Dona P.W. | Hone, Eugene | Bharadwaj, Prashant | Garg, Manohar | Verdile, Giuseppe | Guillemin, Gilles J. | Martins, Ralph N.

Article Type: Review Article

Abstract: Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer’s disease (AD). Targeting mitophagy pathways has been suggested …to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, mitophagy, neuroprotection, nutraceuticals

DOI: 10.3233/JAD-191258

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1273-1297, 2020

Authors: Pople, Christopher B. | Meng, Ying | Li, Daniel Z. | Bigioni, Luca | Davidson, Benjamin | Vecchio, Laura M. | Hamani, Clement | Rabin, Jennifer S. | Lipsman, Nir

Article Type: Review Article

Abstract: Neuromodulation as a treatment strategy for psychiatric and neurological diseases has grown in popularity in recent years, with the approval of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression being one such example. These approaches offer new hope in the treatment of diseases that have proven largely intractable to traditional pharmacological approaches. For this reason, neuromodulation is increasingly being explored for the treatment of Alzheimer’s disease. However, such approaches have variable, and, in many cases, very limited evidence for safety and efficacy, with most human evidence obtained in small clinical trials. Here we review work in animal models …and humans with Alzheimer’s disease exploring emerging neuromodulation modalities. Approaches reviewed include deep brain stimulation, transcranial magnetic stimulation, transcranial electrical stimulation, ultrasound stimulation, photobiomodulation, and visual or auditory stimulation. In doing so, we clarify the current evidence for these approaches in treating Alzheimer’s disease and identify specific areas where additional work is needed to facilitate their clinical translation. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, neuromodulation, photobiomodulation therapy, pulsed ultrasound, transcranial electrical stimulation, transcranial magnetic stimulation

DOI: 10.3233/JAD-200913

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1299-1313, 2020

Authors: Li, Xinquan | Xuan, Weiting | Chen, Dabao | Gao, Huawu | Wang, Guangyun | Guo, Qiaoru | Wang, Yan | Song, Hang | Cai, Biao

Article Type: Research Article

Abstract: It is widely recognized that Alzheimer’s disease (AD) has a complicate link to renin-angiotensin system (RAS). It is known that cerebrovascular disease has some connections with AD, but most of the studies are still conducted in parallel or independently. Although previous research came up with large number of hypotheses about the pathogenesis of AD, it does not include the mechanism of RAS-related regulation of AD. It has been found that many components of RAS have been changed in AD. For example, the multifunctional and high-efficiency vasoconstrictor Ang II and Ang III with similar effects are changed under the action of …other RAS signal peptides; these signal peptides are believed to help improve nerve injury and cognitive function. These changes may lead to neuropathological changes of AD, and progressive defects of cognitive function, which are association with some hypotheses of AD. The role of RAS in AD gradually attracts our attention, and RAS deserved to be considered carefully in the pathogenesis of AD. This review discusses the mechanisms of RAS participating in the three current hypotheses of AD: neuroinflammation, oxidative stress and amyloid-β protein (Aβ) hypothesis, as well as the drugs that regulate RAS systems already in clinical or in clinical trials. It further demonstrates the importance of RAS in the pathogenesis of AD, not only because of its multiple aspects of participation, which may be accidental, but also because of the availability of RAS drugs, which can be reused as therapies of AD. Show more

Keywords: Aβ hypothesis, Alzheimer’s disease, neuroinflammation, oxidative stress, renin-angiotensin system

DOI: 10.3233/JAD-200770

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1315-1338, 2020

Authors: Rewerska-Juśko, Magdalena | Rejdak, Konrad

Article Type: Review Article

Abstract: In a broad sense, the concept of social stigmatization (from the Greek word “stigma”, or sign) refers to the attitude of social disapproval and the negative reception of a specific group of people due to the characteristic features of this group. The problem of stigma affects many people, and it is also present in medicine and affects people with dementia. Social stigma of people with dementia is a worldwide problem. The severity of this phenomenon depends on several factors, including gender, age, level of education, religiosity, cultural differences, and the severity of cognitive disorders. Stigmatization can have numerous negative consequences. …It leads to rejection, discrimination, and exclusion of stigmatized people from participation in various areas of social life. It also affects close relatives. The main goal of this review paper is to present the problem of stigma among people with dementia, discuss the results of represented research that deals with this issue, to approximate the elements that make up this process, and to present the negative consequences of stigma. Detailed knowledge of this phenomenon provides opportunity to reduce the extent of stigma and improve the quality of life people suffering from dementia. It is worth emphasizing the role of an individual approach to the patient and the need to educate the public about dementia. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, stereotypes, social stigma, stigmatization

DOI: 10.3233/JAD-201004

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1339-1343, 2020

Authors: Srivastava, Akriti | Das, Brati | Yao, Annie Y. | Yan, Riqiang

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-β (Aβ), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate …transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement. Show more

Keywords: Alzheimer’s disease, cognition, ionotropic glutamate receptors, long term depression, long term potentiation, metabotropic glutamate receptors, synapse, synaptic plasticity

DOI: 10.3233/JAD-201146

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1345-1361, 2020

Authors: Høilund-Carlsen, Poul F. | Barrio, Jorge R. | Werner, Tom J. | Newberg, Andrew | Alavi, Abass

Article Type: Article Commentary

Abstract: The lengthy debate on the validity of the amyloid hypothesis and the usefulness of amyloid imaging and anti-amyloid therapeutic interventions in dementia continues unabated, even though none of them have been able to convince the medical world of their correctness and clinical value. There are huge financial interests associated with promoting both, but in spite of the large sums of money in their support, no effective anti-amyloid treatments or diagnostic use of amyloid imaging have emerged. There are solid scientific reasons that explain these negative results, and it is time to move forward to other promising options for the benefit …of the patients. Show more

Keywords: Alzheimer’s disease, amyloid hypothesis, amyloid imaging, anti-amyloid therapeutic interventions, clinical usefulness

DOI: 10.3233/JAD-200990

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1363-1366, 2020

Authors: Martín-Jiménez, Paloma | Muñoz-García, Mariana I. | Seoane, David | Roca-Rodríguez, Lucas | García-Reyne, Ana | Lalueza, Antonio | Maestro, Guillermo | Folgueira, Dolores | Blanco-Palmero, Víctor A. | Herrero-San Martín, Alejandro | Llamas-Velasco, Sara | Pérez-Martínez, David A. | González-Sánchez, Marta | Villarejo-Galende, Alberto

Article Type: Short Communication

Abstract: We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.

Keywords: Cognitive impairment, COVID-19, dementia, morbidity, mortality

DOI: 10.3233/JAD-200937

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1367-1372, 2020

Authors: De Luca, Anastasia | Fostinelli, Silvia | Ferrari, Clarissa | Binetti, Giuliano | Benussi, Luisa | Borroni, Barbara | Rossi, Luisa | Rongioletti, Mauro | Ghidoni, Roberta | Squitti, Rosanna

Article Type: Short Communication

Abstract: Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative syndrome. Defects of copper (Cu) and iron (Fe) homeostasis are involved in the development of several neurodegenerative diseases and their homeostasis is interconnected by the Cu-protein ceruloplasmin (Cp), responsible for Fe oxidative state. In this study we assessed Fe, transferrin (Trf), ferritin, Cp specific activity (eCp/iCp), Cp/Trf ratio, and Trf saturation in 60 FTLD patients and 43 healthy controls, and discussed the results in relation to Cu homeostasis. The significant decrease of the eCp/iCp in the FTLD patients supports the involvement of Fe imbalance in the onset and progression of FTLD.

Keywords: Ceruloplasmin, copper, frontotemporal dementia, iron, serum

DOI: 10.3233/JAD-201047

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1373-1380, 2020

Authors: Yilmaz, Ali | Ustun, Ilyas | Ugur, Zafer | Akyol, Sumeyya | Hu, William T. | Fiandaca, Massimo S. | Mapstone, Mark | Federoff, Howard | Maddens, Michael | Graham, Stewart F.

Article Type: Research Article

Abstract: Background: Currently, there is no objective, clinically available tool for the accurate diagnosis of Alzheimer’s disease (AD). There is a pressing need for a novel, minimally invasive, cost friendly, and easily accessible tool to diagnose AD, assess disease severity, and prognosticate course. Metabolomics is a promising tool for discovery of new, biologically, and clinically relevant biomarkers for AD detection and classification. Objective: Utilizing artificial intelligence and machine learning, we aim to assess whether a panel of metabolites as detected in plasma can be used as an objective and clinically feasible tool for the diagnosis of mild cognitive impairment …(MCI) and AD. Methods: Using a community-based sample cohort acquired from different sites across the US, we adopted an approach combining Proton Nuclear Magnetic Resonance Spectroscopy (1 H NMR), Liquid Chromatography coupled with Mass Spectrometry (LC-MS) and various machine learning statistical approaches to identify a biomarker panel capable of identifying those patients with AD and MCI from healthy controls. Results: Of the 212 measured metabolites, 5 were identified as optimal to discriminate between controls, and individuals with MCI or AD. Our models performed with AUC values in the range of 0.72–0.76, with the sensitivity and specificity values ranging from 0.75–0.85 and 0.69–0.81, respectively. Univariate and pathway analysis identified lipid metabolism as the most perturbed biochemical pathway in MCI and AD. Conclusion: A comprehensive method of acquiring metabolomics data, coupled with machine learning techniques, has identified a strong panel of diagnostic biomarkers capable of identifying individuals with MCI and AD. Further, our data confirm what other groups have reported, that lipid metabolism is significantly perturbed in those individuals suffering with dementia. This work may provide additional insight into AD pathogenesis and encourage more in-depth analysis of the AD lipidome. Show more

Keywords: Alzheimer’s disease, 1H NMR, machine learning, metabolomics, plasma markers, targeted mass spectrometry

DOI: 10.3233/JAD-200305

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1381-1392, 2020