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Bibliography on: Alzheimer Disease — Current Literature

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 15 Jan 2021 at 01:32 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT] OR 2020[PDAT] OR 2021[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-01-14

Stutzmann GE (2021)

RyR2 calcium channels in the spotlight-I'm ready for my close up, Dr. Alzheimer!.

Cell calcium, 94:102342 pii:S0143-4160(20)30184-6 [Epub ahead of print].

While various hypotheses surrounding the etiology of Alzheimer's disease (AD) have waxed and waned over the years, the calcium hypothesis of aging [1] has maintained its steady trajectory since the early 1990's, albeit often as the understudy. Here, Yao et al., [2] further implicate intracellular calcium dysregulation in AD pathogenesis, and focus the spotlight on the elusive ryanodine receptor-2 isoform.

RevDate: 2021-01-14

Robbins CB, Grewal DS, Thompson AC, et al (2021)

Reply to Comment on: Choroidal Structural Analysis in Alzheimer Disease, Mild Cognitive Impairment, and Cognitively Healthy Controls.

RevDate: 2021-01-14

James OG, Linares AR, Hellegers C, et al (2021)

Evaluating Alzheimer Disease With Flortaucipir and Florbetapir PET: A Clinical Case Series.

Clinical nuclear medicine pii:00003072-900000000-96257 [Epub ahead of print].

ABSTRACT: Early, accurate diagnosis of Alzheimer disease (AD) is essential but remains challenging. Neuropathological hallmarks of AD are β-amyloid neuritic plaques and tau protein neurofibrillary tangles. 18F-Florbetapir is one of several available PET tracers for imaging cortical fibrillary β-amyloid plaques. 18F-Flortaucipir PET was recently approved for evaluating the distribution and density of aggregated neurofibrillary tangles. We present cases of mild cognitive impairment or suspected AD to depict the nuances of flortaucipir distribution and scan interpretation as well as how combined information from amyloid and tau PET may help with differential diagnosis and prognosis.

RevDate: 2021-01-14

Bacchin R, Salgarello M, Trentin M, et al (2021)

Brain 18F-FDG and 18F-Flumetamol PET Imaging of Fragile X-Associated Tremor Ataxia Syndrome.

Clinical nuclear medicine pii:00003072-900000000-96253 [Epub ahead of print].

ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare movement disorder caused by a 55-to-200 CGG-trinucleotide expansion premutation in the FMR1 gene. Core diagnostic criteria are tremor, ataxia, and T2-weighted hyperintensity of the middle cerebellar peduncles on MRI, but FXTAS encompass a broad spectrum of neurological symptoms. FXTAS pathophysiology is largely unknown, and some animal models and neuropathology findings suggest possible overlap with Alzheimer disease. We report the combined PET imaging of a genetically confirmed FXTAS patient, presenting reduced temporal-frontal 18F-FDG uptake, and pathological cortical deposition of amyloid to 18F-flumetamol PET scan. This report may offer clues to FXTAS pathophysiology.

RevDate: 2021-01-14

Tian DY, Wang J, Sun BL, et al (2020)

Spicy food consumption is associated with cognition and cerebrospinal fluid biomarkers of Alzheimer disease.

Chinese medical journal, 134(2):173-177.

BACKGROUND: Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease (AD). This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid (CSF) biomarkers of AD in the Chinese population.

METHODS: We enrolled 55 AD patients and 55 age- and gender-matched cognitively normal (CN) subjects in a case-control study, as well as a cohort of 131 participants without subjective cognitive decline (non-AD) in a cross-sectional study. Spicy food consumption was assessed using the Food Frequency Questionnaire (FFQ). Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed.

RESULTS: In the case-control study, spicy food consumption was lower in AD patients than that in CNs (4.0 [4.0-8.0] vs. 8.0 [4.5-10.0], P < 0.001); FFQ scores were positively associated with Mini-Mental Status Examination scores in the total sample (r = 0.218, P = 0.014). In the cross-sectional study, the association between spicy food consumption and cognition levels was verified in non-AD subjects (r = 0.264, P = 0.0023). Moreover, higher FFQ scores were significantly associated with higher β-Amyloid (1-42) (Aβ42) levels and lower phospho-tau/Aβ42 and total tau/Aβ42 ratios in the CSF of non-AD subjects (P < 0.05).

CONCLUSION: Spicy food consumption is closely related to higher cognition levels and reversed AD biomarkers in the CSF, suggesting that a capsaicin-rich diet might have the potential to modify the cognitive status and cerebral pathologies associated with AD.

RevDate: 2021-01-14

Giannouli V, M Tsolaki (2021)

Mild Alzheimer Disease, Financial Capacity, and the Role of Depression: Eyes Wide Shut?.

Alzheimer disease and associated disorders pii:00002093-900000000-99254 [Epub ahead of print].

The aim of this study was to assess whether comorbid depression in patients with mild Alzheimer disease (AD) can influence financial capacity. The sample comprised 109 participants divided into 4 groups: mild AD with and without depressive symptoms, and cognitive normal elderly with and without depression. Participants were examined using a number of neuropsychological tests, with an emphasis on the Mini-Mental State Examination, the 15-item Geriatric Depression Scale, and the Legal Capacity for Property Law Transactions Assessment Scale. Financial capacity ascertained as performance in the Legal Capacity for Property Law Transactions Assessment Scale in the group of mild AD patients was severely impaired when depression coexisted, thus clearly differentiating the mild AD group from mild AD with comorbid depression.

RevDate: 2021-01-14

Choudhury P, Ramanan VK, BF Boeve (2021)

APOE ɛ4 Allele Testing and Risk of Alzheimer Disease.

JAMA pii:2775399 [Epub ahead of print].

RevDate: 2021-01-14

Honarvar B, Khaksar E, Jafari F, et al (2020)

Quality of Life in Elders with Suspected Alzheimer Disease: An Urban Health Centers-Based Study from Iran.

Dementia and geriatric cognitive disorders extra, 10(3):143-153 pii:dee-0010-0143.

Background/Aims: Quality of life (QOL) and Alzheimer disease (AD) among older people have been recognized as public health challenges. Here, we investigated the association between QOL and AD in the elders.

Methods: In this cross-sectional study, elderly people were selected from urban health centers (Shiraz, Iran) by multistage cluster random sampling and were interviewed using LEIPAD (for QOL) and Montreal Cognitive Assessment (for AD) questionnaires. The data was analyzed using Mplus (version 6.12) and IBM SPSS (version 25) software.

Results: The participants consisted of 182 elderly with a mean age of 67 ± 5.05 years, and 95 (52.2%) of them were females. There were 161 (88.5%) and 130 (71.4%) cases educated up to 12 years and married, respectively. Furthermore, 46 (25.3%) had low-to-moderate QOL, and 132 (72.5%) were suspected to have AD. QOL was inversely associated with AD, and men (β = -0.310) were more affected than women (β = -0.290). AD (β = -0.298), age (β = -0.288), hypertension (β = -0.267), education (β = 0.260), and body mass index (β = -0.198) were determinants of QOL. Also, physical activity was indirectly associated with QOL (β = 0.076). AD was correlated with the cognitive functioning component of QOL (r = -0.72).

Conclusion: One elder out of 4, did not have desirable QOL and 3 elders out of 4 were suspected to have AD. AD can decrease QOL among the older people. Screening of the elders for AD is recommended to improve their QOL by health centers.

RevDate: 2021-01-14

Hashimoto Y, Kusakari S, Nawa M, et al (2021)

Restoration of the reduced CLSP activity alleviates memory impairment in Alzheimer disease.

Translational psychiatry, 11(1):44.

Calmodulin-like skin protein (CLSP), a secreted peptide, inhibits neuronal death in cell-based Alzheimer's disease (AD) models and transgenic overexpression of the CLSP gene suppresses synaptic loss and memory impairment in AD model mice, APPswe/PS1dE9 double transgenic mice (APP/PS1 mice). Despite the anticipated role of CLSP as an AD-suppressing factor, it remains unanswered whether the insufficiency of the CLSP activity is linked to the AD pathogenesis. In this study, we first show that adiponectin, a CLSP potentiator/protector, dominantly determines the CLSP activity in the central nervous system where there are sufficient concentrations of CLSP, higher concentrations of CLSP inhibitors such as apolipoprotein E, and smaller concentrations of adiponectin. We next show that both the levels of brain adiponectin and the intraneuronal levels of SH3BP5, an important effector of the CLSP signal, are reduced in both AD patients and APP/PS1 mice. Finally, the restoration of the CLSP activity by subcutaneous injection of a hybrid peptide named CLSPCOL consisting of CLSP(1-61) and the collagen-homologous region of adiponectin, which has more potent neuroprotective activity than CLSP, is insensitive to the suppression by the CLSP inhibitors, and is efficiently recruited into brains, alleviates dementia and synaptic loss in the aged APP/PS1 mice. Collectively, these results suggest that the reduction in the CLSP activity, likely caused by the reduction in the levels of adiponectin, leads to the insufficient protection of neurons from neurotoxicity in the AD brains and the restoration of the CLSP activity is a promising strategy for the treatment of AD.

RevDate: 2021-01-14

Sajjadi SA, Ash S, S Cappa (2021)

Glass half full: Preservation of memory in Alzheimer-related primary progressive aphasia.

RevDate: 2021-01-13

Ferrucci F, Jorio M, Marci S, et al (2021)

A Web-Based Application for Complex Health Care Populations: User-Centered Design Approach.

JMIR human factors, 8(1):e18587 pii:v8i1e18587.

BACKGROUND: Although eHealth technology makes it possible to improve the management of complex health care systems and follow up on chronic patients, it is not without challenges, thus requiring the development of efficient programs and graphic user interface (GUI) features. Similar information technology tools are crucial, as health care populations are going to have to endure social distancing measures in the forthcoming months and years.

OBJECTIVE: This study aims to provide adequate and personalized support to complex health care populations by developing a specific web-based mobile app. The app is designed around the patient and adapted to specific groups, for example, people with complex or rare diseases, autism, or disabilities (especially among children) as well as Alzheimer or senile dementia. The app's core features include the collection, labeling, analysis, and sorting of clinical data. Furthermore, it authorizes a network of people around the patient to securely access the data contained in his or her electronic health record.

METHODS: The application was designed according to the paradigms of patient-centered care and user-centered design (UCD). It considers the patient as the main empowered and motivating factor in the management of his or her well-being. Implementation was informed through a family needs and technology perception assessment. We used 3 interdisciplinary focus groups and 2 assessment surveys to study the contexts of app use, subpopulation management, and preferred functions. Finally, we developed an observational study involving 116 enrolled patients and 253 system users, followed by 2 feedback surveys to evaluate the performance and impact of the app.

RESULTS: In the validated general GUI, we developed 10 user profiles with different privacy settings. We tested 81 functions and studied a modular structure based on disease or medical area. This allowed us to identify replicable methods to be applied to module design. The observational study not only showed good family and community engagement but also revealed some limitations that need to be addressed. In total, 42 of 51 (82%) patients described themselves as satisfied or very satisfied. Health care providers reported facilitated communication with colleagues and the need to support data quality.

CONCLUSIONS: The experimented solution addressed some of the health system challenges mentioned by the World Health Organization: usability appears to be significantly improved when the GUI is designed according to patients' UCD mental models and when new media and medical literacy are promoted. This makes it possible to maximize the impact of eHealth products, thereby overcoming some crucial gaps reported in the literature. Two main features seemed to have potential benefit compared with other eHealth products: the modeling, within the app, of both the formal and informal health care support networks and the modular structure allowing for comorbidity management, both of which require further implementation.

RevDate: 2021-01-13

Yao X, Sun C, Fan B, et al (2021)

Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines.

Journal of orthopaedic translation, 26:74-83 pii:S2214-031X(20)30025-5.

Background/objective: Spinal cord injury (SCI) severely and irreversibly damages the central nervous system. Neurotropin (NTP), a nonprotein extract obtained from inflamed rabbit skin inoculated with vaccinia virus, is a drug that has been used for more than sixty years to alleviate neuropathic pain. It also reportedly exerts a neuroprotective role in peripheral nerves and in response to various central nervous system diseases, such as brain injury and Alzheimer disease. However, whether NTP promotes SCI recovery remains unknown. This study evaluated NTP's effects after SCI and explored its underlying mechanisms in a rat contusion model of SCI.

Method: NTP was intraperitoneally administered to adult female Wistar rats subjected to contusion-induced SCI. Functional recovery was evaluated with behavioural scores and electrophysiological examinations. Tissue recovery was assessed with magnetic resonance imaging as well as histological staining with haematoxylin and eosin and Luxol Fast Blue. Neuronal survival and gliosis were observed after NeuN and glial fibrillary acidic protein immunofluorescence. Levels of apoptosis were demonstrated with TdT-mediated dUTP nick-end labeling (TUNEL) staining, Caspase-3 and B-cell lymphoma-2 (Bcl-2) Western blot, and Annexin V/propidium iodide flow cytometry. A protein antibody chip analysis was performed to evaluate the expression levels of 67 rat cytokines.

Results: NTP treatment improved the hindlimb locomotor recovery of the injured animals as well as their electrophysiological outcomes after SCI. A dosage of 50 NTP units/kg was found to optimize the efficacy of NTP. Magnetic resonance imaging revealed that lesion sizes decreased after NTP treatment. The haematoxylin and eosin and Luxol Fast Blue staining showed significant increases in the amount of spared tissue. The NeuN and glial fibrillary acidic protein immunofluorescence revealed that NTP treatment increased neuronal survival and reduced gliosis in tissue samples obtained from the lesion's epicentre. That NTP inhibited apoptosis was confirmed by the decreased number of TUNEL-positive cells, level of Caspase-3 expression, and number of Annexin V/propidium iodide-positive cells, as well as the increased level of Bcl-2 expression. The protein array analysis identified 28 differentially expressed proteins in the NTP group, and the gene ontology (GO) analysis showed that the enriched differentially expressed proteins implicate janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathways. The expression levels of proinflammatory cytokines such as interleukin 6, thymus chemokine-1(TCK-1), and lipopolysaccharide-induced CXC chemokine (LIX) decreased after NTP treatment, whereas the levels of prorepair cytokine hepatocyte growth factor and adiponectin increased.

Conclusion: Our research provides evidence that NTP can improve functional outcomes and alleviate secondary injury after SCI by inhibiting apoptosis and modulating cytokines.

The multicomponent NTP might have broad target spectra in SCI pathophysiology and halt the secondary injury cascade. As a safe drug that features sixty years of clinical use as an analgesic, translating this demonstrated efficacy of NTP to addressing SCI in human patients may potentially be accelerated.

RevDate: 2021-01-13

Chard DT, Alahmadi AAS, Audoin B, et al (2021)

Mind the gap: from neurons to networks to outcomes in multiple sclerosis.

Nature reviews. Neurology [Epub ahead of print].

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.

RevDate: 2021-01-13

Mentis AA, Dardiotis E, Efthymiou V, et al (2021)

Non-genetic risk and protective factors and biomarkers for neurological disorders: a meta-umbrella systematic review of umbrella reviews.

BMC medicine, 19(1):6.

BACKGROUND: The etiologies of chronic neurological diseases, which heavily contribute to global disease burden, remain far from elucidated. Despite available umbrella reviews on single contributing factors or diseases, no study has systematically captured non-purely genetic risk and/or protective factors for chronic neurological diseases.

METHODS: We performed a systematic analysis of umbrella reviews (meta-umbrella) published until September 20th, 2018, using broad search terms in MEDLINE, SCOPUS, Web of Science, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature, ProQuest Dissertations & Theses, JBI Database of Systematic Reviews and Implementation Reports, DARE, and PROSPERO. The PRISMA guidelines were followed for this study. Reference lists of the identified umbrella reviews were also screened, and the methodological details were assessed using the AMSTAR tool. For each non-purely genetic factor association, random effects summary effect size, 95% confidence and prediction intervals, and significance and heterogeneity levels facilitated the assessment of the credibility of the epidemiological evidence identified.

RESULTS: We identified 2797 potentially relevant reviews, and 14 umbrella reviews (203 unique meta-analyses) were eligible. The median number of primary studies per meta-analysis was 7 (interquartile range (IQR) 7) and that of participants was 8873 (IQR 36,394). The search yielded 115 distinctly named non-genetic risk and protective factors with a significant association, with various strengths of evidence. Mediterranean diet was associated with lower risk of dementia, Alzheimer disease (AD), cognitive impairment, stroke, and neurodegenerative diseases in general. In Parkinson disease (PD) and AD/dementia, coffee consumption, and physical activity were protective factors. Low serum uric acid levels were associated with increased risk of PD. Smoking was associated with elevated risk of multiple sclerosis and dementia but lower risk of PD, while hypertension was associated with lower risk of PD but higher risk of dementia. Chronic occupational exposure to lead was associated with higher risk of amyotrophic lateral sclerosis. Late-life depression was associated with higher risk of AD and any form of dementia.

CONCLUSIONS: We identified several non-genetic risk and protective factors for various neurological diseases relevant to preventive clinical neurology, health policy, and lifestyle counseling. Our findings could offer new perspectives in secondary research (meta-research).

RevDate: 2021-01-13

Mesulam M-, Coventry C, Bigio EH, et al (2021)

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Advances in experimental medicine and biology, 1281:33-49.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

RevDate: 2021-01-13

Ahmed M, Marín M, Bouça-Machado R, et al (2021)

Investigating Users' and Other Stakeholders' Needs in the Development of a Personalized Integrated Care Platform (PROCare4Life) for Older People with Dementia or Parkinson Disease: Protocol for a Mixed Methods Study.

JMIR research protocols, 10(1):e22463 pii:v10i1e22463.

BACKGROUND: Dementias-including Alzheimer disease-and Parkinson disease profoundly impact the quality of life of older population members and their families. PROCare4Life (Personalized Integrated Care Promoting Quality of Life for Older Adults) is a European project that recognizes the benefit of technology-based integrated care models in improving the care coordination and the quality of life of these target groups. This project proposes an integrated, scalable, and interactive care platform targeting older people suffering from neurodegenerative diseases, their caregivers, and socio-health professionals. PROCare4Life adopts a user-centered design approach from the early stage and throughout platform development and implementation, during which the platform is designed and adapted to the needs and requirements of all the involved users.

OBJECTIVE: This paper presents the study protocol for investigating users' needs and requirements regarding the design of the proposed PROCare4Life platform.

METHODS: A mixed qualitative and quantitative study design is utilized, including online surveys, interviews, and workshops. The study aimed to recruit approximately 200 participants, including patients diagnosed with dementia or Parkinson disease, caregivers, socio-health professionals, and other stakeholders, from five different European countries: Germany, Italy, Portugal, Romania, and Spain.

RESULTS: The study took place between April and September 2020. Recruitment is now closed, and all the data have been collected and analyzed in order to be used in shaping the large-scale pilot phase of the PROCare4Life project. Results of the study are expected to be published in spring 2021.

CONCLUSIONS: This paper charts the protocol for a user-centered design approach at the early stage of the PROCare4Life project in order to shape and influence an integrated health platform suitable for its intended target group and purpose.

DERR1-10.2196/22463.

RevDate: 2021-01-12

Wood H (2021)

A new diagnostic marker for Alzheimer disease?.

Nature reviews. Neurology [Epub ahead of print].

RevDate: 2021-01-12

Quartey MO, Nyarko JNK, Maley JM, et al (2021)

The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression.

Scientific reports, 11(1):431.

The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1-38), interacts with the AD-related variant, Aβ(1-42), and the predominant physiological variant, Aβ(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1-38) interacts differently with Aβ(1-40) and Aβ(1-42) and, in general, Aβ(1-38) interferes with the conversion of Aβ(1-42) to a β-sheet-rich aggregate. Functionally, Aβ(1-38) reverses the negative impact of Aβ(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1-42) phenotype in Caenorhabditis elegans. Aβ(1-38) also reverses any loss of MTT conversion induced by Aβ(1-40) and Aβ(1-42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1-38) and Aβ(1-42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1-42)/Aβ(1-38) [and Aβ(1-42)/Aβ(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1-42).

RevDate: 2021-01-12

Frey KA (2021)

Molecular Imaging of Extrapyramidal Movement Disorders With Dementia: The 4R Tauopathies.

Seminars in nuclear medicine pii:S0001-2998(20)30126-4 [Epub ahead of print].

Two pathologically distinct neurodegenerative conditions, progressive supranuclear palsy and corticobasal degeneration, share in common deposits of tau proteins that differ both molecularly and ultrastructurally from the common tau deposits diagnostic of Alzheimer disease. The proteinopathy in these disorders is characterized by fibrillary aggregates of 4R tau proteins. The clinical presentations of progressive supranuclear palsy and of corticobasal degeneration are often confused with more common disorders such as Parkinson disease or subtypes of frontotemporal lobar degeneration. Neither of these 4R tau disorders has effective therapy, and while there are emerging molecular imaging approaches to identify patients earlier in the course of disease, there are as yet no reliably sensitive and specific approaches to diagnoses in life. In this review, aspects of the clinical syndromes, neuropathology, and molecular biomarker imaging studies applicable to progressive supranuclear palsy and to corticobasal degeneration will be presented. Future development of more accurate molecular imaging approaches is proposed.

RevDate: 2021-01-12

Smith R, Strain J, Tanenbaum A, et al (2021)

Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease.

Brain connectivity [Epub ahead of print].

AIM: Identify a global resting state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regards to amyloid (A), tau (T), and neurodegeneration (N) biomarkers and estimated years to symptom onset (EYO).

INTRODUCTION: Cross-sectional measures were assessed in MC (n=171) and mutation non-carriers (NC) (n=70) participants. A FC matrix that encompassed multiple resting state networks (RSNs) was computed for each participant.

METHODS: A gFC was compiled as a single index indicating functional connectivity strength. Global FC signature was modeled as a non-linear function of EYO. gFC was linearly associated with other biomarkers used for assessing the AT(N) framework including: cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging.

RESULTS: The gFC was reduced in MC compared to NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR > 0 (demented) compared to either MC CDR 0 (cognitively normal) or NC participants. The gFC varied non-linearly with EYO and initially decreased at EYO = -24 years, followed by a stable period followed by a further decline near EYO =0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, FDG and hippocampal volume.

CONCLUSIONS: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.

RevDate: 2021-01-12

Chen WQ, Wu FF, Lv HB, et al (2021)

Whether cognitive behavioral therapy is effective for Alzheimer's disease: A protocol for systematic review and network meta-analysis.

Medicine, 100(1):e23945.

BACKGROUND: Alzheimer disease (AD) is a progressive neurodegenerative disease characterized by impaired memory and cognitive judgment. It is the leading cause of dementia in the elderly, and its high morbidity and mortality have also brought a significant social burden. So far, there is no method can completely cure Alzheimer's dementia, but there are many non-drug treatments that have been praised by people, especially the cognitive behavioral therapy proposed in recent years. The main purpose of this article is to evaluate the effect of cognitive behavioral therapy on the cognitive function improvement of patients with Alzheimer's dementia.

METHODS: We did a network meta-analysis to identify both direct and indirect evidence in relevant studies. A systematic literature search will be performed in the Cochrane Library, PubMed, and EMBASE from inception to October 2020. We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool.The outcomes investigated were Mini-Mental State Examination and AD Assessment Scale-Cognitive section scores. We did a pair-wise meta-analysis using the fixed-effects model and then did a random-effects network meta-analysis within a Bayesian framework. The = the Assessment of Multiple Systematic Reviews-2 scale, Preferred Reporting Items for Systematic Reviews and Meta-Analyses scale and Grading of Recommendations Assessment, Development and Evaluation were used to assess the quality and evidence grade of the literature. General characteristics of the eligible randomized controlled trials will be summarized and described. Meanwhile, The ADDIS software will be used to perform the network meta-analysis, and the result figures will be generated by STATA 15.0 software.

RESULTS: Using the draft search strategy of databases and after screening,7 randomized controlled trials met the a priori criteria and were included. This network mate-analysis will be published in a peer-reviewed journal.

CONCLUSION: Our study will provide evidence for cognitive behavioral intervention in AD patients. And provide recommendations and guidelines for the clinic.

PROTOCOL REGISTRATION: INPLASY2020110052.

RevDate: 2021-01-11

Jellinger KA (2021)

Pathobiological Subtypes of Alzheimer Disease.

Dementia and geriatric cognitive disorders pii:000508625 [Epub ahead of print].

Alzheimer disease (AD), the most common form of dementia, is a heterogenous disorder with various pathobiological subtypes. In addition to the 4 major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy [MA]), several other clinical variants showing distinct regional patterns of tau burden have been identified: nonamnestic, corticobasal syndromal, primary progressive aphasia, posterior cortical atrophy, behavioral/dysexecutive, and mild dementia variants. Among the subtypes, differences were found in age at onset, sex distribution, cognitive status, disease duration, APOE genotype, and biomarker levels. The patterns of key network destructions parallel the tau and atrophy patterns of the AD subgroups essentially. Interruption of key networks, in particular the default-mode network that is responsible for cognitive decline, is consistent in hetero-genous AD groups. AD pathology is often associated with co-pathologies: cerebrovascular lesions, Lewy pathology, and TDP-43 proteinopathies. These mixed pathologies essentially influence the clinical picture of AD and may accel-erate disease progression. Unraveling the heterogeneity among the AD spectrum entities is important for opening a window to pathogenic mechanisms affecting the brain and enabling precision medicine approaches as a basis for developing preventive and ultimately successful disease-modifying therapies for AD.

RevDate: 2021-01-11

Moscoso A, Grothe MJ, Ashton NJ, et al (2021)

Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease.

JAMA neurology pii:2774467 [Epub ahead of print].

Importance: Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear.

Objective: To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury.

This longitudinal cohort study included data from the Alzheimer's Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol.

Exposures: Plasma p-tau181 and NfL measured with single-molecule array technology.

Main Outcomes and Measures: Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale-Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020.

Results: Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = -0.24, P < .001; CImp: r = 0.34, P < .001) and a prospective decrease in glucose metabolism (CU: r = -0.05, P = .48; CImp: r = -0.27, P < .001) and gray matter volume (CU: r = -0.19, P < .001; CImp: r = -0.31, P < .001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β-positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β-negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures.

Conclusions and Relevance: Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials.

RevDate: 2021-01-11

Busatto GF, de Gobbi Porto FH, Faria DP, et al (2020)

In vivo imaging evidence of poor cognitive resilience to Alzheimer's disease pathology in subjects with very low cognitive reserve from a low-middle income environment.

Alzheimer's & dementia (Amsterdam, Netherlands), 12(1):e12122 pii:DAD212122.

INTRODUCTION: Reduced cognitive reserve (CR) due to very low educational (VLE) levels may influence high dementia rates in low-middle income environments, leading to decreased cognitive resilience (RES) to Alzheimer´s disease (AD) pathology. However, in vivo findings in VLE groups confirming this prediction are lacking.

METHODS: Cognitively impaired patients (with clinically defined AD dementia or amnestic mild cognitive impairment) and cognitively unimpaired older adults (n = 126) were recruited for a positron emission tomography (PET) and magnetic resonance imaging (MRI) investigation in Brazil, including 37 VLE individuals (≤5 years of education). A CR score was generated combining educational attainment and vocabulary knowledge. RES indices to AD pathology were calculated using standardized residuals from linear regression models relating current cognitive performance (episodic memory or overall cognition) to amyloid beta (Aβ) burden Pittsburgh compound-B ([11C]PiB-PET).

RESULTS: Aβ burden was lower in VLE relative to highly-educated subjects (controlling for age, sex, and Mini-Mental Status Exam [MMSE] scores) in the overall cognitively impaired sample, and in dementia subjects when the three clinically defined groups were evaluated separately. In bivariate regression analyses for the overall sample, the RES index based on a composite cognitive score was predicted by CR, socioeconomic status, and hippocampal volume (but not white matter hyperintensities or intracranial volume [ICV]); in the multivariate model, only CR retained significance (and similar results were obtained in the Aβ-positive subsample). In the multivariate model for the overall sample using the RES index based on memory performance, CR, hippocampal volume, and ICV were significant predictors, whereas only CR retained significance in Aβ-positive subjects.

DISCUSSION: Lower CR consistently predicted less resilience to AD pathology in older adults from a low-middle income environment.

RevDate: 2021-01-11

Valadez-Barba V, Cota-Coronado A, Hernández-Pérez OR, et al (2020)

iPSC for modeling neurodegenerative disorders.

Regenerative therapy, 15:332-339 pii:S2352-3204(20)30089-4.

Neurodegenerative disorders such as Parkinson's and Alzheimer's disease, are fundamental health concerns all around the world. The development of novel treatments and new techniques to address these disorders, are being actively studied by researchers and medical personnel. In the present review we will discuss the application of induced Pluripotent Stem Cells (iPSCs) for cell-therapy replacement and disease modelling. The aim of iPSCs is to restore the functionality of the damaged tissue by replacing the impaired cells with competitive ones. To achieve this objective, iPSCs can be properly differentiated into virtually any cell fate and can be strongly translated into human health via in vitro and in vivo disease modeling for the development of new therapies, the discovery of biomarkers for several disorders, the elaboration and testing of new drugs as novel treatments, and as a tool for personalized medicine.

RevDate: 2021-01-11

Prajapat M, Sarma P, Shekhar N, et al (2020)

In silico docking and comparative ADMET profile of different glycogen synthase kinase 3 beta inhibitors as the potential leads for the development of anti-Alzheimer drug therapy.

Journal of advanced pharmaceutical technology & research, 11(4):194-201.

Glycogen synthase kinase 3 beta (GSK3 β) plays a key role in pathologic hyper phosphorylation of tau and plays an important role in the pathogenesis of Alzheimer's disease. In the present study, we have screened a set of potential hits in in silico platform to gain insight regarding binding profile with the target (GSK3 β) from molecular docking, ADME/T, and molecular dynamics (MD) simulations. The three screened compounds 6-BIBEO, 6-BIO, and SB216763 topped the docking score chart when subjected to hard scoring function extraprecision of GLIDE. The active site dynamics study through MD simulations provides insights on residues Asp133, Val135, and Ile62 which are in a state of minimum deviation from their mean special position while they interact with the respective ligands. The same molecules also displayed favorable pharmacokinetic profile, negative Ames test and falls correctly within drug-likeliness rules. These agents can be taken forward further for the development of anti-Alzheimer's drug therapy.

RevDate: 2021-01-11

Jiang W, YanYu , Yao D, et al (2020)

Single Point Mutation from E22-to-K in Aβ Initiates Early-Onset Alzheimer's Disease by Binding with Catalase.

Oxidative medicine and cellular longevity, 2020:4981204.

Amyloid-beta (Aβ) is a critical etiological factor for late-onset familial Alzheimer's disease (AD). However, an early-onset AD has been found to be related with an Aβ mutation in glutamic acid 22-to-lysine (Italian type E22K). Why only one single point mutation at E22 residue induces AD remains unclear. Here, we report that a Chinese familial AD pedigree with E22K mutation was associated with higher levels of serum hydrogen peroxide (H2O2) and lower activity of catalase (a H2O2 degrading enzyme) than controls. Further, we found that E22K binding with catalase caused more severe H2O2 accumulation in the brains of E22K-injected rats than Aβ-injected rats. Unexpectedly, H2O2 bound with the mutation site 22K residue of E22K and elicited more rapid aggregation of E22K than Aβ in vitro. Moreover, H2O2 acted with E22K synergistically to induce higher cellular toxicity than with Aβ. Notably, intrahippocampal infusion of E22K led to more severe plaque deposition, neuron death, and more rapid memory decline than Aβ-injected rats. However, L-cysteine, a H2O2 scavenger, not only prevented self-aggregation of E22K but also reduced H2O2-promoted E22K assembly in vitro; subsequently, it alleviated Alzheimer-related phenotypes. Hence, E22K binding with catalase promotes the early onset of familial AD, and L-cys may reverse this disease.

RevDate: 2021-01-11

Nabavi SM, E Sobarzo-Sánchez (2021)

Parkinson´s and Alzheimer´s Diseases and Natural Products: Pathologies and Medication of the New Times.

Current neuropharmacology, 19(2):112-113.

RevDate: 2021-01-08

Chauhan PS, Yadav D, Koul B, et al (2020)

Recent Advances in Nanotechnology: A Novel Therapeutic System for the Treatment of Alzheimer's Disease.

Current drug metabolism, 21(14):1144-1151.

A amyloid-β (Aβ) plaque formation in the brain is known to be the root cause of Alzheimer's disease (AD), which affects the behavior, memory, and cognitive ability in humans. The brain starts undergoing changes several years before the actual appearance of the symptoms. Nanotechnology could prove to be an alternative strategy for treating the disease effectively. It encompasses the diagnosis as well as the therapeutic aspect using validated biomarkers and nano-based drug delivery systems, respectively. A nano-based therapy may provide an alternate strategy, wherein one targets the protofibrillar amyloid-β (Aβ) structures, and this is followed by their disaggregation as random coils. Conventional/routine drug therapies are inefficient in crossing the blood-brain barrier; however, this hurdle can be overcome with the aid of nanoparticles. The present review highlights the various challenges in the diagnosis and treatment of AD. Meticulous and collaborative research using nanotherapeutic systems could provide remarkable breakthroughs in the early-stage diagnosis and therapy of AD.

RevDate: 2021-01-09

Singh A, Bhatt G, Gujre N, et al (2021)

Karanjin.

Phytochemistry, 183:112641 pii:S0031-9422(20)31256-5 [Epub ahead of print].

Karanjin [IUPAC: 3-methoxy-2-phenylfuro-(2,3-h-chrome-4-ol)], a bioactive furanoflavonoid and a potent biomolecule, was first isolated from Pongamia pinnata (L.). The crude extracts from root, leaf and seed having active constituent karanjin is highly valued in both traditional and modern knowledge systems. This review highlights, critically assesses, and presents the probable biosynthetic pathways of karanjin and its isolation methodologies with a view to actualizing its full potential. Karanjin exhibits multiple health benefits and applications, with evident anti-diabetic, anti-cancer, anti-inflammatory, anti-hyperglycemic, antioxidant, anti-colitis, anti-ulcer, and anti-Alzheimer properties. Consequently, the physiochemical properties and biological effects of karanjin have been detailed and analyzed. The efficacy of karanjin has been attenuated by toxicological studies that have proven karanjin to be non-toxic at physiological conditions as substantiated by in vitro and in vivo studies. In addition, the multiple insect repellent/insecticidal properties of karanjin and its availability as an acaricide/bio-insecticide have been reviewed. This review article underscores and endorses the immense potential for novel drug leads in various medicinal and industrial applications, suggesting a deeper insight into its metabolic fate, bioavailability, and cellular effects that await further investigations.

RevDate: 2021-01-09

Jalili-Baleh L, Nadri H, Forootanfar H, et al (2021)

Chromone-lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities.

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences [Epub ahead of print].

PURPOSE: Alzheimer's disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD.

METHODS: Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD.

RESULTS: The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio.

CONCLUSION: Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. A new chromone-lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aβ aggregation, metal-chelation and antioxidant properties.

RevDate: 2021-01-09

Olajide OJ, Gbadamosi IT, Yawson EO, et al (2021)

Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity.

Journal of molecular neuroscience : MN [Epub ahead of print].

The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-β (Aβ) accumulation and increased glutamate agonist. While previous studies have shown Aβ-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamate-mediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.

RevDate: 2021-01-09

Chang MH, Moonesinghe R, BI Truman (2021)

COVID-19 Hospitalization by Race and Ethnicity: Association with Chronic Conditions Among Medicare Beneficiaries, January 1-September 30, 2020.

Journal of racial and ethnic health disparities [Epub ahead of print].

OBJECTIVES: We assessed the association between hospitalization for illness from COVID-19 infection and chronic conditions among Medicare beneficiaries (MBs) with fee-for-service (FFS) claims by race and ethnicity for January 1-September 30, 2020.

METHODS: We used 2020 monthly Medicare data from January 1-September 30, 2020, reported to the Centers for Medicare and Medicaid Services to compute hospitalization rates per 100 COVID-19 MBs with FFS claims who were hospitalized (ICD-10-CM codes: B97.29 before April 1, 2020; ICD-10-CM codes: U07.1 from April 1, 2020, onward) with or without selected chronic conditions. We used logistic regression to estimate adjusted odds ratios with 95% confidence intervals for association of person-level rate of being hospitalized with COVID-19 and each of 27 chronic conditions by race/ethnicity, controlling for age, sex, and urban-rural residence among MBs.

RESULTS: COVID-19-related hospitalizations were associated with all selected chronic conditions, except osteoporosis and Alzheimer disease/dementia among COVID-19 MBs. The top five conditions with the highest odds for hospitalization among COVID-19 MBs were end-stage renal disease (adjusted odds ratios (aOR): 2.15; 95% CI: 2.10-2.21), chronic kidney disease (aOR: 1.54; 95% CI: 1.52-1.56), acute myocardial infarction (aOR: 1.45; 95% CI: 1.39-1.53), heart failure (aOR: 1.43; 95% CI: 1.41-1.44), and diabetes (aOR: 1.37; 95% CI: 1.36-1.39).

CONCLUSIONS: Racial/ethnic disparities in hospitalization rate persist among MBs with COVID-19, and associations of COVID-19 hospitalization with chronic conditions differ among racial/ethnic groups in the USA. These findings indicate the need for interventions in racial/ethnic populations at the highest risk of being hospitalized with COVID-19.

RevDate: 2021-01-09

Arias JJ, Tyler AM, Douglas MP, et al (2021)

Private payer coverage policies for ApoE-e4 genetic testing.

Genetics in medicine : official journal of the American College of Medical Genetics [Epub ahead of print].

PURPOSE: ApoE-e4 has a well-established connection to late-onset Alzheimer disease (AD) and is available clinically. Yet, there have been no analyses of payer coverage policies for ApoE. Our objective was to analyze private payer coverage policies for ApoE genetic testing, examine the rationales, and describe supporting evidence referenced by policies.

METHODS: We searched for policies from the eight largest private payers (by member numbers) covering ApoE testing for late-onset AD. We implemented content analysis methods to evaluate policies for coverage decisions and rationales.

RESULTS: Seven payers had policies with positions on ApoE testing. Five explicitly state they do not cover ApoE and two apply generic preauthorization criteria. Rationales supporting coverage decisions include: reference to guidelines or national standards, inadequate data supporting testing, characterizing testing as investigational, or that testing would not alter patients' clinical management.

CONCLUSION: Seven of the eight largest private payers' coverage policies reflect standards that discourage ApoE testing due to a lack of clinical utility. As the field advances, ApoE testing may have an important clinical role, particularly considering that disease-modifying therapies are under evaluation by the US Food and Drug Administration. These types of field advancements may not be consistent with private payers' policies and may cause payers to reevaluate existing coverage policies.

RevDate: 2021-01-09

Tan MS, Yang YX, Xu W, et al (2021)

Associations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration.

Alzheimer's research & therapy, 13(1):15.

BACKGROUND: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration.

METHODS: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model.

RESULTS: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process.

CONCLUSIONS: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.

RevDate: 2021-01-08

Nordestgaard LT, Christoffersen M, Afzal S, et al (2021)

Triglycerides as a Shared Risk Factor between Dementia and Atherosclerotic Cardiovascular Disease: A Study of 125 727 Individuals.

Clinical chemistry, 67(1):245-255.

BACKGROUND: Risk factors for atherosclerotic cardiovascular disease such as smoking, hypertension, physical inactivity, and diabetes have also been associated with risk of dementia. Whether hypertriglyceridemia represents a shared risk factor as well remains unknown. We tested the hypothesis that hypertriglyceridemia is associated with increased risk of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke.

METHODS: Using the Copenhagen General Population Study and the Copenhagen City Heart Study, we examined the association between increased plasma triglycerides and risk of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke with Cox regression.

RESULTS: On a continuous scale, higher concentrations of plasma triglycerides were associated with increased risk of non-Alzheimer dementia and ischemic stroke, but not with Alzheimer disease. In age, sex, and cohort adjusted models, the highest percentile of triglycerides (median 629 mg/dL; 7.1 mmol/L) versus the 1-50th percentiles (median 89 mg/dL; 1.0 mmol/L) was associated with hazard ratios of 1.75 (95% confidence interval: 1.17-2.63) for non-Alzheimer dementia, 1.18 (0.73-1.91) for Alzheimer disease, and of 1.89 (1.50-2.38) for ischemic stroke. Corresponding hazard ratios were 1.62 (1.08-2.44), 1.25 (0.77-2.02), and 1.57 (1.24-1.98) in models adjusted multifactorially, and 1.79 (1.16-2.87), 1.18 (0.73-1.92), and 1.46 (1.10-1.95) in models adjusted multifactorially and additionally for apolipoprotein E (APOE) genotype, respectively. Results were similar after excluding individuals who had an event within 2 years after study entry.

CONCLUSIONS: Moderate hypertriglyceridemia was associated with increased risk of both non-Alzheimer dementia and ischemic stroke, highlighting plasma triglycerides as a shared risk factor between dementia and atherosclerotic cardiovascular disease.

RevDate: 2021-01-08

Watts GF, JCL Mamo (2021)

Hypertriglyceridemia and Alzheimer Disease: Opening the Mind to New Therapeutic Opportunities.

Clinical chemistry, 67(1):6-8.

RevDate: 2021-01-08

Nuthakki VK, Yadav Bheemanaboina RR, SB Bharate (2020)

Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity.

Bioorganic chemistry, 107:104568 pii:S0045-2068(20)31866-6 [Epub ahead of print].

Aplysinopsins are a group of marine-derived indole alkaloids that display diverse array of pharmacological effects. However, their effect on anti-Alzheimer targets has not been reported. Herein, we report the synthesis of aplysinopsin (1) and its effect on cholinesterases and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1). It inhibits electric eel acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and human BACE-1 with IC50 values of 33.9, 30.3, and 33.7 µM, respectively, and excellent BBB permeability (Pe 8.92 × 10-6 cm/s). To optimize its sub-micromolar activity, the first-generation analogs were prepared and screened. Two most active analogs 5b and (Z)-8g were found to effectively permeate the BBB (Pe > 5 × 10-6 cm/s). The N-sulphonamide derivative 5b display better cholinesterase inhibition, whereas the other analog (Z)-8g strongly inhibits BACE-1 (IC50 0.78 µM) activity. The analog 5b interacts primarily with PAS of AChE, and thus exhibit a mixed-type of inhibition. In addition, aplysinopsin along with new analogs inhibited the self-induced Aβ1-42 aggregation. The data presented herein indicate that the aplysinopsin-scaffold holds a potential for further investigation as a multi-targeted anti-Alzheimer agent.

RevDate: 2021-01-08

Dolatshahi M, Sabahi M, MH Aarabi (2021)

Pathophysiological Clues to How the Emergent SARS-CoV-2 Can Potentially Increase the Susceptibility to Neurodegeneration.

Molecular neurobiology [Epub ahead of print].

Along with emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, a myriad of neurologic symptoms, associated with structural brain changes, were reported. In this paper, we provide evidence to critically discuss the claim that the survived patients could possibly be at increased risk for neurodegenerative diseases via various mechanisms. This virus can directly invade the brain through olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Infection of the neurons along with peripheral leukocytes activation results in pro-inflammatory cytokine increment, rendering the brain to neurodegenerative changes. Also, occupation of the angiotensin-converting enzyme 2 (ACE-2) with the virus may lead to a decline in ACE-2 activity, which acts as a neuroprotective factor. Furthermore, acute respiratory distress syndrome (ARDS) and septicemia induce hypoxemia and hypoperfusion, which are locally exacerbated due to the hypercoagulable state and micro-thrombosis in brain vessels, leading to oxidative stress and neurodegeneration. Common risk factors for COVID-19 and neurodegenerative diseases, such as metabolic risk factors, genetic predispositions, and even gut microbiota dysbiosis, can contribute to higher occurrence of neurodegenerative diseases in COVID-19 survivors. However, it should be considered that severity of the infection, the extent of neurologic symptoms, and the persistence of viral infection consequences are major determinants of this association. Importantly, whether this pandemic will increase the overall incidence of neurodegeneration is not clear, as a high percentage of patients with severe form of COVID-19 might probably not survive enough to develop neurodegenerative diseases.

RevDate: 2021-01-08

Mozersky J, DS Davis (2020)

Living with Alzheimer Disease and Other Types of Dementia: Stories from Caregivers.

Narrative inquiry in bioethics, 10(2):89-93.

This symposium includes twelve personal narratives from people who have provided care to a spouse, parent, another relative, or friend with Alzheimer disease or related dementias (ADRD). People with ADRDs often face years of cognitive decline with memory and thinking that eventually require help from others to assist with their daily activities. Most people caring for older adults in the US are unpaid family members, friends, or other informal caregivers. People providing care often experience emotional and physical stress, or financial burdens. This symposium also includes three commentaries by experts in the fields of bioethics and philosophy, justice in healthcare, family caregiving, and end of life choices. These narratives provide a forum for exploring caregiver needs, suffering, benefits, and joys, as well as opportunities to improve the way we support caregivers and people with dementia and Alzheimer disease.

RevDate: 2021-01-08

Moussavi Z, Rutherford G, Lithgow B, et al (2021)

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

JMIR research protocols, 10(1):e25144 pii:v10i1e25144.

BACKGROUND: Alzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia.

OBJECTIVE: The objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment.

METHODS: We have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention.

RESULTS: As of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect.

CONCLUSIONS: This protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815.

DERR1-10.2196/25144.

RevDate: 2021-01-08

Pagano K, Tomaselli S, Molinari H, et al (2020)

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms.

Frontiers in neuroscience, 14:619667.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

RevDate: 2021-01-08

El Rabey HA, Rezk SM, Sakran MI, et al (2021)

Green coffee methanolic extract and silymarin protect against CCl4-induced hepatotoxicity in albino male rats.

BMC complementary medicine and therapies, 21(1):19.

BACKGROUND: During the last few decades, patients worldwide have been interested in using alternative medicine in treating diseases to avoid the increased side effects of chemical medications. Green coffee is unroasted coffee seeds that have higher amounts of chlorogenic acid compared to roasted coffee. Green coffee was successfully used to protect against obesity, Alzheimer disease, high blood pressure and bacterial infection.

METHODS: This study aimed to investigate the probable protective activity of the green coffee methanolic extract, silymarin and their combination on CCl4-induced liver toxicity in male rats. Thirty Sprague - Dawley male albino rats were divided into 5 groups; control negative (G1) just got the vehicle (olive oil) and the other four groups received CCl4 dissolved in olive oil through an intraperitoneal injection and were divided into untreated control positive group (G2), the third group (G3) was treated with green coffee methanolic extract, the fourth group (G4) was treated with silymarin, and the fifth group (G5) was treated with a combination of green coffee methanolic extract and silymarin.

RESULTS: In the positive control group treated with CCl4 (G2), the CCl4-induced toxicity increased lipid peroxidation, IL-6, kidney function parameters, liver function enzymes, total cholesterol, triglycerides and low-density lipoproteins, and decreased irisin, antioxidants, CYP450 and high-density lipoprotein levels. Hepatic tissues were also injured. However, treating the injured rats in G3, G4 and G5 significantly improved the altered parameters and hepatic tissues.

CONCLUSIONS: Green coffee methanolic extract, silymarin, and their combination succeeded in protecting the male rats against CCl4 hepatotoxicity due to their antioxidant activity. Effect of green coffee methanolic extract mixed with silymarin in G5 was more efficient than that of green coffee methanolic extract in G3 or silymarin in G4.

RevDate: 2021-01-07

Wang LL, Song YP, Mi JH, et al (2020)

Peptidyl arginine deiminase 4 and its potential role in Alzheimer's disease.

Medical hypotheses, 146:110466 pii:S0306-9877(20)33357-0 [Epub ahead of print].

Alzheimer's disease (AD) is the main cause of dementia, and its pathogenesis is still not clear. Peptidyl arginine deiminases 4(PAD4) as one of the important members of PAD family, is the only protein with nuclear transfer function, it can regulate the expression of many proteins through citrullinating histone. PAD4 can also interact with many transcription factors, involved in regulating gene expression. PAD4 expression is closely related to the inflammatory factors secreted, cell autophagy, tumorigenesis and other neurodegenerative diseases. More importantly, PAD4 and its citrullinated protein were found in cortical and hippocampal neurons of AD patients. To study the expression and regulatory pathway of PAD4 in vivo and in vitro experiments on AD may be of helpful to elucidate the pathogenesis of AD. Meanwhile, detection of anti-citrullinated antibody will have potential value as novel biomarkers of AD.

RevDate: 2021-01-07

Day GS, Gordon BA, McCullough A, et al (2021)

Flortaucipir (tau) PET in LGI1 antibody encephalitis.

Annals of clinical and translational neurology [Epub ahead of print].

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [18 F]flortaucipir PET neuroimaging associated with persistent cognitive impairment and hippocampal atrophy in four recovering LGI1 patients (3 men; median age, 67 [37-88] years). Imaging findings in cases were compared with those observed in age- and gender-similar cognitively normal individuals (n = 124) and individuals with early-symptomatic Alzheimer disease (n = 11). Elevated [18 F]flortaucipir retention was observed in the two LGI1 patients with hippocampal atrophy and persistent cognitive impairment, including one with autopsy-confirmed Alzheimer disease. Tau neuropathology may associate with cognitive complaints and hippocampal atrophy in recovering LGI1 patients.

RevDate: 2021-01-07

Herr M, Ankri J, Diard C, et al (2021)

Removal of Drugs for Alzheimer's Disease from the List of Reimbursable Drugs in France: Analysis of Change in Drug Use, Disease Management and Cognition Using the National Alzheimer Data Bank (BNA).

Drugs & aging [Epub ahead of print].

BACKGROUND: Because of insufficient data about their benefit-risk ratio in real life, drugs used for Alzheimer's disease (AD; cholinesterase inhibitors and memantine) were withdrawn from the list of reimbursable drugs in France on 1 August 2018.

OBJECTIVES: In this context, this study aimed to investigate the effects of the removal of AD drugs from the list of reimbursed drugs among patients followed in memory centres in France, in terms of prevalence and factors associated with drug discontinuation and evolution of disease management and cognition after drug discontinuation.

METHODS: This is an observational study based on data from the National Alzheimer Data Bank ('Banque Nationale Alzheimer' [BNA]), which centralizes information about patients consulting in memory centres. The drug discontinuation rate was estimated among patients receiving AD drugs at the last visit before the end of reimbursement. Factors associated with drug discontinuation were investigated among sociodemographic and disease characteristics, as well as among the use of healthcare resources before the end of reimbursement. We compared the evolution of disease management (psychotropic drugs and non-pharmacological interventions) and Mini-Mental State Examination (MMSE) score during the year following the end of reimbursement among patients with a diagnosis of AD.

RESULTS: Among the 19,380 patients of the study sample (62.5% females, mean age 81 years, 86.8% with a diagnosis of AD), 19.5% discontinued their treatment after the end of reimbursement. The main factors associated with drug discontinuation were the type of dementia and lower MMSE level. Compared with patients with a diagnosis of AD, those with vascular dementia were more likely to stop their treatment, whereas those with dementia with Lewy bodies were less likely to discontinue. Among patients with a diagnosis of AD, drug discontinuation was associated with increased use of psychotropic medications, especially antidepressants, and non-pharmacological interventions afterwards, but there was no difference regarding the evolution of MMSE score.

CONCLUSION: This study provides real-life information about the use of AD drugs after they were withdrawn from reimbursement in France and shows that drug discontinuation was limited among patients followed in memory centres and accompanied by increased use of other healthcare resources.

RevDate: 2021-01-07

Zhuang J, Chen Z, Cai P, et al (2020)

Targeting MicroRNA-125b Promotes Neurite Outgrowth but Represses Cell Apoptosis and Inflammation via Blocking PTGS2 and CDK5 in a FOXQ1-Dependent Way in Alzheimer Disease.

Frontiers in cellular neuroscience, 14:587747.

This study aimed to explore the molecular regulatory network among microRNA-125b (miR-125b), forkhead box Q1 (FOXQ1), prostaglandin-endoperoxide synthase 2 (PTGS2), and cyclin-dependent kinase 5 (CDK5), as well as their effects on cell apoptosis, neurite outgrowth, and inflammation in Alzheimer disease (AD). Rat embryo cerebral cortex neurons and nerve growth factor-stimulated PC12 cells were insulted by Aβ1-42 to construct two AD cellular models. Negative control (NC) inhibitor, miR-125b inhibitor, NC siRNA, FOXQ1 siRNA, PTGS2 siRNA, and CDK5 siRNA were transferred into the two AD cellular models alone or combined. Then, cell apoptosis, neurite outgrowth, proinflammatory cytokines, miR-125b, FOXQ1, PTGS2, and CDK5 expressions were detected. MiR-125b inhibition facilitated neurite outgrowth but suppressed cell apoptosis and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1β, and interleukin 6); meanwhile, it upregulated FOXQ1 but downregulated PTGS2 and CDK5. Furthermore, FOXQ1 inhibition promoted cell apoptosis and proinflammatory cytokines but repressed neurite outgrowth; PTGS2 inhibition achieved the opposite effects; CDK5 inhibition attenuated cell apoptosis, whereas it less affected neurite outgrowth and inflammation. Notably, FOXQ1 inhibition attenuated, whereas PTGS2 inhibition elevated the effect of miR-125b inhibition on regulating neurite outgrowth, cell apoptosis, and proinflammatory cytokines. As for CDK5 inhibition, it enhanced the effect of miR-125b inhibition on regulating cell apoptosis, but less impacted the neurite outgrowth and proinflammatory cytokines. Additionally, PTGS2 inhibition and CDK5 inhibition both reversed the effect of FOXQ1 inhibition on regulating cell apoptosis, neurite outgrowth, and proinflammatory cytokines. In conclusion, targeting miR-125b alleviates AD progression via blocking PTGS2 and CDK5 in a FOXQ1-dependent way.

RevDate: 2021-01-07

Blazhenets G, Frings L, Ma Y, et al (2021)

Validation of the Alzheimer Disease Dementia Conversion-Related Pattern as an ATN Biomarker of Neurodegeneration.

Neurology pii:WNL.0000000000011521 [Epub ahead of print].

OBJECTIVE: To determine whether the Alzheimer's disease dementia conversion-related pattern (ADCRP) on [18F]FDG PET can serve as a valid predictor for the development of Alzheimer's disease dementia, the individual expression of the ADCRP (subject score) and its prognostic value were examined in subjects with mild cognitive impairment and biologically defined Alzheimer's disease.

METHODS: 269 subjects with available [18F]FDG PET, [18F]AV-45 PET, phosphorylated and total tau in CSF, and neurofilament light chain in plasma were included. Following the AT(N) classification scheme, where Alzheimer's disease is defined biologically by in vivo biomarkers of Aβ deposition ("A") and pathological tau ("T"), subjects were categorized to the A-T-, A+T-, A+T+ (Alzheimer's disease), and A-T+ groups.

RESULTS: The mean subject score of the ADCRP was significantly higher in the A+T+ group compared to each of the other group (all p < 0.05) but was similar among the latter (all p > 0.1). Within the A+T+ group, the subject score of ADCRP was a significant predictor of conversion to dementia (HR = 2.02 per z-score increase, p < 0.001), with higher predictive value than of alternative biomarkers of neurodegeneration (total tau and neurofilament light chain). Stratification of A+T+ subjects by the subject score of ADCRP yielded well-separated groups of high, medium, and low conversion risks.

CONCLUSIONS: The ADCRP is a valuable biomarker of neurodegeneration in subjects with mild cognitive impairment and biologically defined Alzheimer's disease. It shows great potential for stratifying the risk and estimating the time to conversion to dementia in subjects with mild cognitive impairment and underlying Alzheimer's disease (A+T+).

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that [18F]FDG PET predicts the development of AD dementia in individuals with MCI and underlying AD as defined by the AT(N) framework.

RevDate: 2021-01-07

Trelle AN, Carr VA, Wilson EN, et al (2021)

Association of CSF Biomarkers with Hippocampal-dependent Memory in Preclinical Alzheimer Disease.

Neurology pii:WNL.0000000000011477 [Epub ahead of print].

OBJECTIVE: To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer's disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).

METHODS: CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied 'target' objects, novel 'foil' objects, and perceptually similar 'lure' objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.

RESULTS: Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.

CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

RevDate: 2021-01-07

Kim YJ, Kim SM, Jeong DH, et al (2021)

Associations between metabolic syndrome and type of dementia: analysis based on the National Health Insurance Service database of Gangwon province in South Korea.

Diabetology & metabolic syndrome, 13(1):4.

BACKGROUND: Metabolic syndrome is a cluster of conditions that occur together, increasing the risk of cardiovascular disease. However, the relationship between metabolic syndrome and dementia has remained controversial. Using nationwide population cohort data, we investigated the association between metabolic syndrome and dementia, according to the dementia type.

METHODS: We analyzed data of 84,144 individuals, in the aged group of more than 60 years, between January 1, 2009, to December 31, 2009, at Gangwon province by using the information of the (Korean) National Health Insurance Service. After eight years of gap, in 2017, we investigated the relationship between metabolic syndrome and dementia. We classified Dementia either as dementia of the Alzheimer type (AD) or vascular dementia (VD). AD and VD were defined as per the criteria of International Classification of Disease, Tenth Revision, Clinical Modification codes. Multiple logistic regression analyses examined the associations between metabolic syndrome or five metabolic syndrome components and dementia. Analyses included factors like age, sex, smoking, alcohol, physical inactivity, previous stroke, and previous cardiac disease.

RESULTS: Metabolic syndrome was associated with AD (OR = 11.48, 95% CI 9.03-14.59), not with VD. Each of five components of metabolic syndrome were also associated with AD. (high serum triglycerides: OR = 1.87, 95% CI 1.60-2.19; high blood pressure: OR = 1.85, 95% CI 1.55-2.21; high glucose: OR = 1.77, 95% CI 1.52-2.06; abdominal obesity: OR = 1.88, 95% CI 1.57-2.25; low serum high-density lipoprotein cholesterol: OR = 1.91, 95% CI 1.63-2.24) However, among components of metabolic syndrome, only the high glucose level was associated with VD. (OR = 1.26, 95% CI 1.01-1.56) body mass index (BMI), fasting glucose, and smoking were also associated with AD. (BMI: OR = 0.951, 95% CI 0.927-0.975; fasting glucose: OR = 1.003, 95% CI 1.001-1.005; smoking: OR = 1.020, 95% CI 1.003-1.039) A history of the previous stroke was associated with both AD and VD. (AD: OR = 1.827, 95% CI 1.263-2.644; VD: OR 2.775, 95% CI 1.747-4.406) CONCLUSIONS: Metabolic syndrome was associated with AD but not with VD. Patients with metabolic syndrome had an 11.48 times more likeliness to develop AD compared to those without metabolic syndrome. VD was associated only with several risk factors that could affect the vascular state rather than a metabolic syndrome. We suggested that the associations between metabolic syndrome and dementia would vary depending on the type of dementia.

RevDate: 2021-01-06

Abu Almaaty AH, Mosaad RM, Hassan MK, et al (2021)

Urtica dioica extracts abolish scopolamine-induced neuropathies in rats.

Environmental science and pollution research international pii:10.1007/s11356-020-12025-y [Epub ahead of print].

Alzheimer's disease (AD) is characterized by alterations in monoamines, oxidative stress, and metabolic dysfunctions. We aim to assess the therapeutic impacts of roots or leaf extract from Urtica dioica (UD; stinging nettle) against scopolamine (SCOP)-induced memory dysfunction, amnesia, and oxidative stress in rats. Spatial memory was assessed by Y maze test. Tissue analyses of norepinephrine (NE), dopamine (DA), serotonin (5-HT), malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH, GSSG), AMP, ADP, and ATP were assessed by HPLC. mRNA levels of Tau and Hsp70 were estimated by PCR. UD extracts particularly nettle root (NR) significantly normalized the SCOP-induced memory deficits even more potent than sermion (SR) and donepezil (DON). Similarly, NR had potent therapeutic impacts on the levels of cortical and hippocampal monoamines e.g. DA, NE, and 5-HT. SCOP induced a dramatic oxidative stress as measured by MDA, NO, and GSSG levels; however, UD extracts showed significant anti-oxidative stress impacts. Additionally, UD extracts restored ATP levels and reduced the levels of AMP and ADP compared to SCOP-treated rats. Furthermore, cortical Tau and hippocampal Hsp70 were modulated by UD extracts particularly NR compared to the SCOP group. In conclusion, UD extracts particularly roots have potential therapeutic impacts against SCOP-induced neuroinflammatory and/or Alzheimer-like phenotype in rats.

RevDate: 2021-01-07

Rivera-Rodriguez C, Cheung G, S Cullum (2021)

Using Big Data to Estimate Dementia Prevalence in New Zealand: Protocol for an Observational Study.

JMIR research protocols, 10(1):e20225 pii:v10i1e20225.

BACKGROUND: Dementia describes a cluster of symptoms that includes memory loss; difficulties with thinking, problem solving, or language; and functional impairment. Dementia can be caused by a number of neurodegenerative diseases, such as Alzheimer disease and cerebrovascular disease. Currently in New Zealand, most of the systematically collected and detailed information on dementia is obtained through a suite of International Residential Assessment Instrument (interRAI) assessments, including the home care, contact assessment, and long-term care facility versions. These versions of interRAI are standardized comprehensive geriatric assessments. Patients are referred to have an interRAI assessment by the Needs Assessment and Service Coordination (NASC) services after a series of screening processes. Previous estimates of the prevalence and costs of dementia in New Zealand have been based on international studies with different populations and health and social care systems. This new local knowledge will have implications for estimating the demographic distribution and socioeconomic impact of dementia in New Zealand.

OBJECTIVE: This study investigates the prevalence of dementia, risk factors for dementia, and drivers of the informal cost of dementia among people registered in the NASC database in New Zealand.

METHODS: This study aims to analyze secondary data routinely collected by the NASC and interRAI (home care and contact assessment versions) databases between July 1, 2014, and July 1, 2019, in New Zealand. The databases will be linked to produce an integrated data set, which will be used to (1) investigate the sociodemographic and clinical risk factors associated with dementia and other neurological conditions, (2) estimate the prevalence of dementia using weighting methods for complex samples, and (3) identify the cost of informal care per client (in number of hours of care provided by unpaid carers) and the drivers of such costs. We will use design-based survey methods for the estimation of prevalence and generalized estimating equations for regression models and correlated and longitudinal data.

RESULTS: The results will provide much needed statistics regarding dementia prevalence and risk factors and the cost of informal care for people living with dementia in New Zealand. Potential health inequities for different ethnic groups will be highlighted, which can then be used by decision makers to inform the development of policy and practice.

CONCLUSIONS: As of November 2020, there were no dementia prevalence studies or studies on informal care costs of dementia using national data from New Zealand. All existing studies have used data from other populations with substantially different demographic distributions. This study will give insight into the actual prevalence, risk factors, and informal care costs of dementia for the population with support needs in New Zealand. It will provide valuable information to improve health outcomes and better inform policy and planning.

DERR1-10.2196/20225.

RevDate: 2021-01-06

Klibanov AL (2021)

Early-Stage Alzheimer Disease Image-guided Therapy Clinical Trial Serendipity: Glymphatic Efflux and Prolonged Meningeal Venous Permeability Enhancement.

RevDate: 2021-01-06

Wani A, Al Rihani SB, Sharma A, et al (2021)

Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway.

Autophagy [Epub ahead of print].

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aβ clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aβ levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.

RevDate: 2021-01-06

Taudte N, Linnert M, Rahfeld JU, et al (2021)

Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis.

The Journal of biological chemistry pii:RA120.016836 [Epub ahead of print].

The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded β-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.

RevDate: 2021-01-06

Shafik AM, Zhang F, Guo Z, et al (2021)

N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.

Genome biology, 22(1):17.

BACKGROUND: N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain.

RESULTS: We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer's disease, which is correlated with reduced protein levels.

CONCLUSIONS: Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer's disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

RevDate: 2021-01-05

Mehta RI, Carpenter JS, Mehta RI, et al (2021)

Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease.

Radiology [Epub ahead of print].

Background Opening of the blood-brain barrier (BBB) induced with MRI-guided focused ultrasound has been shown in experimental animal models to reduce amyloid-β plaque burden, improve memory performance, and facilitate delivery of therapeutic agents to the brain. However, physiologic effects of this procedure in humans with Alzheimer disease (AD) require further investigation. Purpose To assess imaging effects of focused ultrasound-induced BBB opening in the hippocampus of human participants with early AD and to evaluate fluid flow patterns after BBB opening by using serial contrast-enhanced MRI. Materials and Methods Study participants with early AD recruited to a Health Insurance Portability and Accountability Act-compliant, prospective, ongoing phase II clinical trial (ClinicalTrials.gov identifier, NCT03671889) underwent three separate focused ultrasound-induced BBB opening procedures that used a 220-kHz transducer with a concomitant intravenous microbubble contrast agent administered at 2-week intervals targeting the hippocampus and entorhinal cortex between October 2018 and May 2019. Posttreatment effects and gadolinium-based contrast agent enhancement patterns were evaluated by using 3.0-T MRI. Results Three women (aged 61, 72, and 73 years) consecutively enrolled in the trial successfully completed repeated focused ultrasound-induced BBB opening of the hippocampus and entorhinal cortex. Postprocedure contrast enhancement was clearly identified within the targeted brain volumes, indicating immediate spatially precise BBB opening. Parenchymal enhancement resolved within 24 hours after all treatments, confirming BBB closure. Transient perivenous enhancement was consistently observed during the acute phase after BBB opening. Notably, contrast enhancement reappeared in the perivenular regions after BBB closure. This imaging marker is consistent with blood-meningeal barrier permeability and persisted for 24-48 hours before spontaneous resolution. No evidence of intracranial hemorrhage or other adverse effect was identified. Conclusion MRI-guided focused ultrasound-induced blood-brain barrier opening was safely performed in the hippocampi of three participants with Alzheimer disease without any adverse effects. Posttreatment MRI reveals a unique spatiotemporal contrast enhancement pattern that suggests a perivenular immunologic healing response downstream from targeted sites. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Klibanov in this issue.

RevDate: 2021-01-05

Jonathan MC, Adrián SH, A Gonzalo (2021)

Type II nuclear receptors with potential role in Alzheimer disease.

Molecular aspects of medicine pii:S0098-2997(20)30142-4 [Epub ahead of print].

Nuclear receptors are ligand-activated transcription factors that can modulated cellular processes involved in the development, homeostasis, cell proliferation, metabolism, and reproduction through the control of the specific genetic and molecular program. In the central nervous system, they are key regulators of neural stem cell fate decisions and can modulate the physiology of different brain cells. Over the past decades, a large body of evidence has supported that nuclear receptors are potential therapeutic targets for the treatment of neurodegenerative disorders such as Alzheimer's disease, the most common dementia worldwide, and the main cause of disability in later life. This disease is characterized by the progressive accumulation of amyloid-beta peptides and hyperphosphorylated tau protein that can explain alterations in synaptic transmission and plasticity; loss of dendritic spines; increased in reactive microglia and inflammation; reduction of neuronal stem cells number; myelin and vascular alterations that finally leads to increased neuronal death. Here, we present a review of type II no steroidal nuclear receptors that form obligatory heterodimers with the Retinoid X Receptor (RXR) and its potential in the therapeutic of AD. Activation of type II nuclear receptor by synthetic agonist leads to transcriptional regulation of specific genes that acts counteracting against the detrimental effects of amyloid-beta peptides and hyperphosphorylated tau in neuronal cells recovering the functionality of the synapses. But also, activation of type II nuclear receptor leads to modifications in APP metabolism, repression of inflammatory cascade and inductors of the generation of neuronal stem cells and progenitor cells supporting its potential therapeutics role for Alzheimer's disease.

RevDate: 2021-01-05

Kaur I, Kumar A, Behl T, et al (2021)

Recent Advances in Nanotechnology-Based Drug Delivery Approaches for Alzheimer disease.

Current drug targets pii:CDT-EPUB-113032 [Epub ahead of print].

One of the most common form of neurodegenerative disorders, Alzheimer's disease poses a great threat to the patients all over the globe with about 5.7 million cases estimated by the Alzheimer's Association Report of 2018. The disorder is a result of β-amyloid deposition in the brain, deteriorating the cognitive ability and learning processes, commonly in geriatric patients. The review significantly elaborates the superiority of nanotechnological formulations over conventional therapeutic strategies which exhibit numerous side effects, poor pharmacokinetic profiles and limited efficacy, as compared to the nano-medicinal approach. The review recognizes the need to establish an understanding of the transport mechanisms across the blood brain barrier, prior to the nanoparticle studies, followed by discussion on various nano-formulations, evi-dently supported by the outcome of various studies conducted to investigate the drug delivery portfolio of nanomedicines. Furthermore, the review portrays the challenges to overcome in future studies, like nanoparticle fabrication, drug loading capacity, blood residency time, toxicity regime, monitoring long term effects, in-vivo compatibility and production tech-niques, in order to enable the development of an optimized form of drug delivery process, which would achieve significant heights in the biomedical applications and bring about a revolution in the field of medicine and science.

RevDate: 2021-01-05

Fernández-Fierro A, Funes SC, Rios M, et al (2020)

Immune Modulation by Inhibitors of the HO System.

International journal of molecular sciences, 22(1): pii:ijms22010294.

The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.

RevDate: 2021-01-05

Dincer A, Gordon BA, Hari-Raj A, et al (2020)

Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease.

NeuroImage. Clinical, 28:102491.

Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.

RevDate: 2021-01-05

de Rochemonteix M, Napolioni V, Sanyal N, et al (2021)

A Likelihood Ratio Test for Gene-Environment Interaction Based on the Trend Effect of Genotype Under an Additive Risk Model Using the Gene-Environment Independence Assumption.

American journal of epidemiology, 190(1):129-141.

Several statistical methods have been proposed for testing gene-environment (G-E) interactions under additive risk models using data from genome-wide association studies. However, these approaches have strong assumptions from underlying genetic models, such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aimed to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose 2 sets of constraints for: 1) the linear trend effect of genotype and 2) the additive joint effects of gene and environment. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5-fold. We applied the proposed methods to examine the gene-smoking interaction for lung cancer and gene-apolipoprotein E $\varepsilon$4 interaction for Alzheimer disease, which identified 2 interactions between apolipoprotein E $\varepsilon$4 and loci membrane-spanning 4-domains subfamily A (MS4A) and bridging integrator 1 (BIN1) genes at genome-wide significance that were replicated using independent data.

RevDate: 2021-01-04

Zhao J, Jin X, Chen B, et al (2021)

Apathy symptoms increase the risk of dementia conversion: a case-matching cohort study on patients with post-stroke mild cognitive impairment in China.

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society [Epub ahead of print].

BACKGROUND: Apathy is a neuropsychiatric symptom frequently observed in patients with cognitive impairment. It has been found to be a predictor of conversion from mild cognitive impairment (MCI) to dementia of Alzheimer disease type. However, this association between apathy and dementia conversion has not yet been confirmed in vascular MCI, especially post-stroke MCI. The aim of this study was to evaluate whether apathy would increase the risk of dementia conversion in patients with post-stroke MCI after 6 months.

METHOD: A prospective multi-centre cohort study was performed in 14 clinics in seven provinces and cities of China. A total of 989 subjects were included 2 weeks to 6 months after stroke, and met the diagnostic criteria of International Working Group for MCI. Symptoms of apathy were assessed using the apathy subscale of Geriatric Depression Scale. Subjects were divided into an apathy group (n = 128) and a non-apathy group (n = 861). The primary outcome was the dementia conversion after 6 months. To eliminate potential biases, subjects were chosen from 861 non-apathy patients with similarity in seven potential predictors of cognitive impairment to match with the apathy group (n = 128) at a 1:1 ratio, as a matched non-apathy group (n = 128). The dementia conversion rate was compared between the apathy group (n = 128) and its correspondingly matched non-apathy group (n = 128), and the relative risk (RR) was calculated.

RESULTS: The prevalence of apathy in post-stroke MCI was 12.9%. After 6 months, 5.2% of patients with post-stroke MCI converted to dementia. The dementia conversion rate of the apathy group was significantly higher than that of the non-apathy group before case-matching (17.2% vs 3.4%, P < 0.001), and also after case-matching (17.2% vs 6.3%, P < 0.001). Symptoms of apathy increased the risk of conversion from MCI to dementia (RR 2.75, 95% CI 1.272-5.947, P < 0.001).

CONCLUSIONS: For patients with post-stroke MCI, apathy symptoms increase the risk of conversion from MCI to dementia.

RevDate: 2021-01-04

Titov AA, Kobzev MS, Catto M, et al (2021)

Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents.

ACS chemical neuroscience [Epub ahead of print].

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.

RevDate: 2021-01-04

Largent EA, Wexler A, J Karlawish (2021)

The Future Is P-Tau-Anticipating Direct-to-Consumer Alzheimer Disease Blood Tests.

JAMA neurology pii:2774173 [Epub ahead of print].

RevDate: 2021-01-04

Zhou Y, Chen Y, Xu C, et al (2020)

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment.

Frontiers in neuroscience, 14:602508.

Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)-a key component of the innate immune system-in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.

RevDate: 2021-01-04

Harrison AT, McAllister T, McCrea M, et al (2020)

Recovery Profiles after Concussion among Male Student-Athletes and Service Cadets with a Family History of Neurodegenerative Disease: Data from the NCAA-DoD CARE Consortium.

Journal of neurotrauma [Epub ahead of print].

Preliminary evidence indicates that genetic factors associated with having a family history of neurodegenerative disease (fhNDD) may predispose an individual to persistent symptoms and poorer cognitive performance after concussion. No previous study, however, longitudinally examined athletes with (+) and without (-) a fhNDD. Therefore, we aimed to compare clinical symptoms and cognitive performance of fhNDD+ and fhNDD- athletes at baseline and at multiple time points after concussion. Questionnaire data from the Concussion Assessment, Research and Education (CARE) Consortium were used to identify male athletes and cadets with (n = 51) and without (n = 102) a fhNDD (Alzheimer disease, Parkinson disease, mild cognitive impairment, and non-Alzheimer dementia). All athletes completed the SCAT3 symptom checklist and ImPACT test before their sport season and again within 24-48 h of injury, at the unrestricted return-to-play, and at six months post-concussion. Compared with fhNDD-, fhNDD+ individuals demonstrated greater decrements in visual memory (relative to baseline) 24-48 h post-injury (p < 0.05, d = 0.18). In addition, a main effect of group was observed for impulse control. Compared with fhNDD- athletes, fhNDD+ individuals demonstrated greater decrements in impulse control, 24-48 h post-injury, at the return to play, and at six-month assessments (p < 0.01, d = 0.23). These findings suggest that male athletes with a fhNDD may exhibit greater decrements in cognitive performance after concussion. Small, subtle deficits in cognitive performance may still significantly hinder day-to-day function in student-athletes.

RevDate: 2021-01-04

Propson NE, Roy ER, Litvinchuk A, et al (2021)

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging.

The Journal of clinical investigation, 131(1):.

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.

RevDate: 2021-01-02

Carazo-Barrios L, Archidona-Arranz A, Claros-Ruiz A, et al (2021)

Correlation between retinal nerve fibre layer thickness and white matter lesions in Alzheimer's disease.

International journal of geriatric psychiatry [Epub ahead of print].

OBJECTIVES: Early diagnosis in Alzheimer's disease (AD) is crucial in order to implement new therapeutic strategies. The retina is embryologically related to the brain. Thus, the possible usefulness of optical coherence tomography (OCT) in the early detection of AD is currently being studied. Our aim was to study the relationship between retinal nerve fiber layer (RNFL) thickness and AD.

METHODS: We undertook an observational, analytical, cross-sectional study with consecutive sampling of 32 patients with AD or mild cognitive impairment (MCI) and a group of healthy controls (C). The total number of eyes studied was 64. An ophthalmological and a comprehensive neuropsychological evaluation were performed in all participants. Quantification of white matter lesions and study of atrophy of the hippocampus by cerebral magnetic resonance were also performed.

RESULTS: We observed a significant linear trend towards a thinning of RNFL as the degree of cognitive deterioration increased, in the superior and temporal quadrants of the retina. A significant correlation was also noted between the mean thickness of the RNFL of the left temporal quadrant and occipital white matter lesions (r = -0.579, p = 0.038).

CONCLUSIONS: OCT could be a safe, rapid non-invasive tool providing useful biomarkers in the early detection of cognitive deterioration and AD. This article is protected by copyright. All rights reserved.

RevDate: 2021-01-01

Biechele G, Wind K, Blume T, et al (2020)

Microglial Activation in the Right Amygdala-Entorhinal-Hippocampal Complex is Associated with Preserved Spatial Learning in AppNL-G-F mice.

NeuroImage pii:S1053-8119(20)31192-7 [Epub ahead of print].

BACKGROUND: In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo.

METHODS: In 30 AppNL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, 18F-GE-180) and β-amyloid-PET (18F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in AppNL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance.

RESULTS: Voxel-wise analyses in AppNL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning.

CONCLUSION: Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of AppNL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.

RevDate: 2021-01-02

Tsai CL, Erickson KI, Sun HS, et al (2020)

A cross-sectional examination of a family history of Alzheimer's disease and ApoE epsilon 4 on physical fitness, molecular biomarkers, and neurocognitive performance.

Physiology & behavior, 230:113268 pii:S0031-9384(20)30582-5 [Epub ahead of print].

PURPOSE: The present study examined whether the ɛ4 allele of the apolipoprotein E (ApoE) gene impacts molecular biomarkers and neurocognitive performance among individuals at genetic risk for developing Alzheimer's disease (AD). The correlations between physical fitness and molecular/neurocognitive indices were also explored.

METHODS: Fasting blood samples were collected from 162 individuals with a family history of AD (ADFH). There were twenty-two carriers of the ApoE-4 variant (ApoE-4 group). For comparison purposes we randomly selected 22 non-ɛ4 carriers (non-ApoE-4 group) from the ADFH individuals. Circulating inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-8, and IL-15), neuroprotective growth factors (e.g., BDNF, IGF-1, IGF-2, VEGF, and FGF-2), and Amyloid-β peptides (e.g., Aβ1-40 and Aβ1-42), neurocognitive performance [e.g., behavior and brain even-related potentials (ERP)] during a task-switching paradigm, as well as physical fitness scores were measured.

RESULTS: The ApoE-4 group relative to the non-ApoE-4 group was similar with respect to molecular biomarkers, physical fitness, and most measures of neurocognitive performance. However, ADFH individuals that were ɛ4 carriers exhibited significantly higher local switching accuracy costs, worse accuracy as well as smaller ERP P3 amplitudes for the memory-switching condition. Importantly, cardiorespiratory fitness levels were significantly correlated with accuracy for most task-switching conditions, and levels of BDNF, Aβ1-40, and Aβ1-42 collapsed across the two groups even when controlling for the age co-variable, while the ApoE-4 group revealed similar pattern of results.

CONCLUSIONS: These data suggest that individuals with ADFH that were carriers of the ApoE-4 variant performed worse on the task-switching paradigm and that this could be due to compromised task-set and memory updating processes. Physical exercise interventions aimed to enhance cardiorespiratory fitness levels could be a potential AD prevention strategy for ameliorating cognitive function and reducing the accumulation of the Aβ peptides in this high risk group.

RevDate: 2020-12-31

Zhang X, Mei Y, He Y, et al (2020)

Ablating Adult Neural Stem Cells Improves Synaptic and Cognitive Functions in Alzheimer Models.

Stem cell reports pii:S2213-6711(20)30497-5 [Epub ahead of print].

Adult neurogenesis is impaired in the hippocampus of patients with Alzheimer disease (AD) as well as AD models. However, it is far from clear how modulating adult neurogenesis affects AD neuropathology. We confirm that adult hippocampal neurogenesis is impaired in two AD models. Surprisingly, however, cognitive functions are improved in AD models after ablating adult neural stem cells (aNSCs). Ablation of aNSCs does not affect the levels of amyloid β but restores the normal synaptic transmission in the dentate gyrus (DG) granule cells of AD models. Furthermore, calbindin depletion in the DG of AD mice is ameliorated after aNSC ablation, and knocking down calbindin abolishes the effects of aNSC ablation on synaptic and cognitive functions of AD mice. Together, our data suggest that cognitive functions of AD mice are improved after aNSC ablation, which is associated with the restoration of synaptic transmission in the DG granule cells with calbindin as an important mediator.

RevDate: 2020-12-31

Lacerda IB, Santos RL, Belfort T, et al (2020)

Domains of awareness in Alzheimer's disease: the influence of executive function.

International journal of geriatric psychiatry [Epub ahead of print].

OBJECTIVE: Awareness is a developing area in dementia research and the evaluation of its domains has been increasingly included as part of care for people with Alzheimer's Disease (PwAD). Our aim is to examine whether executive dysfunction is associated with awareness domains.

METHODS: A consecutive series of 75 people with mild-to-moderate AD completed assessments about global cognitive function, executive functioning, and their awareness of disease. Their primary caregivers' dyad provided information about demographics, awareness of disease, dementia severity, neuropsychiatric symptoms, and functional status.

RESULTS: Different types of executive dysfunction were presented as a predictor for awareness of disease (cognitive flexibility, inhibitory control, and working memory), of emotional state (short-term memory and attention) and of social functioning and relationships (visuospatial organization, integrative functions, and abstract thinking). Awareness of cognitive functioning and health condition and of functional activity impairments exhibit only global cognitive function as a predictor.

CONCLUSIONS: Findings confirm some degree of independence between awareness domains. The importance of identifying differences in domains of awareness relies in the understanding of awareness as a clinical phenomenon in order to guide the management and support of PwAD and their caregivers. This article is protected by copyright. All rights reserved.

RevDate: 2020-12-31

Lee YH, Im E, Hyun M, et al (2020)

Protein phosphatase PPM1B inhibits DYRK1A kinase through dephosphorylation of pS258 and reduces toxic tau aggregation.

The Journal of biological chemistry pii:RA120.015574 [Epub ahead of print].

Down syndrome (DS) is mainly caused by an extra copy of chromosome 21 (trisomy 21), and patients display a variety of developmental symptoms, including characteristic facial features, physical growth delay, intellectual disability, and neurodegeneration (i.e., Alzheimer's disease; AD). One of the pathological hallmarks of AD is insoluble deposits of neurofibrillary tangles (NFTs) that consist of hyperphosphorylated tau. The human DYRK1A gene is mapped to chromosome 21, and the protein is associated with the formation of inclusion bodies in AD. For example, DYRK1A directly phosphorylates multiple serine and threonine residues of tau, including Thr212. However, the mechanism underpinning DYRK1A involvement in Trisomy 21-related pathological tau aggregation remains unknown. Here, we explored a novel regulatory mechanism of DYRK1A and subsequent tau pathology through a phosphatase. Using LC-MS/MS technology we analyzed multiple DYRK1A-binding proteins, including PPM1B, a member of the PP2C family of Ser/Thr protein phosphatases, in HEK293 cells. We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity. Moreover, PPM1B-mediated dephosphorylation of DYRK1A reduced tau phosphorylation at Thr212, leading to inhibition of toxic tau oligomerization and aggregation. In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity. This finding also suggests that PPM1B reduces the toxic formation of phospho-tau protein via DYRK1A modulation, possibly providing a novel cellular protective mechanism to regulate toxic tau-mediated neuropathology in AD of DS.

RevDate: 2020-12-31

Taleski G, Schuhmacher D, Su H, et al (2020)

Disturbances in PP2A methylation and one-carbon metabolism compromise Fyn distribution, neuritogenesis and APP regulation.

The Journal of biological chemistry pii:RA120.016069 [Epub ahead of print].

The nonreceptor protein tyrosine kinase Fyn and protein Ser/Thr phosphatase 2A (PP2A) are major multifunctional signaling molecules. Deregulation of Fyn and altered PP2A methylation are implicated in cancer and Alzheimer disease (AD). Here, we tested the hypothesis that the methylation state of PP2A catalytic subunit, which influences PP2A subunit composition and substrate specificity, can affect Fyn regulation and function. Using N2a neuroblastoma cell models, we first show that methylated PP2A holoenzymes containing the Bα subunit co-immunoprecipitate and co-purify with Fyn in membrane rafts. PP2A methylation status regulates Fyn distribution and Fyn-dependent neuritogenesis, likely in part by affecting actin dynamics. A methylation incompetent PP2A mutant fails to interact with Fyn. It perturbs the normal partitioning of Fyn and amyloid precursor protein (APP) in membrane microdomains, which governs Fyn function and APP processing. This correlates with enhanced amyloidogenic cleavage of APP, a hallmark of AD pathogenesis. Conversely, enhanced PP2A methylation promotes the nonamyloidogenic cleavage of APP in a Fyn-dependent manner. Disturbances in one-carbon metabolic pathways that control cellular methylation are associated with AD and cancer. Notably, they induce a parallel loss of membrane-associated methylated PP2A and Fyn enzymes in N2a cells and acute mouse brain slices. One-carbon metabolism also modulates Fyn-dependent process outgrowth in N2a cells. Thus, our findings identify a novel methylation dependent PP2A/Fyn signaling module. They highlight the underestimated importance of crosstalks between essential metabolic pathways and signaling scaffolds that are involved in normal cell homeostasis and currently being targeted for cancer and AD treatment.

RevDate: 2020-12-30

He P, Schulz P, MR Sierks (2020)

A conformation specific antibody against Oligomeric β-Amyloid Restores Neuronal Integrity in a Mouse Model of Alzheimer's Disease.

The Journal of biological chemistry pii:RA120.015327 [Epub ahead of print].

Conformationally distinct aggregates of the Amyloid β (Aβ) peptide accumulate in brains of Alzheimer's disease (AD) patients, but the roles of the different aggregates in disease progression are not clear. We previously isolated two single-chain variable domain antibody fragments (scFvs), C6T and A4, that selectively bind different toxic conformational variants of oligomeric Aβ. Here we utilize these scFvs to localize the presence of these Aβ variants in human AD brain and to demonstrate their potential as therapeutic agents for treating AD. Both A4 and C6T label oligomeric Aβ in extracellular amyloid plaques, while C6T also labels intracellular oligomeric Aβ in human AD brain tissue and in an AD mouse model. For therapeutic studies, the A4 and C6T scFvs were expressed in the AD mice by viral infection of liver cells. The scFvs were administered at 2 months of age and mice sacrificed at 9 months. The scFvs contained a peptide tag to facilitate transport across the blood brain barrier. While treatment with C6T only slightly decreased Aβ deposits and plaque-associated inflammation, it restored neuronal integrity to wild-type levels, significantly promoted growth of new neurons, and impressively rescued survival rates to wild type levels. Treatment with A4 on the other hand significantly decreased Aβ deposits, but did not significantly decrease neuroinflammation or promote neuronal integrity, neurogenesis or survival rate. These results suggest that the specific Aβ conformation targeted in therapeutic applications greatly affects the outcome, and the location of the targeted Aβ variants may also play a critical factor.

RevDate: 2020-12-30

Arroyo-Anlló EM, Souchaud C, Ingrand P, et al (2020)

Alexithymia in Alzheimer's Disease.

Journal of clinical medicine, 10(1): pii:jcm10010044.

Alexithymia is widely recognized as the inability to identify and express emotions. It is a construct which consists of four cognitive traits such as difficulty in identifying feelings, describing feelings to others, externally oriented thinking, and limited imaginative capacity. Several studies have linked alexithymia to cognitive functioning, observing greater alexithymia scores associated with poorer cognitive abilities. Despite Alzheimer's disease (AD) being a neurodegenerative pathology characterized by cognitive troubles from the early stages, associated to behavioral and emotional disturbances, very few investigations have studied the alexithymia in AD. These studies have shown that alexithymia scores-assessed with Toronto Alexithymia Scale (TAS)-were greater in AD patients than healthy participants. The objective of the study was to investigate if the alexithymia was present in patients with mild AD. We hypothesized that the AD group would show more alexithymia features than the control group. We evaluated 54 subjects, including 27 patients diagnosed with mild AD and 27 normal healthy controls, using the Shalling Sifneos Psychosomatic Scale (SSPS-R) and a neuropsychological test battery. Using non-parametric statistical analyses-Wilcoxon and Mann-Whitney U tests-we observed that the SSPS-R scores were similar in the AD and control groups. All participants showed SSPS-R scores below to 10 points, which means no-alexithymia. We did not find significant correlations between SSPS-R scores and cognitive variables in both groups (p > 0.22), but we observed a negative association between name abilities and alexithymia, but it does not reach to significance (p = 0.07). However, a significant correlation between SSPS-R score and mood state, assessed using Zerssen Rating Scale, was found in both groups (p = 0.01). Because we did not find a significant difference in the alexithymia assessment between both subject groups, pot hoc analyses were computed for each item of the SSPS-R. We made comparisons of alexithymic responses percentages in each SSPS-R item between AD and control groups, using Fisher's test. We observed that AD patients produced more alexithymic responses in some items of SSPS-R test than the control group, particularly about difficulties to find the words to describe feelings, as well as difficulties of imagination capacity and externally oriented thinking. The present results do not confirm our hypothesis and they do not support the results of previous studies revealing great alexithymia in AD.

RevDate: 2020-12-30

Abate G, Vezzoli M, Polito L, et al (2020)

A Conformation Variant of p53 Combined with Machine Learning Identifies Alzheimer Disease in Preclinical and Prodromal Stages.

Journal of personalized medicine, 11(1): pii:jpm11010014.

Early diagnosis of Alzheimer's disease (AD) is a crucial starting point in disease management. Blood-based biomarkers could represent a considerable advantage in providing AD-risk information in primary care settings. Here, we report new data for a relatively unknown blood-based biomarker that holds promise for AD diagnosis. We evaluate a p53-misfolding conformation recognized by the antibody 2D3A8, also named Unfolded p53 (U-p532D3A8+), in 375 plasma samples derived from InveCe.Ab and PharmaCog/E-ADNI longitudinal studies. A machine learning approach is used to combine U-p532D3A8+ plasma levels with Mini-Mental State Examination (MMSE) and apolipoprotein E epsilon-4 (APOEε4) and is able to predict AD likelihood risk in InveCe.Ab with an overall 86.67% agreement with clinical diagnosis. These algorithms also accurately classify (AUC = 0.92) Aβ+-amnestic Mild Cognitive Impairment (aMCI) patients who will develop AD in PharmaCog/E-ADNI, where subjects were stratified according to Cerebrospinal fluid (CSF) AD markers (Aβ42 and p-Tau). Results support U-p532D3A8+ plasma level as a promising additional candidate blood-based biomarker for AD.

RevDate: 2020-12-30

González RD, Gomes I, Gomes C, et al (2020)

APOE Variants in an Iberian Alzheimer Cohort Detected through an Optimized Sanger Sequencing Protocol.

Genes, 12(1): pii:genes12010004.

The primary genetic risk factor for late onset Alzheimer's disease (LOAD) is the APOE4 allele of Apolipoprotein E (APOE) gene. The three most common variants of APOE are determined by single nucleotide polymorphisms (SNPs) rs429358 and rs7412. Our aim was to estimate allele and genotype frequencies of APOE variants in an Iberian cohort, thus helping to understand differences in APOE-related LOAD risk observed across populations. We analyzed saliva or buccal swab samples from 229 LOAD patients and 89 healthy elderly controls (≥68 years old) from Northern Portugal and Castile and León region, Spain. The genotyping was performed by Sanger sequencing, optimized to overcome GC content drawbacks. Results obtained in our Iberian LOAD and control cohorts are in line with previous large meta-analyses on APOE frequencies in Caucasian populations; however, we found differences in allele frequencies between our Portuguese and Spanish subgroups of AD patients. Moreover, when comparing studies from Iberian and other Caucasian cohorts, differences in APOE2 and APOE4 frequencies and subsequent different APOE-related LOAD risks must be clarified. These results show the importance of studying genetic variation at the APOE gene in different populations (including analyses at a regional level) to increase our knowledge about its clinical significance.

RevDate: 2020-12-29

Ausili A, Gómez-Murcia V, Candel AM, et al (2020)

A comparison of the location in membranes of curcumin and curcumin-derived bivalent compounds with potential neuroprotective capacity for Alzheimer's disease.

Colloids and surfaces. B, Biointerfaces, 199:111525 pii:S0927-7765(20)30882-1 [Epub ahead of print].

Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself. 1H NOESY MAS-NMR analysis supports this notion by showing that the orientation of curcumin was parallel to the plane of the membrane surface close to C2 and C3 of the fatty acyl chains, while the curcumin moiety of 17MD and 21MO positioned close to the polar part of the membrane with the steroid moiety in the centre of the membrane. Molecular dynamics studies were in close agreement with the experimental results with respect to the likely proximity of the protons studied by NMR and show that 17MD and 21MO have a clear tendency to aggregate in a fluid membrane. The anchorage of the bivalent compounds to the membrane leaving the curcumin moiety near the polar part may be very important to facilitate the bioactivity of the curcumin moiety when used as anti-Alzheimer drugs.

RevDate: 2021-01-02

Wang J, Guo MN, Liu ZZ, et al (2020)

PGC-1α reduces Amyloid-β deposition in Alzheimer's disease: Effect of increased VDR expression.

Neuroscience letters, 744:135598 pii:S0304-3940(20)30868-5 [Epub ahead of print].

Amyloid-β (Aβ) is the core component of amyloid plaques of Alzheimer's disease (AD). Recent evidence has confirmed that Aβ triggers neurodegeneration by dramatically suppressing vitamin D receptor (VDR) expression. Thus far, the onset mechanisms and means of preventing AD are largely unknown. Perioxisome proliferator-activated receptor-γ coactivator (PGC-1α), as a transcriptional coactivator of VDR could protect cells against oxidative stress. Thus, upregulation of PGC-1α is a candidate therapeutic strategy for AD. To investigate the effect of PGC-1α in AD, and to illuminate the precise involvement of VDR in the neuroprotective strategy, the varies of molecular of PGC-1α and VDR were studied in APP/PS-1 double transgenic (2xTg-AD) mice at 6 months of age, significant reduction in the expression of PGC-1α and VDR was found in their hippocampus and the cortex. Besides, a specific mouse line, Dlx5/6-Cre:PGC-1αfl/fl in which the PGC-1α deficiency was limited to the hippocampus and the cortex, was used to study the target intervention of PGC-1α, decreased expression of VDR and increased oxidative damage were observed in AD-related brain regions by PGC-1α deficiency. To explore the function and therapeutic strategy of PGC-1α in AD, an adeno-associated virus (AAV) was used to induce PGC-1α overexpressed in the hippocampus of 2xTg-AD mice. Overexpressed PGC-1α results in a remarkable increase in the levels of VDR associated with a significant reduction in the expression of Aβ plaques and of 8-oxo-dG in 2xTg-AD mice. These data may have ramifications for neuroprotective strategies targeting overexpression of PGC-1α in Alzheimer's disease.

RevDate: 2020-12-29

Kang DW, Wang SM, Na HR, et al (2020)

Differential effects of the interaction between the education and APOE ε4 allele on amyloid-beta retention and memory performances in cognitively normal older adults and Alzheimer's disease patients.

Current Alzheimer research pii:CAR-EPUB-112777 [Epub ahead of print].

BACKGROUND: Despite the effect of education and APOE ε4 allele on amyloid-beta (Aβ) retention and memory, previous studies have not dealt with an interaction between two factors on Aβ deposition and memory function in the course of Alzheimer's disease (AD).

OBJECTIVE: To evaluate education by APOE ε4 allele interactions for Aβ retention and neuropsychological test scores in cognitively normal older adults without Aβ deposition [CN(Aβ-), n=45] and Alzheimer's disease patients with Aβ retention [AD(Aβ+), n=33].

METHODS: Multiple regression analyses (adjusted for age, gender) were conducted to examine the effects of education, APOE ε4 allele, and the interaction between the two factors on global, regional Aβ load quantified using [18F]flutemetamol standardized uptake value ratio with the pons as a reference region, and on neuropsychological test scores in each group.

RESULTS: The interaction between education and APOE ε4 allele had an effect on amyloid load in parietal lobes (uncorrected p < 0.05) and striatum (Bonferroni corrected p < 0.05) in each CN(Aβ-) and AD(Aβ+). There was also an interaction effect of education and APOE ε4 allele on the memory performance in each CN(Aβ-) and AD(Aβ+) (uncorrected p < 0.05). APOE ε4 carriers of both groups showed opposing slopes with each other in the correlation between the education years and Aβ load, memory performance.

CONCLUSIONS: The current results suggest a possible explanation of the differential effects of education and APOE ε4 allele interactions on AD pathology and memory function at the beginning and end of AD progress. However, further study with a validating cohort is needed for confirming this explanation.

RevDate: 2020-12-29

Pandey D, Pal T, Sharma A, et al (2020)

Potential Epigenetic Targets for Combating Alzheimer's disease.

Mini reviews in medicinal chemistry pii:MRMC-EPUB-112746 [Epub ahead of print].

Memory remains an obligatory regime of human brain and impaired memory causes serious obstacles in our everyday life. Alzheimer's disease (AD) is one such neurodegenerative disease which is mostly affects elderly population, above the age of 60; marked by cognitive impairment of memory. Besides the known targets of AD against the several etiologies known till date, the zone of epigenetics has recently evolved as an ingenious field in AD. Epigenetic modifications do not affect DNA sequence but only long-term gene expression. Considering the multifactorial complex nature of AD, we herein discuss the various epigenetic targets which might give rise to potential therapeutic approaches. We reviewed the possible epigenetic targets for AD like HDAC, Sirtuins, glial cells, miRNA and epigenetic modifications like DNA methylation. A deeper insight into these target areas can surely evolve AD diagnosis and therapeutics.

RevDate: 2020-12-31

Guyon A, Rousseau J, Lamothe G, et al (2020)

The protective mutation A673T in amyloid precursor protein gene decreases Aβ peptides production for 14 forms of Familial Alzheimer's Disease in SH-SY5Y cells.

PloS one, 15(12):e0237122 pii:PONE-D-20-22117.

The deposition of Aβ plaques in the brain leads to the onset and development of Alzheimer's disease. The Amyloid precursor protein (APP) is cleaved by α-secretase (non-amyloidogenic processing of APP), however increased cleavage by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms plaques. APP mutations mapping to exons 16 and 17 favor plaque accumulation and cause Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) originally found in an Icelandic population reduces BACE1 cleavage by 40%. A series of plasmids containing the APP gene, each with one of 29 different FAD mutations mapping to exon 16 and exon 17 was created. These plasmids were then replicated with the addition of the A673T mutation. Combined these formed the library of plasmids that was used in this study. The plasmids were transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. The production of Aβ peptides was decreased for some FAD mutations due to the presence of the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as for A673T control in SH-SY5Y cells. These preliminary results suggest that the insertion of A673T in APP genes containing FAD mutations might confer a clinical benefit in preventing or delaying the onset of some FADs.

RevDate: 2020-12-28

Baumel BS, Doraiswamy PM, Sabbagh M, et al (2020)

Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review.

Neurology and therapy [Epub ahead of print].

In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body's ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements.

RevDate: 2020-12-28

Walker JM, Richardson TE, Farrell K, et al (2020)

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

Journal of neuropathology and experimental neurology pii:6046165 [Epub ahead of print].

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

RevDate: 2020-12-31

Shi YB, Tu T, Jiang J, et al (2020)

Early Dendritic Dystrophy in Human Brains With Primary Age-Related Tauopathy.

Frontiers in aging neuroscience, 12:596894.

Dystrophic neurites (DNs) are found in many neurological conditions such as traumatic brain injury and age-related neurodegenerative diseases. In Alzheimer's disease (AD) specifically, senile plaques containing silver-stained DNs were already described in the original literature defining this disease. These DNs could be both axonal and dendritic in origin, while axonal dystrophy relative to plaque formation has been more extensively studied. Here, we demonstrate an early occurrence of dendritic dystrophy in the hippocampal CA1 and subicular regions in human brains (n = 23) with primary age-related tauopathy (PART), with neurofibrillary tangle (NFT) burden ranging from Braak stages I to III in the absence of cerebral β-amyloid (Aβ) deposition. In Bielschowsky's silver stain, segmented fusiform swellings on the apical dendrites of hippocampal and subicular pyramidal neurons were observed in all the cases, primarily over the stratum radiatum (s.r.). The numbers of silver-stained neuronal somata and dendritic swellings counted over CA1 to subiculum were positively correlated among the cases. Swollen dendritic processes were also detected in sections immunolabeled for phosphorylated tau (pTau) and sortilin. In aged and AD brains with both Aβ and pTau pathologies, silver- and immunolabeled dystrophic-like dendritic profiles occurred around and within individual neuritic plaques. These findings implicate that dendritic dystrophy can occur among hippocampal pyramidal neurons in human brains with PART. Therefore, as with the case of axonal dystrophy reported in literature, dendritic dystrophy can develop prior to Alzheimer-type plaque and tangle formation in the human brain.

RevDate: 2020-12-29

Kong Y, Xie K, Qiao H, et al (2020)

Case Report: [18F]PI2620 as a Tau Imaging Agent in Posterior Cortical Atrophy.

Frontiers in neurology, 11:566667.

Posterior cortical atrophy (PCA) is widely considered as an atypical variant of Alzheimer disease and is characterized by a progressive decline in visual function. PCA has been investigated from the standpoints of brain structure and metabolism, but tau deposition and its relationship to disease severity still remain unclear. Here, we used a novel tau ligand, [18F]PI2620, to visualize tau deposition in a PCA patient. The results showed that high [18F]PI2620 uptake in posterior cortical regions was associated with clinical manifestations, morphologic changes in the brain observed by magnetic resonance imaging (MRI), and hypometabolism detected by [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET). This is the first report demonstrating a clinical anatomical correspondence between [18F]PI2620 PET results, clinical manifestations, MRI, and [18F]FDG PET findings in a Chinese patient with PCA. The results also support the utility of [18F]PI2620 for visualizing tau aggregation in PCA.

RevDate: 2020-12-28

Kim D, Lee JH, Kim HY, et al (2020)

Fluorescent indolizine derivative YI-13 detects amyloid-β monomers, dimers, and plaques in the brain of 5XFAD Alzheimer transgenic mouse model.

PloS one, 15(12):e0243041 pii:PONE-D-20-14305.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the aberrant production and accumulation of amyloid-β (Aβ) peptides in the brain. Accumulated Aβ in soluble oligomer and insoluble plaque forms are considered to be a pathological culprit and biomarker of the disorder. Here, we report a fluorescent universal Aβ-indicator YI-13, 5-(4-fluorobenzoyl)-7,8-dihydropyrrolo[1,2-b]isoquinolin-9(6H)-one, which detects Aβ monomers, dimers, and plaques. We synthesized a library of 26 fluorescence chemicals with the indolizine core and screen them through a series of in vitro tests utilizing Aβ as a target and YI-13 was selected as the final imaging candidate. YI-13 was found to stain and visualize insoluble Aβ plaques in the brain tissue, of a transgenic mouse model with five familial AD mutations (5XFAD), by a histochemical approach and to label soluble Aβ oligomers within brain lysates of the mouse model under a fluorescence plate reader. Among oligomers aggregated from monomers and synthetic dimers from chemically conjugated monomers, YI-13 preferred the dimeric Aβ.

RevDate: 2020-12-28

Knopman DS, WJ Jagust (2020)

Alzheimer Disease Spectrum: Syndrome and Etiology from Clinical and PET Imaging Perspectives.

RevDate: 2020-12-28

Inagawa T, Yokoi Y, Yamada Y, et al (2020)

Effects of multisession transcranial direct current stimulation as an augmentation to cognitive tasks in patients with neurocognitive disorders in Japan: a study protocol for a randomised controlled trial.

BMJ open, 10(12):e037654 pii:bmjopen-2020-037654.

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with disorders. We present a study protocol for a randomised controlled trial designed to evaluate the safety and efficacy of tDCS combined with cognitive tasks on cognition in such patients.

METHOD AND ANALYSIS: This is a two-arm, parallel-design, randomised, sham-controlled trial, in which participants and raters will be blinded at a single centre. Stratified randomisation will be conducted, and a randomisation sequence will be generated through the Electronic Data Capture system. Patients who met the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for neurocognitive disorders will be recruited and randomised to receive either active (2 mA for 20 min) or sham (stimulation ramped up and down for 1 min) stimulation in 10 sessions over five consecutive days. A direct current will be transferred by a 35 cm2 saline-soaked sponge electrode. An anode will be placed over the left dorsolateral prefrontal cortex, and a cathode will be placed over the right supraorbital cortex. Calculation tasks will be conducted in both arms as a cognitive task for 20 min during the stimulation. This task consists of basic arithmetic questions, such as single-digit addition, subtraction, multiplication and division. The primary outcome will be the mean change in the Alzheimer Disease Assessment Scale-cognition at Day 5 after baseline. Depressive symptoms, as measured by the geriatric depression scale, and quality of life, as measured by the Medical Outcomes Study 36-item Short-Form Health Survey, will also be assessed. Data will be collected at baseline, within 3 days following the final stimulation and 1 month thereafter. The estimated sample size is 46 per group based on the assumptions that an estimated mean difference is -1.61 and SD is 2.7. Mixed models for repeated measures will be used for the statistical analysis.

ETHICS AND DISSEMINATION: The National Center of Neurology and the Psychiatry Clinical Research Review Board (CRB3180006) approved this study. The results of this study will be published in a scientific peer-reviewed journal.

TRIAL REGISTRATION DETAILS: Japan Registry of Clinical Trials jRCTs032180016.

RevDate: 2020-12-28

Yang H, Han W, H Li (2020)

Efficacy and safety of MAO-B inhibitor versus donepezil in Chinese elderly stroke patients with Alzheimer disease: A potential therapeutic option.

Pakistan journal of pharmaceutical sciences, 33(3(Special)):1349-1354.

This pilot study designed to evaluate the efficacy and safety of MAO-B inhibitor in comparison with Donepezil (DNP) in elderly Chinese patients with Alzheimer disease (AD). In the present clinical trial, Chinese elderly patients aged ≥65 years with a confirmed diagnosis of AD were enrolled. The patients received MAO-B inhibitor (Selegiline 5 mg) or DNP 10 mg daily (reference) for 6 months. The efficacy and safety data were collected from 120 patients (60 patients in each group) every 3 weeks until 6 months. The primary endpoints were to assess the change in cognitive score from baseline in both the treatment group. The result of the present study showed that the patients treated with MAO-B inhibitor and DNP have similar efficacy and safety profile Considering the clinical benefit, mean (SD) improvement in sign and symptoms was numerically greater in DNP-treated patients as compared to MAO-B inhibitor at endpoint visit (SIB: 12.3 (3.7) vs 11.3 (4.2); AD severity: 14.2 (3.5); CIBIS+/CIBIC: 10.2 (2.7) vs 9.4 (3.2); ADCS-ADL: 14.3 (4.2) vs 13.2 (3.4); MMSE: 14.3 (3.7) vs 12.2 (3.2), P>0.05 respectively for each comparison). However, a statistical difference in terms of clinical benefit was similar between both the treatment groups (p>0.05). Overall, both the study drugs were found comparable in relieving the symptoms of AD (severity score after end of treatment: 14.2 vs 13.4 respectively; p >0.05). This indicates that MAO-B inhibitor is a potential target for the treatment of AD in China. The results of the present study may help to design a large clinical trial to evaluate the efficacy and safety of MAO-B inhibitor in comparison with DNP in AD patients.

RevDate: 2020-12-28

Singh N, Yadav SS, Rao AS, et al (2020)

Review on Anticancerous Therapeutic Potential of Withania somnifera (L.) Dunal.

Journal of ethnopharmacology pii:S0378-8741(20)33592-3 [Epub ahead of print].

Withania somnifera, commonly known as Ashwagandha, is an important medicinal herb belonging to family Solanaceae. It is widely used in folkloric and Ayurvedic medicines since antiquity. Traditionally, the plant is highly practiced throughout the globe as immunomodulator, anti-inflammatory, anti-stress, anti-parkinson, anti-alzheimer, cardio protective, neural and physical health enhancer, neurodefensive, anti-diabetic, aphrodisiac, memory boosting etc. The plant is also effective in combating various cancer and related problems of colon, mammary, lung, prostate, skin, blood, liver and kidney. Aim of this review. The present review represents the critical assessment of the literature available on the anticancerous role of W. somnifera. The present study throws light on its diverse chemical compounds and the possible mechanisms of action involved. This review also suggests further research strategies to harness the therapeutic potential of this plant.

MATERIALS AND METHODS: The present review is the outcome of a systematic search of scientific literature about 'Withania somnifera and its role in cancer prevention'. The scientific databases viz. Google Scholar, Science Direct, Pubmed and Web of Science were searched from 2001 to 2019. Textbooks, magazines and newspapers were also consulted. This review summarizes all the published literature about its therapeutic potential for the treatment of different types of cancers.

RESULTS: W. somnifera has been widely used in traditional and ayurvedic medicines for treatment of numerous problems related to health and vitality. The plant is a reservoir of diverse phytoconstituents like alkaloids, steroids, flavonoids, phenolics, nitrogen containing compounds and trace elements. Withanolides are the major alkaloids which renders its anticancer potential due to its highly oxygenated nature. The plant is highly effective in combating various types of cancers viz. colon, mammary, lung, prostate, skin, blood, liver and kidney. Previous studies depict that this plant is more effective against breast cancer followed by colon, lung, prostate and blood cancer. Furthermore, from different clinical studies it has been observed that the active constituents of the plant like withaferin-A, withanolide-D have least toxic effects.

CONCLUSION: The present review confirms the various medicinal values of W. somnifera without any significant side effects. Withaferin-A (WA) and Withanolides are its most promising anticancer compounds that play a major role in apoptosis induction. Keeping in mind the anticancerous potential of this plant, it is suggested that this plant may further be investigated and more clinical studies can be performed.

RevDate: 2020-12-28

Russ TC, Harris SE, GD Batty (2020)

RESEARCH LETTER: Pulmonary function and risk of Alzheimer dementia: two-sample Mendelian randomization study.

RevDate: 2020-12-28

Liu M, Zhang J, Zong L, et al (2020)

The differential diagnostic value of the callosal angle and Evans index in mild cognitive impairment and Alzheimer's disease.

Current medical imaging pii:CMIR-EPUB-112647 [Epub ahead of print].

BACKGROUND: Callosal angle (CA) and Evans index (EI) had been considered as imaging biomarkers to diagnosis normal-pressure hydrocephalus as traditional MR measurement methods.

OBJECTIVE: The current study was aimed to evaluate the differential diagnostic value of CA and EI in the mild cognitive impairment (MCI) and Alzheimer's disease (AD).

METHODS: Five-hundred and two subjects were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, which included 168 normal controls (NC), 233 MCI and 101 AD patients. The structural MR images were interactively applied with multiplanar reconstruction to measure the CA and EI.

RESULTS: CA presented no significant difference among NC, MCI and AD groups (H value = 3.848, P value = 0.146), and EI was demonstrated the higher in MCI and AD groups than that in NC groups (P = 0.000 and 0.001, respectively). MCI group had significant larger EI (0.29±0.04) than that (0.27±0.03) in NC group in 70-75 years old sub-groups. ROC showed that the area under the curve was 0.704±0.045 for NC-MCI in 70-75 years old groups. The correlation analysis indicated that EI was significantly negatively related with MMSE scores of MCI patients (r = -0.131, P = 0.046).

CONCLUSION: EI might serve as a screening imaging biomarker for MCI in 70-75 years old, and show limited differential value for the diagnosis of AD. CA could present no diagnostic value for MCI and AD in the current study.

RevDate: 2020-12-28

Mayo S, Benito-León J, Peña-Bautista C, et al (2020)

Recent evidence in epigenomics and proteomics biomarkers for early and minimally invasive diagnosis of Alzheimer's and Parkinson's diseases.

Current neuropharmacology pii:CN-EPUB-112651 [Epub ahead of print].

BACKGROUND: Alzheimer's (AD) and Parkinson's diseases (PD) show deposits of improperly folded modified proteins, so protein expression mechanisms are involved since early stages. Several studies evaluated epigenomics and proteomics profiles in these patients, with promising results. In general, they focused on early, specific, and minimally invasive biomarkers for diagnosis and prognosis of AD and PD.

OBJECTIVES: This review aimed at summarizing results to find the most reliable evidence in the field.

METHOD: A PubMed search was carried out. It was limited to the last 6 years, using a combination of search terms related to AD, PD and epigenetics or proteomics.

RESULTS: Among epigenomics studies, most of them focused on microRNAs (miRNAs) as candidate diagnosis biomarkers for AD or PD from blood samples like miR-342-3p, miR-107, miR-106a-5p, miR-106b-5p, miR-195, and miR-19b. In addition, the DNA methylation has been tested in a few works, obtaining significant differences in some genes (NCAPH2/LMF2 COASY, SPINT1, BDNFTREM1, TREM2, NPAS2, PDE4D), which could be useful for evaluating the disease progression as well as potential risk factors. Regarding proteomics, most of the studies were untargeted and used plasma or serum samples. In general, they highlighted the importance of coagulation, inflammation pathways, and oxidative stress. Among targeted studies, some proteins (phosphorylated tau, C reactive protein (CRP), interleukins, necrosis factors, transferrin, glial fibrillary acidic protein (GFAP),and neurofilaments) showed different plasma levels in AD and PD patients in comparison with healthy participants. Finally, a few studies have identified specific-AD and PD epigenetic and proteomic biomarkers (ApoE and oxidized DJ-1) in comparison with other similar pathologies.

CONCLUSION: In general, there is a common lack of clinical validation of these potential biomarkers, for which its use in the clinical practice is still limited.

RevDate: 2020-12-28

Kim J, YK Kim (2020)

Inflammatory biomarkers in AD: implications for diagnosis.

Current Alzheimer research pii:CAR-EPUB-112650 [Epub ahead of print].

Alzheimer's disease is the most common form of dementia. Due to the lack of effective interventions, early and accurate diagnosis for new interventions are emphasized. However, significant neuronal loss and neuropathological lesions can damage the brain substantially before diagnosis. With our growing knowledge of the role of neuroinflammation in the pathogenesis of Alzheimer's disease, inflammatory biomarkers are attracting increasing interest in the context of diagnosis. This review is focused on the use of inflammatory biomarkers detected through neuroimaging, cerebrospinal fluid, and peripheral blood for diagnosing Alzheimer's disease, and also suggests clinical implications. This review includes the following biomarkers: neuroimaging, various ligands binding to the translocator protein (TSPO); cerebrospinal fluid, soluble triggering receptor expressed on myeloid cells (sTREM2), human cartilage glycoprotein-39 (YKL-40), and monocyte chemoattractant protein 1 (MCP-1), and various biomarkers in peripheral blood. Although accumulating evidence has suggested the potential role of these inflammatory biomarkers in diagnosing AD, there are limitations to their use. However, combining these biomarkers with conventional diagnostic clues such as genotype and amyloid pathology may improve the stratification and selection of patients for targeted early interventions.

RevDate: 2020-12-28

Viayna E, Coquelle N, Cieslikiewicz-Bouet M, et al (2020)

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.

Journal of medicinal chemistry [Epub ahead of print].

The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

RevDate: 2020-12-31

Abd El-Rady NM, Ahmed A, Abdel-Rady MM, et al (2021)

Glucagon-like peptide-1 analog improves neuronal and behavioral impairment and promotes neuroprotection in a rat model of aluminum-induced dementia.

Physiological reports, 8(24):e14651.

BACKGROUND: Alzheimer's disease (AD) is a worldwide severe medical and social burden. Liraglutide (LIR) has neuroprotective effects in preclinical animal models.

AIM: To explore the probable neuroprotective impact of Glucagon-like peptide-1 (GLP-1) on rats' behavior and to elucidate its underlying mechanisms.

METHODS: A total of 24 male albino rats were assigned to control, LIR (300 µg/kg subcutaneously (s.c.)), AD only (100 mg/kg aluminum chloride (AlCl3) orally) and LIR + AD treated groups. Eight radial arm maze was performed. Serum blood glucose, proinflammatory cytokines, oxidative stress markers were measured and hippocampal tissue homogenate neurotransmitters were evaluated. Histopathological and immunofluorescent examinations were performed.

RESULTS: LIR prevents the impairment of learning and improves both working memory and reference memory through significant reduction of serum tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and interferon-γ (INF-γ) and malondialdehyde (MDA) and through the increase of superoxide dismutase (SOD), dopamine, adrenaline, and noradrenaline. LIR also improves hippocampal histological features of ALCL3 administrated rats and decreases the percentage of neuronal loss.

CONCLUSION: LIR normalizes ALCL3 -induced dementia. It improves cognitive dysfunction and ameliorates cerebral damage.

RevDate: 2020-12-23

Holubová M, Lobaz V, Loukotová L, et al (2020)

Chemically modified glycogens: how they influence formation of amyloid fibrils?.

Soft matter [Epub ahead of print].

The formation of amyloid fibrils from certain proteins stays behind a number of pathologies, so-called amyloidoses. Glycosaminoglycans are polysaccharides and are known natural constituents of amyloids in vivo. However, little is known about the effect of other naturally abundant polysaccharides, and even less is known about the effect of chemically modified polysaccharides on the formation of amyloid fibrils. In the case of low-molecular weight compounds, aromatic substances are known to often influence amyloid formation significantly. We investigated the influence of glycogen (GG) and several modifications of GG with cinnamoyl groups, benzoyl groups and phenylacetyl groups. As model systems, hen egg-white lysozyme (HEWL) and amyloid beta peptide (1-42) (Aβ1-42), which is an Alzheimer disease-relevant system, were used. The fluorescence of thioflavin-T (ThT) was used for the rapid detection of fibrils, and the fluorescence results were confirmed by transmission electron microscopy (TEM). Other techniques, such as isothermal titration calorimetry (ITC) and dynamic light scattering (DLS), were employed to determine the interactions between HEWL and the modifications. We achieved similar results with both model systems (HEWL and Aβ1-42). We showed that π-π interactions played an important role in the process of amyloid fibril formation because fundamental changes were observed in this process even with a very small number of groups containing an aromatic ring. It was found that almost all GG modifications accelerated the formation of amyloid fibrils in both model systems, HEWL and Aβ1-42, except for GG-Ph1 (1.6 mol% phenylacetyl groups), which had a retarding effect compared to all other modifications.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

963 Red Tail Lane
Bellingham, WA 98226

206-300-3443

E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )