Publications by authors named "Andrius Baskys"

31 Publications

Opportunities to integrate nutrigenomics into clinical practice and patient counseling.

Eur J Clin Nutr 2022 Apr 20. Epub 2022 Apr 20.

School of Pharmacy, Chapman University, Irvine, CA, USA.

Background: Little progress has been made in translating nutrigenomics knowledge into clinical counseling in the past decade. Currently, clinicians are overwhelmed by nutrigenomics information without the proper scientific guidelines on patient counseling.

Methods: In this study, we conducted a scoping review of the primary literature to assess the current evidence of nutrigenomics counseling. A literature search using PRISMA guidelines identified the current challenges and opportunities facing nutrigenomics counseling in clinical practice.

Results: We identified four main themes: inadequate training, lack of awareness, underdeveloped nutrigenomics counseling skills, and unreliable evidence-based practice information. Many clinicians did not have the necessary knowledge to perform nutrigenomic counseling and were unaware of the available scientific information source. Moreover, there are no guidelines in the scientific community to counsel patients on nutrigenomics testing.

Conclusion: Opportunities exist for government and non-government entities to create an evidence-based information platform using clinical guidelines to integrate nutrigenomics knowledge from bench to bedside successfully.
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http://dx.doi.org/10.1038/s41430-022-01146-xDOI Listing
April 2022

PGxKnow: a pharmacogenomics educational HoloLens application of augmented reality and artificial intelligence.

Pharmacogenomics 2022 03 27;23(4):235-245. Epub 2022 Jan 27.

Assistant Professor, School of Pharmacy, Department of Pharmacy Practice, Chapman University, 9401 Jeronimo Road, Irvine, CA 92618, USA.

To develop and assess an augmented reality tool for pharmacogenomics (PGx) education based on artificial intelligence. A HoloLens application was developed using feedback from three clinical PGx-trained pharmacists. 15 Participants independently reviewed the application and assessed usability using the system usability scale (SUS). Eighteen different frames were developed. Each video module was 2-3 min for the education. The application included textual information and 3D structures of PGx concepts. The mean SUS score for 15 participants (11 pharmacy students and four pharmacists) was 83, with a standard deviation of 6.6. Results suggest that PGxKnow has the potential to bridge the gap in PGx education, further widespread utilization of PGx and boost its impact on precision medicine.
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http://dx.doi.org/10.2217/pgs-2021-0120DOI Listing
March 2022

PGxKnow: a pharmacogenomics educational HoloLens application of augmented reality and artificial intelligence.

Pharmacogenomics 2022 03 27;23(4):235-245. Epub 2022 Jan 27.

Assistant Professor, School of Pharmacy, Department of Pharmacy Practice, Chapman University, 9401 Jeronimo Road, Irvine, CA 92618, USA.

To develop and assess an augmented reality tool for pharmacogenomics (PGx) education based on artificial intelligence. A HoloLens application was developed using feedback from three clinical PGx-trained pharmacists. 15 Participants independently reviewed the application and assessed usability using the system usability scale (SUS). Eighteen different frames were developed. Each video module was 2-3 min for the education. The application included textual information and 3D structures of PGx concepts. The mean SUS score for 15 participants (11 pharmacy students and four pharmacists) was 83, with a standard deviation of 6.6. Results suggest that PGxKnow has the potential to bridge the gap in PGx education, further widespread utilization of PGx and boost its impact on precision medicine.
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http://dx.doi.org/10.2217/pgs-2021-0120DOI Listing
March 2022

Scoping review: the empowerment of Alzheimer's Disease caregivers with mHealth applications.

NPJ Digit Med 2021 Sep 7;4(1):131. Epub 2021 Sep 7.

Western University of Health Sciences, College of Pharmacy, Department of Pharmacy Practice and Administration, Pomona, CA, USA.

Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients' caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver.
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http://dx.doi.org/10.1038/s41746-021-00506-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423781PMC
September 2021

Scoping review: the empowerment of Alzheimer's Disease caregivers with mHealth applications.

NPJ Digit Med 2021 Sep 7;4(1):131. Epub 2021 Sep 7.

Western University of Health Sciences, College of Pharmacy, Department of Pharmacy Practice and Administration, Pomona, CA, USA.

Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients' caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver.
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http://dx.doi.org/10.1038/s41746-021-00506-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423781PMC
September 2021

Artificial Intelligence-Powered Smartphone App to Facilitate Medication Adherence: Protocol for a Human Factors Design Study.

JMIR Res Protoc 2020 Nov 9;9(11):e21659. Epub 2020 Nov 9.

Department of Pharmacy Practice, School of Pharmacy, Chapman University, Irvine, CA, United States.

Background: Medication Guides consisting of crucial interactions and side effects are extensive and complex. Due to the exhaustive information, patients do not retain the necessary medication information, which can result in hospitalizations and medication nonadherence. A gap exists in understanding patients' cognition of managing complex medication information. However, advancements in technology and artificial intelligence (AI) allow us to understand patient cognitive processes to design an app to better provide important medication information to patients.

Objective: Our objective is to improve the design of an innovative AI- and human factor-based interface that supports patients' medication information comprehension that could potentially improve medication adherence.

Methods: This study has three aims. Aim 1 has three phases: (1) an observational study to understand patient perception of fear and biases regarding medication information, (2) an eye-tracking study to understand the attention locus for medication information, and (3) a psychological refractory period (PRP) paradigm study to understand functionalities. Observational data will be collected, such as audio and video recordings, gaze mapping, and time from PRP. A total of 50 patients, aged 18-65 years, who started at least one new medication, for which we developed visualization information, and who have a cognitive status of 34 during cognitive screening using the TICS-M test and health literacy level will be included in this aim of the study. In Aim 2, we will iteratively design and evaluate an AI-powered medication information visualization interface as a smartphone app with the knowledge gained from each component of Aim 1. The interface will be assessed through two usability surveys. A total of 300 patients, aged 18-65 years, with diabetes, cardiovascular diseases, or mental health disorders, will be recruited for the surveys. Data from the surveys will be analyzed through exploratory factor analysis. In Aim 3, in order to test the prototype, there will be a two-arm study design. This aim will include 900 patients, aged 18-65 years, with internet access, without any cognitive impairment, and with at least two medications. Patients will be sequentially randomized. Three surveys will be used to assess the primary outcome of medication information comprehension and the secondary outcome of medication adherence at 12 weeks.

Results: Preliminary data collection will be conducted in 2021, and results are expected to be published in 2022.

Conclusions: This study will lead the future of AI-based, innovative, digital interface design and aid in improving medication comprehension, which may improve medication adherence. The results from this study will also open up future research opportunities in understanding how patients manage complex medication information and will inform the format and design for innovative, AI-powered digital interfaces for Medication Guides.

International Registered Report Identifier (irrid): PRR1-10.2196/21659.
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http://dx.doi.org/10.2196/21659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683257PMC
November 2020

MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system.

Biomaterials 2020 10 28;257:120264. Epub 2020 Jul 28.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China. Electronic address:

Oxidative stress is a major cause of skin injury induced by damaging stimuli such as UV radiation. Currently, owing to their immunomodulatory properties, mesenchymal stem cell-derived exosomes (MSC-Exo), as a nanotherapeutic agent, have attracted considerable attention. Here, we investigated the therapeutic effects of MSC-Exo on oxidative injury in HO-stimulated epidermal keratinocytes and UV-irradiated wild type and nuclear factor-erythroid 2-related factor-2 (Nrf2) knocked down cell and animal models. Our findings showed that MSC-Exo treatment reduced reactive oxygen species generation, DNA damage, aberrant calcium signaling, and mitochondrial changes in HO-stimulated keratinocytes or UV-irradiated mice skin. Exosome therapy also improved antioxidant capacities shown by increased ferric ion reducing antioxidant power and glutathione peroxidase or superoxide dismutase activities in oxidative stress-induced cell and skin injury. In addition, it alleviated cellular and histological responses to inflammation and oxidation in cell or animal models. Furthermore, the NRF2 signaling pathway was involved in the antioxidation activity of MSC-Exo, while Nrf2 knockdown attenuated the antioxidant capacities of MSC-Exo in vitro and in vivo, suggesting that these effects are partially mediated by the NRF2 signaling pathway. These results indicate that MSC-Exo can repair oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Thus, MSC-Exo may be used as a potential dermatological nanotherapeutic agent for treating oxidative stress-induced skin diseases or disorders.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120264DOI Listing
October 2020

The efficacy of transcranial alternating current stimulation for treating post-stroke depression: Study Protocol Clinical Trial (SPIRIT Compliant).

Medicine (Baltimore) 2020 Apr;99(16):e19671

Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.

Background: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation.

Methods: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models.

Discussion: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism.

Trial Registration Number: NCT03903068, pre-results.
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http://dx.doi.org/10.1097/MD.0000000000019671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220515PMC
April 2020

Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice.

Theranostics 2019 14;9(20):5956-5975. Epub 2019 Aug 14.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, P.R. China.

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. : Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. : MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. : Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.
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http://dx.doi.org/10.7150/thno.33872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735367PMC
August 2020

High mobility group box-1 (HMGB1) antagonist BoxA suppresses status epilepticus-induced neuroinflammatory responses associated with Toll-like receptor 2/4 down-regulation in rats.

Brain Res 2019 08 12;1717:44-51. Epub 2019 Apr 12.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, West 5th Road, Xincheng District, Xi'an 710003, PR China. Electronic address:

It has been generally accepted that inflammatory responses induced by status epilepticus (SE) in the brain are associated with microglial activation. One important regulator of microglial activation is high mobility group box-1 (HMGB1) protein. HMGB1 exerts its influence on microglia via various pathways including Toll-like receptor (TLR) subtypes 2 and 4. To explore the HMGB1 role in the SE-induced microglial activation and the involvement of TLRs we conducted in vivo and ex vivo experiments using the HMGB1 antagonist BoxA. Blood-brain barrier (BBB) permeability, brain water content, hippocampal neuroinflammation and neuronal apoptosis were measured 24 h after the pilocarpine induction of status epilepticus (SE) in Sprague-Dawley rats treated with BoxA. In ex vivo experiments, post-SE microglia cells were isolated from the hippocampal CA1 area and subjected to lipopolysaccharide (LPS) stimulation followed by inflammatory cytokine IL-1β and IL-6 by qPCR and HMGB1, TLR2, TLR3 by Western blotting. A significant down-regulation of IL-1β, IL-6 and TNF-α but not HMGB1 was found in BoxA-treated compared to untreated animals. These changes were associated with decreased BBB permeability, reduced hippocampal neuronal apoptosis and reduction in hippocampal microglial activation. We conclude that BoxA-induced suppression of HMGB1-mediated neuroinflammatory responses is associated with TLR-2 and 4 down-regulation and should be explored as a potential therapeutic target.
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http://dx.doi.org/10.1016/j.brainres.2019.04.007DOI Listing
August 2019

Application of pharmacogenetics in clinical practice: problems and solutions.

Authors:
Andrius Baskys

J Neural Transm (Vienna) 2019 01 19;126(1):109-113. Epub 2018 Jun 19.

Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, USA.

This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.
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http://dx.doi.org/10.1007/s00702-018-1894-0DOI Listing
January 2019

A Case of Fronto-Temporal Dementia (FTD) Masquerading as Mood Disorder.

Clin Gerontol 2018 Jan-Feb;41(1):94-100. Epub 2017 Jan 18.

a Memory Disorders Clinic and Riverside Psychiatric Medical Group , Riverside , California , USA.

A 56-year old Chinese female was referred to an academic medical center with atypical, treatment-resistant depression that continued for approximately 3 years after her sister's death. Comprehensive evaluation including neurocognitive testing, EEG, spinal tap, HIV testing and brain MRI revealed behavioral variant of fronto-temporal dementia (bvFTD) with significant frontal and temporal lobe atrophy.This patient's unusual clinical presentation emphasizes the overlap between depression and bvFTD, and underlines the importance of prompt, accurate diagnosis to minimize often-ineffective pharmacological interventions and caregiver burnout.
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http://dx.doi.org/10.1080/07317115.2016.1272518DOI Listing
May 2019

Vascular depression consensus report - a critical update.

BMC Med 2016 Nov 3;14(1):161. Epub 2016 Nov 3.

Departments of Neurology and Psychiatry, Tel Aviv Medical Center, Tel Aviv, Israel.

Background: Vascular depression is regarded as a subtype of late-life depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. Although the term is commonly used in research settings, widely accepted diagnostic criteria are lacking and vascular depression is absent from formal psychiatric manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5 edition - a fact that limits its use in clinical settings. Magnetic resonance imaging (MRI) techniques, showing a variety of cerebrovascular lesions, including extensive white matter hyperintensities, subcortical microvascular lesions, lacunes, and microinfarcts, in patients with late life depression, led to the introduction of the term "MRI-defined vascular depression".

Discussion: This diagnosis, based on clinical and MRI findings, suggests that vascular lesions lead to depression by disruption of frontal-subcortical-limbic networks involved in mood regulation. However, despite multiple MRI approaches to shed light on the spatiotemporal structural changes associated with late life depression, the causal relationship between brain changes, related lesions, and late life depression remains controversial. While postmortem studies of elderly persons who died from suicide revealed lacunes, small vessel, and Alzheimer-related pathologies, recent autopsy data challenged the role of these lesions in the pathogenesis of vascular depression. Current data propose that the vascular depression connotation should be reserved for depressed older patients with vascular pathology and evident cerebral involvement. Based on current knowledge, the correlations between intra vitam neuroimaging findings and their postmortem validity as well as the role of peripheral markers of vascular disease in late life depression are discussed.

Conclusion: The multifold pathogenesis of vascular depression as a possible subtype of late life depression needs further elucidation. There is a need for correlative clinical, intra vitam structural and functional MRI as well as postmortem MRI and neuropathological studies in order to confirm the relationship between clinical symptomatology and changes in specific brain regions related to depression. To elucidate the causal relationship between regional vascular brain changes and vascular depression, animal models could be helpful. Current treatment options include a combination of vasoactive drugs and antidepressants, but the outcomes are still unsatisfying.
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http://dx.doi.org/10.1186/s12916-016-0720-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093970PMC
November 2016

Platinum sensitivity and CD133 expression as risk and prognostic predictors of central nervous system metastases in patients with epithelial ovarian cancer.

BMC Cancer 2014 Nov 17;14:829. Epub 2014 Nov 17.

Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, West Changle Road, No,127, Xi'an 710032 Shaanxi Province People's Republic of China.

Background: To characterize prognostic and risk factors of central nervous system (CNS) metastases in patients with epithelial ovarian cancer (EOC).

Methods: A retrospective analysis of Xijing Hospital electronic medical records was conducted to identify patients with pathologically confirmed EOC and CNS metastases. In addition to patient demographics, tumor pathology, treatment regimens, and clinical outcomes, we compared putative cancer stem cell marker CD133 expression patterns in primary and metastatic lesions as well as in recurrent EOC with and without CNS metastases.

Results: Among 1366 patients with EOC, metastatic CNS lesions were present in 29 (2.1%) cases. CD133 expression in primary tumor was the only independent risk factor for CNS metastases; whilst the extent of surgical resection of primary EOC and platinum resistance were two independent factors significantly associated with time to CNS metastases. Absence of CD133 expression in primary tumors was significantly associated with high platinum sensitivity in both patient groups with and without CNS metastases. Platinum resistance and CD133 cluster formation in CNS metastases were associated with decreased survival, while multimodal therapy including stereotactic radiosurgery (SRS) for CNS metastases was associated with increased survival following the diagnosis of CNS metastases.

Conclusions: These data suggest that there exist a positive association between CD133 expression in primary EOC, platinum resistance and the increased risk of CNS metastases, as well as a less favorable prognosis of EOC. The absence of CD133 clusters and use of multimodal therapy including SRS could improve the outcome of metastatic lesions. Further investigation is warranted to elucidate the true nature of the association between platinum sensitivity, CD133 expression, and the risk and prognosis of CNS metastases from EOC.
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http://dx.doi.org/10.1186/1471-2407-14-829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239390PMC
November 2014

Integration of genomic information in development of pharmacological vascular dementia prevention and treatment strategies.

Authors:
Andrius Baskys

J Alzheimers Dis 2014 ;42 Suppl 3:S267-76

Department of Psychiatry and Division of Health Sciences, School of Medicine, University of California Riverside, Riverside, CA, USA Tyler Village Clinic for Older Adults, Riverside County Department of Mental Health, Riverside, CA, USA.

Treatment of hypertension reduces vascular dementia (VaD) risk but not all anti-hypertensive drugs (AHDs) are equally effective, suggesting drug-gene interactions. To understand this relationship, publicly accessible databases were searched for genes deregulated in VaD and their interactions with AHDs. Genes that were downregulated in association with VaD were MTHFR, SYK, AGT, and RPGRIP1L. Genes that were upregulated in VaD were MMP9 and VEGFA. TNFSF14, AR, and PHLDB2 were also associated with VaD, however, transcription or protein level changes could not be ascertained. Analysis of gene expression data suggests that AHDs differentially regulate VaD-associated genes. Information about AHD up- or downregulation of VaD-associated genes could be used as an empirical basis for the optimal selection of AHDs in clinical trials and, ultimately, for VaD prevention and treatment.
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http://dx.doi.org/10.3233/JAD-140003DOI Listing
June 2015

Calpastatin gene (CAST) is not associated with late onset sporadic Parkinson's disease in the Han Chinese population.

PLoS One 2013 9;8(8):e70935. Epub 2013 Aug 9.

Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China.

Recent studies point to an association between the late-onset sporadic Parkinson's disease (PD) and single nucleotide polymorphisms (SNPs) rs1559085 and rs27852 in Ca(2+)-dependent protease calpain inhibitor calpastatin (CAST) gene. This finding is of interest since loss of CAST activity could result in over activated calpain, potentially leading to Ca(2+) dysregulation and loss of substantia nigra neurons in PD. We explored the association between CAST SNPs and late-onset sporadic PD in the Han Chinese population. The study included 615 evaluable patients (363 male, 252 female) with PD and 636 neurologically healthy controls (380 male, 256 female) matched for age, gender, ethnicity, and area of residence. PD cases were identified from the PD cohort of the Chinese National Consortium on Neurodegenerative Diseases (www.chinapd.cn). A total of 24 tag-SNPs were genotyped capturing 95% of the genetic variation across the CAST gene. There was no association found between any of the polymorphisms and PD in all models tested (co-dominant, dominant-effect and recessive-effect). Similarly, none of the common haplotypes was associated with a risk for PD. Our data do not support a significant association between the CAST gene polymorphisms and late onset sporadic PD in the Han Chinese population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070935PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739781PMC
March 2014

Pharmacological prevention and treatment of vascular dementia: approaches and perspectives.

Exp Gerontol 2012 Nov 13;47(11):887-91. Epub 2012 Jul 13.

Alzheimer's Disease Prevention and Treatment Center, Orange, California, USA.

Vascular dementia (VaD) is a common dementing illness. There are no pharmacological agents with a regulatory approval for its treatment or prevention. Review of published clinical trial reports indicates that early treatment of hypertension, a risk factor for stroke, reduces VaD risk and slows progression. However, unlike stroke, treatment of hyperlipidemia with statin class drugs or treatment of blood clotting abnormalities with acetylsalicylic acid do not appear to have an effect on VaD incidence or progression. Pharmacological agents for treatment of Alzheimer's dementia (AD) such as memantine or acetylcholinesterase inhibitors have small positive effects on cognition in VaD, which are likely due to their action on co-existing AD-related neuropathology. Drug development efforts using novel approaches such as patient stratification by their genotype are needed in order to address the increasing need for effective VaD therapeutics.
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http://dx.doi.org/10.1016/j.exger.2012.07.002DOI Listing
November 2012

PITX3 polymorphism is not associated with Parkinson's disease in a Chinese population.

Neurosci Lett 2011 Nov 21;505(3):260-2. Epub 2011 Oct 21.

Department of Neurology and Neurobiology, Xuanwu Hospital of Capital Medical University, PR China.

Several studies have indicated that three PITX3 single nucleotide polymorphisms (SNPs), rs2281983, rs4919621 and rs3758549, are likely to be associated with Parkinson's disease (PD) in Caucasians. Some studies also suggested an age-of-onset effect. We recently reported that allele and genotype frequencies did not differ between late-onset PD (LOPD) patients and controls for all three SNPs. To extend the analysis to early-onset PD (EOPD) patients, and to test whether an age-of-onset effect exists in Chinese, we genotyped these SNPs in 290 Chinese EOPD patients using a ligase detection reaction (LDR). For all three SNPs, allele and genotype frequencies did not differ between total PD patients and controls, between LOPD patients and controls, between EOPD patients and controls, or between LOPD and EOPD patients. Our results suggest that these PITX3 SNPs do not contribute to the risk of developing PD in EOPD or LOPD in Chinese.
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http://dx.doi.org/10.1016/j.neulet.2011.10.034DOI Listing
November 2011

α-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death.

J Neurochem 2011 Nov 11;119(4):815-25. Epub 2011 Oct 11.

Department of Neurobiology and the Sino-Japan Joint Laboratory on Neurodegenerative Diseases, Key Laboratory of Neurodegenerative Diseases (Capital Medical University), Ministry of Education, Xuanwu Hospital of China Capital Medical University, Beijing, China.

Abnormalities of α-synuclein (α-syn) and NMDA receptors (NMDARs) are implicated in the pathogenesis of Parkinson's disease. However, how these proteins interact with each other has not been elucidated. Here, the effect of α-syn on NMDARs was investigated by examining the alterations of surface NMDAR NR1 subunits in MES23.5 dopaminergic cells transfected with the human α-syn gene as well as in cells treated with extracellularly added human α-syn. As demonstrated previously that α-syn can enter cells in a non-endocytic manner without being degraded by the cellular proteolytic systems, the extracellularly added α-syn entered the cytoplasm of MES23.5 cells in a concentration-dependent manner. Both the α-syn-transfected cells and α-syn-treated cells exhibited increased intracellular α-syn levels and reduced surface NR1 without altering the total NR1. The α-syn-induced surface NR1 reduction was accompanied by suppression of NMDA-elicited intracellular Ca(2+) elevation and reductions of NMDA-induced caspase 3 activation and cell death, which was abolished by hypotonic shock and K(+) depletion, a procedure that blocks clathrin-mediated endocytosis, and by suppression of RAB5B expression with anti-RAB5B oligonucleotides. The data obtained provide evidence for the first time that α-syn may promote clathrin-mediated NMDAR endocytosis.
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http://dx.doi.org/10.1111/j.1471-4159.2011.07460.xDOI Listing
November 2011

Regulating genetic tests: who owns the data?

Authors:
Andrius Baskys

Science 2010 Dec;330(6011):1626; author reply 1626-7

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http://dx.doi.org/10.1126/science.330.6011.1626-bDOI Listing
December 2010

Rab-mediated endocytosis: linking neurodegeneration, neuroprotection, and synaptic plasticity?

Ann N Y Acad Sci 2007 Dec;1122:313-29

Memory Disorders Program, VA HCS Long Beach, 5901 E. 7th St. 06/116 A, Long Beach, CA 90822, USA.

Rab proteins are small GTPases involved in endocytosis and recycling of cell surface molecules. Recently they have been implicated in the etiopathogenesis of several neurodegenerative disorders including Alzheimer's and Lewy body disease. In experiments on organotypic hippocampal cultures, upregulation of Rab protein family member Rab5b after group I metabotropic glutamate receptor (mGluR) stimulation was associated with reduced neuronal vulnerability to excitotoxic injury. This mGluR-mediated neuroprotection was abolished by antisense-induced deficiency of Rab5b. Electrophysiological measurements of excitatory synaptic transmission in the Schaffer collateral-CA1 pathway revealed that mGluR activation that induces neuroprotection also induced long-term depression (LTD) of synaptic transmission. Similar to the neuroprotection, Rab5b deficiency abolished dihydroxyphenylglycine-induced LTD. Together, these findings support the idea that Rab proteins, and the Rab5b protein in particular, may provide a link between neurodegenerative disease, neuroprotection, and synaptic plasticity, as well as possibly being a useful target for pharmacological interventions.
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http://dx.doi.org/10.1196/annals.1403.023DOI Listing
December 2007

Vascular dementia: pharmacological treatment approaches and perspectives.

Clin Interv Aging 2007 ;2(3):327-35

Department of Psychiatry and Human Behavior, University of California at Irvine, Irvine, California, USA.

Vascular dementia is a common condition for which there are no effective approved pharmacological treatments available. Absence of effective treatments creates a difficult situation for those suffering from the disease, their caregivers, and healthcare providers. This review will address our current understanding of the mechanisms of nerve cell damage due to ischemia and summarize available clinical trial data on several commonly used compounds including memantine, donepezil, galantamine, rivastigmine, nimodipine, hydergine, nicergoline, CDP-choline, folic acid, as well as such nonpharmacological approaches as validation therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685259PMC
January 2008

Effects of galantamine on working memory and global functioning in patients with mild cognitive impairment: a double-blind placebo-controlled study.

Am J Alzheimers Dis Other Demen 2005 Sep-Oct;20(5):295-302

Southern California Institute for Research and Education, Graduate School of Education and Psychology, Pepperdine University, Irvine, California, USA.

Mild cognitive impairment (MCI) causes memory impairment and executive function deficits in those with the condition. There is also some evidence that MCI patients are impaired in their daily functioning. Cholinesterase inhibitors have been widely used for patients with Alzheimer's disease (AD), with evidence of improving cognitive function. There is currently no established treatment for MCI, and cholinesterase inhibitors are beginning to be studied in these patients. Galantamine is a cholinesterase inhibitor that also has nicotinic receptor-modulating properties that has been successful in improving AD patients. This study examined the effects of galantamine in patients with MCI in areas of memory, executive functioning, and global functioning. There was a significant improvement in scores on the Functional Activities Questionnaire, which is a measure of global functioning. There were also improvements in the galantamine group on two of six measures in the Cambridge Automated Neuropsychiatric Test Assessment Battery and in immediate free recall on the California Verbal Learning Test.
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http://dx.doi.org/10.1177/153331750502000502DOI Listing
January 2006

Activation of neuroprotective pathways by metabotropic group I glutamate receptors: a potential target for drug discovery?

Ann N Y Acad Sci 2005 Aug;1053:55-73

Southern California Institute for Research and Education, Long Beach, California 90822, USA.

Stroke neuroprotection trials suggest that pharmacological manipulations of a single neuroprotective mechanism are generally ineffective and that new approaches, possibly involving simultaneous manipulations of multiple mechanisms, need to be sought. To identify optimal components for such a multipronged approach, we studied NMDA receptor activation-induced cell death in organotypic hippocampal culture preparations as a model of excitotoxicity. Metabotropic group I glutamate receptor (mGluR) activation by their selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), resulted in concentration-dependent reduction of nerve cell susceptibility to NMDA-mediated injury (neuroprotective effect). The neuroprotection was mediated primarily by mGluR1, required phospholipase C activation, was inhibited by cholesterol-containing methyl-beta-cyclodextrin treatment, and occluded by antipsychotic quetiapine. It was associated with suppression of NMDA currents and prolongation of GABA(A) receptor-mediated currents in DHPG-treated cultures. cDNA microarray analysis of 1128 brain-relevant genes revealed that mGluR-mediated neuroprotection was associated with simultaneous activation of endocytosis, and inactivation of inflammation, cell adhesion, cell death, and transcription-related genes. Antisense inhibition of Rab5b, a gene coding for a small GTPase associated with endocytosis, significantly reduced the mGluR-mediated neuroprotection. These findings expand our understanding of the role that mGluRs play in regulation of nerve cell susceptibility to injury and should facilitate the design of novel therapeutic strategies for stroke and other neurodegenerative diseases.
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http://dx.doi.org/10.1196/annals.1344.006DOI Listing
August 2005

Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis.

Neuropharmacology 2005 ;49 Suppl 1:146-56

Department of Mental Health, VA Health Care System, Mental Illness Research and Education Clinical Center, Long Beach, University of California at Irvine, 06/116A, 5901 East Seventh Street Long Beach, CA, 90822 Irvine, CA, USA.

Group I metabotropic glutamate receptor (mGluR) agonist DHPG reduced nerve cell death caused by their exposure to NMDA ("neuroprotective effect") and attenuated NMDA receptor-mediated currents [Blaabjerg, M., Baskys, A., Zimmer, J., Vawter, M. P., 2003b. Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors. Brain Research, Molecular Brain Research 117, 196-205.]. In the present study, we used organotypic hippocampal culture preparation to examine specific phospholipase C (PLC) inhibitor U73122 effects on DHPG-induced neuroprotection, changes in excitatory synaptic transmission associated with the neuroprotective DHPG treatment and a role of group I mGluR ligands in neurogenesis. Results show that short (10 min) DHPG treatment did not result in neuroprotection but significantly depressed field synaptic potentials (fEPSP) in the Schaffer collateral-CA1 pathway. The fEPSP depression was not affected by the PLC inhibitor U73122. In contrast, prolonged (2-h) treatment of cultures with DHPG induced a significant protective effect that was blocked by a PLC inhibitor U73122 but not by its inactive analog U73343. Voltage-clamp measurements of spontaneous miniature excitatory post-synaptic currents (EPSCs) recorded in CA1 neurons from cultures treated with DHPG (10 microM, 2 h) showed a significant reduction of the EPSC amplitude in DHPG-treated but not control (untreated) cultures. This reduction was completely abolished by U73122, suggesting a PLC involvement. Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64. DHPG (100 microM, 72 h) slightly but not significantly increased the number of TOAD-64 positive cells. The mGluR1 antagonists LY367385 (10 microM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 microM, 72 h) had no effect. These data suggest that (1) prolonged activation of group I mGluRs reduces nerve cell susceptibility to excitotoxic injury in a PLC-dependent manner; (2) this reduction is associated with a PLC-dependent depression of excitatory synaptic transmission; and (3) mGluR1 activation may facilitate neurogenesis.
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http://dx.doi.org/10.1016/j.neuropharm.2005.04.029DOI Listing
December 2005

Understanding regulation of nerve cell death by mGluRs as a method for development of successful neuroprotective strategies.

J Neurol Sci 2005 Mar 15;229-230:201-9. Epub 2004 Dec 15.

06/116 VA Health Care System MIRECC, 5901 E. 7th street, Long Beach, CA 90822, USA.

A common cause of nerve cell death often leading to vascular dementia is ischemic stroke. Attempts to develop clinically effective stroke treatment and prevention strategies based on pharmacological manipulations of a single mechanism have not led to clinical success. Analysis of clinical neuroprotection trials suggests that combination treatments may be more effective. To identify optimal components for such treatment, N-methyl-d-aspartate receptor (NMDAR) activation-induced cell death in organotypic hippocampal preparations was studied as a model of neurodegeneration that occurs in association with stroke or vascular dementia. Pharmacological manipulation of metabotropic glutamate receptors mGluR1 and 5 resulted in significant reduction of nerve cell susceptibility to NMDA-induced injury, suggesting that these receptors may function as physiological regulators of neuronal vulnerability. cDNA microarray analysis of over 1000 brain-related genes performed after the neuroprotective activation of group I metabotropic glutamate receptors (mGluRs) revealed a complex pattern of activation and inactivation of seemingly unrelated genes responsible for regulation of neuronal excitability, inflammation, cell death pathways, cell adhesion and transcriptional activation. Combined pharmacological targeting of these processes may provide basis for clinical trials of effective neuroprotective compounds.
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http://dx.doi.org/10.1016/j.jns.2004.11.028DOI Listing
March 2005

Antisense oligonucleotide against GTPase Rab5b inhibits metabotropic agonist DHPG-induced neuroprotection.

Brain Res 2004 Nov;1028(1):59-65

Southern California Institute for Research and Education (SCIRE), USA.

(S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR1 and 5) agonist reduced NMDA-mediated membrane currents, NMDA-induced cell death and up-regulated Rab5b, a small GTPase involved in endocytosis [M. Blaabjerg, A. Baskys, J. Zimmer and M. P. Vawter, Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors, Molec. Brain Res. 117 (2003) 196-205; M. Blaabjerg, L. Fang, J. Zimmer and A. Baskys, Neuroprotection against NMDA excitotoxicity by group I metabotropic glutamate receptors is associated with reduction of NMDA stimulated currents, Experimental Neurol. 183 (2003) 573-580.]. To examine the role of Rab5b on DHPG-mediated neuroprotection in organotypic hippocampal cultures, we developed antisense oligonucleotide targeted to suppress Rab5b translation. Treatment of cultures with the antisense (24 h) but not scrambled sequence oligonucleotide suppressed DHPG-induced increase in Rab5b expression and significantly disrupted DHPG-induced protection against NMDA toxicity in a concentration-dependent manner (0.01-10 nM). Antisense but not scrambled oligonucleotide treatment reduced NMDA toxicity (to 74.4+/-5.9% of control) and this effect could be blocked by protein kinase C inhibitor staurosporine (0.2 microM) or with the protease inhibitor leupeptin (100 microM). Application of osmotic shock followed by K(+) depletion to disrupt endocytosis abolished the protective effect of DHPG. These data suggest that neuroprotection by DHPG against NMDA-mediated injury may involve facilitation of NMDA receptor endocytosis likely stimulated by DHPG-induced increase in Rab5b synthesis.
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http://dx.doi.org/10.1016/j.brainres.2004.08.064DOI Listing
November 2004

Lewy body dementia: the litmus test for neuroleptic sensitivity and extrapyramidal symptoms.

Authors:
Andrius Baskys

J Clin Psychiatry 2004 ;65 Suppl 11:16-22

Department of Psychiatry and Human Behavior, University of California at Irvine, USA.

Lewy body dementia, also referred to as dementia with Lewy bodies (DLB), is a neurodegenerative disorder now considered to be the second most common cause of dementia after Alzheimer's disease. Postmortem findings suggest that DLB accounts for 20% to 34% of all dementia cases and is often underdiagnosed. Salient features of DLB include fluctuations in cognition, perceptual abnormalities (e.g., visual hallucinations), and mild parkinsonism. Other symptoms include frequent falls, nighttime agitation, and depression. DLB symptomatology can be partly explained by the extensive destruction of dopaminergic and acetylcholinergic pathways caused by neurodegeneration. For this reason, DLB patients are especially vulnerable to the antidopaminergic and anticholinergic actions of most conventional antipsychotics, which makes treatment of the psychotic symptoms of DLB extremely difficult. Patients are particularly sensitive to developing extrapyramidal symptoms (EPS) and also to the potentially fatal complication of neuroleptic sensitivity, which affects approximately 50% of DLB patients. Therefore, a need exists for antipsychotic drugs with less propensity to induce EPS and reduced affinity for dopamine and acetylcholine receptors. Here we review studies evaluating the efficacy and tolerability of atypical antipsychotics for the treatment of psychoses associated with DLB. Olanzapine appears to be poorly tolerated, and risperidone has been associated with high risk of neuroleptic malignant syndrome. Clozapine use remains controversial because of its potent anticholinergic action and risk of agranulocytosis. Quetiapine has been shown to reduce psychiatric manifestations of DLB without causing neuroleptic sensitivity or increasing EPS. Hence, quetiapine is an attractive candidate for the treatment of psychoses in DLB and other dementias.
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August 2004

Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors.

Brain Res Mol Brain Res 2003 Oct;117(2):196-205

Anatomy and Neurobiology, University of Southern Denmark, Odense, Denmark.

Stimulation of group I metabotropic glutamate receptors (mGluRs) has been shown to protect against N-methyl-D-aspartate receptor-mediated cell death, but the underlying cellular mechanism is unknown. Using cDNA microarrays we have now compared gene expressions in organotypic hippocampal slice cultures after neuroprotective activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG; 10 microM, 2 h) with untreated control cultures. Total RNA was extracted from the cultures immediately after the neuroprotective treatment, reverse transcribed to cDNA with incorporation of [32]P-dCTP, and then hybridized to the arrays. Of a total of 1128 genes on the Neuroarray, 33 genes displayed significant changes in expression after DHPG-treatment (six up- and 27 downregulated). These genes have been associated with regulation of synaptic excitation, inflammation, cell adhesion, cell death, and transcription. The small GTPase RAB5B associated with endocytosis emerged as a primary candidate gene for neuroprotection, and its expression was confirmed by Western blot analysis and real time polymerase chain reaction. By providing insight into genes involved in neuroprotection these data may help to identify novel therapeutic targets.
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http://dx.doi.org/10.1016/s0169-328x(03)00321-8DOI Listing
October 2003
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