Alcibiades E. Villarreal

Bio: Alcibiades E. Villarreal is an academic researcher from Acharya Nagarjuna University. The author has contributed to research in topics: Serology & Dementia. The author has an hindex of 7, co-authored 19 publications receiving 311 citations.

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

Abstract: The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

Serum-based protein profiles of Alzheimer's disease and mild cognitive impairment in elderly Hispanics

Abstract: Aim: To describe the biomarker profiles in elderly Panamanians diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI) or no impairment using serum-based biomarkers. Methods: Twenty-four proteins were analyzed using an electrochemiluminescence-based multiplex biomarker assay platform. A biomarker profile was generated using random forest analyses. Results: Two proteins differed among groups: IL-18 and T-lymphocyte-secreted protein I-309. The AD profile was highly accurate and independent of age, gender, education and Apolipoprotein E e4 status. AD and MCI profiles had substantial overlap among the top markers, suggesting common functions in AD and MCI but differences in their relative importance. Conclusion: Our results underscore the potential influence of genetic and environmental differences within Hispanic populations on the proteomic profile of AD.

Cognitive Impairment, Depression, and Cooccurrence of Both among the Elderly in Panama: Differential Associations with Multimorbidity and Functional Limitations.

Abstract: Cognitive impairment and depression are common mental health problems among the elderly, although few studies have examined their cooccurrence in older adults in Latin America. The purpose of this study was to examine cognitive impairment, depression, and cooccurrence of the two conditions and associated factors in a sample of older adults in Panama. This study included 304 community-dwelling elderly (≥ 65 years) individuals. Participants underwent a clinical interview and assessments of cognitive function by the Minimental State Examination and depressive symptoms by the Geriatric Depression Scale. Limitations in basic (BADL) and instrumental (IADL) activities in daily living and the presence of chronic illnesses were recorded. Multinomial regression analysis revealed that cooccurrence of cognitive impairment and depressive symptoms was explained by increasing age (OR: 3.2, 95% CI: 1.20, 8.30), low education (OR: 3.3, 95% CI: 1.33, 8.38), having four or more chronic conditions (OR: 11.5, 95% CI: 2.84, 46.63), and BADL limitations (OR: 5.0, 95% CI: 1.26, 19.68). Less education and limitations in BADL and IADL increased the odds of cognitive impairment alone, while less education and three or more chronic conditions increased the odds of depression alone. These findings underscore the relevance of assessing cognitive impairment in the elderly as part of a long-term approach to managing depression and vice versa.

The Effects of Impaired Cerebral Circulation on Alzheimer's Disease Pathology: Evidence from Animal Studies

Abstract: Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer's disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid-β peptides that form the characteristic plaques in AD brains. Moreover, some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease.

High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Abstract: To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Alzheimer's & Dementia: the Journal of the Alzheimer's Association.

Abstract: i n c y h h i t i a R Last month, Alzheimer’s & Dementia: The Journal of the lzheimer’s Association received acceptance for inclusion n MEDLINE, the bibliographic database of the U.S. Naional Library of Medicine (NLM). Three years since the aunch, this achievement marks an important recognition of he Journal’s scientific merit and contribution to the field of lzheimer’s disease research. The editors, our publishing artners from Elsevier, and our sponsoring colleagues from he Alzheimer’s Association are extremely thankful to the uthors, reviewers, Editorial Board members, and readers or their many valuable contributions. As the official journal of the Alzheimer’s Association, lzheimer’s & Dementia will now be circulated to the active embers of the Association’s new International Society to dvance Alzheimer Research and Treatment (ISTAART) imonthly, as well as other subscribers and libraries. The ournal will continue to cover critical scientific, medical, ocial, and policy issues that investigators and clinicians ace every day, on matters concerning healthy brain aging to ll forms of dementia. Unlike other journals in the field, lzheimer’s & Dementia bridges new thinking across dierse areas of investigation. This interdisciplinary journal rovides the impetus for new scientific initiatives and offers

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Abstract: Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.

Plasma phospho-tau181 increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-positron emission tomography.

Abstract: Introduction We examined and compared plasma phospho-tau181 (pTau181) and total tau: (1) across the Alzheimer's disease (AD) clinical spectrum; (2) in relation to brain amyloid β (Aβ) positron emission tomography (PET), tau PET, and cortical thickness; and (3) as a screening tool for elevated brain Aβ. Methods Participants included 172 cognitively unimpaired, 57 mild cognitively impaired, and 40 AD dementia patients with concurrent Aβ PET (Pittsburgh compound B), tau PET (AV1451), magnetic resonance imaging, plasma total tau, and pTau181. Results Plasma total tau and pTau181 levels were higher in AD dementia patients than those in cognitively unimpaired. Plasma pTau181 was more strongly associated with both Aβ and tau PET. Plasma pTau181 was a more sensitive and specific predictor of elevated brain Aβ than total tau and was as good as, or better than, the combination of age and apolipoprotein E ( APOE ). Discussion Plasma pTau181 may have utility as a biomarker of AD pathophysiology and as a noninvasive screener for elevated brain Aβ.

Current state of Alzheimer's fluid biomarkers.

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.