Publications by authors named "Oscar Lopez"

407 Publications

Systematic Literature Reviews in Kansei Engineering for Product Design-A Comparative Study from 1995 to 2020.

Sensors (Basel) 2021 Sep 30;21(19). Epub 2021 Sep 30.

Department of Mechanical, Energy and Materials Engineering, University Centre of Merida, 06800 Mérida, Spain.

Individual products and models on the market must be specifically differentiated from the rest to meet user demand. In terms of consumer purchasing behaviour, consumers increasingly base their decisions on subjective terms or the impression that the product leaves on them, both in terms of functionality, usability, safety, and price adequacy, and regarding the emotions and feelings that it triggers in them. This demand has lead both Asia and Europe to implement new methodologies to develop new products, such as "emotional design" or Kansei engineering. This paper presents a systematic literature review (SLR) on the most relevant methodologies based on Kansei engineering and their relevant results in the specific discipline of product design, addressing these five questions: (RQ1) How many studies on KE and emotional design are there in the Scopus and Web of Science (WoS) databases from 1995 to February 2021? (RQ2) Which research topics and types of KE are addressed? (RQ3) Who is leading the research on KE and emotional design? (RQ4) What are the benefits and drawbacks of using and applying the methodology? (RQ5) What are the limitations of the current research? We analysed 87 studies focusing on the Kansei methodology used for product design and device technologies (e.g., shape design, actuators, sensors, structure) and aesthetic aspects (e.g., Kansei words selection, the quantification of measured emotions of results, and detected shortcomings), and provided the database with all the collected information. One identified and highlighted sector in the results is the electronic-technological-device sector. Results confirm that this type of methodology has a majority and direct application in these sectors, and they are widely represented in the automotive and electronics industries. Lastly, this SLR provides researchers with a guide for comparative emotional-design work, and facilitates future designers who want to implement emotional design in their work by selecting the specific type according to the results of the SLR.
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http://dx.doi.org/10.3390/s21196532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512474PMC
September 2021

Comparing Pathological Risk Factors for Dementia between Cognitively Normal Japanese and Americans.

Brain Sci 2021 Sep 8;11(9). Epub 2021 Sep 8.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.

The Alzheimer's Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E () genotype. Brain vascular disease burden and brain Aβ burden were measured using white matter lesions (WMLs) and C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aβ standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aβ SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aβ burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aβ burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings.
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http://dx.doi.org/10.3390/brainsci11091180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469296PMC
September 2021

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study.

Cureus 2021 Aug 26;13(8):e17455. Epub 2021 Aug 26.

Critical Care, Centro Medico Punta Cana, Punta Cana, DOM.

Background: Ivermectin is a drug that has been shown to be active against coronavirus disease 19 (COVID-19) in previous studies. Healthcare personnel are highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, we decided to offer them ivermectin as a pre-exposure prophylaxis (PrEP) method.

Purpose: Primary outcome was to measure the number of healthcare workers with symptomatic SARS-CoV-2 infection and a positive reverse transcription polymerase chain reaction (RT-PCR) COVID-19 test in the ivermectin group and in the control group. Secondary outcome was to measure the number of sick healthcare workers with a positive RT-PCR COVID-19 test whose condition deteriorated and required hospitalization and/or an Intensive Care Unit (ICU), or who died, in the ivermectin group and in the control group.

Material And Methods: This observational and retrospective cohort study was carried out in two medical centers, Centro Medico Bournigal (CMBO) in Puerto Plata and Centro Medico Punta Cana (CMPC) in Punta Cana, Dominican Republic. The study began on June 29, 2020, and ended on July 26, 2020. A Statistical Package for Social Sciences (SPSS) Propensity Score Matching procedure was applied in a 1:1 ratio to homogeneously evaluate 271 healthcare personnel that adhered to a PrEP program with ivermectin at a weekly oral (PO) dose of 0.2 mg/kg, and 271 healthcare personnel who did not adhere to the program were assigned as a control group.

Results: In 28 days of follow-up, significant protection of ivermectin preventing the infection from SARS-CoV-2 was observed: 1.8% compared to those who did not take it (6.6%; p-value = 0.006), with a risk reduction of 74% (HR 0.26, 95% CI [0.10,0.71]).  Conclusions: These results suggest that compassionate use of weekly ivermectin could be an option as a preventive method in healthcare workers and as an adjunct to immunizations, while further well-designed randomized controlled trials are developed to facilitate scientific consensus.
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http://dx.doi.org/10.7759/cureus.17455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405705PMC
August 2021

Plasma antioxidants and risk of dementia in older adults.

Alzheimers Dement (N Y) 2021 5;7(1):e12208. Epub 2021 Sep 5.

Department of Nutrition Harvard T.H. Chan School of Public Health Boston Massachusetts USA.

Introduction: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.

Methods: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-β-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD.

Results: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β-carotene, or vitamin E supplements. Higher trans-β-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-β-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29).

Discussion: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.
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http://dx.doi.org/10.1002/trc2.12208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418668PMC
September 2021

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

JAMA Intern Med 2021 Sep 7. Epub 2021 Sep 7.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.

Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.

Design, Setting, And Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.

Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.

Main Outcomes And Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.

Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.

Conclusions And Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
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http://dx.doi.org/10.1001/jamainternmed.2021.5078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424529PMC
September 2021

Metal- and metalloid-based compounds to target and reverse cancer multidrug resistance.

Drug Resist Updat 2021 Sep 6;58:100778. Epub 2021 Aug 6.

Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Electronic address:

Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and even specifically target drug-resistant cancer cells. Based on the paramount importance of platinum drugs in the clinics, two main areas of drug resistance reversal strategies exist: overcoming resistance to platinum drugs as well as multidrug resistance based on ABC efflux pumps. The current review provides an overview of both aspects of drug design and discusses the open questions in the field. The areas of drug resistance covered in this article involve: 1) Altered expression of proteins involved in metal uptake, efflux or intracellular distribution, 2) Enhanced drug efflux via ABC transporters, 3) Altered metabolism in drug-resistant cancer cells, 4) Altered thiol or redox homeostasis, 5) Altered DNA damage recognition and enhanced DNA damage repair, 6) Impaired induction of apoptosis and 7) Altered interaction with the immune system. This review represents the first collection of metal (including platinum, ruthenium, iridium, gold, and copper) and metalloid drugs (e.g. arsenic and selenium) which demonstrated drug resistance reversal activity. A special focus is on compounds characterized by collateral sensitivity of ABC transporter-overexpressing cancer cells. Through this approach, we wish to draw the attention to open research questions in the field. Future investigations are warranted to obtain more insights into the mechanisms of action of the most potent compounds which target specific modalities of drug resistance.
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http://dx.doi.org/10.1016/j.drup.2021.100778DOI Listing
September 2021

Cardiovascular damage phenotypes and all-cause and CVD mortality in older adults.

Ann Epidemiol 2021 11 30;63:35-40. Epub 2021 Jul 30.

School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR; Department of Epidemiology & Pop. Health, Stanford University School of Medicine, Stanford University, Stanford CA; School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR.

Purpose: The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults.

Methods: Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality.

Results: The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59%), cardio-renal (11%), cardiac (15%), multisystem morbidity (6%), and inflammatory (9%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95% CI: 3.95, 6.06).

Conclusions: Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.
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http://dx.doi.org/10.1016/j.annepidem.2021.07.012DOI Listing
November 2021

Examining the causal mediating role of brain pathology on the relationship between diabetes and cognitive impairment: the Cardiovascular Health Study.

J R Stat Soc Ser A Stat Soc 2020 Oct 8;183(4):1705-1726. Epub 2020 May 8.

Johns Hopkins University, Baltimore, and Johns Hopkins Center on Aging and Health, Baltimore, USA.

The paper examines whether leads to incident mild cognitive impairment and dementia through brain hypoperfusion and white matter disease. We performed inverse odds ratio weighted causal mediation analyses to decompose the effect of diabetes on cognitive impairment into direct and indirect effects, and we found that approximately a third of the total effect of diabetes is mediated through vascular-related brain pathology. Our findings lend support for a common aetiological hypothesis regarding incident cognitive impairment, which is that diabetes increases the risk of clinical cognitive impairment in part by impacting the vasculature of the brain.
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http://dx.doi.org/10.1111/rssa.12570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314961PMC
October 2020

Development of tacrine clusters as positively cooperative systems for the inhibition of acetylcholinesterase.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1659-1664

Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway.

The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.
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http://dx.doi.org/10.1080/14756366.2021.1954917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317962PMC
December 2021

Systematic Review: Genetic, Neuroimaging, and Fluids Biomarkers for Frontotemporal Dementia Across Latin America Countries.

Front Neurol 2021 24;12:663407. Epub 2021 Jun 24.

Memory and Neuropsychiatric Clinic (CMYN) Neurology Department, Hospital del Salvador and Faculty of Medicine, University of Chile, Santiago, Chile.

Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.
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http://dx.doi.org/10.3389/fneur.2021.663407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263937PMC
June 2021

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer's Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study.

J Alzheimers Dis 2021 ;82(1):293-305

Computer Science, State University of New York at Binghamton, Binghamton, NY, USA.

Background: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Objective: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD.

Methods: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed.

Results: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections).

Conclusion: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.
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http://dx.doi.org/10.3233/JAD-210199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527573PMC
September 2021

Association Between the APOEɛ2/ɛ4 Genotype and Alzheimer's Disease and Mild Cognitive Impairment Among African Americans.

J Alzheimers Dis 2021 ;81(3):943-948

University of Pittsburgh, School of Nursing, Pittsburgh, PA, USA.

We examined the association between APOEɛ2/ɛ4 with incident Alzheimer's disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer's Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ3/ɛ3 carriers, ɛ2/ɛ4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOEɛ2/ɛ4 genotype is not associated with the incidence of AD and MCI among African Americans.
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http://dx.doi.org/10.3233/JAD-201613DOI Listing
September 2021

Case-cohort study of plasma phospholipid fatty acid profiles, cognitive function, and risk of dementia: a secondary analysis in the Ginkgo Evaluation of Memory Study.

Am J Clin Nutr 2021 07;114(1):154-162

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function.

Objectives: We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk.

Methods: We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics.

Results: Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n-6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: -0.12, -0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n-3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n-3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex.

Conclusions: Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention.
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http://dx.doi.org/10.1093/ajcn/nqab087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277434PMC
July 2021

Direct comparison of the tau PET tracers [F]flortaucipir and [F]MK-6240 in human subjects.

J Nucl Med 2021 Apr 16. Epub 2021 Apr 16.

University of Pittsburgh, United States.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compares two frequently used tau PET tracers, [F]flortaucipir (FTP) and [F]MK-6240, in the same subjects. [F]flortaucipir and [F]MK-6240 scans were collected within two months in 15 elderly subjects varying in terms of clinical diagnosis and cognition. FreeSurfer v5.3 was applied to 3T MR images to segment Braak pathologic regions (I-VI) for PET analyses. Off-target binding was assessed in choroid plexus, meninges, and striatum. SUVR outcomes were determined over 80-100 min ([F]flortaucipir) or 70-90 min ([F]MK-6240) normalized to cerebellar grey matter. Blinded visual interpretation of images was performed by five raters for both medial temporal lobe (MTL) and neocortex (NEO) and an overall (majority) rating determined. Overall visual ratings showed complete concordance between radiotracers for both MTL and NEO. SUVR outcomes were highly correlated (r2>0.92; << 0.001) for all Braak regions except Braak II. The dynamic range of SUVR values in target regions was approximately two-fold higher for [F]MK-6240 compared to [F]flortaucipir. Cerebellar SUV values were similar for [F]MK-6240 and [F]flortaucipir, suggesting that differences in SUVR values are driven by specific signal. Apparent off-target binding in striatum and choroid plexus was often observed with [F]flortaucipir, and most often in meninges with [F]MK-6240. Both [F]MK-6240 and [F]flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in AD and perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. [F]MK-6240 showed greater dynamic range in SUVR estimates, which may be an advantage for detecting very early signal or in longitudinal studies designed to detect small interval changes.
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http://dx.doi.org/10.2967/jnumed.120.254961DOI Listing
April 2021

Dataset of why inclusion matters for Alzheimer's disease biomarker discovery in plasma.

Data Brief 2021 Apr 1;35:106923. Epub 2021 Mar 1.

Department of Chemistry, Vanderbilt University, 5423 Stevenson Center, Nashville, TN 37235, United States.

Here we present a plasma proteomics dataset that was generated to understand the importance of self-reported race for biomarker discovery in Alzheimer's disease. This dataset is related to the article "Why inclusion matters for Alzheimer's disease biomarker discovery in plasma" [1]. Plasma samples were obtained from clinically diagnosed Alzheimer's disease and cognitively normal adults of African American/Black and non-Hispanic White racial and ethnic backgrounds. Plasma was immunodepleted, digested, and isobarically tagged with commercial reagents. Tagged peptides were fractionated using high pH fractionation and resulting fractions analysed by liquid chromatography - mass spectrometry (LC-MS/MS & MS) analysis on an Orbitrap Fusion Lumos mass spectrometer. The resulting data was processed using Proteome Discoverer to produce a list of identified proteins with corresponding tandem mass tag (TMT) intensity information.
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http://dx.doi.org/10.1016/j.dib.2021.106923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988280PMC
April 2021

Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-β in cognitively unimpaired older adults.

Brain Behav Immun 2021 07 15;95:178-189. Epub 2021 Mar 15.

Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

Introduction: Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults.

Methods: A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations.

Results: At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions.

Discussion: In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.
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http://dx.doi.org/10.1016/j.bbi.2021.03.015DOI Listing
July 2021

Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study.

J Thromb Haemost 2021 05 29;19(5):1219-1227. Epub 2021 Mar 29.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.

Objective: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during ≥8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults.

Methods: We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.

Results: Of 20 factors evaluated individually, only higher levels of plasmin-α -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP β = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI β = -0.55, 95% CI: -0.90 to -0.19; FXc β = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.

Conclusions: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.
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http://dx.doi.org/10.1111/jth.15300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136364PMC
May 2021

ENGAGE and EMERGE: Truth and consequences?

Alzheimers Dement 2021 04 3;17(4):692-695. Epub 2021 Mar 3.

Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

The potential benefit of the anti-amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti-amyloid drug therapies. The two trials of 18-month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high-dose EMERGE trial initially also showed no benefit but with longer follow-up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti-amyloid drugs is very substantial as well as the brain amyloid-AD-dementia hypothesis.
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http://dx.doi.org/10.1002/alz.12286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248059PMC
April 2021

Tacrine-sugar mimetic conjugates as enhanced cholinesterase inhibitors.

Org Biomol Chem 2021 03;19(10):2322-2337

Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, NO-4036 Stavanger, Norway.

We have used the Cu(i)-catalyzed azide-alkyne Huisgen cycloaddition reaction to obtain two families of bivalent heterodimers where tacrine is connected to an azasugar or iminosugar, respectively, via linkers of variable length. The heterodimers were investigated as cholinesterase inhibitors and it was found that their activity increased with the length of the linker. Two of the heterodimers were significantly stronger acetylcholinesterase inhibitors than the monomeric tacrine. Molecular modelling indicated that the longer heterodimers fitted better into the active gorge of acetylcholinesterase than the shorter counterparts and the former provided more efficient simultaneous interaction with the tryptophan residues in the catalytic anionic binding site (CAS) and the peripheral anionic binding site (PAS).
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http://dx.doi.org/10.1039/d0ob02588gDOI Listing
March 2021

Dementia in Latin America: Paving the way toward a regional action plan.

Alzheimers Dement 2021 02 20;17(2):295-313. Epub 2020 Nov 20.

Hospital Geral de Fortaleza, University of Fortaleza, Brazil.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.
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http://dx.doi.org/10.1002/alz.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984223PMC
February 2021

[Pneumococcal osteoarticular infections in children admitted to a Pediatric Reference Hospital from Misiones, Argentina. Thirteen years of surveillance].

Rev Argent Microbiol 2021 Jul-Sep;53(3):220-224. Epub 2021 Feb 2.

Universidad Nacional de Misiones, Facultad de Ciencias Exactas Químicas y Naturales, Departamento de Microbiología, Posadas, Misiones, Argentina; Hospital Provincial de Pediatría Dr. Fernando Barreyro, Laboratorio de Bacteriología, Posadas, Misiones, Argentina. Electronic address:

Streptococcus pneumoniae is a rare cause of osteoarticular infections. We describe 5documented cases that occurred in 2005, 2009, 2011, 2015 and 2017 in patients admitted to the Pediatric Provincial Reference Hospital of Misiones. These cases corresponded to a 4-year-old boy and 4 girls aged 11, 10, 6 years and 4 months with a diagnosis of osteomyelitis of the scapula and humerus, arthritis of the hip, ankle and osteomyelitis of the distal fibula. All of them were in good general condition on admission and one of them was seropositive for human immunodeficiency virus. All the recovered isolates were susceptible to β-lactams and only one isolate showed joint resistance to macrolides and tetracycline. Three isolates were serotyped, 2of which carried vaccine serotypes (19F and 7F). Despite its low frequency, the etiology of S.pneumoniae should be considered among the osteoarticular infections. Our findings enhance the role of the Bacteriology laboratory in the diagnosis by microbiological culture and contribute to documenting the epidemiological behavior of this pathogen.
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http://dx.doi.org/10.1016/j.ram.2020.10.003DOI Listing
February 2021

Why Inclusion Matters for Alzheimer's Disease Biomarker Discovery in Plasma.

J Alzheimers Dis 2021 ;79(3):1327-1344

Department of Chemistry, Vanderbilt University, Nashville, TN, USA.

Background: African American/Black adults have a disproportionate incidence of Alzheimer's disease (AD) and are underrepresented in biomarker discovery efforts.

Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults.

Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N = 113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates.

Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86%for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47%for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD.

Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers.
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http://dx.doi.org/10.3233/JAD-201318DOI Listing
September 2021

What Is T+? A Gordian Knot of Tracers, Thresholds, and Topographies.

J Nucl Med 2021 05 31;62(5):614-619. Epub 2020 Dec 31.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials.
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http://dx.doi.org/10.2967/jnumed.120.245423DOI Listing
May 2021

Brownian dynamics simulations of sphere clusters in optical tweezers.

Opt Express 2020 Nov;28(24):36131-36146

Computationally modeling the behavior of wavelength-sized non-spherical particles in optical tweezers can give insight into the existence and stability of trapping equilibria as well as the optical manipulation of such particles more broadly. Here, we report Brownian dynamics simulations of non-spherical particles that account for detailed optical, hydrodynamic, and thermal interactions. We use a T-matrix formalism to calculate the optical forces and torques exerted by focused laser beams on clusters of wavelength-sized spheres, and we incorporate detailed diffusion tensors that capture the anisotropic Brownian motion of the clusters. For two-sphere clusters whose size is comparable to or larger than the wavelength, we observe photokinetic effects in elliptically-polarized beams. We also demonstrate that multiple trapping equilibria exist for a highly asymmetric chiral cluster of seven spheres. Our simulations may lead to practical suggestions for optical trapping and manipulation as well as a deeper understanding of the underlying physics.
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http://dx.doi.org/10.1364/OE.409078DOI Listing
November 2020

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Tuning the activity of iminosugars: novel -alkylated deoxynojirimycin derivatives as strong BuChE inhibitors.

J Enzyme Inhib Med Chem 2021 Dec;36(1):138-146

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Seville, Spain.

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer's agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer's disease through the cholinergic approach.
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http://dx.doi.org/10.1080/14756366.2020.1847101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717699PMC
December 2021

Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance.

Pharmaceuticals (Basel) 2020 Oct 31;13(11). Epub 2020 Oct 31.

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI = 0.88‒2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14‒32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.
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http://dx.doi.org/10.3390/ph13110358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692337PMC
October 2020

Associations of equol-producing status with white matter lesion and amyloid-β deposition in cognitively normal elderly Japanese.

Alzheimers Dement (N Y) 2020 22;6(1):e12089. Epub 2020 Oct 22.

Department of Epidemiology Graduate School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA.

Introduction: Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aβ) deposition.

Methods: From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using C-Pittsburgh compound-B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers.

Results: The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aβ positive, and 51% were equol producers. Equol-producing status (non-producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend  < .01). Equol-producing status was not associated with Aβ status.

Discussion: A randomized-controlled trial of equol targeting WML volume is warranted.
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http://dx.doi.org/10.1002/trc2.12089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580022PMC
October 2020

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 01;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021
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