The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

COVID-19 and Pregnancy: A Dangerous Mix for Bone Turnover and Metabolism Biomarkers in Placenta and Colostrum.

Background: In pregnant women, COVID-19 can alter the metabolic environment, cell metabolism, and oxygen supply of trophoblastic cells and, therefore, have a negative influence on essential mechanisms of fetal development. The purpose of this study was to investigate, for the first time, the effects of COVID-19 infection during pregnancy with regard to the bone turnover and endocrine function of several metabolic biomarkers in colostrum and placenta. Methods: One hundred and twenty-four pregnant mothers were recruited from three hospitals between June 2020 and August 2021 and assigned to two groups: Control group and COVID-19 group. Metabolism biomarkers were addressed in placental tissue and colostrum. Results: Lipocalin-2 and resistin levels were higher in the placenta, revealing an underlying pro-inflammatory status in the gestation period for mothers suffering from COVID-19; a decrease in GLP-1 and leptin was also observed in this group. As for adiponectin, resistin, and insulin, their concentrations showed an increase; a decrease in GLP-1, leptin, and PYY was also reported in the colostrum of mothers suffering from COVID-19 compared with the control group. Conclusions: As for bone turnover, placental samples from mothers with COVID-19 showed lower levels of OPG, while DKK-1 increased compared with the control group. Colostrum samples showed higher levels of OPG, SOST, and PTH in the COVID-19 group, a fact that could have noteworthy implications for energy metabolism, fetal skeletal development, and postnatal bone density and mineralization. Further research is needed to explain the pathogenic mechanism of COVID-19 that may affect pregnancy, so as to assess the short-term and long-term outcomes in infants' health.

Exploring the composition and properties of Centella asiatica metabolites and investigating their impact on BSA glycation, LDL oxidation and α-amylase inhibition.

Centella asiatica (L.) Urb. is a small herbaceous plant belonging to the Apiaceae family that is rich in triterpenes, such as asiaticoside and madecassoside. Centella asiatica finds broad application in promoting wound healing, addressing skin disorders, and boosting both memory and cognitive function. Given its extensive therapeutic potential, this study aimed not only to investigate the Centella asiatica ethanolic extract but also to analyze the biological properties of its organic fractions, such as antioxidant antiglycation capacity, which are little explored. We also identified the main bioactive compounds through spectrometry analysis. The ethanolic extract (EE) was obtained through a static maceration for seven days, while organic fractions (HF: hexane fraction; DF: dichloromethane fraction; EAF: ethyl acetate fraction; BF: n-butanol fraction and HMF: hydromethanolic fraction) were obtained via liquid-liquid fractionation. The concentration of phenolic compounds, flavonoids, and tannins in each sample was quantified. Additionally, the antiglycation (BSA/FRU, BSA/MGO, and ARG/MGO models) and antioxidant (FRAP, ORAC, and DPPH) properties, as well as the ability to inhibit LDL oxidation and hepatic tissue peroxidation were evaluated. The inhibition of enzyme activity was also analyzed (α-amylase, α-glycosidase, acetylcholinesterase, and butyrylcholinesterase). We also evaluated the antimicrobial and cytotoxicity against RAW 264.7 macrophages. The main compounds present in the most bioactive fractions were elucidated through ESI FT-ICR MS and HPLC-ESI-MS/MS analysis. In the assessment of antioxidant capacity (FRAP, ORAC, and DPPH), the EAF and BF fractions exhibited notable results, and as they are the phenolic compounds richest fractions, they also inhibited LDL oxidation, protected the hepatic tissue from peroxidation and inhibited α-amylase activity. Regarding glycation models, the EE, EAF, BF, and HMF fractions demonstrated substantial activity in the BSA/FRU model. However, BF was the only fraction that presented non-cytotoxic activity in RAW 264.7 macrophages at all tested concentrations. In conclusion, this study provides valuable insights into the antioxidant, antiglycation, and enzymatic inhibition capacities of the ethanolic extract and organic fractions of Centella asiatica. The findings suggest that further in vivo studies, particularly focusing on the butanol fraction (BF), may be promising routes for future research and potential therapeutic applications.

Promoting diverse perspectives: Addressing health disparities related to Alzheimer's and all dementias.

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well-resourced, non-Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's-related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14-16, 2021, supported in part by the National Institute on Aging (R13 AG072859-01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities.

Genome-wide identification and comparative analysis of the Amino Acid Transporter (AAT) gene family and their roles during Phaseolus vulgaris symbioses.

Amino acid transporters (AATs) are essential integral membrane proteins that serve multiple roles, such as facilitating the transport of amino acids across cell membranes. They play a crucial role in the growth and development of plants. Phaseolus vulgaris, a significant legume crop, serves as a valuable model for studying root symbiosis. In this study, we have conducted an exploration of the AAT gene family in P. vulgaris. In this research, we identified 84 AAT genes within the P. vulgaris genome sequence and categorized them into 12 subfamilies based on their similarity and phylogenetic relationships with AATs found in Arabidopsis and rice. Interestingly, these AAT genes were not evenly distributed across the chromosomes of P. vulgaris . Instead, there was an unusual concentration of these genes located toward the outer edges of chromosomal arms. Upon conducting motif analysis and gene structural analysis, we observed a consistent presence of similar motifs and an intron-exon distribution pattern among the subfamilies. When we analyzed the expression profiles of PvAAT genes, we noted tissue-specific expression patterns. Furthermore, our investigation into AAT gene expression under rhizobial and mycorrhizal symbiotic conditions revealed that certain genes exhibited high levels of expression. Specifically, ATLa5 and LHT2 was notably upregulated under both symbiotic conditions. These findings point towards a potential role of AATs in the context of rhizobial and mycorrhizal symbiosis in P. vulgaris, in addition to their well-established regulatory functions.

Comparison of Metabolic, Lifestyle and Mental Health Parameters in People with Diabetes and Relatives with and without Family Support.

Purpose: To analyze and compare metabolic, lifestyle and mental health parameters in relatives and people-with-T2DM (PDM) with and without support. Patients and Methods: We included 160 patients with <5 years of diagnosis of T2DM, without disabling complications, and non-smokers, attending a multidisciplinary program for diabetes control, and their accompanying relatives. If the patients or relatives abandoned the program, we contacted them and asked to take laboratory tests and answer surveys regarding anxiety, depression, and perception of their family support. Variables distribution was assessed with the Kolmogorov-Smirnov test. We used ANOVA or Kruskal Wallis Tests, according to variable distribution. Frequencies and percentages are used for categorical values and analyzed with a chi-square test. We separated the participants in four groups: relatives with and without support and PDM with and without support. Results: We included 160 participants, age 51±10, and 54.3% women. Total cholesterol (188±36 vs 204±43 vs 170±34 vs 181±35 mg/dL, p=0.001), LDL-cholesterol (113±35 vs 125±27 vs 101 ±30 vs 109±29, p=0.008), and non-HDL cholesterol (143±32 vs 154 ±30 vs 129±33 vs 135±35 mg/dL, p=0.010) were higher in the group without support. Although patients without family support had lower values, they did not achieve metabolic goals. Weight (75±17 vs 77±19 vs 74.2±10.5 vs 90.2±17.3 kg) and body mass index (28.9±4.8 vs 30.1±4.7 vs 27.4±3.3 vs 33±4.3 kg/m2) were higher in PDM without family support (p<0.001 for both). Conclusion: Support in PDM and their families is important in metabolic control. However, raising awareness among family members to screen for diabetes and changes in lifestyle are points to improve. Including the evaluation of social and family support will allow a more complete assessment to identify barriers to achieving goals.

Clinical Outcomes of a Bi-Aspheric Trifocal Diffractive Intraocular Lens.

Purpose: To assess refractive and visual outcomes post-cataract surgery with bilateral implantation of a bi-aspheric diffractive trifocal intraocular lens (IOL). Methods: A total of 24 patients who underwent bilateral implantation with the Asqelio Trifocal IOL TFLIO130C were evaluated at the 6 months postoperative mark. Key outcome measures included refractive error, photopic monocular and binocular uncorrected and corrected distance visual acuity (UDVA, CDVA), uncorrected and corrected intermediate visual acuity (UIVA, CDIVA) at 60 cm, and uncorrected and corrected near visual acuity (UNVA, CDNVA) at 40 cm. Additionally, monocular and binocular CDNVA were assessed under mesopic conditions. Monocular and binocular defocus curves, and binocular contrast sensitivity under photopic and mesopic conditions, with and without glare, were measured. Catquest-9SF and visual symptoms questionnaires were also administered. Results: Postoperative average values of binocular logMAR photopic CDVA, photopic CDIVA, photopic CDNVA and mesopic CDNVA were -0.01±0.06, 0.03±0.09, 0.02±0.05 and 0.19±0.13, respectively. About 100% of patients showed cumulative CDVA and CDNVA ≥20/25, and CDIVA ≥20/32. The average absolute depth-of-focus was about 4.50D. The average postoperative spherical equivalent was 0.05±0.30D and 100% and 93.75% eyes were within ±1.00D and ±0.50D, respectively. Contrast sensitivity was either within or above normal levels under both photopic and mesopic conditions, both with and without glare, except for 12 cpd under mesopic conditions with glare where the mean falls just below the normal range. Questionnaires revealed that 87.5% of patients were either satisfied or very satisfied with their vision after the surgery, and higher percentages for no difficulty in performing different activities, ranging from 70.83% to 95.83%, were reported. Conclusion: This study demonstrates that the bi-aspheric diffractive trifocal IOL yields very good visual performance across distances, fostering high satisfaction levels and minimal difficulties in daily activities.

Novel avenues of tau research.

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

Yoga practice can reduce metabolic syndrome and cardiovascular risk in climacteric women.

To evaluate the effect of yoga on the frequency of MetS and its impact on cardiovascular risk markers in climacteric women. We recruited 84 sedentary women between 40 and 65 years diagnosed with MetS. Participants were randomly assigned to a 24-week yoga intervention or control group. We evaluated the frequency of MetS and changes in the individual components of MetS at baseline and after 24 weeks. We also assessed the impact of yoga practices on cardiovascular risk through the following markers: High-sensitivity C-reactive Protein (hs-CRP), Lipid Accumulation Product (LAP), Visceral Adiposity Index (VAI), and Atherogenic Index of Plasma (AIP). The frequency of MetS reduced significantly after 24 weeks of yoga practice (- 34.1%; p < 0.001). Statistical analysis showed that the frequency of MetS was significantly lower in the yoga group (65.9%; n = 27) than in the control group (93.0%; n = 40) after 24 weeks (p = 0.002). Regarding the individual components of MetS, yoga practitioners had statistically lower waist circumference, systolic blood pressure, triglycerides, HDLc, and glucose serum concentrations than the control group after 24 weeks. Yoga practitioners also had a significant decrease in hs-CRP serum concentrations (3.27 ± 2.95 mg/L vs. 2.52 ± 2.14 mg/L; p = 0.040) and a lower frequency of moderate or high cardiovascular risk (48.8% vs. 34.1%; p = 0.001) after 24 weeks of practice. The yoga group had LAP values significantly lower than the control group after the intervention period (55.8 ± 38.04 vs. 73.9 ± 40.7; p = 0.039). Yoga practice demonstrated to be an effective therapeutic to manage MetS and reduce cardiovascular risk in climacteric women.

Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER).

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.

Brain Health Registry Study Partner Portal: Novel infrastructure for digital, dyadic data collection.

BACKGROUND: In Alzheimer's disease (AD) research, subjective reports of cognitive and functional decline from participant-study partner dyads is an efficient method of assessing cognitive impairment and clinical progression. METHODS: Demographics and subjective cognitive/functional decline (Everyday Cognition Scale [ECog]) scores from dyads enrolled in the Brain Health Registry (BHR) Study Partner Portal were analyzed. Associations between dyad characteristics and both ECog scores and study engagement were investigated. RESULTS: A total of 10,494 BHR participants (mean age = 66.9 ± 12.16 standard deviations, 67.4% female) have enrolled study partners (mean age = 64.3 ± 14.3 standard deviations, 49.3% female), including 8987 dyads with a participant 55 years of age or older. Older and more educated study partners were more likely to complete tasks and return for follow-up. Twenty-five percent to 27% of older adult participants had self and study partner-report ECog scores indicating a possible cognitive impairment. DISCUSSION: The BHR Study Partner Portal is a unique digital tool for capturing dyadic data, with high impact applications in the clinical neuroscience and AD fields. Highlights The Brain Health Registry (BHR) Study Partner Portal is a novel, digital platform of >10,000 dyads. Collection of dyadic online subjective cognitive and functional data is feasible. The portal has good usability as evidenced by positive study partner feedback. The portal is a potential scalable strategy for cognitive impairment screening in older adults.

From dysbiosis to neuropathologies: Toxic effects of glyphosate in zebrafish.

Glyphosate, a globally prevalent herbicide known for its selective inhibition of the shikimate pathway in plants, is now implicated in physiological effects on humans and animals, probably due to its impacts in their gut microbiomes which possess the shikimate pathway. In this study, we investigate the effects of environmentally relevant concentrations of glyphosate on the gut microbiota, neurotransmitter levels, and anxiety in zebrafish. Our findings demonstrate that glyphosate exposure leads to dysbiosis in the zebrafish gut, alterations in central and peripheral serotonin levels, increased dopamine levels in the brain, and notable changes in anxiety and social behavior. While the dysbiosis can be attributed to glyphosate's antimicrobial properties, the observed effects on neurotransmitter levels leading to the reported induction of oxidative stress in the brain indicate a novel and significant mode of action for glyphosate, namely the impairment of the microbiome-gut-axis. While further investigations are necessary to determine the relevance of this mechanism in humans, our findings shed light on the potential explanation for the contradictory reports on the safety of glyphosate for consumers.

Bioactive compounds from the leaves of Maytenus ilicifolia Mart. ex Reissek: Inhibition of LDL oxidation, glycation, lipid peroxidation, target enzymes, and microbial growth.

ETHNOPHARMACOLOGICAL RELEVANCE: Maytenus ilicifolia Mart. ex Reissek, a medicinal plant used for treating gastritis, ulcers, and gastric disorders, possesses therapeutic properties attributed to diverse leaf compounds-terpenoids, alkaloids, flavonoids, phenols, and tannins, reflecting the ethnopharmacological knowledge of traditional users. AIMS OF THE STUDY: We aimed to assess the antioxidant and antiglycant capacities of Maytenus ilicifolia's ethanolic extract and organic fractions, identify bioactive compounds through HPLC-MS/MS analysis, and conduct phytochemical assessments. We also assessed their potential to inhibit digestive and cholinesterase enzymes, mitigate oxidation of human LDL and rat hepatic tissue, and examine their antimicrobial and cytotoxic properties. MATERIALS AND METHODS: Organic fractions (hexane - HF-Mi, dichloromethane - DMF-Mi, ethyl acetate - EAF-Mi, n-butanol - BF-Mi, and hydromethanolic - HMF-Mi) were obtained via liquid-liquid partitioning. Antioxidant (DPPH, FRAP, ORAC) and antiglycant (BSA/FRU, BSA/MGO, ARG/MGO/LDL/MGO models) capacities were tested. Phytochemical analysis employed HPLC-MS/MS. We also studied the inhibitory effects on α-amylase, acetylcholinesterase, butyrylcholinesterase, human LDL and rat hepatic tissue oxidation, antimicrobial activity, and cytotoxicity against RAW 264.7 macrophages. RESULTS: HPLC-ESI-MS/MS identified antioxidant compounds such as catechin, quercetin, and kaempferol derivatives. Ethanolic extract (EE-Mi) and organic fractions demonstrated robust antioxidant and antiglycant activity. EAF-Mi and BF-Mi inhibited α-amylase (2.42 µg/mL and 7.95 µg/mL) compared to acarbose (0.144 µg/mL). Most organic fractions exhibited ∼50% inhibition of acetylcholinesterase and butyrylcholinesterase, rivaling galantamine and rivastigmine. EAF-Mi, BF-Mi, and EE-Mi excelled in inhibiting lipid peroxidation. All fractions, except HMF-Mi, effectively countered LDL oxidation, evidenced by the area under the curve. These fractions protected LDL against lipid peroxidation. CONCLUSION: This study unveils Maytenus ilicifolia's ethanolic extract and organic fractions properties. Through rigorous analysis, we identify bioactive compounds and highlight their antioxidant, antiglycant, enzyme inhibition, and protective properties against oxidative damage. These findings underline its significance in modern pharmacology and its potential applications in healthcare.

Enfermedad pulmonar por Mycobacterium intracellulare, un reto diagnóstico. Reporte de caso / Lung disease due to Mycobacterium intracellulare. A diagnostic challenge, Case report

La incidencia de infección por micobacterias no tuberculosas (MNT) y el número de casos han ido en aumento, especialmente en mujeres y personas mayores, teniendo en los Estados Unidos entre el 2008 y 2015 una incidencia de 4.16 a 6.69 por 100000 entre las mujeres y de 12.70 a 18.37 por 100000, entre los mayores de 65 años. "Los pacientes con compromiso estructural del parénquima pulmonar, antecedente de inmunosupresión o inmunodeficiencia tienen mayor riesgo de desarrollar infección por MNT". Sin embargo, se han presentado informes de pacientes inmunocompetentes en asociación con opacidades nodulares y bronquiectasias. Se trata de una mujer de 79 años con antecedente de tuberculosis pulmonar documentada en dos oportunidades: último proceso infeccioso en el año 2021. Recibió manejo por seis meses de esquema vigente con tetraconjugado. Actualmente acude a consulta con cuadro clínico de más de seis meses de evolución dados por pérdida de peso de más del 10 % en un año, disnea a moderados esfuerzos y tos con expectoración purulenta. Al examen físico se encontró índice de masa corporal (IMC) bajo, tórax hipoexpansible con estertores tipo crépitos en ambos hemitórax. En la tomografía de tórax se evidenciaron bronquiectasias generalizadas, algunas áreas de árbol en gemación y lesiones cavitadas. Se consideró la realización de fibrobroncoscopia con lavado broncoalveolar documentándose baciloscopias negativas, con cultivo positivo para micobacteria no tuberculosa. Se solicitó tipificación de micobacterias con coloración de Kinyoun, y pruebas bioquímicas a partir de cepas de cultivo del lavado broncoalveolar, con reporte positivo para Mycobacterium intracellulare. Se inició por lo tanto manejo con azitromicina 500 mg, rifampicina 600 mg y etambutol 975 mg diarios. Los profesionales sanitarios deben ser conscientes de la posible infección por MNT sobre todo existiendo afectación estructural pulmonar previa, basando el tratamiento en la sospecha clínica y/o las circunstancias epidemiológicas.

The incidence of non-tuberculous mycobacterial (NTM) infection and the number of cases have been increasing, especially in women and the elderly, having EE. Between 2008 and 2015 an incidence of 4.16 to 6.69 per 100,000 among women and from 12.70 to 18.37 per 100,000 among those over 65. "Patients with structural involvement of the pulmonary parenchyma, history of immunosuppression or immunodeficiency have a higher risk of developing NTM infection". However, immunocompetent patients have been reported in association with nodular opacities and bronchiectasis. This is a 79-year-old woman with a history of pulmonary tuberculosis documented on 2 occasions: the last infectious process in 2021. It received management for 6 months of the current tetraconjugate schema. He is currently in consultation with a clinical picture of more than 6 months of evolution given by weight loss of more than 10% in a year, dyspnea to moderate efforts and cough with purulent expectoration. Physical examination revealed low body mass index (BMI) and, a hypoexpandable thorax with a crescent-like sternum in both hemithorax. Chest tomography revealed widespread bronchiectasis, some groaning tree areas and cavitated lesions. Bronchoscopy fibro bronchoscopy with bronchoalveolar lavage has been reported negative bacilloscopies, positive culture for non-tuberculosis mycobacteria. Mycobacteria typing, Kinyoun coloration, and biochemical tests were requested from bronchoalveolar lavage culture strains with positive reports for Mycobacterium intracellulare. Management was therefore initiated with azithromycin 500 mg, rifampin 600 mg and ethambutol 975mg daily. Healthcare professionals should be aware of possible NTM infection especially existing prior lung structural involvement based on clinical suspicion and/or epidemiological circumstances.

Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations.

Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well-defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the basis of biomarker features and the two need to be coordinated. The Alzheimer's Association Research Roundtable (AARR) Spring 2021 meeting discussed the implementation of preclinical AD staging criteria, and provided recommendations for how they may best be incorporated into clinical trials research. Discussion also included what currently available tools for global clinical trials may best define populations in preclinical AD trials, and if are we able to differentiate preclinical from clinical stages of the disease. Well-defined AD staging criteria are key to improving early detection, diagnostics, clinical trial enrollment, and identifying statistically significant clinical changes, and researchers discussed how emerging blood biomarkers may help with more efficient screening in preclinical stages.

Alzheimer's Targeted Treatments: Focus on Amyloid and Inflammation.

Alzheimer's disease (AD) is the major cause of dementia that is now threatening the lives of billions of elderly people on the globe, and recent progress in the elucidation of the pathomechanism of AD is now opening venue to tackle the disease by developing and implementing "disease-modifying therapies" that directly act on the pathophysiology and slow down the progression of neurodegeneration. A recent example is the success of clinical trials of anti-amyloid b antibody drugs, whereas other therapeutic targets, e.g., inflammation and tau, are being actively investigated. In this dual perspective session, we plan to have speakers from leading pharmas in the field representing distinct investments in the AD space, which will be followed by the comment from scientific leadership of the Alzheimer's Association who will speak on behalf of all stakeholders. Neuroscientists participating in the Society for Neuroscience may be able to gain insights into the cutting edge of the therapeutic approaches to AD and neurodegenerative disorders, and discuss future contribution of neuroscience to this field.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

DCAF13 and RNF114 participate in the regulation of early porcine embryo development.

In brief: Ubiquitination plays a pivotal role in a multitude of cellular functions; however, the precise contributions of various ubiquitin ligases in governing early developmental processes remain largely unexplored. This study revealed that the E3 ubiquitin ligases DCAF13 and RNF114 are both necessary for the normal regulation of early porcine embryo development. Abstract: Ubiquitylation is required for normal regulation of many biological functions by modulating several protein facets such as structure, stability, interaction, localization, and degradation. In this study, we explored the roles of two E3 ubiquitin ligases (E3s), the DDB1- and CUL4-associated factor 13 (DCAF13) and the Ring finger protein 114 (RNF114), in the regulation of porcine embryo development. Attenuation of DCAF13 mRNA decreased embryo development at the blastocyst stage, while the development of RNF114-attenuated embryos was not significantly different than that of control embryos. The average number of cells per blastocyst was decreased in DCAF13-attenuated embryos and increased in RNF114-attenuated embryos compared to controls. The relative mRNA abundance of the histone methyltransferase SUV39H1, which regulates histone H3 lysine 9 trimethylation (H3K9me3), was increased in both DCAF13- and RNF114-attenuated embryos, but nuclear immunofluorescence signal for H3K9me3 on day 3 embryos was not significantly altered between attenuated and control embryos. Nuclear immunofluorescence signal for H3K4m3 was decreased in DCAF13-attenuated embryos, but it was increased in RNF114-attenuated embryos compared to controls. Attenuation of DCAF13 and RNF114 mRNAs increased transcript levels for the DNA recombinase RAD51 and decreased expression of phosphorylated histone H2A.X (γH2AX), which suggests an impact on DNA damage repair. In addition, lower mRNA expression of the lysine demethylases 5B (KDM5B) and 5C (KDM5C), both involved in embryo genome activation and DNA repair, was detected in DCAF13-attenuated embryos. These findings indicated that both DCAF13 and RNF114 have important roles in the regulation of the early development of porcine embryos.

Decision making in clinical trials: Interim analyses, innovative design, and biomarkers.

The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease-modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1-2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies.