Background
Hispanics/Latinos (H/Ls) comprise 18% of the U.S. population but only about 5% of NIH‐funded Alzheimer’s disease research participant samples. Exclusion of this ethnic group – the largest ...in the U.S. – limits our interpretation or research findings and understanding of the causes of disparities. The Engaging Communities of Hispanics for Aging Research (ECHAR) Network is a collaborative, transdisciplinary network aimed at engaging, educating, and motivating H/Ls for participation in AD/ADRD research by addressing several barriers to inclusion, including health literacy and AD/ADRD‐related communication. In addition to improving H/L recruitment that will allow us to better examine AD/ADRD health disparities, ECHAR contributes to the development of inclusion science.
Method
Relying on a community‐engaged approach, ECHAR employs a novel method – Boot Camp Translation (BCT) – to translate medical jargon into action‐based, community relevant messages. Over the course of several months, community stakeholders work closely with the research team to develop AD/ADRD communication that is more effectively consumed by local communities. An additional objective of ECHAR is to invite BCT participants to form local community advisory boards (CABs). By joining the research infrastructure, CAB members help develop and guide effective strategies to further improve community relations and inclusion.
Result
We have three established research teams in metropolitan areas with large H/L populations (Houston, TX; Denver, CO; Las Vegas, NV) carrying out BCTs in each of these cities throughout this year. Building off prior work from our group, the BCTs will help answer two questions: (1) What are key messages about AD/ADRD that are locally relevant to these communities? (2) How do we best disseminate these messages to local communities? Our work thus far has demonstrated a need for locally tailored messaging and strategies for dissemination (i.e., precision recruitment).
Conclusion
The ECHAR Network aims to (1) establish CABs and train them on AD/ADRD in three cities; (2) develop key, culturally‐informed, AD/ADRD‐related materials as well as dissemination and evaluation strategies for H/L recruitment; and (3) develop sustainable research infrastructure to enhance outreach by supporting health disparities investigators and pilot grants. This approach is a first of its kind in the context of H/Ls and AD/ADRD recruitment.
The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, ...migration, and cell-cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC
, 1,100 nmol/L) inhibits cancer cell migration and viability and reduces tumor growth, metastasis, and angiogenesis
Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC
values of 103 and 78 nmol/L, respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of STAT3, without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial-to-mesenchymal transition by a loss of cell polarity and inhibition of cell surface actin-based extensions to ultimately result in detachment from the substratum. Prolonged incubation (120 hours) in MBQ-167 decreases metastatic cancer cell viability with a GI
of approximately 130 nmol/L, without affecting noncancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G
-M cell-cycle arrest and subsequent apoptosis, especially of the detached cells.
, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by approximately 90%. In conclusion, MBQ-167 is 10× more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42.
.
Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy ...success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy.
To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins.
Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells.
Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.
Introduction
Cognitive decline is common in Parkinson’s disease (PD). Calculating personalized risk of cognitive decline in PD would allow for appropriate counseling, early intervention with ...available treatments, and inclusion in disease-modifying trials.
Methods
Data were from the Parkinson’s Progression Markers Initiative
de novo
cohort. Baseline scores were calculated for Lifestyle for Brain Health (LIBRA) and the Montreal Parkinson Risk of Dementia Scale (MoPaRDS) per prior literature and preliminary Parkinson’s disease Risk Estimator for Decline In Cognition Tool (pPREDICT) by attributing a point for fourteen posited risk factors. Baseline and 5-year follow-up composite cognitive scores (CCSs) were calculated from a neuropsychological battery and used to define cognitive decliners (PD-decline) versus maintainers (PD-maintain).
Results
The PD-decline group (
n
= 44) had higher LIBRA (6.76 ± 0.57,
p
< 0.05), MoPaRDS (2.45 ± 1.41,
p
< 0.05) and pPREDICT (4.52 ± 1.66,
p
< 0.05) scores compared to the PD-maintain group (
n
= 263; LIBRA 4.98 ± 0.20, MoPaRDS 1.68 ± 1.16, pPREDICT 3.38 ± 1.69). Area-under-the-curve (AUC) for LIBRA was 0.64 (95% confidence interval CI, 0.55–0.73), MoPaRDS was 0.66 (95% CI, 0.58–0.75) and for pPREDICT was 0.68 (95% CI, 0.61–0.76). In linear regression analyses, LIBRA (
p
< 0.05), MoPaRDS (
p
< 0.05) and pPREDICT (
p
< 0.05) predicted change in CCS. Only age stratified by sex (
p
< 0.05) contributed significantly to the model for LIBRA. Age and presence of hallucinations (
p
< 0.05) contributed significantly to the model for MoPaRDS. Male sex, older age, excessive daytime sleepiness, and moderate–severe motor symptoms (all
p
< 0.05) contributed significantly to the model for pPREDICT.
Conclusion
Although MoPaRDS is a PD-specific tool for predicting cognitive decline relying on only clinical features, it does not focus on potentially modifiable risk factors. LIBRA does focus on potentially modifiable risk factors and is associated with prediction of all-cause dementia in some populations, but pPREDICT potentially demonstrates improved performance in cognitive decline risk calculation in individuals with PD and may identify actionable risk factors. As pPREDICT incorporates multiple potentially modifiable risk factors that can be obtained easily in the clinical setting, it is a first step in developing an easily assessable tool for a personalized approach to reduce dementia risk in people with PD.
Apathy was identified as a feature of HIV early in the epidemic; however, there are no systematic reviews of the diverse literature on the sociodemographic and clinical correlates of apathy in HIV ...disease.
The current study adopted a hybrid systematic-narrative review methodology in which we used PRISMA guidelines to identify, summarize, and critique peer-reviewed, empirical studies of apathy in HIV disease in the era of combination antiretroviral therapy.
A total of 34 studies of apathy in persons living with HIV (PLWH) were identified. Findings across these studies showed that apathy was reliably related to the structure of grey and white matter pathways commonly implicated in apathy, poorer everyday functioning, education, and other neuropsychiatric symptoms (e.g., depression). Apathy was not reliably associated with age, sex, race/ethnicity, cognition, and clinical markers of HIV disease.
The current review does not provide rigorous quantitative estimates of clinical correlates of apathy, and the exclusion criteria of non-English and non-peer reviewed publications introduces risk of bias and Type I error.
Apathy occurs at higher rates in PLWH and is linked to neuroanatomical differences, as well as negative outcomes for everyday functions, aspects of neurocognition, and neuropsychiatric symptoms. As such, apathy is an important component to consider in the clinical assessment, diagnosis, and management of neurocognitive disorders in PLWH. Future work is needed to replicate existing findings with larger sample sizes and longitudinal designs, examine apathy as a multi-dimensional construct, and develop evidence-based treatments for apathy in PLWH.
•Apathy occurs at higher rates in persons with HIV disease.•Apathy in HIV is linked to everyday functioning and neuropsychiatric problems.•Assessment, diagnosis, and management of apathy is clinically important in HIV.
Abstract
Objective
Acculturation has been linked to health outcomes in Hispanics/Latinos (H/Ls). However, there is equivocal evidence of a relationship between acculturation and neuropsychological ...outcomes. Various factors limit the ability to subject the evidence to systematic/meta-analytic review. We sought to examine the current state of the literature in the context of H/Ls and neuropsychology and describe the various limitations of measuring acculturation across the lifespan.
Method
Applying a scoping review approach, we identified unique stand-alone (e.g., questionnaires) measures of acculturation. We focused on psychometric (e.g., internal consistency) and other characteristics (e.g., language, structure/format) and description of the validation samples (e.g., cultural background/country of origin).
Results
A total of 40 unique acculturation measures were identified. Measures spanned various domains (e.g., language proficiency, food preference, music choice), and relied heavily on linguistic behavioral characteristics. Internal consistency varied from unacceptable to clinically acceptable ranges. Variable approaches to development and validation were reported. Validation samples varied from 22 to 2,048 respondents (median = 380), most of which represented a general adult population. Only eight measures were validated for use in pediatric populations; none were developed specifically for use with older adults.
Conclusions
Published measures are outdated, evidence highly variable psychometric and methodological weaknesses, and lack a lifespan perspective. Several themes in the types of items considered elemental to the acculturative process are revealed and findings are summarized via an “ABC” framework, categorizing items as antecedents, behaviors, and consequent acculturative changes, that lends itself to clinical and research settings.
Various factors, such as age, cardiovascular concerns, and lifestyle patterns, are associated with risk for cognitive decline and Alzheimer's disease (AD). Risk scores model predictive risk of ...developing a disease (e.g., dementia, stroke). Many of these scores have been primarily developed in largely non-Hispanic/Latino (non-H/L) White samples and little is known about their applicability in ethno-racially diverse populations.
The primary aim was to examine the relationship between three established risk scores and cognitive performance. These relationships were compared across ethnic groups.
We conducted a cross-sectional study with a multi-ethnic, rural-dwelling group of participants (Mage = 61.6±12.6 years, range: 40-96 years; 373F:168M; 39.7% H/L). The Cardiovascular Risk Factors, Aging and Dementia (CAIDE), Framingham Risk Score (FRS), and Washington Heights-Inwood Columbia Aging Project (WHICAP) score were calculated for each participant.
All three scores were significantly associated with cognition in both H/L and non-H/L groups. In H/Ls, cognition was predicted by FRS: β= -0.08, p = 0.022; CAIDE: β= -0.08, p < 0.001; and WHICAP: β= -0.04, p < 0.001. In non-H/Ls, cognition was predicted by FRS: β= -0.11, p < 0.001; CAIDE: β= -0.14, p < 0.001; and WHICAP: β= -0.08, p < 0.001. The strength of this relationship differed between groups for FRS t(246) = -4.61, p < 0.001 and CAIDE t(420) = -3.20, p = 0.001, but not for WHICAP t(384) = -1.03, p = 0.30, which already includes ethnicity in its calculation.
These findings support the utility of these three risk scores in predicting cognition while underscoring the need to account for ethnicity. Moreover, our results highlight the importance of cardiovascular and other demographic factors in predicting cognitive outcomes.
•Trends in anxiety symptom endorsement were detected across demographic factors.•Differential item functioning partially explained differences in anxiety by sex.•The impact of detected differential ...item functioning was not adverse.•The Beck Anxiety Inventory is a valid measure of anxiety for diverse groups.
Evaluating measurement bias is vital to ensure equivalent assessment across diverse groups. One approach for evaluating test bias, differential item functioning (DIF), assesses item-level bias across specified groups by comparing item-level responses between groups that have the same overall score. Previous DIF studies of the Beck Anxiety Inventory (BAI) have only assessed bias across age, sex, and disease duration in monolingual samples. We expand this literature through DIF analysis of the BAI across age, sex, education, ethnicity, cognitive status, and test language.
BAI data from a sample (n = 527, mean age=61.4 ± 12.7, mean education=10.9 ± 4.3, 69.3% female, 41.9% Hispanic/Latin American) from rural communities in West Texas, USA were analyzed. Item response theory (IRT) / logistic ordinal regression DIF was conducted across dichotomized demographic grouping factors. The Mann-Whitney U test and Hedge's g standardized mean differences were calculated before and after adjusting for the impact of DIF.
Significant DIF was demonstrated in 10/21 items. An adverse impact of DIF was not identified when demographics were assessed individually. Adverse DIF was identified for only one participant (1/527, 0.2%) when all demographics were aggregated.
These results might not be generalizable to a sample with broader racial representation, more severe cognitive impairment, and higher levels of anxiety.
Minimal item-level bias was identified across demographic factors considered. These results support prior evidence that the BAI is valid for assessing anxiety across age and sex while contributing new evidence of its clinical relevance across education, ethnicity, cognitive status, and English/Spanish test language.
Cognitive impairment is increasingly recognized as a characteristic feature of Parkinson's disease (PD), yet relatively little is known about its underlying neurobiology. Previous investigations ...suggest that dementia in PD is associated with subcortical atrophy, but similar studies in PD with mild cognitive impairment have been mixed. Variability in cognitive phenotypes and diversity of PD symptoms suggest that a common neuropathological origin results in a multitude of impacts within the brain. These direct and indirect impacts of disease pathology can be investigated using network analysis. Functional connectivity, for instance, may be more sensitive than atrophy to decline in specific cognitive domains in the PD population. Fifty‐eight participants with PD underwent a neuropsychological test battery and scanning with structural and resting state functional MRI in a comprehensive whole‐brain association analysis. To investigate atrophy as a potential marker of impairment, structural gray matter atrophy was associated with cognitive scores in each cognitive domain using voxel‐based morphometry. To investigate connectivity, large‐scale networks were correlated with voxel time series and associated with cognitive scores using distance covariance. Structural atrophy was not associated with any cognitive domain, with the exception of visuospatial measures in primary sensory and motor cortices. In contrast, functional connectivity was associated with attention, executive function, language, learning and memory, visuospatial, and global cognition in the bilateral hippocampus, left putamen, olfactory cortex, and bilateral anterior temporal poles. These preliminary results suggest that cognitive domain‐specific networks in PD are distinct from each other and could provide a network signature for different cognitive phenotypes.
Cognitive impairment in patients Parkinson's disease was tested for association with functional connectivity using fMRI. Intrinsic connectivity network time series were correlated with all voxel time series, and then voxel and network associations with five cognitive test domains were examined using distance covariance. Results suggest that, for cognitive impairment in patients with Parkinson's disease, each cognitive domain is associated with a unique functional connectivity fingerprint.
Objective: Increasing evidence points to mild alterations in everyday functioning early in the course of Alzheimer's disease and related dementias (ADRD), despite prior research suggesting functional ...declines occur primarily in later stages. However, daily function assessment is typically accomplished with subjective self- or informant-report, which can be prone to error due to various factors. Performance-based functional assessments (PBFAs) allow for objective evaluation of daily function abilities, but little is known on their sensitivity to the earliest ADRD-related brain alterations. We aimed to determine the neural correlates of three different PBFAs in a pilot study. Method: A total of 40 older participants (age = 70.9 ± 6.5 years; education = 17.0 ± 2.6 years; 51.5% female; 10.0% non-White; 67.5% cognitively normal) completed standardized PBFAs related to medication management (MM), finances (FIN), and communication abilities (COM). Participants underwent diffusion tensor imaging (DTI) scans, from which mean fractional anisotropy (FA) composite scores of late- (LMF) and early myelinated (EMF) fibers were calculated. Linear regression analyses controlling for age and global cognition were used to assess the relationship of PBFAs with FA. Results: Better performance on MM was associated with higher mean FA on LMF composite (t38 = 2.231, p = .032), while FIN and COM were not (ps > .05). PBFAs were not associated with EMF (p > .05). Conclusions: Our preliminary findings demonstrate better performance on a PBFA of medication management is associated with higher FA in late-myelinated white matter tracts. Despite a small sample size, these results are consistent with growing evidence that performance-based functional assessments may be a useful tool in identifying early changes related to ADRD.
Key Points
Question: Are performance-based functional assessments (PBFAs) sensitive to early white matter changes related to neurodegeneration? Findings: A PBFA related to medication management abilities was more sensitive to early white matter changes than traditional cognitive tests or self-/informant-report measures of daily function. Importance: Demanding functional assessments might be more sensitive than classic assessments to early neuropathological changes. Next Steps: Additional cross-sectional and longitudinal data in a diverse sample are needed to extend these results.
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