A call for clinical trial globalization in Alzheimer's disease and related dementia.

BACKGROUND: The burden of Alzheimer's disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms. METHODS: We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and the International Trials Registry Platform. An additional systematic review and expert consensus interviews were conducted to identify barriers for conducting clinical trials in LMICs. FINDINGS: Among 1237 disease-modifying therapies tested in ADRD clinical trials, only 11.6% have been or are conducted in emerging economies (upper-middle income [9.6%] and low-middle income [2.0%]). We identified several limitations for trial implementation including a lack of financial resources, low industry presence, regulatory obstacles, and operational barriers INTERPRETATION: Although LMICs bear the greatest burden of ADRD globally, substantial development of clinical trial platforms to address this inequity and health disparity is lacking.

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer's Symposium.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Neuropsychological assessment in rare pediatric neurogenetic disorders: considerations for cross-cultural clinical research.

Neuropsychological assessment in rare neurodevelopmental disorders has provided clinicians and researchers with a more comprehensive view of natural history as well as opportunities for additional endpoints in treatment trials. While challenges to protocol development have been addressed in the literature, cultural considerations have been overly broad resulting in limited utility when including mixed international samples. Using experiences over the past five years with the development of ten different protocols for neurogenetic rare diseases, this paper presents further considerations for protocol development that are culturally sensitive to international samples. Recommendations are offered across areas including participants from multiple countries; cognitive, sensory and motor impairments; psychometrics; and assessment logistics. A neuropsychological assessment selection checklist that guides researchers and clinicians through considerations and a standard operating procedure that provides guidance on thinking through the assessment process are offered.

Relationship between Residential Segregation, Later-Life Cognition, and Incident Dementia across Race/Ethnicity.

Systemic racism leads to racial/ethnic residential segregation, which can result in health inequities. We examined if the associations between residential segregation and later-life cognition and dementia differed based on segregation measure and by participant race/ethnicity. Tests of memory (n = 4616), language (n = 4333), visuospatial abilities (n = 4557), and incident dementia (n = 4556) were analyzed in older residents of Northern Manhattan, New York (mean age: 75.7 years). Segregation was measured at the block group-level using three indices: dissimilarity, isolation, and interaction. We fit multilevel linear or Cox proportional hazards models and included a race/ethnicity × segregation term to test for differential associations, adjusting for socioeconomic and health factors. Living in block groups with higher proportions of minoritized people was associated with -0.05 SD lower language scores. Living in block groups with higher potential contact between racial/ethnic groups was associated with 0.06-0.1 SD higher language scores. The findings were less pronounced for other cognitive domains and for incident dementia. Non-Hispanic Black adults were most likely to experience negative effects of neighborhood segregation on cognition (language and memory) and dementia. All indices partly capture downstream effects of structural racism (i.e., unequal distributions of wealth/resources) on cognition. Therefore, desegregation and equitable access to resources have the potential to improve later-life cognitive health.

Assessment of Racial/Ethnic Disparities in Timeliness and Comprehensiveness of Dementia Diagnosis in California.

Importance: The US aging population is rapidly becoming more racially and ethnically diverse. Early diagnosis of dementia is a health care priority. Objective: To examine the associations between race/ethnicity and timeliness of dementia diagnosis and comprehensiveness of diagnostic evaluation. Design, Setting, and Participants: This retrospective cross-sectional study used 2013-2015 California Medicare fee-for-service data to examine the associations of race/ethnicity, individual factors, and contextual factors with the timeliness and comprehensiveness of dementia diagnosis. Data from 10 472 unique beneficiaries were analyzed. The sample was selected on the basis of the following criteria: presence of 1 or more claims; no diagnoses of dementia or mild cognitive impairment in 2013 to 2014; continuous enrollment in Medicare Parts A and B; Asian, Black, Hispanic, or White race/ethnicity; and incident diagnoses of dementia or mild cognitive impairment in January through June 2015. Data analyses were conducted from November 1, 2019, through November 10, 2020. Main Outcomes and Measures: Timeliness of diagnosis, defined as incident diagnosis of mild cognitive impairment vs dementia, and comprehensiveness of diagnostic evaluation, defined as presence of the following services in claims within 6 months before or after the incident diagnosis date: specialist evaluation, laboratory testing, and neuroimaging studies. Results: The sample comprised 10 472 unique Medicare beneficiaries with incident diagnoses of dementia or mild cognitive impairment (6504 women [62.1%]; mean [SD] age, 82.9 [8.0] years) and included 993 individuals who identified as Asian (9.5%), 407 as Black (3.9%), 1255 as Hispanic (12.0%), and 7817 as White (74.6%). Compared with White beneficiaries, those who identified as Asian (odds ratio, 0.46; 95% CI, 0.38-0.56), Black (odds ratio, 0.73; 95% CI, 0.56-0.94), or Hispanic (odds ratio, 0.62; 95% CI, 0.52-0.72) were less likely to receive a timely diagnosis. Asian beneficiaries (incidence rate ratio, 0.81; 95% CI, 0.74-0.87) also received fewer diagnostic evaluation elements. These associations remained significant after adjusting for age, sex, comorbidity burden, neighborhood disadvantage, and rurality. Conclusions and Relevance: These findings highlight substantial disparities in the timeliness and comprehensiveness of dementia diagnosis. Public health interventions are needed to achieve equitable care for people living with dementia across all racial/ethnic groups.

Get Moving! Increases in Physical Activity Are Associated With Increasing Functional Connectivity Trajectories in Typically Aging Adults.

Background: Physical activity closely relates to cognition and brain structure as we age. However, the neural mechanisms underlying this relationship in humans remain less clear. Functional connectivity (FC), measured by task-free functional MRI (tf-fMRI) is a dynamic marker of network activity and may be a sensitive indicator of the brain's response to exercise over time. We aimed to test the longitudinal relationship between physical activity and FC trajectories in functionally normal older adults. Methods: Two hundred and twelve functionally normal, longitudinally-followed older adults completed the Physical Activity Scale for the Elderly (PASE) and tf-fMRI scans at each visit [mean = 1.5 visits (range:1-3)]. We studied FC of the default mode network (DMN), frontal-parietal (FP), subcortical networks (SubCort), and frontal-subcortical inter-network connectivity (FS), given that previous studies implicate these regions in age-related changes. Linear mixed-effects models examined the relationship between within-person changes in PASE and FC (in SD units), covarying for age, sex, education and systemic cardiovascular risk factors (heart rate, BMI and systolic blood pressure). We additionally examined models covarying for DTI fractional anisotropy (FA) and mean diffusivity (MD) of tracts underlying networks of interest, as a marker of cerebrovascular disease. Furthermore, we examined the longitudinal relationship between PASE and neuropsychological trajectories. Results: In our first model, within-subject increases in physical activity tracked with increasing SubCort (ß = 0.33, p = 0.007) and FS inter-network (ß = 0.27, p = 0.03) synchrony, while between-subject parameters did not reach significance (ß = -0.042 to -0.07, ps > 0.37). No significant longitudinal associations were observed between PASE and DMN (ß = -0.02 p = 0.89) or FP networks (ß = 0.15, p = 0.23). Adjusting for markers of cerebrovascular health (FA/MD) did not change estimated effects (SubCort: ß = 0.31, p = 0.01, FS inter-network: ß = 0.28, p = 0.03). Associations between changes in physical activity and neuropsychological trajectories were small (ß = -0.14 to 0.002) and did not reach statistical significance (p-values >0.42). Conclusions: Our findings suggest that changes in exercise over time are specifically associated with frontal-subcortical processes in older adults. This relationship appears to be independent of cardio- or cerebrovascular disease, possibly driven by a more direct neural response to exercise.

BHA-CS: A novel cognitive composite for Alzheimer's disease and related disorders.

INTRODUCTION: Composite scores based on psychometrically rigorous cognitive assessments are well suited for early diagnosis and disease monitoring. METHODS: We developed and cross-validated the Brain Health Assessment-Cognitive Score (BHA-CS), based on a brief computerized battery, in 451 cognitively normal (CN) and 399 cognitively impaired (mild cognitive impairment [MCI] or dementia) older adults. We investigated its long-term reliability and reliable change indices at longitudinal follow-up (N = 340), and the association with amyloid beta (Aß) burden in the CN subgroup with Aß positron emission tomography (N = 119). RESULTS: The BHA-CS was accurate at detecting cognitive impairment and exhibited excellent long-term stability. Reliable decline over one year was detected in 75% of participants with dementia, 44% with MCI, and 3% of CN. Among CN, the Aß-positive group showed worse longitudinal performance on the BHA-CS compared to the Aß-negative group. DISCUSSION: The BHA-CS is sensitive to cognitive decline in preclinical and prodromal neurodegenerative disease.

Linguistic and Cultural Acceptability of a Spanish Translation of the Ohio State University Traumatic Brain Injury Identification Method Among Community-Dwelling Spanish-Dominant Older Adults.

OBJECTIVE: Our objective was to (1) evaluate the linguistic and cultural acceptability of a Spanish translation of the Ohio State University traumatic brain injury identification method (OSU TBI-ID) and (2) to assess the usability and acceptability of a tablet-based version of this instrument in a cohort of Spanish-dominant older adults. SETTING: University clinical research center and local community center. PARTICIPANTS: Community-dwelling Spanish-dominant adults age 50 years or older without dementia residing in the Bay Area of California (N=22). DESIGN: Cross-sectional cohort study. MAIN OUTCOME MEASURES: Qualitative assessment of linguistic or cultural acceptability of a Spanish translation of the OSU TBI-ID as well as usability or acceptability of a tablet-based self-administered version of this instrument. RESULTS: The Spanish translation had high linguistic and cultural acceptability and was further optimized based on participant feedback. Cognitive interviews to review survey wording revealed high levels of homogeneity in the clinical definitions and synonyms given by participants-for example, results for the clinical term "Quedó Inconsciente/Pérdida (temporal) de la conciencia" (To be unconscious/[Temporary] loss of consciousness) used in the survey included "perder el conocimiento" (loss of consciousness), "knockeado" (knocked out), "No es que esté dormida, porque está inconsciente, pero su corazón está todavía palpitando" (it's not that they're sleeping, because they're unconscious, but their heart is still palpitating). The tablet interface had low observer-based usability, revealing that participants with <13 years of education (n=6) had more difficulty using the tablet which could be improved with minor changes to the coding of the application and minimal in-person technology support. Acceptability of the tool was low among all but 1 participant. CONCLUSION: This linguistically optimized Spanish translation of the OSU TBI-ID is recommended for use as a semistructured interview among Spanish-dominant older adults. Although the tablet-based instrument may be used by interviewers as an efficient electronic case report form among older adults, further research is needed, particularly among older adults with varying levels of education, to validate this instrument as a self-administered survey.