Citations

AbstractBackgroundWeakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.MethodIn 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).ResultSignificant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).ConclusionThe contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.

AbstractBackgroundThe higher prevalence and incidence of later life dementia among older Black Americans compared to older White Americans is incompletely understood and understudied. HATS is designed as a companion to the Mayo Clinic Study of Aging (MCSA) with a focus on identification of modifiable cardiovascular contributions to brain health among Black older adults living in urban areas in the upper Midwest.MethodHATS is enrolling 300 U.S. Black Minnesotans from the Twin Cities area aged 55 to 90 years without advanced dementia. Enrollment started 4/2023 and is expected to be complete by the end of 2025. Recruitment is primarily community‐based, led by two community engagement partners, the Linc and the Hue‐MAN Partnership. Electronic health record‐based recruitment will begin in 2024. Data collection includes medical comorbidities, structural and social determinants of health, cardiovascular health, functional status, physical performance, specific and non‐specific blood‐based biomarkers of Alzheimer’s disease, and comprehensive assessment of cognitive and neuropsychiatric status. Brain MRIs will be obtained on a subset of participants. A core component of HATS is distribution of meaningful health information back to participants and their community, guided by input from the HATS community engagement partners. The HATS cohort will serve as an initial effort to develop age and education adjusted normative cognitive test data for urban Black older adults in the upper Midwest.ResultAs of January 22 2024, HATS has enrolled 40 participants with a mean age of 70 years (range 51‐90) and mean education of 15 years. Mean informant‐reported Everyday Cognition scale‐12 score is 1.1 (range 1‐1.7), mean Short Test of Mental Status (STMS) score is 31 (range 24‐37), and CDR sum of boxes scores range from 0‐4 consistent with enrollment of participants with normal and mildly impaired cognition.ConclusionHATS is a novel longitudinal cohort study that is well‐positioned to advance understanding of risk factors for dementia among Black Americans living in urban areas in the upper Midwest. Recruitment is ongoing with a focus on enrolling older adults with a wide range of cognitive function. Ongoing community engagement is a central feature of HATS.

AbstractBackgroundPeople living with dementia have high rates of emergency department (ED) use and hospitalizations. Identifying factors that influence acute care utilization is important. We examined the influence of physical activity levels on risk of hospitalization and emergency department (ED) use in a population of older people living with mild cognitive impairment (MCI) or dementia.MethodsWe included people with a diagnosis of MCI or dementia followed in Community Internal Medicine at Mayo Clinic, age 55 years and older, who had a clinic visit between June 1, 2019 and June 30, 2021 and had completed a social determinants of health questionnaire about physical activity levels. Physical activity was classified based on responses to questions about time spent exercising per week and rated as sufficiently active (≥150 minutes per week), insufficiently active (10‐140 minutes) or physically inactive (0 minutes). The risk of hospitalization and ED visits across physical activity levels was examined using quasi‐Poisson regression and presented as rate ratios (95% confidence interval (CI)), with adjustment for demographics, Charlson Comorbidity Index, marital status, living arrangement and body mass index.ResultsA total of 3090 persons living with MCI (n = 1308) or dementia (n = 1782) were included. People who were physically inactive were more likely to be older, female, not married, obese, have higher comorbid burden and a dementia diagnosis (p<0.001). Hospitalization and ED visit rates in those who were physically inactive were approximately double the rates for the sufficiently active group (p<0.001). Compared with those who were sufficiently active, people who were physically inactive had a significantly higher risk of hospitalization (rate ratio 1.73, 95% CI 1.30‐2.31) and ED visits (rate ratio 1.59, 95% CI 1.26‐2.01).ConclusionsPhysical inactivity in older people living with MCI or dementia is associated with an increased risk of ED visits and hospitalization. Targeted physical activity interventions could potentially impact on acute care utilization in this population. Our findings emphasize an area for public health promotion in people living with MCI or dementia.

AbstractBackgroundMidlife vascular risk factors are associated with an increased risk of dementia. However, the overall contribution of modifiable vascular risk factors in midlife and late‐life to dementia remains unclear. In this study, we quantified population attributable fractions, which account for risk factor prevalence and strength of relative risks, of incident dementia from vascular risk factors measured in midlife and early late‐life.MethodWe used 33 years of prospective cohort data in the Atherosclerosis Risk in Communities Study. Incident dementia (community surveillance and algorithmic diagnosis with expert clinical adjudication) was ascertained from baseline (1987‐1989) through December 31, 2020. We quantified population attributable fractions of incident dementia by age 80 from the combination of hypertension (systolic blood pressure ≥130, diastolic blood pressure ≥80, or use of medication), diabetes (fasting glucose ≥126, non‐fasting glucose ≥200, self‐reported physician diagnosis of diabetes, or use of medication for diabetes/insulin), and self‐reported current cigarette smoking (at least one risk factor versus none) measured at different ages (45‐54 [n = 7,731], 55‐64 [n = 12,273]; 65‐74 [n = 6,660]). We also computed attributable fractions stratified by sex, apolipoprotein ε4 genotype, and self‐reported race.ResultThe prevalence of having one or more of the vascular risk factors was 61.6% (95% CI: 60.5, 62.7%) at age 45‐54 and increased to 77.5% (95% CI: 76.5, 78.5%) by age 65‐74. Population attributable fractions of dementia increased from 22.7% (95% CI: 15.3, 30.1%) for vascular risk factors measured at age 45‐54 to 45.4% (95% CI: 32.5, 58.3%) for vascular risk factors assessed at age 65‐74 (see Figure). Attributable fractions were larger in females, participants without apolipoprotein ε4 alleles, and Black participants (Figure).ConclusionBetween 23% to 45% of incident dementia cases by age 80 were attributed to a combination of hypertension, diabetes, or current smoking up through age 74. Attributable fractions for the combined impact of vascular risk varied by key demographics. Public health strategies targeting modifiable vascular risk factors could reduce dementia risk and increase healthy lifespan.

Abstract Objective To evaluate the effectiveness of multiple decision aid strategies in promoting high quality shared decision making for prevention of stroke in patients with non-valvular atrial fibrillation. Design Cluster randomized controlled trial. Setting Six academic medical centers in the United States. Participants Patient participants were aged ≥18 with a diagnosis of non-valvular atrial fibrillation, at risk for stroke (CHA 2 DS 2 -VASc ≥1 for men, ≥2 for women), and scheduled for a clinical appointment to discuss stroke prevention strategies. Participating clinicians were those who manage stroke prevention strategies for participating patients. Intervention Patients were randomized to use a patient decision aid or usual care; clinicians were randomized to use an encounter decision aid or usual care with all participating patients. Main outcome measures Primary outcome measures were quality of shared decision making measured by OPTION12, knowledge of atrial fibrillation and its management, and decisional conflict. Results 1117 participants across six sites were included in the analysis. Compared with usual care, the combined use of both the patient decision aid and the encounter decision aid improved the quality of shared decision making (adjusted mean difference 12.1 (95% confidence interval (CI) 8.0 to 16.2; P<0.001), improved patients’ knowledge (odds ratio 1.68 (95% CI 1.35 to 2.09; P<0.001), and reduced patients’ decisional conflict (adjusted mean difference −6.3 (95% CI −9.6 to −3.1; P<0.001). Statistically significant improvements were also observed with the encounter decision aid alone versus usual care for all three outcomes and with the patient decision aid alone versus usual care for quality of shared decision making and knowledge. No important differences were observed in treatment choices for stroke prevention or in participants’ satisfaction. No statistically significant difference in the length of visit across study groups was detected. Conclusion Patients who received any decision aid (encounter decision aid, patient decision aid, or both) had lower decisional conflict, better shared decision making, and greater knowledge than those receiving no decision aid, except for the effect of the patient decision aid on decisional conflict, which did not reach statistical significance. The study establishes that use of either pre-visit or in-visit decision aids individually or in combination is advantageous compared with usual care. Trial registration ClinicalTrials.gov NCT04357288 .

Background Sinonasal mucosal melanoma has poor survival despite multimodality treatment. While the impact of immunotherapy (IT) on metastatic cutaneous melanoma is well-defined, there are relatively little data on sinonasal mucosal melanoma. Objective We sought to define immunotherapy outcomes in patients with sinonasal mucosal melanoma. Methods A retrospective cohort study evaluated patients treated with IT during their overall treatment strategy for SNMM. Patient demographics, treatment, and survival outcomes were recorded. Results 52 patients had IT treatment for SNMM from 2000 to 2022, with an average age of 69.1 ± 11.9 years. The most common treatment was surgery with radiation and IT ( n = 26, 50%). Most regimens consisted of a combination of Nivolumab and Ipilimumab ( n = 17, 32.7%) or pembrolizumab ( n = 14, 26.9%). 44.2% of patients experienced reported complications. Overall survival at 1-, 2-, and 5 years was 86.9%, 74.1%, and 39.1%, respectively. Conclusion Approximately half of patients will have a local response following immunotherapy, but it is rare to have improvement at metastatic locations. Further research within our group will assess optimal timing and markers that are predictive of response.

Abstract Background The language symptomology associated with semantic variant primary progressive aphasia (svPPA), namely word finding difficulties with loss of word meaning, leads to multimodal communication difficulties. Given that communication plays an intricate role in establishing and sustaining relationships, svPPA can impact relationships, including those with spouses, in a manner that can only be understood by firsthand experiences. This study aimed to describe a spouse’s experiences of communicating with an individual with svPPA along with the role of communication supports and expectations for speech‐language therapy. Method A semi‐structured interview using open‐ended questions was conducted with the spouse of an individual with svPPA. The interview transcript was reviewed and analyzed using thematic analysis by both authors. Result The themes that emerged when discussing living with an individual with svPPA included: the role of communication in their prior life; changes in communication and behavior; emotional impact; adjustments and accommodations; and community engagement and supports. Themes associated with communication supports included: external tools; adaptive strategies; individualization and adaptation; and utility. The spouse in the current study described a tool, specifically a notebook in the form of a dictionary that was initiated and developed by the individual with svPPA. The tool increased his confidence in communication as it aided comprehension and recognition of words. Caregiver inclusion, learning about the patient, and evolving strategies are themes surrounding the spouse’s expectations from speech therapy. Conclusion The study revealed challenges in the spouse of an individual with svPPA understanding and expressing thoughts to her partner, which resulted in feeling more distant as well as changes in social dynamics. The study also describes the benefits of communication supports for both the spouse and the individual with svPPA. Additionally, the study revealed the important role the SLP, and the community plays in enhancing well‐being. Although the findings from the current study cannot be ubiquitously generalized, it provides insight into the changing dynamics of a couple navigating svPPA and reiterates the importance of including patients and their care partners in treatment planning and the benefit of communication supports and speech therapy across the disease course.

AbstractBackgroundThe HEAD study aims to collect a large dataset of multiple tau‐PET tracers to provide robust anchor values for tau‐PET harmonization. Here, we tested the hypothesis that anchoring two tau tracer uptake values using head‐to‐head measurements has the potential to generate an accurate universal tau‐PET scale, named Uniτ(tau).MethodsWe assessed 200 individuals across the aging and AD spectrum (Training:HEAD data freeze 2.0, n=185; Testing:UPitt dataset (Gogola et al.), n=15) with [18F]Flortaucipir and [18F]MK‐6240 tau‐PET. SUVRs were processed to a common 8mm FWHM, with inferior cerebellar gray matter as the reference region (Pascoal et al.). Uniτ explored two anchoring/harmonization methods. First, we examined within‐tracer anchoring by creating anchor values based on the mean SUVR of Youngs (<25 years) and 95th percentile voxels from cognitively impaired individuals. Second, we explored within‐ plus between‐tracer anchoring, employing linear (e.g., piecewise) and non‐linear regressions. To address the inherent problem of discontinuity of piecewise transformations, we implemented two smoothing methods at the inflection point between equations, transforming them into a continuous function.ResultsUniτ scale anchoring within‐tracer resulted in similar estimates for high values, but less accurate in the lower range (Figure 1,2). Anchoring within‐ plus between‐tracer improved estimate consistency, with the piecewise transformation generating the best results. The piecewise smoothing equation yielded estimates comparable to those obtained from the piecewise method without smoothing. This allowed for the use of a single formula. In addition, this leads to more robust results when the goal is to study longitudinal changes in the scale (data not shown). UPitt testing dataset showed similar results to the training set (Figure 3).ConclusionOur preliminary findings suggest that anchoring tau‐PET values both within and between tracers has the potential to harmonize tau‐PET tracers, while preserving their characteristics. Currently, piecewise smoothing is the preferred method for Uniτ, but we are continuously fine‐tuning scale parameters as we acquire more data. The final scale parameters will be determined based on extensive training and testing data from multiple tracers. This cautious methodology holds the promise of delivering reliable, robust, and reproducible results, ensuring safe usage of the scale in clinical trials, and potentially paving the way for future use in clinical practice.

AbstractBackgroundThe association between [18F]Flortaucipir (FTP) and [18F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.Method113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [18F]MK6240, [18F]FTP and Aß‐PET scans. Images were processed using the inferior cerebellar grey (CG) as the reference region, with subjects categorized by Aß status. Stepwise linear fitting identified off‐target (OFF) regions impacting tracer associations within the whole cortex, Braak and temporal‐meta regions of interest (ROIs). OFF regions included were a composite mask (pallidum, putamen, caudate ‐ PPC) to address collinearity in subcortical nuclei, as well as the region with the greatest partial volume effects (PVE) on the ROI (meninges, choroid plexus, and the hotspot medial to entorhinal cortices (EC)). Akaike information criteria (AIC) analyses tested linear models with various off‐target regions.ResultPPC and PVE regions influenced tracer association in on‐target regions. PPC binding is associated with age. PPC and meninges retention, along with Aß status interaction, demonstrated the best model fit for the whole cortex (Figure 1). Weighting factors derived from the whole cortex model were applied to Braak regions and temporal meta‐ROI. Braak III‐VI and temporal‐meta ROI showed optimal models including OFF regions and Aß status interaction (Figure 2). Forcing the whole equation gave optimal results. For Braak I (EC), adding the OFF covariates only was the best model. For Braak II (hippocampus), the best model included OFF regions and the interaction with Aß status (Figure 2). Forcing the whole cortex equation onto Braak I and Braak II yielded suboptimal fits.ConclusionHarmonizing tau‐PET tracers involves considering significant covariates. Integrating meningeal and age‐related off‐target regions enhances [18F]MK6240 and [18F]FTP association in on‐target regions, further improved by Aß status inclusion. While the whole cortex model may not suit early ROI, it proves effective for Braak III and beyond. Creating an equation for tracer translation necessitates incorporating meningeal and subnuclei off‐target retention.

AbstractBackgroundNormative models (NM) of brain metrics based on large, diverse populations offer novel strategies to detect individual brain abnormalities. To create an age‐dependent statistical model of brain microstructure over the human lifespan, we built the largest multi‐site NM of white matter (WM) diffusion tensor imaging (DTI) metrics based on 54,591 subjects. We used state‐of‐the‐art tools to adjust for site‐dependent effects.MethodWe used Hierarchical Bayesian Regression (HBR) to determine the age trajectory and lifespan centile curves (ages 3‐100 years) by merging data from different sections of the lifespan. We analyzed 19 international public datasets with the ENIGMA‐DTI protocol. Mean fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AxD, RD) were extracted for 21 bilateral ROIs from the JHU‐WM atlas and the whole WM skeleton. Regressions were run with each metric per ROI as a function of age and sex, and the DTI protocol as the batch effect (37 protocols). Z‐scores were derived for 81 patients with Alzheimer’s disease (AD; mean age: 77y±8.4, 46M/35F) and 225 MCI participants (mean age: 75.1y±8.1, 127M/98F) and extreme deviations (Z>|2|) were quantified for each condition. ROI‐wise areas under the ROC curve were calculated to determine the classification accuracy of the Z‐scores.ResultThe average FA for the overall WM skeleton reached its peak value at 27 years, with minima for MD, RD and AxD at 47, 42 and 54 years, respectively. We found extreme FA deviations (Z>2) for MCI (AUC=0.67) and AD (AUC=0.66) in the genu of the corpus callosum, extreme RD deviations (Z<2) in the tapetum (AUC=0.73) and Extreme AxD deviations (Z>2) for MCI in the superior longitudinal fasciculus (AUC=0.65). See Figures 1 & 2.ConclusionNM of brain microstructure with HBR yielded lifespan trajectories for widely‐used DTI metrics. By pooling large scale multi‐site dMRI to create a statistical reference, single subject deviations are detectable across the lifespan for AD and MCI. These NM will be publicly available to the research community.