Jack, Clifford R.

AbstractINTRODUCTIONWhile Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care.METHODSIn 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm.RESULTSSignificant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted.DISCUSSIONThe myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

Abstract Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer’s Disease Neuroimaging Initiative, n = 53) and who had Alzheimer’s disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer’s Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer’s disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

Purpose: Population-based evidence in the interrelationships among hearing, brain structure, and cognition is limited. This study aims to investigate the cross-sectional associations of peripheral hearing, brain imaging measures, and cognitive function with speech-in-noise performance among older adults. Method: We studied 602 participants in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) brain magnetic resonance imaging (MRI) ancillary study, including 427 ACHIEVE baseline (2018–2020) participants with hearing loss and 175 Atherosclerosis Risk in Communities Neurocognitive Study Visit 6/7 (2016–2017/2018–2019) participants with normal hearing. Speech-in-noise performance, as outcome of interest, was assessed by the Quick Speech-in-Noise (QuickSIN) test (range: 0–30; higher = better). Predictors of interest included (a) peripheral hearing assessed by pure-tone audiometry; (b) brain imaging measures: structural MRI measures, white matter hyperintensities, and diffusion tensor imaging measures; and (c) cognitive performance assessed by a battery of 10 cognitive tests. All predictors were standardized to z scores. We estimated the differences in QuickSIN associated with every standard deviation ( SD ) worse in each predictor (peripheral hearing, brain imaging, and cognition) using multivariable-adjusted linear regression, adjusting for demographic variables, lifestyle, and disease factors (Model 1), and, additionally, for other predictors to assess independent associations (Model 2). Results: Participants were aged 70–84 years, 56% female, and 17% Black. Every SD worse in better-ear 4-frequency pure-tone average was associated with worse QuickSIN (−4.89, 95% confidence interval, CI [−5.57, −4.21]) when participants had peripheral hearing loss, independent of other predictors. Smaller temporal lobe volume was associated with worse QuickSIN, but the association was not independent of other predictors (−0.30, 95% CI [−0.86, 0.26]). Every SD worse in global cognitive performance was independently associated with worse QuickSIN (−0.90, 95% CI [−1.30, −0.50]). Conclusions: Peripheral hearing and cognitive performance are independently associated with speech-in-noise performance among dementia-free older adults. The ongoing ACHIEVE trial will elucidate the effect of a hearing intervention that includes amplification and auditory rehabilitation on speech-in-noise understanding in older adults. Supplemental Material: https://doi.org/10.23641/asha.25733679

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aβ (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients ( n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Abstract Introduction Meta-analytic studies support that insomnia is a risk factor for cognitive decline and dementia, but limited accounting of confounders reduces their validity. Further, it is unclear whether these associations are driven by specific insomnia phenotypes. In this study, we aimed to assess the relationship between insomnia and longitudinal global cognitive decline in community-dwelling older adults after considering self-reported sleep duration changes and other important characteristics. Methods From the Mayo Clinic Study of Aging (MCSA) cohort, we identified all (age>=50yo) cognitively unimpaired participants at baseline without comorbid neurological disease with at least two previous comprehensive neuropsychological evaluations. Participants with at least two occurrences of insomnia ICD diagnosis (by EMR and Rochester Epidemiological Project data) at least 30 days apart were classified as having insomnia, and those without any instance of diagnosis were considered negative for insomnia. Changes in sleep duration were assessed using the question #16 of BDI-2 and categorized in reduced sleep (yes/no). We fit mixed-effect regression models to assess whether insomnia was associated with standardized global cognitive scores, after adjusting for age, sex, education, APOEe4, composite cardiovascular and metabolic conditions scores, anxiety/depression, reduced sleep, OSA (ICD diagnosis), alcoholism (CAGE≥2), and pain (NSAIDs use). Number of cognitive assessments and time from baseline were included as both fixed and random effects. Multiple interactions (e.g. insomnia*reduced sleep) were included. A backward stepwise procedure maintaining the hierarchical principal for interactions was utilized to reach the most parsimonious models. Results 3063 participants (50.24% males, aged 70±9.73 at baseline) were included. Insomnia alone was not associated with a decrease in global cognition, but when combined with subjective reduction in sleep duration at baseline it was associated with a -0.19 (95% CI: -0.32, -0.07; interaction p=0.01) reduction in global cognitive scores. This was equivalent to approximately 3 additional years of age or 6 cardiometabolic comorbidities at baseline. The effect size was greater than those associated with baseline cognition for having any APOE e4 allele (-0.12) and alcoholism (-0.15). Conclusion Insomnia with reduced sleep duration phenotype is a potentially modifiable risk factor for cognitive decline in older adults. Further studies with objective sleep measures are necessary for objective confirmation. Support (if any) NIA/NIH

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.