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<jats:title>Abstract</jats:title><jats:sec><jats:title>INTRODUCTION</jats:title><jats:p>We compared white matter hyperintensities (WMHs) in early‐onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups in the Longitudinal Early‐Onset Alzheimer's Disease Study.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using <jats:italic>t</jats:italic>‐tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group.</jats:p></jats:sec><jats:sec><jats:title>DISCUSSION</jats:title><jats:p>EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>This study represents a comprehensive characterization of WMHs in sporadic EOAD.</jats:p></jats:list-item> <jats:list-item><jats:p>WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD.</jats:p></jats:list-item> <jats:list-item><jats:p>Greater WMH volumes are associated with worse performance on global cognitive tests.</jats:p></jats:list-item> <jats:list-item><jats:p>EOAD participants have higher WMH volumes compared with CN and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups across all brain regions.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>

<jats:title>Abstract</jats:title><jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Investigation of learning slopes in early‐onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early‐onset dementia with and without β‐amyloid positivity</jats:p></jats:sec><jats:sec><jats:title>METHOD</jats:title><jats:p>Data from 310 participants in the Longitudinal Early‐Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric—the learning ratio (LR)—outperformed other learning slope calculations across analyses</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Learning slopes appear to be sensitive to early‐onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>Learning is impaired in amyloid‐positive EOAD, beyond cognitive severity scores alone.</jats:p></jats:list-item> <jats:list-item><jats:p>Amyloid‐positive EOAD participants perform worse on learning slopes than amyloid‐negative participants.</jats:p></jats:list-item> <jats:list-item><jats:p>Learning ratio appears to be the learning metric of choice for EOAD participants.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>The Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset &lt;65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [<jats:italic>n</jats:italic> = 89], amyloid‐positive EOAD [<jats:italic>n</jats:italic> = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; <jats:italic>n</jats:italic> = 70]).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (<jats:italic>APOE</jats:italic>) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in <jats:italic>APOE</jats:italic> ε4 allele carrier status appearing to be relevant.</jats:p></jats:sec><jats:sec><jats:title>HIGHLIGHTS</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups.</jats:p></jats:list-item> <jats:list-item><jats:p>EOAD participants were homozygous apolipoprotein E (<jats:italic>APOE</jats:italic>) ε4 carriers at higher rates than the EOnonAD group.</jats:p></jats:list-item> <jats:list-item><jats:p>Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>

<jats:title>Abstract</jats:title><jats:p>On September 25 and 26, 2021, the Alzheimer's Association hosted the first meeting focused on people with early‐onset Alzheimer's disease (EOAD)—sometimes referred to as younger onset Alzheimer's disease (AD). Though a diagnosis of AD can be devastating at any age, those with a younger onset—defined as symptoms developing prior to 65 years of age—face unique challenges. EOAD occurs when people are in the prime of their lives, often with multiple responsibilities including careers, community activities, and raising children and caring for older family members. These challenges warrant special consideration and study, yet people with EOAD are often excluded from AD research because of their atypical age of onset. To help fill this gap, we designed and launched the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) to enroll and follow 500 people with EOAD from &gt; 15 sites in the United States, which the National Institute on Aging funded in 2018. The September 2021 meeting was designed to inform people with EOAD and their family members and caregivers about the latest research on the biology of EOAD, treatments in the pipeline, practical considerations about legal and financial arrangements for families, and the support networks available to them. More than 217 registrants attended.</jats:p>