Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

{"title":"Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease","authors":"Brittani R. Price,&nbsp;Keenan A. Walker,&nbsp;Jaclyn M. Eissman,&nbsp;Vidyani Suryadevara,&nbsp;Lindsey N. Sime,&nbsp;Timothy J. Hohman,&nbsp;Marcia N. Gordon","doi":"10.1002/trc2.70139","DOIUrl":"10.1002/trc2.70139","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone–immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).</li>\u0000 \u0000 <li>Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.</li>\u0000 \u0000 <li>Sex differences in innate and adaptive immunity could contribute to AD progression.</li>\u0000 \u0000 <li>Effects of menopausal hormone therapy on immunity in AD remain understudied.</li>\u0000 \u0000 <li>Future studies to explore sex differences in immune function during AD are needed.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health and Aging Brain Study–Health Disparities (HABS-HD) methods and partner characteristics","authors":"Melissa E. Petersen,&nbsp;Zhengyang Zhou,&nbsp;James R. Hall,&nbsp;Nicole Phillips,&nbsp;Karin L. Meeker,&nbsp;Matthew T. Borzage,&nbsp;Meredith N. Braskie,&nbsp;Alexandra L. Clark,&nbsp;Yonggang Shi,&nbsp;Robert A. Rissman,&nbsp;Fan Zhang,&nbsp;Raul Vintimilla,&nbsp;Antonio Casas,&nbsp;Jill Rhodes,&nbsp;Robert C. Barber,&nbsp;Leigh Johnson,&nbsp;Kristine Yaffe,&nbsp;Arthur W. Toga,&nbsp;Sid E. O'Bryant,&nbsp;for the HABS-HD Study Team","doi":"10.1002/trc2.70140","DOIUrl":"10.1002/trc2.70140","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The Health and Aging Brain Study–Health Disparities (HABS-HD) is an ongoing prospective study aimed at understanding brain health and aging. The current work provides a description of the cohort baseline characteristics and outlines the study methodology.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We analyzed available data from &lt;i&gt;n&lt;/i&gt; = 1066 non-Hispanic Black (NHB), &lt;i&gt;n&lt;/i&gt; = 1425 Hispanic, and &lt;i&gt;n&lt;/i&gt; = 1349 non-Hispanic White (NHW) partners who were actively enrolled in HABS-HD. Descriptive statistics are presented for each racial/ethnic group across demographic, medical, and diagnostic characteristics. Differences in select amyloid (A), tau (T), and neurodegenerative (N) biomarkers spanning proteomic and neuroimaging were examined along with groupwise differences for cognitive test performance and select social determinants of health (SDoH) factors.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The characteristics of the cohort revealed significant groupwise differences in age, education, sex, and cognitive diagnosis. Higher rates of cognitive impairment (mild cognitive impairment [MCI] and dementia) were found in NHB and Hispanic compared to NHW partners, despite the latter group being older. There were also higher rates of hypertension and diabetes among NHB and Hispanic compared to NHW partners. Differences were also found across many plasma (A/T[N]) biomarkers and select neuroimaging measures, including meta-region of interest and white matter hyperintensities. Positron emission tomography amyloid positivity rates (but not tau positivity) were found to differ, with higher rates observed among NHW (15% amyloid positivity) compared to NHB (3%) partners. Groups also differed by select SDoH factors, including household income, insurance, having a health-care provider, and Area Deprivation Index. All cognitive measures also revealed groupwise differences.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The baseline cohort characteristics for HABS-HD reveal significant group differences spanning demographic, medical, cognitive, and biological factors (including A/T[N] biomarkers), which are all critical to understand as they relate to aging and age-related diseases.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The Health and Aging Brain Study–Health Disparities (HABS-HD) cohort baseline characteristics and study methodol","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144814823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles","authors":"Mackenzie Jarchow,&nbsp;Ira Driscoll,&nbsp;Brianne M. Breidenbach,&nbsp;Noah Cook,&nbsp;Catherine L. Gallagher,&nbsp;Sterling C. Johnson,&nbsp;Sanjay Asthana,&nbsp;Bruce P. Hermann,&nbsp;Mark A. Sager,&nbsp;Kaj Blennow,&nbsp;Henrik Zetterberg,&nbsp;Cynthia M. Carlsson,&nbsp;Gwendlyn Kollmorgen,&nbsp;Clara Quijano-Rubio,&nbsp;Dane B. Cook,&nbsp;Dena B. Dubal,&nbsp;Ozioma C. Okonkwo","doi":"10.1002/trc2.70133","DOIUrl":"10.1002/trc2.70133","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves neuroinflammation, neurodegeneration, and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the &lt;i&gt;KLOTHO&lt;/i&gt; gene (KL-VS&lt;sub&gt;HET&lt;/sub&gt;). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes related to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO&lt;sub&gt;2peak&lt;/sub&gt;)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS&lt;sub&gt;HET&lt;/sub&gt; compared to noncarriers (KL-VS&lt;sub&gt;NC&lt;/sub&gt;).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (&lt;i&gt;n&lt;/i&gt; = 136; Mean&lt;sub&gt;AGE&lt;/sub&gt;(SD) = 62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, apolipoprotein E (&lt;i&gt;APOE)&lt;/i&gt; 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO&lt;sub&gt;2peak&lt;/sub&gt; and &lt;i&gt;KLOTHO&lt;/i&gt; genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau&lt;sub&gt;181&lt;/sub&gt;], Aβ&lt;sub&gt;42&lt;/sub&gt;/Aβ&lt;sub&gt;40&lt;/sub&gt;, pTau&lt;sub&gt;181&lt;/sub&gt;/Aβ&lt;sub&gt;42&lt;/sub&gt;). Analyses were repeated for CSF biomarkers of &lt;span&gt;neurodegeneration&lt;/span&gt; (total tau [tTau], α-synuclein [α-syn], neurofilament light polypeptide [NfL]), &lt;span&gt;synaptic dysfunction&lt;/span&gt; (neurogranin [Ng]), and &lt;span&gt;neuroinflammation&lt;/span&gt; (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed in myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], interleukin 6 [IL-6], S100 calcium-binding protein B [S100B]).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The interaction between VO&lt;sub&gt;2peak&lt;/sub&gt; and KL-VS&lt;sub&gt;HET&lt;/sub&gt; was significant for tTau (&lt;i&gt;p&lt;/i&gt; = 0.05), pTau&lt;sub&gt;181&lt;/sub&gt; (&lt;i&gt;p&lt;/i&gt; = 0.03), Ng (&lt;i&gt;p&lt;/i&gt; = 0.02), sTREM2 (&lt;i&gt;p&lt;/i&gt; = 0.03), and YKL-40 (&lt;i&gt;p&lt;/i&gt; = 0.03), such that lower levels of each biomarker were observed for KL-VS&lt;sub&gt;HET&lt;/sub&gt; who were more fit. No significant KL-VSxVO&lt;sub&gt;2peak&lt;/sub&gt; interactions were observed for Aβ&lt;sub&gt;42&lt;/sub&gt;/Aβ&lt;sub&gt;40&lt;/sub&gt;, pTau&lt;sub&gt;181&lt;/sub&gt;/Aβ&lt;sub&gt;42&lt;/sub&gt;, α-syn, NfL, GFAP, IL-6 or S100B (all &lt;i&gt;P&lt;/i&gt;s&gt;0.09).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; CONCLUSIONS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We r","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing MCID for evaluating clinical relevance of AD therapeutic interventions","authors":"Jamie L. Hamilton,&nbsp;Rebecca L. M. Fuller,&nbsp;Noopur Modi,&nbsp;Cristina Sampaio","doi":"10.1002/trc2.70138","DOIUrl":"10.1002/trc2.70138","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>With the recent approval of disease-modifying treatments for mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) by the United States Food and Drug Administration (FDA), Medicines and Healthcare products Regulatory Agency (MHRA), European Medicine Agency's Committee for Medicinal Products for Human Use (EMA/CHMP) entities, there is a growing sense of urgency and renewed efforts to reassess and understand what constitutes a clinically meaningful benefit in the context of new treatments for AD care, despite the discordance between regulatory entities in regulatory decision-making. While the concept of minimal clinically important difference (MCID) was introduced many years ago, there remains an ongoing debate about how best to evaluate and define clinical benefit in the context of emerging and new therapies for dementia. In this perspective piece, we assess how MCID can be applied to common endpoints and identify areas where MCID application or generation could be useful to enable a better valuation of therapeutic innovation. We offer recommendations for greater consistency in measures used to define MCID, and encourage the prioritized use of patient-reported measures in early AD to build fieldwide consensus for MCID estimation methods and application in AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>There is no gold standard or field-wide consensus on what constitutes a clinically meaningful change in Alzheimer's disease (AD) progression trajectories.</li>\u0000 \u0000 <li>Anchor-based minimal clinically important difference (MCID) may be used as a tool that can be leveraged for greater contextualization of the clinical relevance of a treatment effect.</li>\u0000 \u0000 <li>Patient-reported outcomes (PROs) should be used to define MCID, particularly within mild cognitive impairment (MCI), prodrome/mild AD groups.</li>\u0000 \u0000 <li>Greater consistency is needed in the outcome measures used to detect cognitive and functional change to define MCID. This will enable MCID comparisons and support replications of MCID estimates across AD populations.</li>\u0000 \u0000 <li>Observational data can augment the clinical characterization and impact of treatment effect and help establish a “ground truth” MCID.</li>\u0000 \u0000 <li>MCID estimates for AD outcomes may be used in regulatory submissions to help contextualize the importance of a statistically significant treatment effect.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"White matter microstructure mediates the association between cardiorespiratory fitness and cognitive performance in older adults","authors":"Emma M. Tinney,&nbsp;Aaron E. L. Warren,&nbsp;Amanda O'Brien,&nbsp;Hannah Odom,&nbsp;Meishan Ai,&nbsp;Bradley P. Sutton,&nbsp;Shivangi Jain,&nbsp;Chaeryon Kang,&nbsp;Haiqing Huang,&nbsp;Lu Wan,&nbsp;Lauren E. Oberlin,&nbsp;George Grove,&nbsp;John M. Jakicic,&nbsp;Audrey M. Collins,&nbsp;Kelsey R. Sewell,&nbsp;Jeffrey M. Burns,&nbsp;Eric D. Vidoni,&nbsp;Edward McAuley,&nbsp;Arthur F. Kramer,&nbsp;Kirk I. Erickson,&nbsp;Charles H. Hillman","doi":"10.1002/trc2.70125","DOIUrl":"10.1002/trc2.70125","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Here, we leveraged a novel analysis framework capable of resolving individual fiber populations at the within-voxel level—fixel-based analysis (FBA)—to analyze three metrics of white matter organization from diffusion-weighted MRI scans: fiber density (FD), fiber cross-section (FC), and their combined measure (FDC). Using a cross-sectional sample of 636 cognitively unimpaired older adults aged 65 to 80 years (mean age = 69.8 years; 71% female), we hypothesized that FBA metrics would be associated with CRF and that this variation in FBA metrics would mediate associations between CRF and cognitive performance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In whole-brain analyses, higher CRF was associated with greater FD, FC, and FDC. Furthermore, these FBA-derived metrics statistically mediated the relationship between CRF and cognitive performance in the domains of visuospatial abilities, processing speed, working memory, and executive function/attentional control, but not episodic memory.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings highlight the potential for CRF in the preservation of multiple aspects of cognition as a function of white matter micro- and macro-structural properties. Our results provide novel insights into the neurobiological mechanisms of fitness-related cognitive resilience.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Higher cardiorespiratory fitness (CRF) is linked to better white matter integrity in older adults.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Fixel-based analysis reveals CRF associations with fiber density and cross-section.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-human positron emission tomography study of intranasal insulin in aging and MCI","authors":"Kiran K. Solingapuram Sai,&nbsp;Jennifer M. Erichsen,&nbsp;Krishna K. Gollapelli,&nbsp;Ivan Krizan,&nbsp;Mack Miller,&nbsp;Naresh Damuka,&nbsp;Thomas C. Register,&nbsp;Courtney Sutphen,&nbsp;Suzanne Craft","doi":"10.1002/trc2.70123","DOIUrl":"10.1002/trc2.70123","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Intranasal insulin (INI) is being explored to treat Alzheimer's disease and other conditions. The method of intranasal delivery has been shown to affect outcomes, requiring validation prior to clinical investigation. We conducted a first-in-human positron emission tomography (PET) study using a novel radiotracer, [&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-NOTA-insulin, administered intranasally with a specialized device (Aptar Cartridge Pump System) to evaluate the kinetics of insulin uptake and distribution in the brain.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;[&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-NOTA-insulin was intranasally administered (≈ 0.037 ± 0.001 GBq) to adults who were cognitively normal (CN, &lt;i&gt;n&lt;/i&gt; = 7) or had mild cognitive impairment (MCI, &lt;i&gt;n&lt;/i&gt; = 9). A dynamic 40 minute brain PET scan, followed by a 15 minute whole-body PET/computed tomography scan was acquired. Physiologic parameters were measured at baseline, during, and post-scan. Brain uptake and time-activity curves were determined for fused PET/magnetic resonance imaging images.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Radiochemistry was optimized for producing [&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-NOTA-insulin with high radiochemical purity (&gt; 99%) and molar activity (95 GBq/µmol). No safety issues were identified. PMOD analyses showed whole-brain average standard uptake value (SUV;g/mL) ≈ 0.68 ± 0.01; radioactivity in the brain and whole body were undetectable by 40 and 60 minutes post radiotracer administration respectively. Elevated (&lt;i&gt;p&lt;/i&gt; &lt; 0.01) SUVs averaged over the 40 minute period after INI administration were observed for 11 regions: olfactory cortex, hippocampus, parahippocampus, amygdala, superior and middle temporal pole, insula, caudate, putamen, thalamus, and anterior cingulum. Time-activity curves showed different uptake patterns for MCI and CN groups. Baseline pulse pressure, plasma insulin, and phosphorylated tau217 correlated with uptake for subgroups based on cognitive status and sex.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Discussion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;[&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-NOTA-insulin is a safe and effective PET radiotracer for validating intranasal delivery of insulin to the brain in humans and revealed significant insulin uptake in multiple brain regions. Future studies should incorporate such validation before initiating clinical trials of intranasally administered agents. Further investigation of mechanisms underlying differences in INI uptake among clinical subgroups is also needed.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive intervention combining group and personalized language therapy in primary progressive aphasia: Quantitative and qualitative findings","authors":"Tijana Simic,&nbsp;Laura Laird,&nbsp;Rudra Patel,&nbsp;Monica Lavoie,&nbsp;Maria Martinez,&nbsp;Paula Gosse,&nbsp;Alexandra Santos,&nbsp;David Tang-Wai,&nbsp;Regina Jokel,&nbsp;Carmela Tartaglia,&nbsp;Elizabeth Rochon","doi":"10.1002/trc2.70132","DOIUrl":"10.1002/trc2.70132","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Increasingly, studies are demonstrating language and communication improvement after behavioral interventions for primary progressive aphasia (PPA), and the caregiver perspective has been highlighted as critically important to determining treatment success in this population. This is an exploratory study investigating a comprehensive, person-centered intervention promoting everyday communication, functional independence, and quality of life for people with PPA (PwPPA) and their caregivers.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Four intervention programs were run separately in 6 to 8 week blocks with a total of 14 dyads (PwPPA and caregiver) enrolled. Group sessions lasted 2 hours and included communication strategy training, PPA education from multidisciplinary experts, speech therapy for PwPPA, and a support group for caregivers (blocks 1 and 2). Personalized language exercises were assigned for home practice, using apps or paper-and-pencil tasks. Quantitative and qualitative outcomes were measured before and after each treatment block and included: the Revised Western Aphasia Battery (WAB-R) Aphasia Quotient (AQ) and subtest scores, content information units (CIUs) on the WAB-R picture description task, and qualitative content analysis of semi-structured interviews, gathered from both PwPPA and caregivers.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;No statistically significant changes were noted in mean WAB-AQ score pre- to post-intervention. Mean CIUs produced on the WAB-R picture description task pre- to post-intervention increased and approached significance (&lt;i&gt;β&lt;/i&gt; = 2.7; confidence interval: −0.45, 5.86, &lt;i&gt;p&lt;/i&gt; = 0.09). Qualitative findings from PwPPA and caregivers were very positive, and underscored the sense of community, improved language, communication, and well-being, and access to multidisciplinary expertise and resources afforded by the program.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Further investigation into the most appropriate assessment tools and intervention approaches for PPA is warranted and has the potential to make a significant positive impact on PwPPA and their families.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;We combined quantitative and qualitative measures of efficacy in treating primary progressive aphasia.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Language skil","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patterns and predictors of cholinesterase inhibitor use in dementia with Lewy bodies","authors":"Rachel J. Heo,&nbsp;Ahmed Negida,&nbsp;Kathryn A. Wyman-Chick,&nbsp;James R. Bateman,&nbsp;Federico Rodriguez-Porcel,&nbsp;Brian D. Berman,&nbsp;Nitai Mukhopadhyay,&nbsp;Matthew J. Barrett","doi":"10.1002/trc2.70136","DOIUrl":"10.1002/trc2.70136","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Current evidence supports the use of cholinesterase inhibitors (ChEIs) as the first-line symptomatic treatment for improving cognition in dementia with Lewy bodies (DLB). Little is known about current prescribing patterns of ChEIs in DLB. This study aimed to identify the patterns and predictors of ChEI prescribing in patients with DLB in the United States.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Using the TriNetX database, we identified 20,643 US patients ages 45 to 90 who were diagnosed with DLB between 2004 and 2024. We only included those with more than one documented diagnosis. Prescription data and patterns for donepezil, rivastigmine, galantamine, and memantine were analyzed. We used multivariate logistic regression models to estimate the odds of ChEI prescription based on demographic factors.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We found that 51.9% of DLB patients were ever prescribed a ChEI, and those who were prescribed a ChEI had a greater diagnosis interval. Patients who were prescribed ChEIs were more likely to be Hispanic (odds ratio [OR] 1.36, 95% confidence interval [CI]: 1.15, 1.59) and reside in the Midwest (OR 1.93, 95% CI: 1.76, 2.13), while Black patients were less likely to be prescribed ChEIs (OR 0.80, 95% CI: 0.71, 0.91). Of patients prescribed ChEIs, the median time between the first and last prescription was 13.4 months (interquartile range: 1.1, 32.9), and donepezil was the most commonly prescribed (76.9%) followed by rivastigmine (35.6%) and galantamine (3.9%). Over the 20-year study period, there was a gradual increase in the rate of prescribing of ChEIs, and the prescribing frequency of individual ChEIs remained relatively stable.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; CONCLUSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Despite evidence supporting their tolerability and efficacy, ChEIs are under-prescribed in DLB patients within the United States, and there are differences in prescribing based on race, ethnicity, and region. There is a need to understand the reasons for under-prescribing ChEIs in DLB, so interventions focused on increasing use can be developed.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Despite proven tolerability and efficacy, cholinesterase inhibitors (ChEIs) are under-prescribed in dementia with Lewy bodies (DLB).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Race, ethnicity, and region significantly a","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive decline across five cognitive batteries: Sample size implications for clinical trials","authors":"Andrea R. Zammit,&nbsp;Ana W. Capuano,&nbsp;Lisa L. Barnes,&nbsp;Julie A. Schneider,&nbsp;Reisa A. Sperling,&nbsp;David A. Bennett,&nbsp;Francine Grodstein","doi":"10.1002/trc2.70137","DOIUrl":"10.1002/trc2.70137","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We evaluated the statistical power for a theoretical randomized trial of anti-amyloid treatment in preclinical Alzheimer's Disease across five cognitive composites in preclinical Alzheimer's Disease across five cognitive composites: Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC); Preclinical Alzheimer's Composite with Semantic Processing (PACC5); Preclinical Alzheimer's Cognitive Composite (PACC); and global and episodic memory composites.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We utilized annual cognitive assessments from 517 decedents (78.2 ± 4.7years; 72% female) with &lt;i&gt;post mortem&lt;/i&gt; pathologic Alzheimer's disease (AD) to represent amyloid positivity. We calculated sample sizes to detect 30% reduction in 5-year slopes of cognitive decline for equal size treatment versus placebo groups across composites.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Estimated sample sizes for APCC (&lt;i&gt;n&lt;/i&gt; = 1633, 95% confidence interval [CI] 1400–1823), PACC (&lt;i&gt;n&lt;/i&gt; = 1822, 95% CI 1612–2122), and episodic memory (&lt;i&gt;n&lt;/i&gt; = 3141 95%CI 2563–3732) were larger than for PACC5 (&lt;i&gt;n&lt;/i&gt; = 1424, 95% CI 1249–1575). Sample size estimates were similar between PACC5 and the global composite (&lt;i&gt;n&lt;/i&gt; = 1267, 95%CI 1336–1407).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Small changes in composites, such as addition of semantic fluency in PACC5, could be considered as part of approaches to improve statistical power.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; HIGHLIGHTS&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;We evaluated statistical power of a theoretical 5-year randomized trial testing anti-amyloid treatments in early Alzheimer's across five cognitive composite endpoints.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;We leveraged annual cognitive assessment in Rush Alzheimer's Disease Center cohorts and used &lt;i&gt;post mortem&lt;/i&gt; pathologic AD to represent amyloid positivity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Preclinical Alzheimer's Composite with Semantic Processing (PACC5) required significantly lower sample size to achieve power for a 30% reduction in cognitive slope than Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (PACC).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;PACC5 had better statistical power than Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC) and a","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiorespiratory fitness modifies the relationship between arterial stiffness and cerebral blood flow independent of physical activity","authors":"Brianne M. Breidenbach,&nbsp;Ira Driscoll,&nbsp;Matthew P. Glittenberg,&nbsp;Adam J. Paulsen,&nbsp;Sara Fernandes-Taylor,&nbsp;Tarun Naren,&nbsp;Grant S. Roberts,&nbsp;Talia L. Brach,&nbsp;Mackenzie M. Jarchow,&nbsp;Leah E. Symanski,&nbsp;Anna Y. Gaul,&nbsp;Sarah R. Lose,&nbsp;Leonardo A. Rivera-Rivera,&nbsp;Sterling C. Johnson,&nbsp;Sanjay Asthana,&nbsp;Bradley T. Christian,&nbsp;Dane B. Cook,&nbsp;Oliver Wieben,&nbsp;Ozioma C. Okonkwo","doi":"10.1002/trc2.70130","DOIUrl":"10.1002/trc2.70130","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Central arterial stiffness and cerebral blood flow (CBF) are inversely related. Poor cardiorespiratory fitness (CRF) and low physical activity (PA) are related to both higher arterial stiffness and lower CBF. The present study examined (i) whether CRF or PA moderate the relationship between arterial stiffness and CBF, and (ii) whether the intensity or the type of PA needs to be considered.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Participants (&lt;i&gt;N&lt;/i&gt; = 78, Mean&lt;sub&gt;AGE&lt;/sub&gt; = 64.2±6.14, 72% female) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were categorized into low, average, and high fitness groups based on maximal graded exercise treadmill test performance. PA was assessed using the CHAMPS (Community Health Activities Model Program for Seniors) questionnaire. Based on hours/week, participants were classified as meeting the recommended 2.5 h of moderate intensity PA per week (PA Rec Met). Weekly hours of moderate and low intensity PA were calculated as activities of &gt; 3 or &lt; 3 metabolic equivalents, respectively. Activity type was categorized as exercise-, sports/leisure- and work-related. Arterial stiffness was measured as aortic pulse wave velocity (aoPWV) by 2D phase contrast magnetic resonance imaging (MRI). CBF was assessed by 4D flow MRI in the internal carotid arteries (ICAs), cavernous ICAs, middle cerebral arteries (MCAs), and via two composite measures of total and global flow.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The association between aoPWV and CBF differed by fitness levels, with a negative relationship in the low fitness group and positive relationships in the average and high fitness groups (all &lt;i&gt;P&lt;/i&gt;s&lt;0.05). Significant moderating effects on the relationships between aoPWV and CBF were also observed for PA Rec Met (all &lt;i&gt;P&lt;/i&gt;s&lt;0.05), moderate intensity (&lt;i&gt;p &lt;/i&gt;= 0.05), and exercise-related (all &lt;i&gt;p’&lt;/i&gt;s &lt; 0.02) PA.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Average or high fitness, meeting the PA guidelines, and more specifically, moderate intensity and exercise-related PA seem to attenuate the negative relationship between aoPWV on CBF.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Higher cardiorespiratory fitness (CRF) reduces the negative impact of aortic pulse wave velocity (aoPWV) on cerebral blood ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144624315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}