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Associations of hippocampal volumes, brain hypometabolism, and plasma NfL with amyloid, tau, and cognitive decline
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.70005
Feng-Feng Pan, Qi Huang, Chu-Chung Huang, Yao Lu, Liang Cui, Lin Huang, Yihui Guan, Fang Xie, Qi-Hao Guo

INTRODUCTION

Various indicators of neurodegeneration (N) are used in the assessment of neuronal injury in Alzheimer's disease (AD). The heterogeneity of such indicators is less clear.

METHODS

A total of 416 individuals with different cognitive statuses were recruited for this study. Differential associations of hippocampal volume (HV), 18F-fluorodeoxyglucose positron emission tomography (FDG PET) standardized uptake value ratios (SUVRs), and plasma neurofilament light chain (NfL) levels with amyloid beta (Aβ)–tau pathology and cognitive impairment were examined.

RESULTS

HV decreased early during the high Aβ burden but tau-negative stage. FDG PET SUVRs and plasma NfL levels notably changed at tau-positive stages. HV and plasma NfL correlated with cognitive scores in the early to middle stages, while FDG PET SUVRs aligned with cognitive decline from the middle to late stages. Hippocampal atrophy and inferior parietal hypometabolism increased the risk of cognitive impairment in A+T+, while adding NfL+ had no additional impact within the distinct A/T groups.

DISCUSSION

Different indicators of N have varying relationships to AD pathology and cognitive impairment.

Highlights

  • Hippocampal atrophy emerges early with a high amyloid beta burden and exacerbates during the tau-positive phase.
  • Brain hypometabolism and elevated plasma neurofilament light chain (NfL) levels appear mainly in tau-positive stages.
  • Hippocampal volume and plasma NfL levels correlate with cognitive decline in the early to middle stages, while 18F-fluorodeoxyglucose positron emission tomography standardized uptake value ratios in the middle to late stages.
  • Hippocampal atrophy and inferior parietal hypometabolism raise the risk of cognitive impairment in amyloid/tau–positive individuals while adding NfL+ shows no additional effect.
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引用次数: 0
Register now for the Tau Global Conference, April 24 and 25, in London and online
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.70020
<p>Registration is open for the 2025 Tau Global Conference, which brings together three major tau-focused conferences (Global Tau, EuroTau, and CurePSP Neuro) and is hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. Taking place April 24 and 25 in London, UK, and online, the Tau Global Conference plays a critical role in bringing together interdisciplinary researchers and perspectives to move tau research forward.</p><p>The hybrid conference provides a forum for members of academia, industry, philanthropy, and government to explore tau-related biology, biomarkers, therapeutics, and phenotypes; enhance interdisciplinary collaboration and alignment to address challenges in tau research; and foster talent development and secure funding for the study of tauopathies, with a focus on early-career researchers.</p><p>The program aims to provide a deeper understanding of research advancements in tauopathies, including primary tauopathies such as progressive supranuclear palsy, cortical basal degeneration, and frontotemporal dementia, as well as key issues impacting the tau research community.</p><p>Questions about the Tau Global Conference may be sent to [email protected].</p><p>In early December 2024, the bipartisan Building Our Largest Dementia (BOLD) Reauthorization Act was signed into law. The bill, which passed unanimously out of Congress, reauthorizes the BOLD Infrastructure for Alzheimer's Act (P.L.115-406) and will enable public health departments to implement effective dementia interventions.</p><p>“In the 5 years since the initial BOLD Act was signed into law, public health departments across the country have been making a real-world impact by successfully implementing effective Alzheimer's interventions, such as increasing early detection and diagnosis and reducing risk,” said Robert Egge, Alzheimer's Impact Movement (AIM) president and Alzheimer's Association chief public policy officer. “Today's reauthorization will build on this progress and expand the law's impact further into communities.”</p><p>The BOLD Reauthorization Act was championed by Sens. Susan Collins (R-Maine), Catherine Cortez Masto (D-Nev.), Shelley Moore Capito (R-W.Va.), and Tim Kaine (D-Va.) in the Senate, and Reps. Brett Guthrie (R-Ky.), Paul Tonko (D-N.Y.), Chris Smith (R-N.J.), and Maxine Waters (D-Calif.) in the House.</p><p>“We are grateful to the bill's sponsors for their tremendous bipartisan leadership in introducing the bipartisan BOLD Reauthorization Act and their steadfast commitment to the Alzheimer's and dementia community,” continued Egge.</p><p>The BOLD Act has been essential to creating and growing a public health infrastructure for dementia across the country. Through the law, the Centers for Disease Control and Prevention (CDC) has provided funding to state, local, and tribal public health departments to help them improve brain health in their communities. Since 2018, the CDC has made 66 awards to 45 states and local
{"title":"Register now for the Tau Global Conference, April 24 and 25, in London and online","authors":"","doi":"10.1002/alz.70020","DOIUrl":"https://doi.org/10.1002/alz.70020","url":null,"abstract":"&lt;p&gt;Registration is open for the 2025 Tau Global Conference, which brings together three major tau-focused conferences (Global Tau, EuroTau, and CurePSP Neuro) and is hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. Taking place April 24 and 25 in London, UK, and online, the Tau Global Conference plays a critical role in bringing together interdisciplinary researchers and perspectives to move tau research forward.&lt;/p&gt;&lt;p&gt;The hybrid conference provides a forum for members of academia, industry, philanthropy, and government to explore tau-related biology, biomarkers, therapeutics, and phenotypes; enhance interdisciplinary collaboration and alignment to address challenges in tau research; and foster talent development and secure funding for the study of tauopathies, with a focus on early-career researchers.&lt;/p&gt;&lt;p&gt;The program aims to provide a deeper understanding of research advancements in tauopathies, including primary tauopathies such as progressive supranuclear palsy, cortical basal degeneration, and frontotemporal dementia, as well as key issues impacting the tau research community.&lt;/p&gt;&lt;p&gt;Questions about the Tau Global Conference may be sent to [email protected].&lt;/p&gt;&lt;p&gt;In early December 2024, the bipartisan Building Our Largest Dementia (BOLD) Reauthorization Act was signed into law. The bill, which passed unanimously out of Congress, reauthorizes the BOLD Infrastructure for Alzheimer's Act (P.L.115-406) and will enable public health departments to implement effective dementia interventions.&lt;/p&gt;&lt;p&gt;“In the 5 years since the initial BOLD Act was signed into law, public health departments across the country have been making a real-world impact by successfully implementing effective Alzheimer's interventions, such as increasing early detection and diagnosis and reducing risk,” said Robert Egge, Alzheimer's Impact Movement (AIM) president and Alzheimer's Association chief public policy officer. “Today's reauthorization will build on this progress and expand the law's impact further into communities.”&lt;/p&gt;&lt;p&gt;The BOLD Reauthorization Act was championed by Sens. Susan Collins (R-Maine), Catherine Cortez Masto (D-Nev.), Shelley Moore Capito (R-W.Va.), and Tim Kaine (D-Va.) in the Senate, and Reps. Brett Guthrie (R-Ky.), Paul Tonko (D-N.Y.), Chris Smith (R-N.J.), and Maxine Waters (D-Calif.) in the House.&lt;/p&gt;&lt;p&gt;“We are grateful to the bill's sponsors for their tremendous bipartisan leadership in introducing the bipartisan BOLD Reauthorization Act and their steadfast commitment to the Alzheimer's and dementia community,” continued Egge.&lt;/p&gt;&lt;p&gt;The BOLD Act has been essential to creating and growing a public health infrastructure for dementia across the country. Through the law, the Centers for Disease Control and Prevention (CDC) has provided funding to state, local, and tribal public health departments to help them improve brain health in their communities. Since 2018, the CDC has made 66 awards to 45 states and local ","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Functional insight into East Asian–specific genetic risk loci for Alzheimer's disease
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.14553
Minyoung Cho, Soumilee Chaudhuri, Shiwei Liu, Tamina Park, Yen-Ning Huang, Thea Rosewood, Paula J. Bice, Andrew J. Saykin, Hong-Hee Won, Kwangsik Nho

INTRODUCTION

The functional study of genetic risk factors for Alzheimer's disease (AD) provides insights into the underlying mechanisms and identification of potential therapeutic targets. Investigating AD-associated genetic loci identified in East Asian populations using single-nucleus RNA-sequencing data may identify novel functional genetic contributors.

METHODS

Cell type–specific expression quantitative trait loci (eQTL) and peak-to-gene links were used to identify functional genes associated with 26 genetic loci from seven genome-wide association studies (GWAS) for AD in East Asians.

RESULTS

KCNJ6 and MAPK1IP1L were identified as significant eQTLs with AD risk loci. AD risk loci were in peaks related to four genes, with CLIC4 being connected across different cell types. Genes identified in European and East Asian GWAS interacted within networks and were enriched in AD pathology pathways in astrocytes.

DISCUSSION

Our findings suggest KCNJ6 and CLIC4 as novel AD-associated functional genes, providing insight into the genetic architecture of AD in East Asians.

Highlights

  • Integrated functional analysis of Alzheimer's disease (AD) loci in seven East Asian genome-wide association studies (GWAS) was performed.
  • Cell type–specific expression quantitative trait loci (eQTLs) and assay for transposase-accessible chromatin peaks were used to identify AD functional genes.
  • An AD risk variant was linked to KCNJ6 through an oligodendrocyte progenitor cell–specific eQTL.
  • An AD risk variant maps to open chromatin, linked to CLIC4 across six cell types.
  • Astrocyte differentially expressed genes by AD pathology are enriched in East Asian and European GWAS genes.
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引用次数: 0
The U.S. POINTER neurovascular ancillary study: Study design and methods
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.14574
Tina E. Brinkley, Katelyn R. Garcia, Gary F. Mitchell, Charles H. Tegeler, Aarti Sarwal, John Bennett, Dalane W. Kitzman, Iris Leng, Laura D. Baker, Mark A. Espeland, Heather M. Snyder, Jurgen A. Claassen, Margie J. Bailey, Hossam A. Shaltout

INTRODUCTION

POINTER Neurovascular (POINTER-NV) is an ancillary study that leverages the rich infrastructure and design of the U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to investigate neurovascular mechanisms that may underlie intervention effects on key brain outcomes.

METHODS

A comprehensive neurovascular assessment is conducted at baseline, Month 12, and Month 24 using a variety of complementary non-invasive techniques including transcranial Doppler ultrasound, carotid ultrasound, echocardiography, tonometry, and continuous blood pressure and heart rate monitoring. Measurements are acquired at rest and during orthostatic challenges, hyperventilation, and carbon dioxide inhalation.

RESULTS

The primary outcomes are baroreflex sensitivity and cerebral autoregulation. Secondary outcomes include aortic, carotid, and cerebral hemodynamics and various measures of autonomic function and vascular structure and function.

DISCUSSION

POINTER-NV will provide critical insight into neurovascular mechanisms that may change with intensive lifestyle modification and promote improvements in cognition and overall brain health.

Highlights

  • This study takes advantage of U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to address key gaps in the field.
  • POINTER Neurovascular (POINTER-NV) will provide insight into neurovascular mechanisms underlying dementia.
  • POINTER-NV may help shed light on modifiable vascular contributions to dementia.
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引用次数: 0
Insight into the etiology of Alzheimer's disease from GLP-1R knockout mice: Commentary on “Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes”
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.70033
Garth J. Thompson
<p><i>Alzheimer's & Dementia</i> recently published a study by Wang et al.,<span><sup>1</sup></span> which demonstrated a link between semaglutide, an agonist for the glucagon-like peptide-1 receptor (GLP-1R), and reduced diagnosis of Alzheimer's disease (AD). The authors used statistical methods to simulate a clinical trial (e.g., propensity score matching) and discovered that the ratio of a first-time diagnosis of AD compared to no diagnosis was substantially lower in patients receiving the GLP-1R agonist semaglutide for diabetes. A significant difference in this ratio held even when considering factors such as sex, age, and obesity status.</p><p>The etiology of AD is complex. In addition to amyloid beta plaques and tau tangles, AD symptoms also include changes to brain function, oxygen and glucose metabolism, and the balance of these factors across the entire brain.<span><sup>2, 3</sup></span> GLP-1R has high concentrations across much of the central nervous system.<span><sup>4</sup></span> While semaglutide does not pass the blood–brain barrier, it can pass through tanycytes lining ventricle walls and thus enter several brain regions protected by the blood–brain barrier.<span><sup>4</sup></span> Therefore, a neurological mechanism for the protective effect of GLP-1R agonism in preventing AD seems likely. However, the functional and metabolic effects of GLP-1R at the scale of the entire brain remain poorly understood.</p><p>My group recently published a study of GLP-1R in the context of diabetes,<span><sup>5</sup></span> but I had not considered that work in the context of AD until I read the recent study by Wang et al.<span><sup>1</sup></span> While unexpected, this context was intriguing, as my group's work may help explain the connection between GLP-1R and AD.<span><sup>5</sup></span> In our study, we compared mice lacking the gene for GLP-1R (<i>GLP1R</i>) to matched wild-type mice. In both groups, we investigated the whole brain's response to exogenous glucose using positron emission tomography and deuterium magnetic resonance spectroscopy. We also examined the correlation of functional neural signals between different brain regions, or “functional connectivity,” measured with functional magnetic resonance imaging (fMRI). In the GLP-1R–deficient mice, we observed dramatic differences from the wild-type mice. The uptake of glucose (Figure 1A) and the rate of glucose metabolism were reduced in these mice, and this was correlated with a decrease both in functional connectivity (Figure 1B), and a decrease of band-limited signal power in brain networks (Figure 1C).<span><sup>5</sup></span></p><p>Intriguingly, a similar dramatic reduction of glucose uptake and glucose metabolic rate has also been observed in human patients with AD.<span><sup>3</sup></span> Comparing this to functional connectivity is difficult as most human studies perform “global signal regression.” In this type of pre-processing, the “global signal” is calculated as the a
{"title":"Insight into the etiology of Alzheimer's disease from GLP-1R knockout mice: Commentary on “Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes”","authors":"Garth J. Thompson","doi":"10.1002/alz.70033","DOIUrl":"https://doi.org/10.1002/alz.70033","url":null,"abstract":"&lt;p&gt;&lt;i&gt;Alzheimer's &amp; Dementia&lt;/i&gt; recently published a study by Wang et al.,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; which demonstrated a link between semaglutide, an agonist for the glucagon-like peptide-1 receptor (GLP-1R), and reduced diagnosis of Alzheimer's disease (AD). The authors used statistical methods to simulate a clinical trial (e.g., propensity score matching) and discovered that the ratio of a first-time diagnosis of AD compared to no diagnosis was substantially lower in patients receiving the GLP-1R agonist semaglutide for diabetes. A significant difference in this ratio held even when considering factors such as sex, age, and obesity status.&lt;/p&gt;&lt;p&gt;The etiology of AD is complex. In addition to amyloid beta plaques and tau tangles, AD symptoms also include changes to brain function, oxygen and glucose metabolism, and the balance of these factors across the entire brain.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; GLP-1R has high concentrations across much of the central nervous system.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; While semaglutide does not pass the blood–brain barrier, it can pass through tanycytes lining ventricle walls and thus enter several brain regions protected by the blood–brain barrier.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Therefore, a neurological mechanism for the protective effect of GLP-1R agonism in preventing AD seems likely. However, the functional and metabolic effects of GLP-1R at the scale of the entire brain remain poorly understood.&lt;/p&gt;&lt;p&gt;My group recently published a study of GLP-1R in the context of diabetes,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; but I had not considered that work in the context of AD until I read the recent study by Wang et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; While unexpected, this context was intriguing, as my group's work may help explain the connection between GLP-1R and AD.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; In our study, we compared mice lacking the gene for GLP-1R (&lt;i&gt;GLP1R&lt;/i&gt;) to matched wild-type mice. In both groups, we investigated the whole brain's response to exogenous glucose using positron emission tomography and deuterium magnetic resonance spectroscopy. We also examined the correlation of functional neural signals between different brain regions, or “functional connectivity,” measured with functional magnetic resonance imaging (fMRI). In the GLP-1R–deficient mice, we observed dramatic differences from the wild-type mice. The uptake of glucose (Figure 1A) and the rate of glucose metabolism were reduced in these mice, and this was correlated with a decrease both in functional connectivity (Figure 1B), and a decrease of band-limited signal power in brain networks (Figure 1C).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Intriguingly, a similar dramatic reduction of glucose uptake and glucose metabolic rate has also been observed in human patients with AD.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Comparing this to functional connectivity is difficult as most human studies perform “global signal regression.” In this type of pre-processing, the “global signal” is calculated as the a","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Life span policies and macroeconomic transition will help the 21st-century brain health revolution in developing countries
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.70006
Cyprian M. Mostert, Chinedu Udeh-Momoh, Manasi Kumar, Murad Khan, Shehzad Ali, Kendi Muchungi, Gloria Chemutai, Cynthia Smith, Dominic Trepel, Harris Eyre, Lukoye Atwoli, Zul Merali

In 2022, the World Health Organization (WHO) issued the Intersectoral Global Action Plan for Epilepsy and Other Neurological Disorders for 2022 to 2031, emphasizing important connections between brain health, population well-being, and economic growth. A year later, the WHO followed up with strategic guidelines aimed at enhancing brain health outcomes in developing countries. However, critical gaps remain. Our policy forum paper advocates for policies that target brain health across all stages of life, starting with measures to reduce the consumption of alcohol, sugar, and tobacco. Additionally, we propose the integration of school meal programs and social pension schemes as essential lifespan policies to safeguard brain health. To support these policies, developing countries must implement key macroeconomic reforms. These include revising international trade agreements, strengthening tax systems, curbing illicit financial flows, eliminating financial exclusions, and expanding social welfare systems. Such reforms are critical for creating an environment that supports long-term brain health initiatives.

Highlights

  • The are critical gaps in the WHO policy framework for brain health.
  • We advocate policies that target brain health across all stages of life, starting with measures to reduce alcohol, sugar, and tobacco consumption.
  • Additionally, we propose integrating school meal programs and social pension schemes as essential lifespan policies to safeguard brain health.
  • To support these policies, developing countries must implement key macroeconomic reforms.
  • By adopting these measures, developing countries can lead the charge in advancing the 21st-century brain health agenda, fostering both societal well-being and sustainable economic development.
{"title":"Life span policies and macroeconomic transition will help the 21st-century brain health revolution in developing countries","authors":"Cyprian M. Mostert,&nbsp;Chinedu Udeh-Momoh,&nbsp;Manasi Kumar,&nbsp;Murad Khan,&nbsp;Shehzad Ali,&nbsp;Kendi Muchungi,&nbsp;Gloria Chemutai,&nbsp;Cynthia Smith,&nbsp;Dominic Trepel,&nbsp;Harris Eyre,&nbsp;Lukoye Atwoli,&nbsp;Zul Merali","doi":"10.1002/alz.70006","DOIUrl":"https://doi.org/10.1002/alz.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>In 2022, the World Health Organization (WHO) issued the Intersectoral Global Action Plan for Epilepsy and Other Neurological Disorders for 2022 to 2031, emphasizing important connections between brain health, population well-being, and economic growth. A year later, the WHO followed up with strategic guidelines aimed at enhancing brain health outcomes in developing countries. However, critical gaps remain. Our policy forum paper advocates for policies that target brain health across all stages of life, starting with measures to reduce the consumption of alcohol, sugar, and tobacco. Additionally, we propose the integration of school meal programs and social pension schemes as essential lifespan policies to safeguard brain health. To support these policies, developing countries must implement key macroeconomic reforms. These include revising international trade agreements, strengthening tax systems, curbing illicit financial flows, eliminating financial exclusions, and expanding social welfare systems. Such reforms are critical for creating an environment that supports long-term brain health initiatives.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The are critical gaps in the WHO policy framework for brain health.</li>\u0000 \u0000 <li>We advocate policies that target brain health across all stages of life, starting with measures to reduce alcohol, sugar, and tobacco consumption.</li>\u0000 \u0000 <li>Additionally, we propose integrating school meal programs and social pension schemes as essential lifespan policies to safeguard brain health.</li>\u0000 \u0000 <li>To support these policies, developing countries must implement key macroeconomic reforms.</li>\u0000 \u0000 <li>By adopting these measures, developing countries can lead the charge in advancing the 21st-century brain health agenda, fostering both societal well-being and sustainable economic development.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cognitive vulnerability to glucose fluctuations: A digital phenotype of neurodegeneration
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.70001
Luciana Mascarenhas Fonseca, Zoë W. Hawks, Michal Schnaider Beeri, Lanee Jung, Yogish Kudva, Shafaq Rizvi, Jane Bulger, Elizabeth Grinspoon, Kamille Janess, Martin J. Sliwinski, Richard E. Pratley, Michael R. Rickels, Ruth S. Weinstock, Jasmeer P. Chhatwal, Pia Kivisäkk, Laura Thi Germine, Naomi S. Chaytor

INTRODUCTION

Cognition is reduced at low and high glucose, reflecting cognitive vulnerability to glucose (CVG) fluctuations. The impact of glucose fluctuations on the aging brain remains unclear. We examined whether CVG is associated with plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration.

METHODS

Participants included N = 114 adults with type 1 diabetes assessed for processing speed and sustained attention using ecological momentary assessment (EMA) combined with continuous glucose monitoring (CGM). We characterized associations between CVG and amyloid beta (Aβ) 42/40, phosphorylated tau (p-tau) 181 and 217, neurofilament light chain, and glial fibrillary acidic protein.

RESULTS

CVG was associated with all plasma biomarkers, except Aβ 42/40. CVG for sustained attention exhibited strong associations with p-tau biomarkers that persisted across covariate specifications.

DISCUSSION

CVG may be a useful digital phenotype of AD. It remains unclear whether CVG contributes to versus arises from neurodegeneration. We consider possible mechanisms linking cognitive vulnerability and long-term glucose variability to the development of neuropathology.

Highlights

  • Cognitive vulnerability to glucose (CVG) may be a useful digital phenotype of neurodegeneration.
  • We used cognitive ecological momentary assessment and continuous glucose monitoring to investigate CVG's associations with plasma biomarkers.
  • Associations of CVG for sustained attention and phosphorylated tau 181 remained significant across covariates.
  • We discuss possible mechanisms relating glucose variability, cognition, and neurodegeneration.
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引用次数: 0
Novel plasma biomarkers of amyloid plaque pathology and cortical thickness: Evaluation of the NULISA targeted proteomic platform in an ethnically diverse cohort
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.14535
Xuemei Zeng, Anuradha Sehrawat, Tara K. Lafferty, Yijun Chen, Mahika Rawat, M. Ilyas Kamboh, Victor L. Villemagne, Oscar L. Lopez, Ann D. Cohen, Thomas K. Karikari
<div> <section> <h3> INTRODUCTION</h3> <p>Proteomic evaluation of plasma samples could accelerate the identification of novel Alzheimer's disease (AD) biomarkers. We evaluated the novel NUcleic acid Linked Immuno-Sandwich Assay (NULISA) proteomic method in an ethnically diverse cohort.</p> </section> <section> <h3> METHODS</h3> <p>Plasma biomarkers were measured with NULISA in the Human Connectome Project, a predominantly preclinical biracial community cohort in southwestern Pennsylvania. Selected biomarkers were additionally measured using Simoa and Quest immunoassays and compared.</p> </section> <section> <h3> RESULTS</h3> <p>On NULISA, phosphorylated tau (p-tau217, p-tau231, and p-tau181), glial fibrillary acidic protein (GFAP), and microtubule-associated protein tau (MAPT-tau) showed the top significant association with amyloid beta (Aβ) positron emission tomography (PET) status, followed by the neuroinflammation markers C-C motif ligand 2 (CCL2), chitotriosidase 1 (CHIT1) and interleukin-8 (CXCL8), and the synaptic marker neurogranin (NRGN). Biomarkers associated with cortical thickness included astrocytic protein chitinase-3-like protein 1 (CHI3L1), cytokine CD40 ligand (CD40LG), brain-derived neurotrophic factor (BDNF), the Aβ-associated metalloprotein TIMP3 (tissue inhibitor of metalloprotein 3), and ficolin 2 (FCN2). Furthermore, moderate to strong between-platform correlations were observed for various assays.</p> </section> <section> <h3> DISCUSSION</h3> <p>NULISA multiplexing advantage allowed concurrent assessment of established and novel plasma biomarkers of Aβ pathology and neurodegeneration.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Classical Alzheimer's disease (AD) biomarkers measured using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) with next-generation sequencing readout (NULISAseq) CNS panel showed strong concordance with those measured using established immunoassay methods from Quanterix and Quest, with glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) exhibiting the strongest correlation.</li> <li>NULISAseq proteomic analysis identified several plasma biomarkers strongly associated with AD pathology in a biracial community cohort of older adults. Notably, phosphorylated tau-217 (p-tau217), GFAP, and p-tau231 displayed the strongest association with amyloid beta (Aβ) pathology
{"title":"Novel plasma biomarkers of amyloid plaque pathology and cortical thickness: Evaluation of the NULISA targeted proteomic platform in an ethnically diverse cohort","authors":"Xuemei Zeng,&nbsp;Anuradha Sehrawat,&nbsp;Tara K. Lafferty,&nbsp;Yijun Chen,&nbsp;Mahika Rawat,&nbsp;M. Ilyas Kamboh,&nbsp;Victor L. Villemagne,&nbsp;Oscar L. Lopez,&nbsp;Ann D. Cohen,&nbsp;Thomas K. Karikari","doi":"10.1002/alz.14535","DOIUrl":"https://doi.org/10.1002/alz.14535","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;Proteomic evaluation of plasma samples could accelerate the identification of novel Alzheimer's disease (AD) biomarkers. We evaluated the novel NUcleic acid Linked Immuno-Sandwich Assay (NULISA) proteomic method in an ethnically diverse cohort.&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;Plasma biomarkers were measured with NULISA in the Human Connectome Project, a predominantly preclinical biracial community cohort in southwestern Pennsylvania. Selected biomarkers were additionally measured using Simoa and Quest immunoassays and compared.&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;On NULISA, phosphorylated tau (p-tau217, p-tau231, and p-tau181), glial fibrillary acidic protein (GFAP), and microtubule-associated protein tau (MAPT-tau) showed the top significant association with amyloid beta (Aβ) positron emission tomography (PET) status, followed by the neuroinflammation markers C-C motif ligand 2 (CCL2), chitotriosidase 1 (CHIT1) and interleukin-8 (CXCL8), and the synaptic marker neurogranin (NRGN). Biomarkers associated with cortical thickness included astrocytic protein chitinase-3-like protein 1 (CHI3L1), cytokine CD40 ligand (CD40LG), brain-derived neurotrophic factor (BDNF), the Aβ-associated metalloprotein TIMP3 (tissue inhibitor of metalloprotein 3), and ficolin 2 (FCN2). Furthermore, moderate to strong between-platform correlations were observed for various assays.&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;NULISA multiplexing advantage allowed concurrent assessment of established and novel plasma biomarkers of Aβ pathology and neurodegeneration.&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;Classical Alzheimer's disease (AD) biomarkers measured using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) with next-generation sequencing readout (NULISAseq) CNS panel showed strong concordance with those measured using established immunoassay methods from Quanterix and Quest, with glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) exhibiting the strongest correlation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;NULISAseq proteomic analysis identified several plasma biomarkers strongly associated with AD pathology in a biracial community cohort of older adults. Notably, phosphorylated tau-217 (p-tau217), GFAP, and p-tau231 displayed the strongest association with amyloid beta (Aβ) pathology","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14535","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prescription opioid use and cognitive function in older adults with chronic pain: A population-based longitudinal cohort study
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.70002
Yu-Jung Jenny Wei, Almut G. Winterstein, Siegfried Schmidt, Roger B. Fillingim, Stephan Schmidt, Michael J. Daniels, Steven T. DeKosky

INTRODUCTION

Whether prescription opioid exposure, duration, and dose are associated with cognitive function remains inconclusive.

METHODS

A longitudinal cohort among 3097 older adults with chronic pain and without dementia was conducted using Health and Retirement Study (HRS) linked to Medicare data from 2006 to 2020. Prescription opioid exposure, cumulative use for ≥ 90 days, and high-dose use (≥ 90 morphine milligram equivalents [MME] daily) were assessed biennially. Memory score and dementia probability were derived from HRS cognitive measures and analyzed using linear mixed-effects models.

RESULTS

Adjusted memory decline and dementia probability were not statistically different between patients with (vs. without) opioid exposure and between patients with cumulative use for ≥ 90 days (vs. < 90 days) but were higher between participants with high-dose opioid use (vs. low-dose) at the end of the follow-up.

DISCUSSION

Prescription opioid exposure and duration were not associated, but high-dose opioid use was associated with greater memory decline and dementia probability.

Highlights

  • Opioid use versus no use was not related to memory decline and dementia probability.
  • Long-term opioid use was not related to memory decline and dementia probability.
  • High-dose opioid use was related to greater memory decline and dementia probability.
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引用次数: 0
Plasma Alzheimer's disease biomarker relationships with incident abnormal amyloid PET
IF 13 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-24 DOI: 10.1002/alz.14629
Petrice M. Cogswell, Heather J. Wiste, Stephen D. Weigand, Terry M. Therneau, Michael E. Griswold, Joel B. Braunstein, Tim West, Philip B. Verghese, Jonathan Graff-Radford, Alicia Algeciras-Schimnich, Val J. Lowe, Christopher G. Schwarz, Matthew L. Senjem, Jeffrey L. Gunter, David S. Knopman, Prashanthi Vemuri, Ronald C. Petersen, Clifford R. Jack Jr.

INTRODUCTION

Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A−) individuals.

METHODS

We included 290 A−, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A− to A+ and with rate of amyloid PET change.

RESULTS

Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p-tau217), and Amyloid Probability Score 2 were associated with 1.29 (P = 0.09), 1.38 (P < 0.001), and 1.20 (P = 0.05) increases, respectively, in the hazard of progression from A− to A+ and 0.27 (P = 0.16), 0.50 (P = 0.007), and 0.28 (P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change.

DISCUSSION

Plasma %p-tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial.

Highlights

  • Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive.
  • The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2.
  • Age and apolipoprotein E ε4 carriership were also important predictors.
  • These markers may be useful for enrichment of a primary prevention trial.
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引用次数: 0
期刊
Alzheimer's & Dementia
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