Steven E. Arnold, Suzanne Hendrix, Jessie Nicodemus-Johnson, Newman Knowlton, Victoria J. Williams, Jeffrey M. Burns, Monica Crane, Alison J. McManus, Sanjeev N. Vaishnavi, Zoe Arvanitakis, Judith Neugroschl, Karen Bell, Bianca A. Trombetta, Becky C. Carlyle, Pia Kivisäkk, Hiroko H. Dodge, Rudolph E. Tanzi, Patrick D. Yeramian, Kent Leslie
{"title":"苯丁酸钠和牛磺熊二醇对阿尔茨海默病的生物效应。","authors":"Steven E. Arnold, Suzanne Hendrix, Jessie Nicodemus-Johnson, Newman Knowlton, Victoria J. Williams, Jeffrey M. Burns, Monica Crane, Alison J. McManus, Sanjeev N. Vaishnavi, Zoe Arvanitakis, Judith Neugroschl, Karen Bell, Bianca A. Trombetta, Becky C. Carlyle, Pia Kivisäkk, Hiroko H. Dodge, Rudolph E. Tanzi, Patrick D. Yeramian, Kent Leslie","doi":"10.1002/trc2.12487","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome).</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (<i>n</i> = 51) versus placebo (<i>n</i> = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (<i>n</i> = 34). In the PB and TURSO group (<i>n</i> = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).</li>\n \n <li>Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.</li>\n \n <li>The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.</li>\n \n <li>PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.</li>\n \n <li>Supports further clinical development of PB and TURSO in neurodegenerative diseases.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 3","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310855/pdf/","citationCount":"0","resultStr":"{\"title\":\"Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease\",\"authors\":\"Steven E. 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CSF interleukin-15 increased from baseline to Week 24 within the placebo group (<i>n</i> = 34). In the PB and TURSO group (<i>n</i> = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. 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Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease
INTRODUCTION
Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology.
METHODS
The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome).
RESULTS
PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups.
DISCUSSION
While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD.
Highlights
Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).
Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.
The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.
PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.
Supports further clinical development of PB and TURSO in neurodegenerative diseases.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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