Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women

Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg–1·d–1, and has not been experimentally...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of nutrition 2020-12, Vol.150 (12), p.3224-3230
Hauptverfasser: Ennis, Madeleine A, Ong, Anna-Joy, Lim, Kenneth, Ball, Ronald O, Pencharz, Paul B, Courtney-Martin, Glenda, Elango, Rajavel
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 3230
container_issue 12
container_start_page 3224
container_title The Journal of nutrition
container_volume 150
creator Ennis, Madeleine A
Ong, Anna-Joy
Lim, Kenneth
Ball, Ronald O
Pencharz, Paul B
Courtney-Martin, Glenda
Elango, Rajavel
description Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg–1·d–1, and has not been experimentally determined. The aim was to determine TAA requirements (dietary phenylalanine in the absence of tyrosine) during early and late gestation using the indicator amino acid oxidation (IAAO, with L-[1-13C]leucine) technique. Nineteen healthy pregnant women (age 22–38 y) were studied at a range of phenylalanine intakes (5 to 100 mg·kg–1·d–1) in early (13–19 wk) and/or late (33–39 wk) pregnancy for a total of 51 study days. Graded test intakes were provided as 8 hourly isonitrogenous and isocaloric meals. Breath samples were collected for13C enrichment analysis on an isotope ratio mass spectrometer. A plasma sample was collected and analyzed for phenylalanine and tyrosine concentrations on an amino acid analyzer. The TAA requirement in early and late pregnancy was calculated using 2-phase linear regression crossover analysis that identified breakpoints in13CO2production (the requirement) in response to phenylalanine intakes. TAA requirement during early pregnancy was 44 mg·kg–1·d–1(95% CI: 28.3, 58.8) and during late pregnancy was 50 mg·kg–1·d–1(95% CI: 36.1, 63.1). In early and late pregnancy, plasma phenylalanine and tyrosine concentrations rose linearly in response to graded phenylalanine intakes. Our results suggest that the current EAR of 36 mg·kg–1·d–1for TAAs is underestimated. When compared with results previously determined in nonpregnant adults, early pregnancy requirements were similar (43 compared with 44 mg·kg–1·d–1, respectively). During late pregnancy, a 14% higher TAA requirement was observed when compared with early pregnancy. The results from this study have potential implications for creating gestation stage-specific TAA recommendations.
doi_str_mv 10.1093/jn/nxaa317
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7726121</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/jn/nxaa317</oup_id><els_id>S0022316622024154</els_id><sourcerecordid>2460764662</sourcerecordid><originalsourceid>FETCH-LOGICAL-c481t-e5ffd61289376045c76de4a967e7987bbe4d5fcd536f16f8c0388fbaaf701eaf3</originalsourceid><addsrcrecordid>eNp9kUFrFDEcxYNY7Fq9-AEkIIIIY5NJJpm5CEtb28KCIorHkEn-2WaZSbbJTHG_vZHdliriKYf83st7eQi9ouQDJR073YTT8FNrRuUTtKANp5WghDxFC0LqumJUiGP0POcNIYTyrn2GjhmjbctJt0D9uYdJpx1epjjqyRu8HH2IeGm8xV_hdvYJRghTxudz8mGNL3QadlgHi1d6AnwJeSqyGLAP-Ar0MN3s8JcE66DDhH_Eon2BjpweMrw8nCfo-6eLb2dX1erz5fXZclUZ3tKpgsY5K2jddkwKwhsjhQWuOyFBdq3se-C2ccY2TDgqXGsIa1vXa-0koaAdO0Ef977buR_BmpI66UFtkx9LQRW1V3_eBH-j1vFOSVmXd2kxeHcwSPF2LsXU6LOBYdAB4pxVzQWRggtRF_TNX-gmzimUeoWSRIiO102h3u8pk2LOCdxDGErU7-nUJqjDdAV-_Tj-A3q_VQHe7oE4b_9vxPcclM--85BUNh6CAVu2NJOy0f9L9gsrc7Wi</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2470669425</pqid></control><display><type>article</type><title>Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Ennis, Madeleine A ; Ong, Anna-Joy ; Lim, Kenneth ; Ball, Ronald O ; Pencharz, Paul B ; Courtney-Martin, Glenda ; Elango, Rajavel</creator><creatorcontrib>Ennis, Madeleine A ; Ong, Anna-Joy ; Lim, Kenneth ; Ball, Ronald O ; Pencharz, Paul B ; Courtney-Martin, Glenda ; Elango, Rajavel</creatorcontrib><description>Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg–1·d–1, and has not been experimentally determined. The aim was to determine TAA requirements (dietary phenylalanine in the absence of tyrosine) during early and late gestation using the indicator amino acid oxidation (IAAO, with L-[1-13C]leucine) technique. Nineteen healthy pregnant women (age 22–38 y) were studied at a range of phenylalanine intakes (5 to 100 mg·kg–1·d–1) in early (13–19 wk) and/or late (33–39 wk) pregnancy for a total of 51 study days. Graded test intakes were provided as 8 hourly isonitrogenous and isocaloric meals. Breath samples were collected for13C enrichment analysis on an isotope ratio mass spectrometer. A plasma sample was collected and analyzed for phenylalanine and tyrosine concentrations on an amino acid analyzer. The TAA requirement in early and late pregnancy was calculated using 2-phase linear regression crossover analysis that identified breakpoints in13CO2production (the requirement) in response to phenylalanine intakes. TAA requirement during early pregnancy was 44 mg·kg–1·d–1(95% CI: 28.3, 58.8) and during late pregnancy was 50 mg·kg–1·d–1(95% CI: 36.1, 63.1). In early and late pregnancy, plasma phenylalanine and tyrosine concentrations rose linearly in response to graded phenylalanine intakes. Our results suggest that the current EAR of 36 mg·kg–1·d–1for TAAs is underestimated. When compared with results previously determined in nonpregnant adults, early pregnancy requirements were similar (43 compared with 44 mg·kg–1·d–1, respectively). During late pregnancy, a 14% higher TAA requirement was observed when compared with early pregnancy. The results from this study have potential implications for creating gestation stage-specific TAA recommendations.</description><identifier>ISSN: 0022-3166</identifier><identifier>EISSN: 1541-6100</identifier><identifier>DOI: 10.1093/jn/nxaa317</identifier><identifier>PMID: 33188409</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; amino acid requirements ; Amino acids ; Amino Acids, Aromatic - administration &amp; dosage ; Breakpoints ; Carbon Isotopes ; Catecholamines ; Diet ; Female ; Gestation ; Humans ; indicator amino acid oxidation ; Isotope Labeling ; Isotope ratios ; Leucine ; Meals ; Nutrient Requirements and Optimal Nutrition ; Nutritional Requirements ; Oxidation ; Oxidation-Reduction ; Phenylalanine ; Phenylalanine - administration &amp; dosage ; Pregnancy ; Pregnant Women ; Protein biosynthesis ; Protein synthesis ; Regression analysis ; stable isotopes ; Tyrosine ; Tyrosine - administration &amp; dosage ; Womens health</subject><ispartof>The Journal of nutrition, 2020-12, Vol.150 (12), p.3224-3230</ispartof><rights>2020 American Society for Nutrition.</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition. 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.</rights><rights>Copyright American Institute of Nutrition Dec 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-e5ffd61289376045c76de4a967e7987bbe4d5fcd536f16f8c0388fbaaf701eaf3</citedby><cites>FETCH-LOGICAL-c481t-e5ffd61289376045c76de4a967e7987bbe4d5fcd536f16f8c0388fbaaf701eaf3</cites><orcidid>0000-0001-6835-1366 ; 0000-0002-1263-2676 ; 0000-0002-9380-1725</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33188409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ennis, Madeleine A</creatorcontrib><creatorcontrib>Ong, Anna-Joy</creatorcontrib><creatorcontrib>Lim, Kenneth</creatorcontrib><creatorcontrib>Ball, Ronald O</creatorcontrib><creatorcontrib>Pencharz, Paul B</creatorcontrib><creatorcontrib>Courtney-Martin, Glenda</creatorcontrib><creatorcontrib>Elango, Rajavel</creatorcontrib><title>Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women</title><title>The Journal of nutrition</title><addtitle>J Nutr</addtitle><description>Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg–1·d–1, and has not been experimentally determined. The aim was to determine TAA requirements (dietary phenylalanine in the absence of tyrosine) during early and late gestation using the indicator amino acid oxidation (IAAO, with L-[1-13C]leucine) technique. Nineteen healthy pregnant women (age 22–38 y) were studied at a range of phenylalanine intakes (5 to 100 mg·kg–1·d–1) in early (13–19 wk) and/or late (33–39 wk) pregnancy for a total of 51 study days. Graded test intakes were provided as 8 hourly isonitrogenous and isocaloric meals. Breath samples were collected for13C enrichment analysis on an isotope ratio mass spectrometer. A plasma sample was collected and analyzed for phenylalanine and tyrosine concentrations on an amino acid analyzer. The TAA requirement in early and late pregnancy was calculated using 2-phase linear regression crossover analysis that identified breakpoints in13CO2production (the requirement) in response to phenylalanine intakes. TAA requirement during early pregnancy was 44 mg·kg–1·d–1(95% CI: 28.3, 58.8) and during late pregnancy was 50 mg·kg–1·d–1(95% CI: 36.1, 63.1). In early and late pregnancy, plasma phenylalanine and tyrosine concentrations rose linearly in response to graded phenylalanine intakes. Our results suggest that the current EAR of 36 mg·kg–1·d–1for TAAs is underestimated. When compared with results previously determined in nonpregnant adults, early pregnancy requirements were similar (43 compared with 44 mg·kg–1·d–1, respectively). During late pregnancy, a 14% higher TAA requirement was observed when compared with early pregnancy. The results from this study have potential implications for creating gestation stage-specific TAA recommendations.</description><subject>Adult</subject><subject>amino acid requirements</subject><subject>Amino acids</subject><subject>Amino Acids, Aromatic - administration &amp; dosage</subject><subject>Breakpoints</subject><subject>Carbon Isotopes</subject><subject>Catecholamines</subject><subject>Diet</subject><subject>Female</subject><subject>Gestation</subject><subject>Humans</subject><subject>indicator amino acid oxidation</subject><subject>Isotope Labeling</subject><subject>Isotope ratios</subject><subject>Leucine</subject><subject>Meals</subject><subject>Nutrient Requirements and Optimal Nutrition</subject><subject>Nutritional Requirements</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Phenylalanine</subject><subject>Phenylalanine - administration &amp; dosage</subject><subject>Pregnancy</subject><subject>Pregnant Women</subject><subject>Protein biosynthesis</subject><subject>Protein synthesis</subject><subject>Regression analysis</subject><subject>stable isotopes</subject><subject>Tyrosine</subject><subject>Tyrosine - administration &amp; dosage</subject><subject>Womens health</subject><issn>0022-3166</issn><issn>1541-6100</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFrFDEcxYNY7Fq9-AEkIIIIY5NJJpm5CEtb28KCIorHkEn-2WaZSbbJTHG_vZHdliriKYf83st7eQi9ouQDJR073YTT8FNrRuUTtKANp5WghDxFC0LqumJUiGP0POcNIYTyrn2GjhmjbctJt0D9uYdJpx1epjjqyRu8HH2IeGm8xV_hdvYJRghTxudz8mGNL3QadlgHi1d6AnwJeSqyGLAP-Ar0MN3s8JcE66DDhH_Eon2BjpweMrw8nCfo-6eLb2dX1erz5fXZclUZ3tKpgsY5K2jddkwKwhsjhQWuOyFBdq3se-C2ccY2TDgqXGsIa1vXa-0koaAdO0Ef977buR_BmpI66UFtkx9LQRW1V3_eBH-j1vFOSVmXd2kxeHcwSPF2LsXU6LOBYdAB4pxVzQWRggtRF_TNX-gmzimUeoWSRIiO102h3u8pk2LOCdxDGErU7-nUJqjDdAV-_Tj-A3q_VQHe7oE4b_9vxPcclM--85BUNh6CAVu2NJOy0f9L9gsrc7Wi</recordid><startdate>20201201</startdate><enddate>20201201</enddate><creator>Ennis, Madeleine A</creator><creator>Ong, Anna-Joy</creator><creator>Lim, Kenneth</creator><creator>Ball, Ronald O</creator><creator>Pencharz, Paul B</creator><creator>Courtney-Martin, Glenda</creator><creator>Elango, Rajavel</creator><general>Elsevier Inc</general><general>Oxford University Press</general><general>American Institute of Nutrition</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6835-1366</orcidid><orcidid>https://orcid.org/0000-0002-1263-2676</orcidid><orcidid>https://orcid.org/0000-0002-9380-1725</orcidid></search><sort><creationdate>20201201</creationdate><title>Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women</title><author>Ennis, Madeleine A ; Ong, Anna-Joy ; Lim, Kenneth ; Ball, Ronald O ; Pencharz, Paul B ; Courtney-Martin, Glenda ; Elango, Rajavel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-e5ffd61289376045c76de4a967e7987bbe4d5fcd536f16f8c0388fbaaf701eaf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>amino acid requirements</topic><topic>Amino acids</topic><topic>Amino Acids, Aromatic - administration &amp; dosage</topic><topic>Breakpoints</topic><topic>Carbon Isotopes</topic><topic>Catecholamines</topic><topic>Diet</topic><topic>Female</topic><topic>Gestation</topic><topic>Humans</topic><topic>indicator amino acid oxidation</topic><topic>Isotope Labeling</topic><topic>Isotope ratios</topic><topic>Leucine</topic><topic>Meals</topic><topic>Nutrient Requirements and Optimal Nutrition</topic><topic>Nutritional Requirements</topic><topic>Oxidation</topic><topic>Oxidation-Reduction</topic><topic>Phenylalanine</topic><topic>Phenylalanine - administration &amp; dosage</topic><topic>Pregnancy</topic><topic>Pregnant Women</topic><topic>Protein biosynthesis</topic><topic>Protein synthesis</topic><topic>Regression analysis</topic><topic>stable isotopes</topic><topic>Tyrosine</topic><topic>Tyrosine - administration &amp; dosage</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ennis, Madeleine A</creatorcontrib><creatorcontrib>Ong, Anna-Joy</creatorcontrib><creatorcontrib>Lim, Kenneth</creatorcontrib><creatorcontrib>Ball, Ronald O</creatorcontrib><creatorcontrib>Pencharz, Paul B</creatorcontrib><creatorcontrib>Courtney-Martin, Glenda</creatorcontrib><creatorcontrib>Elango, Rajavel</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of nutrition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ennis, Madeleine A</au><au>Ong, Anna-Joy</au><au>Lim, Kenneth</au><au>Ball, Ronald O</au><au>Pencharz, Paul B</au><au>Courtney-Martin, Glenda</au><au>Elango, Rajavel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women</atitle><jtitle>The Journal of nutrition</jtitle><addtitle>J Nutr</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>150</volume><issue>12</issue><spage>3224</spage><epage>3230</epage><pages>3224-3230</pages><issn>0022-3166</issn><eissn>1541-6100</eissn><abstract>Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg–1·d–1, and has not been experimentally determined. The aim was to determine TAA requirements (dietary phenylalanine in the absence of tyrosine) during early and late gestation using the indicator amino acid oxidation (IAAO, with L-[1-13C]leucine) technique. Nineteen healthy pregnant women (age 22–38 y) were studied at a range of phenylalanine intakes (5 to 100 mg·kg–1·d–1) in early (13–19 wk) and/or late (33–39 wk) pregnancy for a total of 51 study days. Graded test intakes were provided as 8 hourly isonitrogenous and isocaloric meals. Breath samples were collected for13C enrichment analysis on an isotope ratio mass spectrometer. A plasma sample was collected and analyzed for phenylalanine and tyrosine concentrations on an amino acid analyzer. The TAA requirement in early and late pregnancy was calculated using 2-phase linear regression crossover analysis that identified breakpoints in13CO2production (the requirement) in response to phenylalanine intakes. TAA requirement during early pregnancy was 44 mg·kg–1·d–1(95% CI: 28.3, 58.8) and during late pregnancy was 50 mg·kg–1·d–1(95% CI: 36.1, 63.1). In early and late pregnancy, plasma phenylalanine and tyrosine concentrations rose linearly in response to graded phenylalanine intakes. Our results suggest that the current EAR of 36 mg·kg–1·d–1for TAAs is underestimated. When compared with results previously determined in nonpregnant adults, early pregnancy requirements were similar (43 compared with 44 mg·kg–1·d–1, respectively). During late pregnancy, a 14% higher TAA requirement was observed when compared with early pregnancy. The results from this study have potential implications for creating gestation stage-specific TAA recommendations.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33188409</pmid><doi>10.1093/jn/nxaa317</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-6835-1366</orcidid><orcidid>https://orcid.org/0000-0002-1263-2676</orcidid><orcidid>https://orcid.org/0000-0002-9380-1725</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0022-3166
ispartof The Journal of nutrition, 2020-12, Vol.150 (12), p.3224-3230
issn 0022-3166
1541-6100
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7726121
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Adult
amino acid requirements
Amino acids
Amino Acids, Aromatic - administration & dosage
Breakpoints
Carbon Isotopes
Catecholamines
Diet
Female
Gestation
Humans
indicator amino acid oxidation
Isotope Labeling
Isotope ratios
Leucine
Meals
Nutrient Requirements and Optimal Nutrition
Nutritional Requirements
Oxidation
Oxidation-Reduction
Phenylalanine
Phenylalanine - administration & dosage
Pregnancy
Pregnant Women
Protein biosynthesis
Protein synthesis
Regression analysis
stable isotopes
Tyrosine
Tyrosine - administration & dosage
Womens health
title Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T18%3A37%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Dietary%20Aromatic%20Amino%20Acid%20Requirements%20During%20Early%20and%20Late%20Gestation%20in%20Healthy%20Pregnant%20Women&rft.jtitle=The%20Journal%20of%20nutrition&rft.au=Ennis,%20Madeleine%20A&rft.date=2020-12-01&rft.volume=150&rft.issue=12&rft.spage=3224&rft.epage=3230&rft.pages=3224-3230&rft.issn=0022-3166&rft.eissn=1541-6100&rft_id=info:doi/10.1093/jn/nxaa317&rft_dat=%3Cproquest_pubme%3E2460764662%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2470669425&rft_id=info:pmid/33188409&rft_oup_id=10.1093/jn/nxaa317&rft_els_id=S0022316622024154&rfr_iscdi=true