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Poor CVH was determined using Life's Essential 8 (LE8) and reversing standardized\n                      <jats:italic>z<\/jats:italic>\n                      \u2010scores (LE8\n                      <jats:italic>\n                        <jats:sub>z<\/jats:sub>\n                      <\/jats:italic>\n                      <jats:sub>_rev<\/jats:sub>\n                      ). The plasma proteome was examined as a potential mediator or moderator of LE8\n                      <jats:italic>\n                        <jats:sub>z<\/jats:sub>\n                      <\/jats:italic>\n                      <jats:sub>_rev<\/jats:sub>\n                      \u2019s effects on quantitative diffusion\u2010weighted magnetic resonance imaging (dMRI) metrics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      LE8\n                      <jats:sub>z_rev<\/jats:sub>\n                      was significantly associated with deteriorated WM microstructural integrity, as reflected by lower tract\u2010averaged fractional anisotropy (dMRI\u2010FA\n                      <jats:sub>mean<\/jats:sub>\n                      ), (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u00a0\u00b1\u00a0standared error (SE): \u22120.00152\u00a0\u00b1\u00a00.0003,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001) and higher tract\u2010averaged orientation dispersion (dMRI\u2010OD\n                      <jats:sub>mean<\/jats:sub>\n                      ), (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u00a0\u00b1\u00a0SE:+0.00081\u00a0\u00b1\u00a00.00017,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001). Ten strongly mediating plasma proteins of 1463 were identified, with leptin as the principal driver.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Poor CVH is linked to poor WM microstructural integrity measures (lower FA\n                      <jats:sub>mean<\/jats:sub>\n                      and higher OD\n                      <jats:sub>mean<\/jats:sub>\n                      ), mostly mediated through leptin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Up to 3953 UK Biobank participants were selected for this study.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Poor cardiovascular health (CVH) was determined using Life's Essential 8.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The plasma proteome was examined as a potential mediator or moderator of poor CVH's effect on dMRI metrics.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Ten plasma proteins were identified with strong mediating effects, with leptin being the principal driver.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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