James Sarah-Naomi, Manning Emily N, Storey Mathew, Nicholas Jennifer M, Coath William, Keuss Sarah E, Cash David M, Lane Christopher A, Parker Thomas, Keshavan Ashvini, Buchanan Sarah M, Wagen Aaron, Harris Mathew, Malone Ian, Lu Kirsty, Needham Louisa P, Street Rebecca, Thomas David, Dickson John, Murray-Smith Heidi, Wong Andrew, Freiberger Tamar, Crutch Sebastian J, Fox Nick C, Richards Marcus, Barkhof Frederik, Sudre Carole H, Barnes Josephine, Schott Jonathan M
MRC Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Science, University College London, London, UK.
Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
Brain Commun. 2023 Aug 18;5(5):fcad225. doi: 10.1093/braincomms/fcad225. eCollection 2023.
We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease (); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [ = -0.09 (95% confidence interval: -0.11, -0.06), < 0.01], neurite density index [ = -0.17 (-0.22, -0.12), < 0.01] and higher mean diffusivity [ = 0.14 (-0.10, -0.17), < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [ = -0.04 (-0.08, -0.01), = 0.03)] and higher mean diffusivity [ = 0.06 (0.01, 0.11), = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [ = -0.06 (-0.09, -0.02) < 0.01], neurite density index [ = -0.10 (-0.17, -0.03), < 0.01] and higher mean diffusivity [ = 0.09 (0.04, 0.14), < 0.01]}. Significant sex interactions ( < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health.
我们研究了认知正常的70岁左右人群中外观正常的白质微观结构完整性与同时测量的脑健康和认知、人口统计学、遗传学以及一生心血管健康之间的关联。1946年3月同一周出生的参与者（英国1946年出生队列）在70岁左右接受了PET-MRI检查。平均标准化的外观正常白质完整性指标（分数各向异性、平均扩散率、神经突密度指数和方向离散指数）来自扩散MRI。采用线性回归来检验外观正常白质指标与以下各项之间的关联：（i）同时测量的指标，包括全脑体积、白质高信号体积、PET淀粉样蛋白和认知；（ii）人口统计学和遗传预测因素的影响，包括性别、儿童期认知、教育程度、社会经济地位以及阿尔茨海默病的遗传风险；（iii）成年期的收缩压和舒张压以及心血管健康（弗雷明汉心脏研究心血管风险评分）。检验了性别交互作用。统计学显著性包括错误发现率校正（5%）。362名参与者符合纳入标准（平均年龄70岁，49%为女性）。较高的白质高信号体积与较低的分数各向异性[β = -0.09（95%置信区间：-0.11，-0.06），P < 0.01]、神经突密度指数[β = -0.17（-0.22，-0.12），P < 0.01]以及较高的平均扩散率[β = 0.14（-0.10，-0.17），P < 0.01]相关；淀粉样蛋白（在男性中）与较低的分数各向异性[β = -0.04（-0.08，-0.01），P = 0.03]和较高的平均扩散率[β = 0.06（0.01，0.11），P = 0.02]相关。晚年（69岁）的弗雷明汉心脏研究心血管风险评分与外观正常的白质相关{较低的分数各向异性[β = -0.06（-0.09，-0.02），P < 0.01]、神经突密度指数[β = -0.10（-0.17，-0.03），P < 0.01]以及较高的平均扩散率[β = 0.09（0.04，0.14），P < 0.01]}。中年心血管健康（53岁）与70岁时外观正常的白质之间出现了显著的性别交互作用（P < 0.05）：边际效应图显示，仅在女性中，外观正常的白质与较高的中年弗雷明汉心脏研究心血管风险评分（较低的分数各向异性和神经突密度指数）、中年收缩压（较低的分数各向异性、神经突密度指数和较高的平均扩散率）和舒张压（较低的分数各向异性和神经突密度指数）以及43至53岁之间更大的血压变化（较低的分数各向异性和神经突密度指数）相关，独立于白质高信号体积。总之，70岁左右人群中外观正常的白质微观结构完整性较差与脑小血管疾病、淀粉样蛋白（在男性中）以及晚年心血管健康的指标相关，表明外观正常的白质如何能够为明显的白质疾病提供额外信息。我们的研究结果进一步表明，更大的“中年”心血管风险和更高的血压仅与女性中外观正常的白质微观结构完整性较差相关，这表明女性大脑可能更容易受到中年血压和心血管健康的影响。
