Department of Psychiatry, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada.
Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada.
Mol Neurodegener. 2023 Jul 29;18(1):50. doi: 10.1186/s13024-023-00631-6.
Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally.
Data were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003-2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions).
Of 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aβ42 (standardized β [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aβ42/40 (p = 0.01); higher p-tau (9.67% [3.96-15.70%]; p = 0.001), t-tau (7.71% [2.70-12.97%]; p = 0.002), p-tau/Aβ42 (p < 0.001), and t-tau/Aβ42 (p = 0.001). NPSnotMBI was associated only with lower Aβ42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99-6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49-1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aβ40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia.
These findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care.
疾病修饰药物的使用需要更好地检测阿尔茨海默病（AD）。轻度认知障碍（MCI）利用认知能力下降来识别风险群体；同样，轻度行为障碍（MBI）利用行为改变来识别。将 MBI 纳入 MCI 可以提高痴呆症的预测能力，优于传统的纳入神经精神症状（NPS）的方法。在这里，为了确定是否加入 MBI 可以更好地识别 AD，我们探讨了 MCI 中 MBI 与脑脊液生物标志物[β-淀粉样蛋白（Aβ）、磷酸化 tau（p-tau）和总 tau（tau）-ATN]之间的横断面和纵向关联。
数据来自两个独立的基于转诊的队列，ADNI（平均[SD]随访 3.14[1.07]年）和 MEMENTO（4.25[1.40]年），收集时间为 2003-2021 年。暴露基于三组分层：1）符合 MBI 标准的 NPS；2）常规测量的 NPS（NPSnotMBI）；3）无 NPS。分别对队列进行了以下分析：1）NPS 状态与 ATN 生物标志物之间的横断面关联（线性回归）；2）MBI 和 NPSnotMBI 与 ATN 生物标志物的 4 年纵向重复测量关联（分层线性混合效应模型-LME）；3）新发痴呆的发生率（Cox 比例风险回归）。
在 510 名 MCI 参与者中，352 名来自 ADNI（43.5%为女性；平均[SD]年龄 71.68[7.40]岁），158 名来自 MEMENTO（46.2%为女性；68.98[8.18]岁）。在 ADNI 中，MBI 与较低的 Aβ42 相关（标准化β[95%CI]，-5.52%[-10.48-(-0.29)%]；p=0.039）和 Aβ42/40（p=0.01）；较高的 p-tau（9.67%[3.96-15.70%]；p=0.001），t-tau（7.71%[2.70-12.97%]；p=0.002），p-tau/Aβ42（p<0.001）和 t-tau/Aβ42（p=0.001）。NPSnotMBI 仅与较低的 Aβ42/40 相关（p=0.045）。LME 显示出相似的 4 年 AD 特异性生物标志物 MBI 图谱，NPSnotMBI 仅与较高的 t-tau 相关。MBI 有更高的痴呆发生率（HR[95%CI]，3.50[1.99-6.17；p<0.001）。NPSnotMBI 与无 NPS 无差异（HR 0.96[0.49-1.89]；p=0.916）。在 MEMENTO 中，MBI 对所有生物标志物的效应幅度和方向相似，但 Aβ40 降低幅度更大。MBI 发生痴呆的 HR 为 3.93（p=0.004），NPSnotMBI 为 1.83（p=0.266）。在 MBI 进展为痴呆的患者中，81%发展为 AD 痴呆。
这些发现支持 NPS 符合 MBI 标准的生物学基础，NIA-AA ATN 临床分期继续纳入 MBI，以及 MBI 标准对提高患者入选疾病修饰药物试验或临床护理的识别能力的实用性。
