Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
Department of Psychiatry, Hamad Medical Corporation, PO BOX 3050, Doha, Qatar.
Alzheimers Res Ther. 2022 Dec 19;14(1):190. doi: 10.1186/s13195-022-01139-9.
Neuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer's disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol.
We aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology.
One hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms' changes over time, baseline CSF cortisol and DHEAS, and AD pathology.
Higher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months.
Higher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia.
神经精神症状是痴呆管理的重要治疗目标，并且可以在神经退行性疾病的早期临床阶段出现。阿尔茨海默病（AD）中报告了皮质醇升高，并与认知衰退速度加快有关。皮质醇升高与感知到的压力、抑郁和焦虑有关。硫酸脱氢表雄酮（DHEAS）具有已知的抗糖皮质激素作用，可能抵消皮质醇的作用。
我们旨在研究脑脊液（CSF）皮质醇和 DHEAS 水平是否与（1）基线时的神经精神症状相关，（2）3 年内神经精神症状的变化相关，以及（3）这些关联是否与 AD 病理学相关或独立于 AD 病理学。
我们纳入了 118 名在记忆诊所进行前瞻性研究的参与者，包括认知障碍患者（n = 78），即轻度认知障碍或轻度痴呆，以及认知正常的志愿者（n = 40）。使用神经精神疾病问卷（NPI-Q）评估神经精神症状。在基线时获得 CSF 皮质醇和 DHEAS 以及 CSF AD 生物标志物。在基线时进行了 18 个月和 36 个月的随访，重新评估了神经精神症状。我们构建了线性回归模型来研究基线神经精神症状、CSF 生物标志物指示的 AD 病理学以及 CSF 皮质醇和 DHEAS 之间的关系。我们使用重复测量混合方差分析模型来研究随着时间的推移神经精神症状的变化、基线 CSF 皮质醇和 DHEAS 与 AD 病理学之间的关联。
在控制包括 AD 病理状态在内的协变量后，较高的 CSF 皮质醇与基线时较高的 NPI-Q 严重程度评分相关（B = 0.085 [0.027; 0.144]，p = 0.027；r = 0.277）。特别是，较高的 CSF 皮质醇与较高的基线抑郁/烦躁、焦虑和冷漠/漠不关心评分相关。无论 AD 状态如何，较高的 CSF 皮质醇也与 NPI-Q 评分随时间的显著增加相关（p = 0.036，η = 0.207），但在控制 BMI 和使用精神药物后，这种关联不再显著。CSF DHEAS 与基线时的 NPI-Q 评分或随时间的变化均无关联。皮质醇不能介导基线 NPI-Q 与 36 个月内临床痴呆评定总和盒的变化之间的关联。
较高的 CSF 皮质醇可能反映或导致基线时更严重的神经精神症状，以及 3 年内更明显的恶化，与 AD 病理学的存在无关。我们的研究结果还表明，针对 HPA 轴的干预措施可能有助于治疗痴呆患者的神经精神症状。
