Objective:Neuropsychiatric symptoms concerning mood are common in Alzheimer's disease (AD), but it is unclear if they are etiologically related to AD pathophysiology or due to factors considered to be non-pathogenic, such as small vessel cerebrovascular disease. New generation clinical trials for AD often enroll participants with evidence of AD pathophysiology, indexed by amyloid PET scanning, but who are cognitively asymptomatic. We used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to examine the extent to which depressive symptoms are associated with amyloid pathophysiology and small vessel cerebrovascular disease, in the form of white matter hyperintensities (WMH).Participants and Methods:The A4 study randomizes cognitively healthy older adults with evidence of amyloid pathophysiology on PET scanning. We used screening data, which included amyloid status (positive, negative) by visual read, amyloid PET standard uptake value ratio (SUVR) in cortical regions, and MRI data acquired in a subset (n=1,197, mean age 71.6 +/- 4.8 years, 57% women) to quantitate total WMH volume. Depressive symptoms were evaluated with the 15-item Geriatric Depression Scale, which we used both as a continuous variable and to define 'depressed' and 'non-depressed' groups, based on a cut score of > 5. We examined whether 1) depressive symptoms and proportion of depressed individuals differed between amyloid positive and negative groups, 2) there is a relationship between amyloid SUVR and depressive symptoms that differs as a function of amyloid positivity status, and 3) there is a relationship between WMH volume and depressive symptoms that differs as a function of amyloid positivity status.Results:Although depressive symptom severity did not differ between groups (t=0.14, p=0.88), a greater proportion of individuals were classified as depressed in the amyloid negative group than the amyloid positive group (3.5% vs. 1.9%, X2=4.60, p=0.032). Increased amyloid SUVR was associated with increased GDS scores among amyloid positive individuals (r=0.117, p=0.002) but not among amyloid negative individuals (r=0.006, p=0.68, Positivity Status x SUVR interaction on GDS: ß=0.817, p=0.029). Increased WMH was associated with higher GDS scores (ß=0.105, p=0.017) but not differentially in amyloid positive and negative participants (Positivity Status x WMH interaction on GDS: ß=-0.010, p=0.243).Conclusions:These analyses have several implications. First, individuals who are screened to participate in a clinical trial but do not have evidence of amyloidosis may be misattributing concerns about underlying AD pathophysiology to depressive symptoms. Second, the severity of AD pathophysiology, indexed by amyloid PET SUVR, may drive a small increase in depressive symptomatology among individuals over visual diagnostic thresholds. Third, small vessel cerebrovascular changes are additionally associated with depressive symptoms but in a manner that is independent of AD pathophysiology. Overall, depressive symptoms and depression are likely multiply determined among prospective clinical trial participants for preclinical AD.

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44 临床试验数据能否帮助我们了解抑郁症状在阿尔茨海默病中的作用？

目的：与情绪相关的神经精神症状在阿尔茨海默病（AD）中很常见，但尚不清楚它们在病因学上是否与 AD 病理生理学相关，或者是由于被认为是非致病因素，如小血管脑血管疾病。新一代 AD 临床试验通常会招募具有 AD 病理生理学证据（通过淀粉样蛋白 PET 扫描索引）但认知上无症状的参与者。我们使用来自无症状阿尔茨海默病抗淀粉样蛋白治疗 (A4) 研究的筛选数据来检查抑郁症状与淀粉样蛋白病理生理学和小血管脑血管疾病（以白质高信号 (WMH) 的形式）相关的程度。 参与者和方法：A4 研究将认知健康的老年人随机分组，并通过 PET 扫描发现淀粉样蛋白病理生理学证据。我们使用的筛查数据包括通过目视读取的淀粉样蛋白状态（阳性、阴性）、皮质区域淀粉样蛋白 PET 标准摄取值比 (SUVR) 以及在子集中获取的 MRI 数据（n = 1,197，平均年龄 71.6 +/- 4.8）年，57% 女性）来量化 WMH 总量。使用 15 项老年抑郁量表评估抑郁症状，我们将其用作连续变量，并根据 > 5 的切分来定义“抑郁”和“非抑郁”组。我们检查是否 1) 抑郁淀粉样蛋白阳性组和阴性组之间的症状和抑郁个体比例不同，2) 淀粉样蛋白 SUVR 和抑郁症状之间存在随淀粉样蛋白阳性状态而变化的关系，3) WMH 量和抑郁症状之间存在关系，结果：虽然抑郁症状的严重程度在各组之间没有差异（t = 0.14，p = 0.88），但淀粉样蛋白阴性组中被归类为抑郁症的个体比例高于淀粉样蛋白阳性组（ 3.5% 与 1.9%，X2=4.60，p=0.032）。淀粉样蛋白 SUVR 增加与淀粉样蛋白阳性个体的 GDS 评分增加相关（r=0.117，p=0.002），但与淀粉样蛋白阴性个体无关（r=0.006，p=0.68，GDS 的阳性状态 x SUVR 相互作用：ß=0.817，p =0.029）。WMH 增加与较高的 GDS 评分相关（ß=0.105，p=0.017），但在淀粉样蛋白阳性和阴性参与者中没有差异（阳性状态 x GDS 上的 WMH 相互作用：ß=-0.010，p=0.243）。结论：这些分析表明几个影响。首先，经过筛选参加临床试验但没有淀粉样变性证据的个体可能会将对 AD 潜在病理生理学的担忧错误地归因于抑郁症状。其次，AD 病理生理学的严重性（以淀粉样蛋白 PET SUVR 为指标）可能会导致个体抑郁症状小幅增加，超过视觉诊断阈值。第三，小血管脑血管变化还与抑郁症状相关，但与 AD 病理生理学无关。总体而言，临床前 AD 的前瞻性临床试验参与者的抑郁症状和抑郁可能是多重决定的。