From the Clinical Memory Research Unit (E.B., E.S., N.C., O.H., S.P.), Department of Clinical Sciences, Lund University; Department of Neurology(E.B.), Skåne University Hospital, Malmö, Sweden; Department of Clinical Science (C.E.), Cogstate, London, United Kingdom; and Memory Clinic (E.S., O.H., S.P.), Skåne University Hospital, Malmö, Sweden.
Neurology. 2022 Sep 13;99(11):e1142-e1153. doi: 10.1212/WNL.0000000000200817. Epub 2022 Jul 14.
Identifying a clinically meaningful change in cognitive test score is essential when using cognition as an outcome in clinical trials. This is especially relevant because clinical trials increasingly feature novel composites of cognitive tests. Our primary objective was to establish minimal clinically important differences (MCIDs) for commonly used cognitive tests, using anchor-based and distribution-based methods, and our secondary objective was to investigate a composite cognitive measure that best predicts a minimal change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB).
From the Swedish BioFINDER cohort study, we consecutively included cognitively unimpaired (CU) individuals with and without subjective or mild cognitive impairment (MCI). We calculated MCIDs associated with a change of ≥0.5 or ≥1.0 on CDR-SB for Mini-Mental State Examination (MMSE), ADAS-Cog delayed recall 10-word list, Stroop, Letter S Fluency, Animal Fluency, Symbol Digit Modalities Test (SDMT) and Trailmaking Test (TMT) A and B, and triangulated MCIDs for clinical use for CU, MCI, and amyloid-positive CU participants. For investigating cognitive measures that best predict a change in CDR-SB of ≥0.5 or ≥1.0 point, we conducted receiver operating characteristic analyses.
Our study included 451 cognitively unimpaired individuals, 90 with subjective cognitive decline and 361 without symptoms of cognitive decline (pooled mean follow-up time 32.4 months, SD 26.8, range 12-96 months), and 292 people with MCI (pooled mean follow-up time 19.2 months, SD 19.0, range 12-72 months). We identified potential triangulated MCIDs (cognitively unimpaired; MCI) on a range of cognitive test outcomes: MMSE -1.5, -1.7; ADAS delayed recall 1.4, 1.1; Stroop 5.5, 9.3; Animal Fluency: -2.8, -2.9; Letter S Fluency -2.9, -1.8; SDMT: -3.5, -3.8; TMT A 11.7, 13.0; and TMT B 24.4, 20.1. For amyloid-positive CU, we found the best predicting composite cognitive measure included gender and changes in ADAS delayed recall, MMSE, SDMT, and TMT B. This produced an AUC of 0.87 (95% CI 0.79-0.94, sensitivity 75%, specificity 88%).
Our MCIDs may be applied in clinical practice or clinical trials for identifying whether a clinically relevant change has occurred. The composite measure can be useful as a clinically relevant cognitive test outcome in preclinical AD trials.
在临床试验中，当认知被用作结果时，识别认知测试分数的临床有意义变化至关重要。这是因为临床试验越来越多地采用新的认知测试组合。我们的主要目标是使用基于锚定和基于分布的方法，确定常用认知测试的最小临床重要差异（MCIDs），我们的次要目标是研究最佳预测临床痴呆评定量表总和框（CDR-SB）最小变化的综合认知测量。
从瑞典 BioFINDER 队列研究中，我们连续纳入认知正常（CU）个体，无论是否存在主观或轻度认知障碍（MCI）。我们为 Mini-Mental State Examination（MMSE）、ADAS-Cog 延迟回忆 10 字列表、Stroop、字母 S 流畅性、动物流畅性、符号数字模态测试（SDMT）和 Trailmaking 测试（TMT）A 和 B 的 CDR-SB 变化≥0.5 或≥1.0 计算了 MCIDs，为 CU、MCI 和淀粉样蛋白阳性 CU 参与者确定了用于临床使用的 MCIDs 三角。为了研究最佳预测 CDR-SB 变化≥0.5 或≥1.0 点的认知测量，我们进行了接收器操作特征分析。
我们的研究纳入了 451 名认知正常的个体，其中 90 名有主观认知减退，361 名没有认知减退的症状（平均随访时间 32.4 个月，SD 26.8，范围 12-96 个月），292 名有 MCI（平均随访时间 19.2 个月，SD 19.0，范围 12-72 个月）。我们在一系列认知测试结果中确定了潜在的三角 MCIDs（认知正常；MCI）：MMSE-1.5，-1.7；ADAS 延迟回忆 1.4，1.1；Stroop 5.5，9.3；动物流畅性：-2.8，-2.9；字母 S 流畅性-2.9，-1.8；SDMT：-3.5，-3.8；TMT A 11.7，13.0；和 TMT B 24.4，20.1。对于淀粉样蛋白阳性 CU，我们发现最佳预测综合认知测量包括性别以及 ADAS 延迟回忆、MMSE、SDMT 和 TMT B 的变化。这产生了 0.87 的 AUC（95%CI 0.79-0.94，灵敏度 75%，特异性 88%）。
我们的 MCIDs 可用于临床实践或临床试验，以确定是否发生了临床相关变化。该综合测量在 AD 临床试验中作为一种具有临床意义的认知测试结果可能很有用。
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