In this post, I link to and excerpt from Clinically Relevant Changes for Cognitive Outcomes in Preclinical and Prodromal Cognitive Stages: Implications for Clinical Alzheimer Trials [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Neurology. 2022 Sep 13;99(11):e1142-e1153. doi: 10.1212/WNL.0000000000200817. Epub 2022 Jul 14.
The above article has been cited in three articles in PubMed.
There are 110 similar articles in PubMed.
All that follows is from the above resource.
Abstract
Background and Objectives
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).
Methods
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.
Results
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%).
Discussion
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.
____________________________________________
The minimal clinically important difference (MCID) is defined as the smallest change on a measure that is reliably associated with a meaningful change in a patient’s clinical status, function, or quality of life.1 It is important to decide the smallest change in an outcome that constitutes a clinically meaningful change—that is, MCID—to interpret whether, for example, the treatment effect measured using a cognitive test is clinically relevant or whether a change in cognitive testing during a clinical follow-up represents a clinically meaningful change in cognition. MCIDs are thus necessary to make accurate clinical decisions and to design clinical trials with the statistical power to detect an effect equal to or greater than the MCID.2
The aims of this study were (1) to establish cutoffs for cognitive test changes for use to conclude whether a meaningful magnitude of treatment effect has been achieved and (2) to investigate which single and combinations of cognitive test differences best corresponds to a clinically meaningful decline. In addition to examining the second aim in cognitively unimpaired (CU) participants and participants with mild cognitive impairment (MCI), we also examined this in Aβ-positive CU participants because this is a group of special interest in present and future clinical AD trials.7
Methods
Population
The participants in the study were consecutively included from the prospective Swedish BioFINDER study (biofinder.se), and participants for this study were enrolled from July 6, 2009, to March 4, 2015. The population consisted of 451 CU individuals and 292 people classified as experiencing mild cognitive impairment (MCI). In the CU group, 90 individuals experienced subjective cognitive decline, and 361 people were cognitively healthy controls based on a structured assessment. The individuals were followed up longitudinally (for CU pooled mean for all different tests 32.4 months (pooled SD 26.8, range 12–96 months), MCI pooled mean 19.2 months (pooled SD 19.0, range 12–72 months), with a mean number of data points of 1588 for CU and 727 for MCI.
MCI was defined according to the performance on a comprehensive neuropsychological battery, as previously described.8 All cognitively unimpaired individuals had a Clinical Dementia Rating—Sum of Boxes at inclusion of 0. Participants with MCI were excluded after converting to major neurocognitive disorder. Participants were assessed by physicians well experienced in dementia disorders, underwent a physical examination, MRI scan, lumbar punction, and cognitive assessments, and were rated with the CDR. Participants experiencing cognitive symptoms at baseline (subjective cognitive disease or MCI) were followed up annually, while participants without cognitive symptoms at baseline were examined every second year by physicians.
Cognitive Tests
Eight cognitive tests were examined in this study, covering the cognitive domains of executive function, attention, episodic and semantic memory, and visuospatial function. Participants were examined with the Mini-Mental State Examination (MMSE), the Alzheimer Disease Assessment Scale (ADAS) 10-word delayed recall, Letter S Fluency, Animal Fluency, Stroop Color and Word Test (Stroop), Trailmaking Tests A and B, and Symbol Digit Modalities Test. Further explanation of tests, what they assess, and how points are counted are described in eMethods*.
*eMethods – I could not find a link to this in the article. There is a link to Supplemental Files, a 3 page PDF.
Clinical Dementia Rating
Clinical Dementia Rating (CDR)* is an ordinal scale with scores of 0–3 points used to quantify the functional effect of cognitive impairment (0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, and 3 = severe) in domains (box scores) of memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.9,10 Participants in this study were rated on the CDR by a thorough review of patient records where dementia experts assessed cognitive symptoms and activities of daily living (ADL) in comprehensive semistructured interviews with patients and informants, including informant-based questionnaires of ADL (the functional activities questionnaire)11 and cognitive symptoms (the CIMP-QUEST)12 (supported if necessary by cognitive test results). The CDR scale provides a quantitative index of impairment, referred to as the Sum of Boxes or CDR-SB (range of 0–18), and may also be scored in the CDR global severity stage score (range 0–3) using an algorithm. An increase in the CDR-SB score has been identified as having both face and predictive validity to identify people who are later diagnosed with probable AD or another dementia.13 For predementia AD, a single box score increment of either 0.5 or 1.0 has been proposed to capture efficacy and clinical relevance for early AD.14 A change of 1 in CDR-SB could be either a change of 0.5 points in 2 boxes or a change of 1 point in 1 box.
*Clinical Dementia Rating Summary – 5-page PDF
Glossary
AD Alzheimer Disease ADAS Alzheimer’s Disease Assessment Scale ADL activities of daily living AIC Akaike Information Criterion AUC area under the ROC curve CDR-SB clinical dementia rating—sum of boxes CU cognitively unimpaired ES estimates of effect size FDA Food and Drug Administration MCI mild cognitive impairment MCID minimal clinically important difference MMSE Mini-Mental State Examination PACC preclinical Alzheimer cognitive composite RCI reliable change index SDMT Symbol Digit Modalities Test SRM standardized response mean TMT Trailmaking Test
