BackgroundAdvanced diffusion‐based MRI biomarkers may provide insight into microstructural and perfusion changes associated with neurodegeneration and cognitive decline.PurposeTo assess longitudinal microstructural and perfusion changes using apparent diffusion coefficient (ADC) and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) parameters in cognitively impaired (CI) and healthy control (HC) groups.Study TypeProspective/longitudinal.PopulationTwelve CI patients (75% female) and 13 HC subjects (69% female).Field Strength/Sequence3 T; Spin‐Echo‐IVIM‐DWI.AssessmentTwo MRI scans were performed with a 12‐month interval. ADC and IVIM‐DWI metrics (diffusion coefficient [D] and perfusion fraction [f]) were generated from monoexponential and biexponential fits, respectively. Additionally, voxel‐based correlations were evaluated between change in Montreal Cognitive Assessment (ΔMoCA) and baseline imaging parameters.Statistical TestsAnalysis of covariance with sex and age as covariates was performed for main effects of group and time (false discovery rate [FDR] corrected) with post hoc comparisons using Bonferroni correction. Partial‐η2 and Hedges' g were used for effect‐size analysis. Spearman's correlations (FDR corrected) were used for the relationship between ΔMoCA score and imaging. P < 0.05 was considered statistically significant.ResultsSignificant differences were found for the main effects of group (HC vs. CI) and time. For group effects, higher ADC, IVIM‐D, and IVIM‐f were observed in the CI group compared to HC (ADC: 1.23 ± 0.08.10−3 vs. 1.09 ± 0.07.10−3 mm2/sec; IVIM‐D: 0.82 ± 0.01.10−3 vs. 0.73 ± 0.01.10−3 mm2/sec; and IVIM‐f: 0.317 ± 0.008 vs. 0.253 ± 0.009). Significantly higher ADC, IVIM‐D, and IVIM‐f values were observed in the CI group after 12 months (ADC: 1.45 ± 0.05.10−3 vs. 1.50 ± 0.07.10−3 mm2/sec; IVIM‐D: 0.87 ± 0.01.10−3 vs. 0.94 ± 0.02.10−3 mm2/sec; and IVIM‐f: 0.303 ± 0.007 vs. 0.332 ± 0.008), but not in the HC group at large effect size. ADC, IVIM‐D, and IVIM‐f negatively correlated with ΔMoCA score (ρ = −0.49, −0.51, and −0.50, respectively).Data ConclusionThese findings demonstrate that longitudinal differences between CI and HC cohorts can be measured using IVIM‐based metrics.Level of Evidence2Technical Efficacy Stage2