Clinical utility of diffusion MRI-derived measures of cortical microstructure in a real-world memory clinic setting

Abstract

Objective: To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI).

Methods: The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD⁺), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices.

Results: A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A-T-. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A-T- progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A-T- patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%).

Interpretation: Results support the clinical utility of cortical microstructure to aid prognosis, especially in A-T- patients. Further work will investigate other complexities of the real-world clinical setting, including A-T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.

Figure 1

Cortical microstructural metrics. This figure shows a cross‐sectional image of diffusion based metrics related to the three directional components of diffusion within the cortical gray matter.

Figure 2

Micro‐ and macrostructural group differences. This figure shows micro‐ and macrostructural values across the AT continuum that includes MCI and Dementia groups. CVF, cortical volume fraction; CT, cortical thickness; HVF, hippocampal volume fraction.

Figure 3

CSF markers: Amyloid (A) and Tau (T) flow diagram. Flow diagram shows performance testing structure of the CSF AT biomarkers. The test was conducted in the MCI A−T− and A+T+ groups, by comparing against the clinical status (MCI clinical status: Converted or Stable). The expected profile for MCI Converted is A+T+, and the expected profile for MCI Stable is A−T−. As seen in the figure, mixed AT profiles (A−T+, or A+T−) were excluded, in order to reduce the potential for including inaccurately classified cases.

Figure 4

AngleR flow diagram in MCI A−T−. Flow diagram shows the performance testing structure of AngleR conducted in the MCI A−T− group, for comparison against the clinical profile (MCI clinical status: Converted or Stable). AngleR status, positive (+) or negative (−), was determined by the cutoff defined as the best point with the highest value obtained by averaging sensitivity and 1 − specificity.

Figure 5

AngleR diagnostic power in MCI A−T− and MCI A+T+ stable vs converted. Panel (A) shows separation between stable and converted MCI A−T− using whole‐brain AngleR value. Panel (B) shows separation between stable and converted MCI A−T− and A+T+ using whole‐brain AngleR value. AD, Alzheimer's disease; CBS, corticobasal syndrome; DLB, Dementia with Lewy body; PCA, posterior cortical atrophy; PSP, progressive supranuclear palsy.