Corneal Confocal Microscopy: a Surrogate Endpoint for Neurodegeneration in Clinical Trials


CCM in Dementia

It is difficult for individuals at-risk of dementia to undertake routine screening tests. The ADDF diagnostic accelerator program has stated that there is a need for non-invasive, accurate and reliable biomarkers for dementia. This study investigates the diagnostic accuracy of corneal confocal microscopy (CCM) a non-invasive imaging biomarker for neurodegeneration and brain volumetric MRI to distinguish patients with MCI and dementia from controls.

The diagnosis of MCI and dementia was based on the ICD-10 criteria. 183 subjects aged 53-92 underwent CCM and corneal nerve quantification expressed as fiber density (CNFD, fibers/mm2), length (CNFL, mm/mm2) and branch density (CNBD branches/mm2), and brain volume quantification expressed as percentage of intracranial volume.

Aged-matched controls (n=36), subjects with MCI (n=80) and dementia (n=67) were studied. Subjects with MCI had a significantly lower whole-brain volume (70.6±3.4 vs 73.1±3.1, P<0.05), CNFD (24.5±9.6 vs 32.0±7.5, P<0.0001), CNFL (17.2±6.5 vs 22.9±6.0, P<0.0001) and CNBD (59.3±35.7 vs 90.9±46.5, P=0.001), but no difference in volume of hippocampus, cortical gray matter or ventricles compared with controls. Subjects with dementia had a significantly higher ventricular volume (4.8±2.4 vs 2.8±1.3, P=0.001) and lower volume of the whole-brain (67.2±3.2 vs 73.1±3.1, P<0.0001), hippocampus (0.3±0.08 vs 0.5±0.05, P<0.0001), gray matter (23.4±3.4 vs 28.8±3.1, P<0.0001), compared with controls. Volume of the whole-brain, hippocampus, gray matter and ventricles, CNFD, CNFL, CNBD distinguished patients with dementia from controls with area under the curve (AUC): 92%, 89%, 87%, 79%, 81%, 76% and 72%, respectively. Volume of the whole-brain, hippocampus, gray matter and ventricles could not distinguish subjects with MCI from controls with AUC: 70%, 61%, 61% and 65%, however, CNFD, CNFL and CNBD could with AUC: 75%, 81% and 75%.

Brain MRI and CCM show progressive neuronal loss in patients with MCI and dementia but only CCM can distinguish subjects with MCI from those without cognitive impairment.