Diffusion Magnetic Resonance Histograms as a Surrogate Marker and Predictor of Disease Progression in CADASIL

Abstract

Background and Purpose-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. MRI is sensitive in detecting preclinical involvement and changes over time. However, little is known about correlations between MRI metrics and clinical measures on a longitudinal scale. In this study, we assessed the role of quantitative MRI (T2-lesion volume and diffusion tensor imaging [DTI]-derived metrics) in monitoring and predicting disease progression. Methods-Sixty-two CADASIL subjects were followed prospectively over a period of 26.3Ϯ1.2 months. Dual-echo scans, DTI scans, and clinical scales were obtained at baseline and at follow-up. T2-lesion volumes were determined quantitatively, and histograms of mean diffusivity (MD) were produced. Results-At follow-up, T2-lesion volumes and MD histogram metrics had changed significantly (all PϽ0.01). Lesion volumes and average MD correlated with clinical scores at baseline. Changes of average MD correlated with changes of the Rankin score, the National Institutes of Health Stroke Scale score, and the structured interview for the diagnosis of Alzheimer dementia and multiinfarct dementia score (all PϽ0.01). On multivariate analysis, average MD and systolic blood pressure at baseline were predictors of changes of average MD during follow-up. Moreover, average MD was the main predictor of clinical progression. Sample size estimates showed that the number of individuals required to detect a treatment effect in an interventional trial may be reduced when using MD histograms as an end point. Conclusions-This

Longitudinal change of small-vessel disease-related brain abnormalities

“…79 In a longitudinal study, in 62 CADASIL subjects the changes in mean diffusivity correlated with changes in the Rankin score, national institute of health stroke scale and structured interview for the diagnosis of dementia of the Alzheimer type, multiinfarct dementia and dementias of other aetiology within a 2-year observation period. 28 Diffusion tensor imaging was also used in early detection 80,81 and monitoring of disease progression from mild cognitive impairment to Alzheimer's disease. 82 Sample size calculation based on 2-year follow-up data in CADASIL patients showed that one would need 1,944 subjects per treatment arm to show a treatment effect of 20% with an 80% power when mean diffusivity is used as the trial outcome.…”

“…82 Sample size calculation based on 2-year follow-up data in CADASIL patients showed that one would need 1,944 subjects per treatment arm to show a treatment effect of 20% with an 80% power when mean diffusivity is used as the trial outcome. 28 …”

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…Many of the other tests mentioned here are measured against the clock, ie, speed-dependent tests 89 . Patients with CADASIL exhibit markedly slow performance in this type of test.…”

“…In the future, neurobiological markers of early injury will probably be used in studies trying to influence the onset and progression of clinical changes; this should help reducing the number of patients needed in therapeutic studies. The search for these markers in MR studies involving analysis of the patterns of appearance and progression of atrophy and accumulation of white matter lesions and other typical structural changes is under way, as well as analyses of diffusion histograms and metabolic relations as assessed by spectroscopy 89,[132][133][134][135] . The main marker of disease progression is, unfortunately, increasing age, which can be seen as a non modifiable risk factor.…”

Multimodal MRI of Cerebral Small Vessel Disease

“…Accordingly, MD histogram parameters have been reported to correlate more with clinical scores than WMH visual rating scales and volumetric data in cSVD both cross sectionally and longitudinally. Furthermore they were more sensitive than clinical scales in detecting change over time [101][102][103][104][105][106] . There are data indicating that the much simpler, quicker and widely available (DWI) derived ADC can be used similarly to DTI derived MD to quantify brain damage due to cSVD (findings of Gunda et al to be published) (Figure 3 and 4).…”