The onset of MS-related progressive brain tissue loss (PBTL) precedes clinical disease onset by 5 to 6 years.

Dr. Christina Azevedo (University of Southern California, CA, USA) and colleagues aimed to estimate the onset of disease-related progressive brain tissue loss (PBTL), defined as the age at which an MS patient’s thalamic atrophy curve starts to deviate from expected normal aging [1]. To this end, they created an artificial intelligence (AI)-based Digital Twin for every patient. A total of 4,968 3T brain MRIs were analyzed: 2,483 MRIs of 520 individuals with MS and 2,485 MRIs of 2,053 healthy controls, age ranging from 16 to 89.

To construct the Digital Twin model, the researchers used normal aging data to augment longitudinal data from a well-fitted spline model; they then compared different mixed spline models and identified the model with the best fit. The final covariates in this model included age, sex, baseline thalamic volume, age at clinical onset, lifetime disease-modifying treatment (DMT) exposure, and intracranial volume (ICV). Based on tenfold cross-validation, the final model reached a repeated measure correlation coefficient of 0.88 (P<0.01).

The results showed that the onset of disease-related PBTL preceded clinical MS onset by a mean of 5.1 ± 3.8 years, and a median of 6 (IQR 3.1–8.1) years. Just over half (55.4%) of the investigated patients could be classified as having an earlier PBTL onset, while 44.6% were classified as having simultaneous PBTL and clinical onset. These results showed remarkable consistency with the reported timing of premorbid rise in serum neurofilament light chain (NfL). Patients with earlier PBTL onset were/had statistically significantly:

• more likely to be women: 78.5% vs 59.7% (P<0.001);
• older at clinical symptom onset: 36.9 vs 29.3 years (P<0.001);
• older at study entry: 44.5 vs 40.4 years (P<0.001);
• lower T2-lesion volumes at study entry: 3,776 vs 5,719 (P<0.001);
• larger thalamic volumes at study entry: 9.4 vs 9.1 (P=0.012).

“Although PBTL onset is not synonymous with the true biological disease onset, it should be closer to the biological onset than the clinical onset we currently observe,” noted Dr. Azevedo. She added that a more precise estimate of disease onset may lead to a better understanding of the natural history of MS and the early events in disease pathogenesis.

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