Background and rationale. Multiple sclerosis (MS) is characterized by three major clinical forms: 1) relapsing-remitting (RR) phenotype (initial manifestation in 85-90% of subjects with MS) with acute neurologic dysfunctions (i.e. relapses) followed by partial or complete recovery periods (i.e. remissions); 2) secondary progressive (SP) phenotype in which, after some years of RR disease course, the acute phases become less and less frequent and are substituted by a steady progression of disability; 3) primary progressive (PP) phenotype in which disability progresses without relapses from the disease onset. Neuroimaging evidence unveiled different structural abnormalities in the brain between the RR and SP sub-groups while diverse functional abnormalities in the cortical neural synchronization were revealed by resting state electroencephalographic (rsEEG) rhythms [1]. It is an open issue, and one of the most relevant unmet needs in MS clinical research, how to predict the evolution of MS from RR to SP and whether the cortical neural connectivity from rsEEG rhythms can help in this regard. Aim. This 2-year project aims at testing if rsEEG markers are related to clinical features of MS over 4-8 years of disease evolution. Objectives. Test if rsEEG markers of neural connectivity can predict and monitor the disease evolution in MS from RR towards SP in a group of MS patients with RR. Design and phases. The study will be based on clinical and rsEEG data in 50 RR patients and 41 age-matched healthy control subjects (HC). All raw data in the HC subjects are already available in our archive. Those of more than 100 RR patients are available only at baseline. In this study, we will re-call those patients and collect clinical and rsEEG data at 4-8 year follow-up in 50 of them (estimated 50% of drop outs). Statistical analysis will test the hypothesis reported in the above "Objectives".
Essential reference
[1]Babiloni et al., 2016;PMID: 26111485
Innovative aim. This 2-year innovative project aims at testing if rsEEG markers based on functional connectivity of cortical sources of rsEEG rhythms are abnormal in MS patients, and if they can reflect different neurophysiologic abnormalities in MS sub-types (phenotypes) such as RR and SP. The confirmation of the hypotheses would have a great impact on the clinical management of persons with MS. At present, the therapeutic index of available treatments is far from obtimal: therapies are effective but carry substantial risks. It would be a seminal advancemet to be able to predict who is at risk of shifting from a RR to a SP disease course and who is not. This novel methodology may enrich the neurophysiological assessment of MS patients at the different stages of the disease.
Future advancements:
Outcome at short-medium term (15 months after this project). Cross-validation study in an independent population with the same protocol.
Outcome at long term (24 months after this project). Study of the relationship among brain arousal and functional connectivity, autonomous nervous system (ANS), neuroinflammation, neuroprotection of healthy lifestyle, and MS symptoms (RR, SP). The present protocol may be extended to: 1) structural magnetic resonance imaging (MRI) of brain volume, gray/white matter vascular lesions, spectroscopy of neural integrity and neuroinflammation, and regional cerebral blood flow; 2) resting state functional MRI of brain connectivity; 3) neuroinflammation indexes in cerebrospinal fluid; 4) heart rate variability probing ANS; 6) lifestyle survey (diet, physical exercise, social inclusion, quality of life), and 5) measurements of motor control, visuomotor integration, and balance.
Outcome at short-medium term (15 months from the end of this project). The results of this project may motivate a clinical trial combining the recording of rsEEG markers of neural connectivity with telemonitored healthy lifestyle (diet, physical exercise, and social inclusion), yoga techniques, and cognitive training improving global cortical functions. The MS patients may be selected based on the clinical and rsEEG markers used in the present project. Telemonitoring may be done based on the platform DECIDE (www.eu-decide.eu), developed by the applicant with GARR and other Partners.
Outcome at long term (36 months from the end of this project). Study of the long-term clinical follow-up at 12 and 24 months of the clinical trial.
Scientific and clinical outcome of the expected findings. Compared with the HC group, the RR group may show abnormalities in those rsEEG markers of neural connectivity (baseline data). Compared to the baseline, 4-8 year follow-ups may exhibit more severe rsEEG functional cortical dis-connectivity related to the worsening in the clinical symptoms. The results may encourage to repeat the data collection and analysis in those MS patients at 6-10 year follow-up.
Economic outcome of the expected findings. Based on AISM source (2017), there are about 114,000 males and females with MS in Italy in 2017 with 3,400 new cases any year (diagnosis at 20-40 years old). The average annual direct cost per MS person was of about 45,000 Euro, so the whole cost for the Public National Health Service was about 5 billion Euro (AISM source). It is expected that the project outcome inspires the enrichment of the neurophysiological assessment of MS patients at the different stages of RR and SP to perform the best clinical and pharmacological intervention. If this is true for 1% MS patients, there will be an annual saving of 50 million Euro and a new life for 1,420 individuals. This impact would be based only on the cost of this project.