PMS Patients Research Articles

Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome

BackgroundPhelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD).ObjectivesTo assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels.Methods70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC.ResultsOur sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001).ConclusionsWe replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.

Evaluation of Lesion Burden in Pediatric Patients with Multiple Sclerosis by Computer Aided Algorithm and Comparison with Standard Detection Methods

Background: The aim of this retrospective study was to assess the lesion burden in pediatric patients with multiple sclerosis (pMS) using a computer-assisted algorithm, specifically the VolBrain program. The study aimed to compare the performance of this automated tool with traditional detection methods performed by neuroimaging analysts, providing valuable insights into the potential of automated tools for lesion quantification in pMS. Materials and Methods: The study cohort consisted of 20 PMS patients, aged 10-18 years, registered at Atatürk University Research Hospital. Lesion assessment was performed using the VolBrain program (by an anatomist) and standard detection methods (by a neuroradiologist) using T2 SPACE dark matter sequences. Statistical analysis included Wilcoxon and Pearson correlation tests, and the study adhered to ethical considerations and standardised magnetic resonance imaging (MRI) protocols. Results: In this study, pMS patients aged 10-18 years, the cohort consisted of 60% females (n=12) and 40% males (n=8). The mean age for females was 15.67±1.969 and for males 14.50±2.20 years (p=0.24). Plaque count analysis showed a statistically significant difference between radiologist and VolBrain assessment in all pMS patients (p=0.021). Significant differences were also observed in female pMS patients (p=0.034) but not in males (p=0.362). Correlations between radiologist and VolBrain assessments showed significant associations in both female and male patients, with strong correlations observed for plaque number, lesion burden and Expanded Disability Status Scale (EDSS) scores (p&amp;lt;0.01). Conclusions: This study demonstrates the potential of the VolBrain programme in assessing lesion burden in pMS patients. The observed correlations with traditional methods and clinical parameters support the concurrent validity of VolBrain and emphasise its potential clinical relevance. Incorporating automated tools into routine clinical practice could improve the accuracy of lesion quantification and thus contribute to improved monitoring and management of pMS.

PP98 Phelan-McDermid syndrome: Methodology For Creating A Patient Adapted Version Of A Clinical Practice Guideline

IntroductionPhelan-McDermid syndrome (PMS) is a chromosomal disorder caused by the loss of the end of chromosome 22, that is manifested as a neurodevelopmental disorder. Providing an adapted version of a guideline was seen as essential, as currently, there are no such booklets based on an international guideline for PMS patients, families and caregivers. The European Reference Networks (ERN) Guidelines programme results from a call for proposals funded (DG SANTE/2018/B3/030) for the development of Clinical Practice Guidelines (CPG) and Clinical Decision Tools in the area of rare diseases. Based on this European consortium, the purpose of this study is to describe how two Spanish HTA agencies, OSTEBA-BIOEF (Basque Office for Health Technology Assessment) and AETSA (Andalusian Health Quality Assessment Department) methodologically support the ERN-ITHACA (Rare malformation syndromes and rare intellectual and neurodevelopmental disorders) in the development of a comprehensive patient booklet based on a CPG to be used as an adjunct in the management of PMS syndrome that will be published in 2023.MethodsA preliminary booklet was created by HTA agencies using the new European guideline for PMS and a Dutch guideline. The booklet structure is an adaptation based on a European Commission template with the guidance of the methodological Handbook#11.ResultsThrough a comprehensive adaptation, following the PMS guideline and the Handbook #11, a booklet is developed for the PMS patients. Composed by 28 pages in DIN A5 format were introduction, diagnosis, treatment, pregnancy, do’s, supportive care, social networks (including a QR code) and a glossary are included. The selection of a symbol, colors at a chromatic level, a typography and graphical elements as illustrations were created as a corporate identity. Clinical experts and patient representatives that have participated in the creation of the guideline will assess and validate the booklet.ConclusionsCollaboration between agencies, clinicians and patients is critical to obtain evidence-based products adapted to the needs of patients and people involved in their care.

Association of MRI leptomeningeal enhancement with disability worsening in progressive multiple sclerosis: A clinical and post-mortem study

Background: Leptomeningeal enhancement (LME) has been described as a biomarker of meningeal inflammation in multiple sclerosis (MS). Objective: The aim of this study was to (1) assess if LME is predictive of disability worsening in progressive MS (pMS) patients and (2) investigate the pathological substrates of LME in an independent post-mortem MS series. Methods: In total, 115 pMS patients were imaged yearly with 1.5T MRI, using post-contrast CUBE 3D FLAIR for LME detection. Endpoint: to identify the baseline variables predictive of confirmed disability worsening (CDW) at 24 months follow-up. Post-mortem, inflammation, and structural changes of the leptomeninges were assessed in 12 MS/8 control brains. Results: LME (27% of patients at baseline) was associated with higher EDSS and lower brain volume (nBV). LME was unchanged in most patients over follow-up. LME at baseline MRI was independently associated with higher risk of 24 months CDW (HR 3.05, 95% CI 1.36–6.84, p = 0.007) in a Cox regression, including age, nBV, T2 lesion volume, high-efficacy treatments, and MRI disease activity. Post-mortem, focal structural changes (fibrosis) of the leptomeninges were observed in MS, usually associated with inflammation (Kendall’s Tau 0.315, p < 0.0001). Conclusions: LME is frequently detected in pMS patients using 1.5T MRI and is independently predictive of disability progression. LME could result from both focal leptomeningeal post-inflammatory fibrosis and inflammation.

Comorbidities in Patients with Multiple Sclerosis and How Lifestyle Behaviors Can Change the Comorbidities, Role of the Family Physician and Neurologist

Introduction: Comorbidity can be defined as any additional disease that coexists in an individual with a given index disease, which is not an obvious complication of the index disease. Physical and mental comorbid conditions are common among persons with MS. Searching Strategy and Selection Criteria: We identified relevant articles in English for this review by searching PubMed, for articles published between January 1, 2017, and Feb 28, 2023, and reference lists from relevant articles. Comorbidities in MS: The most prevalent comorbidities in MS are depression (23.7%), anxiety (21.9%), hypertension (18.6%), hypercholesterolemia (10.9%), and chronic lung disease (10%). Lifestyle Behaviors: In the last years, multiple studies shown that the exercise can improve not only the physical part, also the mental health and quality of life. In the recent years several studies concludes that the Paleolithic diet have good results in the relieve of the symptoms of MS like fatigue and the cognitive functions. It ?s well know that the stress, depression, and anxiety have a high prevalence in MS patients. In one cross-sectional study of RRMS and PMS patients, the patients with RRMS reported a higher emotional support, affection support and positive social interaction. Conclusion: Having lifestyle changes like exercise, good nutrition and supplementation can reduce the risk of the mention comorbidities also have a positive result in the psychological and social area diminishing symptoms and mental diseases.

Influence of Cardiorespiratory Fitness and MRI Measures of Neuroinflammation on Hippocampal Volume in Multiple Sclerosis Patients (S27.007)

<h3>Objective:</h3> To investigate whether higher cardiorespiratory fitness (CRF) may limit the detrimental effects of neuroinflammation on hippocampal volume in the main multiple sclerosis (MS) clinical phenotypes. <h3>Background:</h3> The hippocampus is a clinically-relevant brain region that is characterized by neuroplasticity and neurogenesis also in adults. Neuroinflammation and CRF may specifically influence hippocampal integrity, thus modulating the processes promoting neurogenesis and neuroprotection that contribute to the preservation of functions. <h3>Design/Methods:</h3> Brain structural MRI scans and maximum oxygen consumption (VO₂max), a proxy of CRF, were acquired from 81 MS patients (27 relapsing-remitting [RR] and 54 progressive [P]), and 47 age- and sex-matched healthy controls (HC). White matter T2-hyperintense lesion volume (T2-LV) and choroid plexus volume (CPV) were quantified as neuroinflammatory measures. Associations of T2-LV, CPV and CRF with normalized brain (NBV), gray matter (NGMV), thalamic (NTV) and hippocampal volumes were assessed using linear regression analysis. Stepwise hierarchical regression models were used to evaluate the independent contribution of demographic, clinical, T2-LV, CPV and VO₂max in explaining the aforementioned volumes. <h3>Results:</h3> In MS, higher T2-LV was significantly associated with lower global and regional brain volumes (standardized-β from −0.706 to −0.356, p≤0.009), except for NGMV (p=0.105). Higher CPV was significantly associated only with lower NBV and NTV in both RRMS and PMS patients (standardized-β from −0.545 to −0.290, p≤0.045). Higher VO₂max was significantly associated only with higher normalized hippocampal volume only in RRMS patients (standardized-β=0.448, p=0.013). Using stepwise hierarchical regression models, T2-LV in both RRMS (ΔR²=0.124, p=0.043) and PMS patients (ΔR²=0.095, p=0.028) and VO₂max only in RRMS patients (ΔR²=0.153, p=0.014) were found to explain a significant portion of hippocampal volume variance. <h3>Conclusions:</h3> By exerting beneficial neurotrophic effects, a higher CRF may have a specific neuroprotective role for the hippocampus, mainly in the early phases of MS. <b>Disclosure:</b> Mr. Morozumi has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Albergoni has nothing to disclose. Monica Margoni has received research support from MAGNIMS. Elisabetta Pagani has nothing to disclose. Alessandro Meani has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

In-vivo characterization of macro- and microstructural injury of the subventricular zone in relapsing-remitting and progressive multiple sclerosis.

The subventricular zone (SVZ) represents one of the main adult brain neurogenesis niche. In-vivo imaging of SVZ is very challenging and little is known about MRI correlates of SVZ macro- and micro-structural injury in multiple sclerosis (MS) patients. The aim of the present study is to evaluate differences in terms of volume and microstructural changes [as assessed with the novel Spherical Mean Technique (SMT) model, evaluating: Neurite Signal fraction (INTRA); Extra-neurite transverse (EXTRATRANS) and mean diffusivity (EXTRAMD)] in SVZ between relapsing-remitting (RR) or progressive (P) MS patients and healthy controls (HC). We are also going to explore whether SVZ microstructural injury correlate with caudate (a nucleus that is in the vicinity of the SVZ) or thalamus (another well-defined grey matter area which is further from SVZ than caudate) volume and clinical disability. Clinical and brain MRI data were prospectively acquired from 20 HC, 101 RRMS, and 50 PMS patients. Structural and diffusion metrics inside the global SVZ, normal appearing (NA-) SVZ, caudate and thalamus were collected. We found a statistically significant difference between groups in terms of NA-SVZ EXTRAMD (PMS>RRMS>HC; p = 0.002), EXTRATRANS (PMS>RRMS>HC; p<0.0001), and INTRA (HC>RRMS>PMS; p = 0.009). Multivariable models showed that NA-SVZ metrics significantly predicted caudate (R 2 = 0.21, p < 0.0001), but not thalamus, atrophy. A statistically significant correlation between EXTRAMD and EXTRATRANS of the NA-SVZ and EDSS (r=0.25, p=0.003 and r=0.24, p = 0.003, respectively) was found. These findings were confirmed in analyses restricted to RRMS, but not to PMS patients. In conclusion, the microstructural damage we observed within the NA-SVZ of MS patients - reflecting higher free water content (higher EXTRAMD), cytoarchitecture disruption and astrogliosis (higher EXTRATRANS and lower INTRA) - was more evident in the progressive as compared to the relapsing phases of MS. These abnormalities were significantly associated with a more pronounced caudate atrophy and higher clinical disability scores. Our findings may support the neuroprotective role of SVZ in MS patients.

Mechanisms of Injury in Adolescent Trauma Patients With a Positive Marijuana Screen.

Marijuana use among adolescents may have increased after its legalization in the United States. An association between violence and marijuana use in adults has been demonstrated in previous reports. We hypothesized that adolescent trauma patients presenting with a positive marijuana screen (pMS) are more likely to have been injured by gunfire or knives and will have more severe injuries overall, compared to patients with a negative marijuana screen (nMS). The 2017 Trauma Quality Improvement Program database was queried for adolescent (13-17years old) pMS patients and compared to adolescents who tested negative for all substance/alcohol. Patients with positive polysubstance/alcohol were excluded. From 8257 adolescent trauma patients, 2060 (24.9%) had a pMS with a higher rate of males in the pMS group (76.3% vs 64.3%, P < .001). The pMS group presented more frequently after gun (20.3% vs 7.9%, P < .001) or knife trauma (5.7% vs 3.0%, P < .001) and less frequently after falls (8.9% vs 15.6%, P < .001) and bicycle collisions (3.3% vs 4.8%, P = .002). The rate of serious thoracic injury (AIS ≥3) was higher for pMS patients (16.7% vs 12.0%, P < .001), and more pMS patients required emergent operation (14.9% vs 10.6%, P < .001). In our adolescent patient population, one quarter tested positive for marijuana. These patients are more likely to be injured by guns and/or knives suffering serious injuries, and often require immediate operative intervention. A marijuana cessation program for adolescents can help improve outcomes in this high-risk patient group.

In vivo quantification of brain soma and neurite density abnormalities in multiple sclerosis.

Soma and neurite density imaging (SANDI) is a new biophysical model that incorporates soma in addition to neurite density, thus possibly providing more specific information about the complex pathological processes of multiple sclerosis (MS). To discriminate the pathological abnormalities of MS white matter (WM) lesions, normal-appearing (NA) WM and cortex and to evaluate the associations among SANDI-derived measures, clinical disability, and conventional MRI variables. Twenty healthy controls (HC) and 23 MS underwent a 3T brain MRI. Using SANDI on diffusion-weighted sequence, the fractions of neurite (fneurite) and soma (fsoma) were assessed in WM lesions, NAWM, and cortex. Compared to HC WM, MS NAWM showed lower fneurite (false discovery rate [FDR]-p = 0.011). In MS patients, WM lesions showed lower fneurite and fsoma compared to both HC and MS NAWM (FDR-p < 0.001 for all). In the cortex, MS patients had lower fneurite and fsoma compared to HC (FDR-p ≤ 0.009). Compared to both HC and RRMS, PMS patients had lower fneurite in NAWM (vs HC: FDR-p < 0.001; vs RRMS: FDR-p = 0.003) and cortex (vs HC: FDR-p < 0.001; vs RRMS: p = 0.031, not surviving FDR correction), and lower cortical fsoma (vs HC: FDR-p < 0.001; vs RRMS: FDR-p = 0.009). Compared to HC, PMS also showed a higher fsoma in NAWM (FDR-p = 0.015). Fneurite and fsoma in the different brain compartments were correlated with age, phenotype, disease duration, disability, WM lesion volumes, normalized brain, cortical, and WM volumes (r from -0.761 to 0.821, FDR-p ≤ 0.4). SANDI may represent a clinically relevant model to discriminate different neurodegenerative phenomena that gradually accumulate through MS disease course.

Diagnostic Cerebrospinal Fluid Biomarker in Early and Late Onset Multiple Sclerosis.

Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients (p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.

Cardiovascular autonomic dysfunction in multiple sclerosis-findings and relationships with clinical outcomes and fatigue severity.

This study evaluates cardiovascular autonomic dysfunction (CAD) in multiple sclerosis (MS) and explores if CAD is related to clinical outcomes and fatigue severity. A total of 53 MS patients (30 relapsing-remitting, RRMS; 23 progressive, PMS) and 30 healthy controls were evaluated. TaskForce® Monitor was used to assess impedance cardiography parameters, heart rate (HRV), and blood pressure (BPV) variability during head-up tilt test (HUTT). Expiration/inspiration (E/I) ratio was assessed in response to a deep breathing test. Fatigue severity was evaluated using Chalder Fatigue Scale (CFQ). Compared to controls, PMS patients were characterized by increased sympathetic-parasympathetic ratio at rest (p < 0.01), decreased resting values of parasympathetic parameters (high-frequency HRV, p < 0.05; E/I ratio, p < 0.001), and index of contractility (p < 0.05), whereas RRMS patients showed reduced E/I ratio (p < 0.01). Compared to RRMS group, PMS patients had higher sympathovagal ratio and lower cardiac inotropy parameters (p < 0.05). No intergroup differences were observed for cardiovascular and autonomic function test parameters after HUTT. PMS and low CFQ physical score were identified as independent predictors of sympathetic hyper-reactivity as measured with HRV. Greater disability and male sex were predictors of diastolic BP increase and reduced cardiac inotropy parameters, and older age was predictor of decreased vagal tone (E/I ratio, high-frequency HRV). Cardiovascular autonomic modulation is altered in MS and highly dependent on disease variant, disability level, fatigue severity, and patients' demographics.

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals.

Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

Cerebral blood flow dependency on systemic arterial circulation in progressive multiple sclerosis.

To determine the relationship between systemic arterial blood flow (SABF) and cerebral perfusion measures in multiple sclerosis (MS) patients. Cerebral perfusion and SABF were assessed in 118 patients (75 clinically isolated syndrome (CIS)/relapsing-remitting MS and 43 progressive MS) through MRI examination with dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and Doppler ultrasound, respectively. Measures of mean transit time (MTT) and time-to-peak (TTP), measured in seconds, of the normal-appearing whole brain (NAWB) and gray matter (GM) were calculated. Blood flow through the bilateral common carotid and vertebral arteries (in mL/min) represents the SABF. Whole brain volume (WBV) and body mass index (BMI) were used as additional covariates. Higher systolic blood pressure was associated with lower SABF (-0.256, p = 0.006). In the total MS sample, higher SABF was associated with shorter MTT and TTP of the NAWB (r = -0.256, p = 0.007 and r = -0.307, p = 0.001) and GM (r = -0.239, p = 0.012 and r = -0.3, p = 0.001). The SABF and TTP associations were driven by the PMS patients (r = -0.451, p = 0.004 and r = -0.451, p = 0.011). Only in PMS, SABF remained a significant predictor of NAWB (standardized β = -0.394, p = 0.022) and GM TTP (standardized β = -0.351, p = 0.037). MTT and TTP were significantly lower in patients within lower SABF quartiles when compared to the higher quartiles (age-, sex-, BMI-, and WBV-adjusted ANCOVA p < 0.025). The direct relationship between systemic and cerebral blood flow seen in PMS patients may suggest failure in cerebrovascular reactivity mechanisms and insufficient perfusion control. Cerebral blood flow in PMS may be increasingly dependent on the SABF. • In progressive multiple sclerosis (MS) patients, the systemic arterial blood flow (SABF) is associated with perfusion-based measure of time-to-peak (TTP) of the normal-appearing whole brain (r = -0.451, p = 0.004) and gray matter (r = -0.451, p = 0.004). • Cerebral blood flow in progressive MS is directly dependent on systemic arterial blood flow and may be influenced by blood pressure changes. • Neurovascular unit impairment may play an important role in MS pathophysiology and contribute towards greater clinical disability.

Association between circulating MicroRNAs (hsa-miR-92a-1* and hsa-miR-454) and multiple sclerosis phenotypes and activity statu

Efficient diagnosis of multiple sclerosis (MS) disease along with early prediction of its progression will ultimately lead to better management, control of complications and improvement of therapeutic outcomes and patient’s well-being. Blood based biomarkers like circulating microRNAs represent a non- invasive, fast, and easily measured markers with a promising potential. This work intended to assess the relative expression of circulating hsa-miR-454 and hsa-miR-92a-1* as a diagnostic and prognostic tool among Egyptian MS patients in terms of correlation to disease type and severity. hsa-miR-454 and hsa-miR-92a-1* relative expression was measured in the plasma of 31 MS patients, relapsing remitting MS (RRMS, n=21) and progressive MS (PMS, n=10) and 20 age and sex matched normal controls by using reverse transcription followed by real time PCR. Disease severity assessment was done in the form of patient expanded disability status scale (EDSS) evaluation. Relative expression of hsa-miR-454 and hsa-miR-92a-1* did not show a statistically significant difference between MS cases and controls. However, hsa-miR-454 was significantly higher among RRMS patients in comparison to PMS patients (P = 0.04). Additionally, both markers showed a statistically significant upregulation among patients in disease exacerbation in comparison to patients in remission (P = &lt;0.01) and both showed a negative correlation with EDSS. In conclusion, microRNAs may represent potential valuable non-invasive biomarkers for assessment of MS type (RRMS vs PMS), as well as for prediction of disease activity and severity in MS patients.

Cerebrospinal fluid of progressive multiple sclerosis patients reduces differentiation and immune functions of oligodendrocyte progenitor cells.

Oligodendrocyte progenitor cells (OPCs) are responsible for remyelination in the central nervous system (CNS) in health and disease. For patients with multiple sclerosis (MS), remyelination is not always successful, and the mechanisms differentiating successful from failed remyelination are not well‐known. Growing evidence suggests an immune role for OPCs, in addition to their regenerative role; however, it is not clear if this helps or hinders the regenerative process. We studied the effect of cerebrospinal fluid (CSF) from relapsing MS (rMS) and progressive MS (pMS) patients on primary OPC differentiation and immune gene expression and function. We observed that CSF from either rMS or pMS patients has a differential effect on the ability of mice OPCs to differentiate into mature oligodendrocytes and to express immune functions. CSF of pMS patients impaired differentiation into mature oligodendrocytes. In addition, it led to decreased major histocompatibility complex class (MHC)‐II expression, tumor necrosis factor (TNF)‐α secretion, nuclear factor kappa‐B (NFκB) activation, and less activation and proliferation of T cells. Our findings suggest that OPCs are not only responsible for remyelination, but they may also play an active role as innate immune cells in the CNS.

Urine neopterin in childhood acute demyelinating diseases: Potential for differential diagnosis

Inflammatory demyelinating diseases of the central nervous system (CNS) in childhood include clinically and radiologically defined diseases such as acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). Differentiation between these phenotypes can be difficult and cases not meeting established diagnostic criteria may remain without any specific diagnosis for months. Laboratory markers can assist in the diagnosis and management of these diseases. Previous studies suggest serum kynurenine-tryptophan pathway products and serum neopterin as biomarkers for CNS autoimmune diseases. Because urine is a reliable and repeatable source for analysis of these products with the additional advantage of easy sampling, we measured neopterin concentrations in serum and urine samples, urinary biopterin and serum kynurenine-tryptophan levels in autoimmune demyelinating diseases of CNS: pediatric multiple sclerosis (pMS, n = 27), MOGAD (n = 10), NMOSD (n = 5) patients and a control group consisting of healthy children or children with non-inflammatory diseases (n = 13), total 55 children. Methods were high performance liquid chromatography (HPLC) for neopterin, biopterin and creatinine in urine and kynurenine and tryptophan in serum; ELISA was used for serum neopterin. Comparison for biomarkers between all diagnostic groups showed urinary neopterin values were significantly higher in the pMS group (p = 0.002). The cut-off point determined by ROC analysis indicated urinary neopterin >167.75 µmol/mol creatinine could distinguish the patients from the controls with a sensitivity of 71% and specificity of 90%. The most significant difference was between the pMS and control groups (p = 0.002) while no difference was observed between pMS patients who were in relapse or stable state. Therefore, urinary neopterin appeared as a potential marker that could differentiate pMS from other demyelinating patient groups MOGAD and NMOSD as well as from controls. The fact that pteridine pathway products had not been studied in urine and serum in children with demyelinating disease before highlights the novelty of this study. If further research in larger samples confirm the present results, these molecules might assist the differential diagnosis of pMS from other demyelinating CNS diseases.

Marijuana Use Associated with Decreased Mortality in Trauma Patients.

The incidence of trauma patients with a positive marijuana screen (pMS) is increasing but the effects of marijuana on outcomes have varied in previous studies. A recent statewide analysis demonstrated decreased mortality for intensive care unit (ICU) trauma patients with pMS. Thus, we hypothesized a pMS to be associated with a decreased risk of mortality for all trauma patients. The 2017 Trauma Quality Improvement Program (TQIP) database was queried for adult (≥18years-old) pMS patients, who were compared to patients negative for all drugs and alcohol (nDS). Patients not drug tested or testing positive for drug(s)/alcohol other than marijuana were excluded. Multivariable logistic regression was used to evaluate risk of mortality after controlling for known predictors of mortality including age, sex, injury severity, vital signs, and comorbidities. Additional subgroup analyses were performed for ICU patients and younger adults (<40years-old). From 141737 tested patients, 23310 (16.4%) had an isolated pMS. Patients with pMS were younger (P < .001) but had a similar median injury severity score (ISS) (9, P = .42) compared to nDS patients. On multivariable analysis the associated risk of mortality was lower for pMS (OR .79, .71-.87, P < .001) compared to nDS patients. Subgroups analyses also demonstrated decreased associated risk of mortality for ICU and younger patients (both P < .05). Patients with a pMS had decreased associated risk of mortality compared to nDS patients, including subgroups of ICU and younger patients. These findings require corroboration with future prospective clinical study and basic science evaluation to ascertain the exact pathophysiologic basis and thereby target potential interventions.

Impact of COVID-19 lockdown on progressive multiple sclerosis patients.

IntroductionThe COVID-19 pandemic caused major changes in the lifestyle and in the access to health services worldwide. Progressive multiple sclerosis (pMS) patients are a vulnerable population at high risk of disability worsening.Objective and MethodsThe objective of this study was to assess the health outcomes of COVID-19 lockdown in a cohort of 225 pMS patients.ResultsWorsening of neurological disability (19.7%) and fatigue (32.4%), depression (30.4%), and weight increase (28.3%) were observed in pMS patients during lockdown, along with discontinuation of regular physical exercise (47.1%) and of physical therapy (59.3%).ConclusionThese results highlight the adverse impact, on pMS patients, of the public health measures implemented for the containment of the pandemic.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10072-022-05909-z.

Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis.

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms.

Diffusion tensor imaging reveals greater microstructure damage in lesional tissue that shrinks into cerebrospinal fluid in multiple sclerosis.

Atrophied T2 lesion volume (LV), reflecting the complete transformation of lesions into cerebrospinal fluid (CSF), has been associated with disease progression in multiple sclerosis (MS). The underlying damage leading to lesion destruction remains poorly understood. The objective of this study was to use diffusion tensor imaging (DTI) to investigate the extent of microstructural tissue damage at baseline in lesions that subsequently transform into CSF. Ninety-nine MS patients (67 relapsing-remitting MS [RRMS] and 32 progressive PMS [PMS]) were imaged at baseline and after an average of 5.3 ± 0.6 years of follow-up. Assessments included T2 LV and DTI at baseline and atrophied T2 LV over follow-up. Lesioned areas that became atrophied T2 LV were compared to those that did not. Baseline lesional DTI metrics were compared between RRMS versus PMS patients and between patients with disability progression (DP, n = 35) versus non-DP (n = 64), using ANCOVA models. Lesion tissue that developed into atrophied T2 LV had significantly different baseline DTI parameters compared to nonatrophied T2-LV tissue (p<0.001), with the largest effect for free-water (d = 2.739). Baseline tissue characteristics of future atrophied T2 LV were not significantly different between groups. However, DP patients developed greater atrophied T2 LV (377 vs. 83 mm3 , p < 0.001). Extensive microstructural damage characterizes lesions replaced by CSF, independently of disease phenotype or future DP. Greater atrophied T2 LV predicts DP.