Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients\' lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient\'s experience and self-assessed impact of treatment on daily life.

Serum neurofilament light chain (sNfL) levels have been proposed as a biomarker of the clinical activity, disability progression, and response to treatment of people with multiple sclerosis (PwMS); however, questions remain about its implementation in clinical practice. Ocrelizumab (OCR) has proven effective in improving clinical and radiological outcomes and reducing sNfL levels. This real-life study followed the sNfL levels of 30 PwMS treated for 12 months with OCR and evaluated the usefulness of this biomarker for their short-term prognosis, considering expanded disability status scale (EDSS), annualized relapse rate (ARR), radiological activity, and NEDA-3 values. OCR reduced ARR in 83% of PwMS and radiological activity in 80%. EDSS was maintained, while NEDA-3 was achieved in 70% at 12 months. OCR produced an early reduction in sNfL levels (at 3 months). At baseline, greater MRI-evaluated radiological activity was associated with higher sNfL levels. sNfL levels over the first 12 months of treatment did not predict a suboptimal response or sustained control of the disease. Longer-term studies are needed to explore the predictive usefulness of sNfL levels in PwMS treated with high-efficacy drugs.

Parkinson\'s disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient-clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient-clinician partnerships.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient\'s experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

OBJECTIVE: We previously analysed the preparedness to deliver a disease-modifying Alzheimer\'s treatment in the United Kingdom and predicted substantial wait times. This study updates the prediction for the National Health Service (NHS) in England, using an improved model and newer data.
METHODS: We reviewed published data on capacity for diagnosis of cognitive impairment combined with expert input and constructed a model for wait times to access from 2023 to 2043. The model tracks patients from initial evaluation in primary care, cognitive testing by a dementia specialist, confirmatory biomarker testing with positron emission tomography (PET) scans or examination of cerebrospinal fluid and infusion delivery. Capacity for specialist visits and PET scans are assumed to be capacity constrained, and cerebrospinal fluid testing and infusion delivery to be scalable.
RESULTS: Capacity constraints were projected to result in substantial wait times: patients referred to specialists based on a brief cognitive test, which is the current standard of care, would expect an overall initial wait times of 56 months in 2023, increasing to 129 months in 2029 and then falling slowly to around 100 months. Use of a blood test for the confirmation of Alzheimer\'s pathology as an additional triage step, would reduce wait times to around 17 to 25 months.
CONCLUSIONS: The NHS England lacks capacity to provide timely access to a disease-modifying treatment, which is estimated to result in significant wait times and potentially avoidable disease progression. Better diagnostic tools at initial evaluation may reduce delays.

BACKGROUND: It has not previously been clarified if COVID-19 triggers disease activity and increases the risk of hospitalisation with COVID-19 in patients with multiple sclerosis. We examined the association between COVID-19 and the use of systemic corticosteroids prescriptions and hospital contacts at neurological departments as proxies of disease activity among patients with multiple sclerosis. Furthermore, we examined whether patients with multiple sclerosis were more likely to be hospitalised with COVID-19 compared to references.
METHODS: This study was based on nationwide health registries with data on the Danish population of 2,222,946 individuals with a positive COVID-19 PCR test. To study disease activity our study population consisted of all patients with multiple sclerosis and a positive COVID-19 PCR test. Our proxies for disease activity were compared after versus before a positive COVID-19 PCR test using a binomial regression model. Adjustments were made for age, sex, comorbidity, length of multiple sclerosis diagnosis, calendar period, vaccination, and immunomodulatory treatment. To study the risk of hospitalisation with COVID-19 in patients with multiple sclerosis our study population here consisted of all Danish citizens with a COVID-19 positive PCR test. In logistic regression models we estimated odds ratio (OR) for hospitalisation with COVID-19 in patients with multiple sclerosis relative to patients affected with other autoimmune diseases (inflammatory bowel disease/rheumatoid arthritis), and relative to individuals from the general population. Adjustments were made for age, sex, comorbidity, vaccination, and calendar period. To examine the impact of disease-modifying treatment, the risk of hospitalisation with COVID-19 was estimated in those with disease-modifying treatment versus those without any disease-modifying treatment.
RESULTS: We included 7358 patients with multiple sclerosis and a positive COVID-19 PCR test. The adjusted incidence rate ratio (aIRR) for having corticosteroid prescriptions after COVID-19 in patients with multiple sclerosis was 0.93 (95 % CI 0.78 - 1.10), and the aIRR for hospital contacts at neurological departments/admissions with multiple sclerosis as primary diagnosis after COVID-19 infection was 1.10 (95 % 1.00-1.22). Adjusted OR (aOR) for hospitalisation with COVID-19 in the 30 days after a positive COVID-19 PCR test was 3.21 (95 % CI 2.75-3.74) compared to patients with other autoimmune diseases and the aOR was 5.34 (95 % CI 4.65-6.14) for patients with multiple sclerosis compared to all other individuals in the general population with a positive test. We found no increased risk of hospitalisations with COVID-19 in patients with multiple sclerosis using disease-modifying treatment 6 months prior to a positive COVID-19 PCR test compared to patients with multiple sclerosis without disease-modifying treatment (aOR 0.94 (95 % CI 0.69-1.27)).
CONCLUSIONS: In this nationwide cohort of patients with multiple sclerosis, COVID-19 did not seem to trigger multiple sclerosis disease activity (based on proxy variables). We found a significantly increased risk of being hospitalised with COVID-19 in the first 30 days after a positive COVID-19 PCR test in patients with multiple sclerosis irrespective of the type of reference population. In patients with multiple sclerosis, the use of disease-modifying treatment did not increase the risk of hospitalisation with COVID-19.

Family planning is essential for establishing Multiple Sclerosis (MS) prognosis, treatment decision, and disease monitoring. We aimed to generate an expert consensus addressing recommendations for family planning in MS patients of childbearing age. Initially, a committee comprising seven neurologists, experts in the MS field, identified the topics to be addressed. Then, the committee elaborated on different evidence-based preliminary statements. Next, using the Delphi methodology, a panel of neurologists manifested their level of agreement on the different statements using a Likert-type scale. Consensus was reached when ⩾70% of respondents expressed an agreement or disagreement using a five-point scale. Consensus was achieved on 47 out of 63 recommendations after three rounds of evaluations. The panel considered it essential to address family planning in all patients of childbearing age. There was also consensus that treatment should not be delayed due to the patient\'s desire for pregnancy. Additionally, in highly active patients, planning the pregnancy in the medium to long term using depletory drugs such as cladribine or alemtuzumab might represent a useful strategy. However, risks of adverse effects on the fetus due to drug-associated secondary autoimmunity should be addressed when alemtuzumab is considered. Moreover, the maintenance of natalizumab during pregnancy in very active patients reached expert consensus. Also, the panel supported the use of certain disease-modifying treatment (DMT) during lactation in selected cases. Our results identified specific areas of pregnancy planning in MS patients, where different treatment strategies might be considered to facilitate a safe and successful pregnancy while maintaining clinical and radiological stability.

BACKGROUND: Spinal cord lesions in multiple sclerosis (MS) are an important contributor to disability. Knowledge on the effect of disease-modifying treatment (DMT) on spinal lesion formation in MS is sparse, as cord outcome measures are seldom included in MS treatment trials. We aim to investigate whether intermediate- or high-efficacy DMTs (i/hDMT) can reduce spinal lesion formation, compared with low-efficacy DMTs (lDMT) and/or no treatment.
METHODS: Relapse-onset MS patients with ≥2 spinal MRIs (interval >3 months and <10 years) were retrospectively identified. The i/hDMT-group was defined as patients who were treated with i/hDMTs during ≥90% of spinal MRI follow-up time. Controls received lDMTs and/or no treatment ≥90% of follow-up duration. In a secondary analysis, only patients using lDMT for ≥90% of follow-up were considered controls. Patients were matched using propensity-scores. Cox proportional hazards models were used to estimate the risk of new spinal lesions.
RESULTS: 323 patients had ≥2 spinal cord MRIs. 49 satisfied i/hDMT and 168 control group criteria. 34 i/hDMT patients were matched to 83 controls. Patients in the i/hDMT-group were significantly less likely to develop new cord lesions at follow-up (HR 0.29 [0.12-0.75], p = 0.01). When the i/hDMT-group was matched to only controls using lDMT ≥90% of follow-up time (n = 17 and n = 25, respectively), there was no statistically significant difference (HR 1.01 [0.19-5.24], p = 0.99).
CONCLUSIONS: Treatment with intermediate- or high-efficacy DMTs reduces the risk of new spinal cord lesions compared with matched patients receiving no treatment and/or lDMTs. No conclusions could be drawn on whether i/hDMTs provide a larger risk reduction compared to only lDMTs (control group receiving lDMTs ≥90% of follow-up time).

(1) Background: Alzheimer\'s disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer\'s Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (-4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations.

BACKGROUND: Cladribine is a nucleoside analogue interfering with synthesis and repair of DNA. Treatment with cladribine leads to a preferential reduction in lymphocytes, resulting in profound depletion of B-cells with a rapid recovery of naïve B-cells, while T-cell show a lesser but long-lasting depletion It is approved for treatment of relapsing multiple sclerosis (MS). Cladribine tablets 3.5 mg/kg bodyweight are administered in two yearly treatment courses, each including two treatment series lasting 4 or 5 days, one at the start of the first month and the other at the start of the second month.
OBJECTIVE: To describe treatment patterns of cladribine in a real-world setting.
METHODS: Registry based observational cohort study with prospectively enrolled cases from December 2017 through June 2021. The data source is The Danish Multiple Sclerosis Registry, which is a near complete nationwide population-based registry. Outcomes were length of the treatment, preceding and following treatments, treatment response, and safety data.
RESULTS: In total 268 patients had started therapy with cladribine tablets, 89 men and 179 women, with a median age of 40 years (interquartile range (IQR) 32-48. The disease course was relapsing-remitting MS in 97.8% of the patients, and at treatment start the median time from disease onset was 8.1 years (IQR 4.2-14.5) and EDSS 2.5 (IQR 1.5-3.5). Thirty-four patients (12.7%) were treatment naïve while 56 (20.9%) had received one previous disease-modifying therapy (DMT), 67 (25.0%) two, and 111 (41.4%) three or more previous DMTs. In total, 214 (80.0%) patients had completed the full treatment of two courses of cladribine, while 54 (20.0%) had received only one course of cladribine tablets. The median follow-up time after cladribine initiation was 34.7 months (IQR 23.3-43.7). Compared with an annualized relapse rate (ARR) of 0.67 (95% CI [0.56, 0.79]) in the year prior to start of cladribine, ARR was reduced to 0.11 (95% CI [0.08, 0.15]) in year 0-2 after 3-month re-baseline with cladribine (84.8% reduction). Adverse events, reported in 44 (16.4%) of the patients, were mild or moderate, and herpes zoster was only reported in 2 patients. In total, 30 (11.2%) patients discontinued cladribine treatment, of whom 7 (2.6%) discontinued because of adverse effects and 12 (4.5%) discontinued because of disease activity.
CONCLUSIONS: In this nationwide review of all Danish patients starting therapy with cladribine tablets in a real-world setting, cladribine treatment was safe, and the therapeutic response was as expected from previous clinical trials. A prolonged observation period is necessary to assess the long-term benefit and risk of cladribine.