Springer Science and Business Media LLC

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, making it a major public health issue. Anti-amyloid and anti-tau antibodies are the most advanced therapeutic approach at present. Three drugs (lecanemab, donanemab and aducanumab) are on track to be marketed in the coming months. In this systematic review, we review all Phase 2 and Phase 3 clinical trials conducted in this indication and the particularities of the molecules tested. The PubMed and ClinicalTrials.gov databases were searched through February 2023 for Phase 2 and 3 clinical trials involving passive anti-amyloid or anti-tau immunotherapies with published results. This review has been compiled in compliance with the PRISMA checklists. Of the 165 studies found and after eliminating duplicates, 40 studies had their results published on PubMed and/or ClinicalTrials.gov. Eight anti-amyloid molecules and four anti-tau molecules were the subject of Phase 2 studies, seven anti-amyloids were the subject of Phase 3 trials, and two molecules were granted early marketing approval by the US Food and Drug Administration (FDA). The results were compiled in summary tables showing the primary endpoints used, results, age of the study population and specific adverse events for these molecules. Passive immunotherapy in AD is largely dominated by anti-amyloid antibodies, which are more numerous and more advanced in the pipeline. Lecanemab, donanemab and aducanumab are distinguished by their relative efficacy in terms of cognitive and functional evaluation but also by a decrease in amyloid and tau proteins in the brain. These three molecules have in common that they bind to N-terminal ends of amyloid fibrils and plaques. The findings of their studies raise the question of which criteria to apply when choosing which patient will receive them when marketed, such as the apoliprotein E gene’s fourth allele (APOE4) genetic status of patients. The large number of negative studies may also raise the question of the criteria for defining the disease and the possible interest in redefining it on biological grounds to offer a more personalized medicine to patients suffering from neurodegenerative diseases.

Pulmonary arterial venous malformation (PAVM) is an abnormal vascular malformation between pulmonary arteries and veins characterized by varying degrees of right-to-left shunts (RLS). Cryptogenic stroke (CS) due to paradoxical embolism (PE) caused by PAVM is relatively rare in the clinic. We report the case of a 54-year-old right-handed woman who presented with sudden-onset left-sided limb weakness for 2 h. A physical examination revealed normal vital signs but weakness in her left upper and lower limbs, graded as 1/5 using the Medical Research Council scale. Her National Institutes of Health Stroke Scale (NIHSS) score was 8, and her modified Rankin scale (mRS) was 4. Brain diffusion-weighted imaging showed acute infarction in the right basal ganglia and the radiation crown but brain magnetic resonance angiography found no obvious abnormality. A transcranial Doppler ultrasound with bubble study (TCD-b) found the rain curtain sign of microbubbles in the left middle cerebral artery, reflecting significant RLS. Transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) were conducted to distinguish between intra- and extracardiac shunts. A pulmonary computerized tomography angiogram (CTA) demonstrated a PAVM. We considered the patient had CS due to PE caused by PAVM. Thrombolytic therapy within the time window was performed. Then, transcatheter device occlusion of the arteriovenous fistula was successfully undertaken, and the patient carried on with rehabilitation training. At a 15-month follow-up, there were no catheter-related complications or recurrent stroke, and her NIHSS and mRS scores were both 0. PAVM is an important risk factor for PE and CS and should not be ignored as a possible etiology in stroke patients without any other risk factors. CTA of the pulmonary artery is the recommended gold standard for diagnosing and locating a PAVM. Thrombolytic therapy within the time window combined with transcatheter device occlusion of arteriovenous malformation and rehabilitation training may benefit the recovery of patients with CS caused by PE resulting from PAVM.

Over the last two decades, there has been no novel acute treatment for migraine to address the large unmet medical need in Chinese patients. Lasmiditan, a novel selective serotonin 1F receptor agonist (ditan), is anticipated to bring clinical benefit in Chinese patients with migraine. The CENTURION study is a multi-country, placebo-controlled phase 3 study designed to assess the first attack efficacy and the consistency of response of lasmiditan in acute treatment of migraine. This subpopulation analysis pooled Chinese patients’ data from the primary cohort and additional extended enrollment cohort which was not published previously. This is the first analysis focusing on lasmiditan’s efficacy and safety in Chinese patients with migraine and aims to provide relevant evidence for Chinese physicians. Patients were randomized 1:1:1 to one of the three treatment groups for four attacks: (a) lasmiditan 100 mg; (b) lasmiditan 200 mg; or (c) control group. Primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in at least two out of three attacks. Secondary endpoints included pain relief, sustained pain freedom, and disability freedom. In total, 281 Chinese patients (lasmiditan 100 mg, 95; lasmiditan 200 mg, 92; control, 94) were treated for at least one migraine attack. Both doses of lasmiditan showed improvement versus placebo for pain freedom at 2 h after first attack, with lasmiditan 200 mg showing nominal significance. An early onset of effect was observed with lasmiditan versus placebo. Both doses of lasmiditan showed better results for all key secondary endpoints versus placebo. The most commonly reported treatment-emergent adverse event across all groups was dizziness. In the Chinese population, lasmiditan was better than placebo for both primary endpoints and key secondary endpoints with an acceptable safety profile. No new safety signals were detected in the Chinese population. These findings are generally consistent with those observed in the CENTURION study published data and the established product profile. NCT03670810.

Mixed treatment comparisons (MTCs) are increasingly important in the assessment of the benefit–risk profile of pharmaceutical treatments for relapsing–remitting multiple sclerosis (RRMS). Interpretation of MTCs requires a clear understanding of the methods of analysis and population studied. The objectives of this work were to compare MTCs of pharmaceutical treatments for RRMS, including a detailed description of differences in populations, treatments assessed, methods used and findings; and to discuss key considerations when conducting an MTC. Fourteen databases were searched until July 2019 to identify MTCs (published during or after 2010) in adults (at least 18 years of age) with RRMS or rapidly evolving severe RRMS treated with any form of pharmaceutical treatment. No language restriction was imposed. Twenty-seven MTCs assessing 21 treatments were identified. Comparison highlighted many differences in conduct and reporting between MTCs relating to the patient populations or treatments included, duration of follow-up and outcomes of interest measured. The lack of similarity between the MTCs leads to questions about variability in the robustness of analyses and makes comparisons between studies challenging. Given the importance of MTCs for healthcare decision-making, it is imperative that reporting of methods, results and assumptions is clear and transparent to allow accurate interpretation of findings. For MTCs to be relevant, the choice of outcome measures should reflect clinical practice. Combination of treatments or of outcomes measured at different points of time should be avoided, as should imputation without justification. Furthermore, all approved treatment options should be included and updates of MTCs should be conducted when data for new treatments are published.

Published estimates of Alzheimer’s disease (AD) progression do not capture the full disease continuum. This study provides transition probabilities of individuals with amyloid-β (Aβ+) pathology across the disease continuum. Patient-level longitudinal data from the National Alzheimer’s Coordinating Center were used to estimate progression rates. Progression rates through five clinically defined AD stages—asymptomatic, mild cognitive impairment due to AD (MCI-AD), mild AD dementia, moderate AD dementia, severe AD dementia—and death were measured as transition probabilities. Rates were assessed in “incident” patients who recently entered the stage, controlling for covariates. Transition probabilities were generated from multinomial logit regression models that predicted an individual’s health state as a function of health state at the previous visit and adjusted for time between initial and follow-up visits, age, sex, years of education, and concomitant symptomatic AD medications. Annual transition probabilities to more severe dementia stages for surviving incident Aβ+ patients were as follows: asymptomatic to MCI-AD, 40.8%; MCI-AD to mild AD dementia or worse, 21.8%; mild AD dementia to moderate AD dementia or worse, 35.9%; moderate AD dementia to severe AD dementia, 28.6%. Transition probabilities to less severe dementia stages were: 5.3% annual reversion from MCI-AD to asymptomatic, 3.0% mild AD dementia to MCI-AD, 1.8% moderate AD dementia to mild AD dementia, and 1.3% for severe AD dementia to moderate AD dementia. These transition probabilities reflect the full continuum of AD progression in Aβ+ individuals and can be used to assess the impact of treatment on expected transitions.

Similar white matter hyperintensities (WMH) burden may have varied cognitive outcomes in patients with cerebral small vessel disease (CSVD). This study aimed to evaluate whether blood–brain barrier (BBB) permeability is associated with cognitive impairment (CI) heterogeneity in patients with WMH. We recruited 51 participants with WMH. We evaluated WMH burden using the Fazekas scale and WMH volume on structural magnetic resonance imaging (MRI), and assessed BBB permeability using dynamic contrast-enhanced (DCE)-MRI. We used permeability–surface area product (PS) from the Patlak model to represent BBB permeability. All patients underwent Mini-Mental State Examination (MMSE), Boston Naming Test (BNT) and animal verbal fluency test (VFT) for cognitive assessment. We divided patients into CI and non-CI groups based on their MMSE scores (< 27 or ≥ 27) and used multiple linear regression models to investigate the associations between MRI parameters and cognitive function. Patients in the two groups did not differ in Fazekas scores and WMH volume. However, patients in the CI group showed significantly higher PS in the WMH regions than those in non-CI group (1.89 × 10−3 versus 1.00 × 10−3, p = 0.032 in periventricular WMH [PVWMH]; 1.27 × 10−3 versus 0.74 × 10−3, p = 0.043 in deep WMH [DWMH]), indicating the breakdown of BBB in the CI group. In all patients with WMH, increased BBB permeability in PVWMH and DWMH was significantly associated with lower cognitive and language function after adjustment for age, education level (EL) and intracranial volume (ICV). In the CI group, this correlation remained significant. WMH volume was not associated with cognitive performance in either all patients or those with CI. BBB impairment might be a more sensitive indicator for cognitive and language dysfunction than WMH volume in patients with WMH and possibly explains the heterogeneity of cognitive performance in patients with similar WMH burden.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. While chronic fatigue is a common manifestation of SMA, the field lacks comprehensive data to assess the extent of its impact. Cure SMA, an SMA patient advocacy organization, conducted an online survey of its adults with SMA community members to measure the impact of fatigue. All survey respondents were asked to complete questions on demographics, use of SMA treatment, and quality of life, but respondents were randomized to receive three of the following fatigue instruments: the Modified Fatigue Impact Scale (MFIS), Multidimensional Fatigue Inventory (MFI), Fatigue Severity Scale (FSS), PedsQL™ Multidimensional Fatigue (PedsQL MF) Scale, and Spinal Muscular Atrophy Health Index (SMA-HI) fatigue modules. Scales were evaluated for reliability and overall fatigue scores were evaluated by multivariate regression models to determine which variables were related to the final scores of each instrument. A total of 253 adults completed the online survey. When measured against the general population, statistically significant differences were found among adults with SMA for certain variables within each measurement instrument. However, there did not appear to be differences in fatigue levels among key subgroups within the SMA population. This was the first use of more than two fatigue questionnaires simultaneously in SMA. The lack of a consistent relationship between SMA severity and fatigue levels was surprising. This may be related to the lack of specificity of the instruments for this population. An SMA-specific scale is needed to evaluate differences in fatigue impact across the SMA population.