Outcome Measure In Clinical Trials Research Articles

Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review

BackgroundThe use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes.MethodsA systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included.Results8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2–3). Trials using a COM recruited fewer participants (409 (198.8–851.5) vs 584 (300–1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important.ConclusionsCOM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.

Quantitative muscle magnetic resonance imaging in limb-girdle muscular dystrophy type R1 (LGMDR1): A prospective longitudinal cohort study.

Limb-girdle muscular dystrophy (LGMD) type R1 (LGMDR1) is the most common subtype of LGMD in Europe. Prospective longitudinal data, including clinical assessments and new biomarkers such as quantitative magnetic resonance imaging (qMRI), are needed to evaluate the natural course of the disease and therapeutic options. We evaluated eight thigh and seven leg muscles of 13 LGMDR1 patients (seven females, mean age 36.7 years, body mass index 23.9 kg/m2) and 13 healthy age- and gender-matched controls in a prospective longitudinal design over 1 year. Clinical assessment included testing for muscle strength with quick motor function measure (QMFM), gait analysis and patient questionnaires (neuromuscular symptom score, activity limitation [ACTIVLIM]). MRI scans were performed on a 3-T MRI scanner, including a Dixon-based sequence, T2 mapping and diffusion tensor imaging. The qMRI values of fat fraction (FF), water T2 relaxation time (T2), fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were analysed. Within the clinical outcome measures, significant deterioration between baseline and follow-up was found for ACTIVLIM (p= 0.029), QMFM (p= 0.012). Analysis of qMRI parameters of the patient group revealed differences between time points for both FF and T2 when analysing all muscles (FF: p< 0.001; T2: p= 0.016). The highest increase of fat replacement was found in muscles with an FF of between 10% and 50% at baseline. T2 in muscles with low-fat replacement increased significantly. No significant differences were found for the diffusion metrics. Significant correlations between qMRI metrics and clinical assessments were found at baseline and follow-up, while only T2 changes in thigh muscles correlated with changes in ACTIVLIM over time (ρ = -0.621, p< 0.05). Clinical assessments can show deterioration of the general condition of LGMDR1 patients. qMRI measures can give additional information about underlying pathophysiology. Further research is needed to establish qMRI outcome measures for clinical trials.

The importance of including Long COVID outcomes when developing novel treatments for acute COVID-19.

The ongoing COVID-19 pandemic continues to present surges in infections demonstrating the persistent threat posed by COVID-19. Amidst efforts to develop effective treatments for acute COVID-19, there is a growing recognition of the need to address Long COVID. This manuscript reviews the current landscape of acute COVID-19 treatments and highlights the opportunity to incorporate Long COVID as a key outcome measure in clinical trials. Our analysis includes a review of current US clinical trials investigating acute COVID-19 treatments. Of the 19 studies that met our inclusion criteria, only one study currently incorporates Long COVID measurements. In our review, we argue there are 7 compelling reasons to include Long Covid measurements, including: (1) Long COVID is not rare (2) Long COVID is debilitating to individuals and has a high societal cost (3) Those at high risk of severe COVID-19 are also at higher risk of developing Long COVID if they are infected with COVID-19 (4) Treatments for acute COVID-19 may reduce the risk of Long COVID (5) Measures exist to track Long COVID (6) Long COVID considerations are potentially important for acute COVID-19 treatment decision-making (7) Deaths and hospitalizations due to COVID-19 are increasingly rare, creating an opportunity for other important clinical endpoints to be considered In conclusion, while not every trial needs to include assessments of Long COVID, it is worth the research burden to include assessments where possible as this could facilitate the uptake of acute COVID-19 treatments that lessen the societal burden of Long COVID.

Application of Patient-Reported Outcome Measurements in Adult Tumor Clinical Trials in China: Cross-Sectional Study.

International health policies and researchers have emphasized the value of evaluating patient-reported outcomes (PROs) in clinical studies. However, the characteristics of PROs in adult tumor clinical trials in China remain insufficiently elucidated. This study aims to assess the application and characteristics of PRO instruments as primary or secondary outcomes in adult randomized clinical trials related to tumors in China. This cross-sectional study identified tumor-focused randomized clinical trials conducted in China between January 1, 2010, and June 30, 2022. The ClinicalTrials.gov database and the Chinese Clinical Trial Registry were selected as the databases. Trials were classified into four groups based on the use of PRO instruments: (1) trials listing PRO instruments as primary outcomes, (2) trials listing PRO instruments as secondary outcomes, (3) trials listing PRO instruments as coprimary outcomes, and (4) trials without any mention of PRO instruments. Pertinent data, including study phase, settings, geographic regions, centers, participant demographics (age and sex), funding sources, intervention types, target diseases, and the names of PRO instruments, were extracted from these trials. The target diseases involved in the trials were grouped according to the American Joint Committee on Cancer Staging Manual, 8th Edition. Among the 6445 trials examined, 2390 (37.08%) incorporated PRO instruments as part of their outcomes. Within this subset, 26.82% (641/2390) listed PRO instruments as primary outcomes, 52.72% (1260/2390) as secondary outcomes, and 20.46% (489/2390) as coprimary outcomes. Among the 2,155,306 participants included in these trials, PRO instruments were used to collect data from 613,648 (28.47%) patients as primary or secondary outcomes and from 74,287 (3.45%) patients as coprimary outcomes. The most common conditions explicitly using specified PRO instruments included thorax tumors (217/1280, 16.95%), breast tumors (176/1280, 13.75%), and lower gastrointestinal tract tumors (173/1280, 13.52%). Frequently used PRO instruments included the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire-30, the visual analog scale, the numeric rating scale, the Traditional Chinese Medicine Symptom Scale, and the Pittsburgh Sleep Quality Index. Over recent years, the incorporation of PROs has demonstrated an upward trajectory in adult randomized clinical trials on tumors in China. Nonetheless, the infrequent measurement of the patient's voice remains noteworthy. Disease-specific PRO instruments should be more effectively incorporated into various tumor disease categories in clinical trials, and there is room for improvement in the inclusion of PRO instruments as clinical trial end points.

Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.

Outcome Measures of Clinical Trials in Pediatric Chronic Kidney Disease

Outcome Measures of Clinical Trials in Pediatric Chronic Kidney Disease

The Natural History of Retinal Sensitivity Loss in Diabetic Macular Ischemia over One Year Evaluated by Microperimetry.

Background/Objectives: This one-year prospective observational study, conducted at two centers, aimed to report the natural history of retinal sensitivity (RS) loss in diabetic macular ischemia (DMI). Methods: Patients with stable-treated proliferative diabetic retinopathy (PDR) were recruited if there was evidence of DMI on optical coherence tomography angiography, defined as a foveal avascular zone ≥ 0.5 mm2 or parafoveal capillary dropout ≥ 1 quadrant. The minimal visual acuity required for performing microperimetry (MP) was ≥54 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent 20/80). The overall RS (oRS) and pointwise sensitivity (PWS) within the 3 × 3 mm macula were assessed at baseline and twelve months. A value <25 decibels (dB) was defined as impaired RS, and a decrease of 2 and 7 dB was regarded as mild and severe loss, respectively. Results: A total of 88 patients (97 eyes) were included. No statistically significant MP changes were detected at one year. However, 10% of the cohort lost oRS ≥ 2 dB, and 73% lost ≥2 dB PWS in ≥5 loci, whereas 1% lost oRS ≥ 7 dB, and 4% lost ≥7 dB PWS in ≥5 loci. The foveola and temporal parafovea were the most vulnerable to severe RS loss. Compared to their counterpart, eyes with baseline oRS ≥ 25 dB had significantly more RS loss in the macula and superior parafovea (55% versus 32% and 53% versus 28%, both p = 0.01). Conclusions: Rather than oRS loss, ≥2 dB loss in PWS in ≥5 loci is a more feasible outcome measure for clinical trials in DMI.

Detection of structural lesions of the sacroiliac joints in patients with spondyloarthritis: A comparison of T1-weighted 3D spoiled gradient echo MRI and MRI-based synthetic CT versus T1-weighted turbo spin echo MRI.

To investigate the detection of erosion, sclerosis and ankylosis using 1mm 3D T1-weighted spoiled gradient echo (T1w-GRE) MRI and 1mm MRI-based synthetic CT (sCT), compared with conventional 4mm T1w-TSE. Prospective, cross-sectional study. Semi-coronal 4mm T1w-TSE and axial T1w-GRE with 1.6mm slice thickness and 0.8mm spacing between overlapping slices were performed. The T1w-GRE images were processed into sCT images using a commercial deep learning algorithm, BoneMRI. Both were reconstructed into 1mm semi-coronal images. T1w-TSE, T1w-GRE and sCT images were assessed independently by 3 expert and 4 non-expert readers for erosion, sclerosis and ankylosis. Cohen's kappa for inter-reader agreement, exact McNemar test for lesion frequencies and Wilcoxon signed-rank test for confidence in lesion detection were used. Nineteen patients with axial spondyloarthritis were evaluated. T1w-GRE increased inter-reader agreement for detecting erosion (kappa 0.42 vs 0.21 in non-experts), increased detection of erosion (57 vs 43 of 152 joint quadrants) and sclerosis (26 vs 17 of 152 joint quadrants) among experts, and increased reader confidence for scoring erosion and sclerosis. sCT increased inter-reader agreement for detecting sclerosis (kappa 0.69 vs 0.37 in experts) and ankylosis (0.71 vs 0.52 in non-experts), increased detection of sclerosis (34 vs 17 of 152 joint quadrants) and ankylosis (20 vs 13 of 76 joint halves) among experts, and increased reader confidence for scoring erosion, sclerosis and ankylosis. T1w-GRE and sCT increase sensitivity and reader confidence for the detection of erosion, sclerosis and ankylosis, compared with T1w-TSE. These methods improve the detection of sacroiliac joint structural lesions and might be a useful addition to SIJ MRI protocols both in routine clinical care and as structural outcome measures in clinical trials.

Vitamin E (Alpha-tocopherol) Central Nervous System (CNS) Effects [Increasing Ramified Microglia; Decreasing Astrocytosis; Decreasing Oxidative Stress Biomarkers; Slowing Amyotrophic Lateral Sclerosis (ALS) Progression from Early to Advanced Disease] and Respiratory System Effects [Decreasing Vital Capacity Loss with Age by Increasing Alpha-tocopherol and Decreasing Gamma-tocopherol; Improving Resistance to Respiratory Bacterial Infections] Require Proper Dose/Dose Exposure Time and Outcome Measures for Future

Vitamin E (Alpha-tocopherol) Central Nervous System (CNS) Effects [Increasing Ramified Microglia; Decreasing Astrocytosis; Decreasing Oxidative Stress Biomarkers; Slowing Amyotrophic Lateral Sclerosis (ALS) Progression from Early to Advanced Disease] and Respiratory System Effects [Decreasing Vital Capacity Loss with Age by Increasing Alpha-tocopherol and Decreasing Gamma-tocopherol; Improving Resistance to Respiratory Bacterial Infections] Require Proper Dose/Dose Exposure Time and Outcome Measures for Future

The Edmonton Symptom Assessment System is a valid, reliable, and responsive tool to assess symptom burden in decompensated cirrhosis.

While there is a growing need for interventions addressing symptom burden in patients with decompensated cirrhosis (DC), the lack of validated symptom assessment tools is a critical barrier. We investigated the psychometric properties of the revised Edmonton Symptom Assessment System (ESAS-r) in a longitudinal cohort of patients with DC. Adult outpatients with DC were prospectively recruited from a liver transplant center and completed ESAS-r at baseline and week 12. We examined reliability, floor/ceiling effects, structural validity, and known-groups validity. We examined the convergent and predictive validity of ESAS-r with health-related quality of life using the Short Form Liver Disease Quality of Life (SF-LDQOL) and responsiveness to changes in anxiety and depression using the Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9 from baseline to week 12. From August 2018 to September 2022, 218 patients (9% Child-Pugh A, 59% Child-Pugh B, and 32% Child-Pugh C) were prospectively recruited and completed the ESAS-r, SF-LDQOL, Patient Health Questionnaire-9, and Hospital Anxiety and Depression Scale at baseline and week 12 (n = 135). ESAS-r had strong reliability (Cronbach's alpha 0.86), structural validity (comparative fit index 0.95), known-groups validity (Child-Pugh A: 25.1 vs. B: 37.5 vs. C: 41.4, p = 0.006), and convergent validity (r = -0.67 with SF-LDQOL). Floor effects were 9% and ceiling effects were 0.5%. Changes in ESAS-r scores from baseline to week 12 significantly predicted changes in SF-LDQOL (β = -0.36, p < 0.001), accounting for 30% of the variation. ESAS-r was strongly responsive to clinically meaningful changes in SF-LDQOL, Patient Health Questionnaire-9, and Hospital Anxiety and Depression Scale. ESAS-r is a reliable, valid, and responsive tool for assessing symptom burden in patients with DC and can predict changes in health-related quality of life. Future directions include its implementation as a key outcome measure in cirrhosis care and clinical trials.

Validation of the Investigator Global Assessment of Chronic Hand Eczema (IGA–CHE): a new clinician reported outcome measure of CHE severity

The Investigator Global Assessment of Chronic Hand Eczema (IGA–CHE) is a novel Clinician-Reported Outcome measure that allows investigators to assess cross-sectional CHE global disease severity using clinical characteristics of erythema, scaling, lichenification/hyperkeratosis, vesiculation, oedema, and fissures as guidelines for overall severity assessment. This study aimed to evaluate the psychometric properties of the IGA–CHE for use as an outcome measure in CHE clinical trials and clinical practice. Psychometric analyses were performed using data from a sample of 280 patients with moderate to severe CHE from a phase 3 trial of delgocitinib cream, pooled across treatment groups. Test–retest reliability results were moderate to strong with kappa coefficients ranging from 0.63 to 0.76. Correlations with measures assessing related concepts were moderate or strong (range 0.65–0.72) and exceeded a priori hypotheses, providing evidence of convergent validity. Known-groups validity was supported by statistically significant differences between severity groups (< 0.001). Within-group effect sizes were consistently larger for improved groups compared to stable groups, providing evidence of ability to detect change. Anchor-based analyses generated within-subject meaningful change estimates ranging from – 0.8 to – 2.3. A correlation weighted average suggested a single value of – 1.7 in change from baseline. These findings provide evidence the IGA–CHE scale has strong reliability, construct validity, and ability to detect change, supporting its use as an endpoint in CHE clinical trials and clinical practice. Based on the evidence, 2-level changes in IGA–CHE score are considered a conservative meaningful change threshold; however, findings also indicate 1-level change in IGA–CHE scores reflects a clinically meaningful improvement for patients.Clinical trial registration: NCT04871711.

Analysis of caregiver perspectives on patients with mucopolysaccharidosis II treated with pabinafusp alfa: results of qualitative interviews in Japan

BackgroundMucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers’ experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews.MethodsSemi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience.ResultsSeven caregivers from 16 trial sites participated, representing seven children aged 8–18 years who had received pabinafusp alfa for 3.3–3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa.ConclusionCaregivers’ perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa’s potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.

Facioscapulohumeral Muscular Dystrophy European Patient Survey: Assessing Patient Reported Disease Burden and Preferences in Clinical Trial Participation.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive muscle weakness leading to permanent disability. There are no curative treatments, however, there are several upcoming clinical trials testing new therapies in FSHD. This study aimed to explore the disease burden and patient preferences of people with FSHD to ensure that clinical trials can be designed to include outcome measures that are relevant and important to patients. A survey was developed with a steering committee clinicians and physiotherapists with relevant experience in the disease, patient representatives, a registry expert and industry consultants. Themes of the survey included; participant demographics, disease progression and impact on function, factors encouraging or discouraging clinical trial participation, and positive outcomes of a clinical trial. 1147 participants responded to the online survey, representing 26 countries across Europe and a range of disease severities. The study highlighted the key symptoms causing concern for FSHD patients - muscle weakness and mobility issues - reflecting what participants want targeted for future therapies. The need for clear information and communication throughout clinical trials was emphasised. Factors most encouraging trial participation included access to new investigational therapies, access to trial results and benefits for the FSHD community. Factors most discouraging trial participation included travel related issues and fear of side effects. The results from this study identify the patient reported burden of FSHD and should provide researchers and industry with areas of therapeutic research that would be meaningful to patients, as well as supporting the development of patient centric outcome measures in clinical trials.

The Multiple Odysseys in Research and Clinical Care for Neurogenetic Conditions.

Neurogenetic conditions (NGC; e.g., fragile X, Angelman, Prader-Willi syndromes) represent the cause for intellectual or developmental disabilities in up to 60% of cases. With expanded diagnostic options and an increasing focus on the development of gene therapies comes the potential of improved quality of life for individuals with NGCs and their families. However, these emerging initiatives also bring new challenges and considerations for NGC researchers and clinicians, including considerations for supporting caregivers and assuring outcome measures for clinical trials adequately reflect the lived experiences of people with NGCs. This paper summarizes the advances and current and future challenges of research and clinical service provision for people with NGCs and their caregivers.

Neurological, psychiatric, and sleep investigations after treatment of anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis in Spain: a prospective cohort study

Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is an autoimmune disorder that can be treated with immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterise the clinical features of patients with anti-LGI1 encephalitis for 1 year starting within the first year after initial immunotherapy. For this prospective cohort study, we recruited patients with anti-LGI1 encephalitis as soon as possible after they had received conventional immunotherapy for initial symptoms; patients were recruited from 21 hospitals in Spain. Patients were excluded if they had an interval of more than 1 year since initial immunotherapy, had pre-existing neurodegenerative or psychiatric disorders, or were unable to travel to Hospital Clínic de Barcelona (Barcelona, Spain). Patients visited Hospital Clínic de Barcelona on three occasions-the first at study entry (visit 1), the second 6 months later (visit 2), and the third 12 months after the initial visit (visit 3). They underwent neuropsychiatric and videopolysomnography assessments at each visit. Healthy participants who were matched for age and sex and recruited from Hospital Clínic de Barcelona underwent the same investigations at study entry and at 12 months. Cross-sectional comparisons of clinical features between groups were done with conditional logistic regression, and binary logistic regression was used to assess associations between cognitive outcomes at 12 months and clinical features before initial immunotherapy and at study entry. Between May 1, 2019, and Sept 30, 2022, 42 participants agreed to be included in this study. 24 (57%) participants had anti-LGI1 encephalitis (mean age 63 years [SD 12]; 13 [54%] were female and 11 [46%] were male) and 18 (43%) were healthy individuals (mean age 62 years [10]; 11 [61%] were female and seven [39%] were male). At visit 1 (median 88 days [IQR 67-155] from initiation of immunotherapy), all 24 patients had one or more symptoms; 20 (83%) patients had cognitive deficits, 20 (83%) had psychiatric symptoms, 14 (58%) had insomnia, 12 (50%) had rapid eye movement (REM)-sleep behaviour disorder, nine (38%) had faciobrachial dystonic seizures, and seven (29%) had focal onset seizures. Faciobrachial dystonic seizures were unnoticed in four (17%) of 24 patients and focal onset seizures were unnoticed in five (21%) patients. At visit 1, videopolysomnography showed that 19 (79%) patients, but no healthy participants, had disrupted sleep structure (p=0·013); 15 (63%) patients and four (22%) healthy participants had excessive fragmentary myoclonus (p=0·039), and nine (38%) patients, but no healthy participants, had myokymic discharges (p=0·0051). These clinical and videopolysomnographic features led to additional immunotherapy in 15 (63%) of 24 patients, which resulted in improvement of these features in all 15 individuals. However, at visit 3, 13 (65%) of 20 patients continued to have cognitive deficits. Persistent cognitive deficits at visit 3 were associated with no use of rituximab before visit 1 (odds ratio [OR] 4·0, 95% CI 1·5-10·7; p=0·0015), REM sleep without atonia at visit 1 (2·2, 1·2-4·2; p=0·043), and presence of LGI1 antibodies in serum at visit 1 (11·0, 1·1-106·4; p=0·038). Unsuspected but ongoing clinical and videopolysomnography alterations are common in patients with anti-LGI1 encephalitis during the first year or more after initial immunotherapy. Recognising these alterations is important as they are treatable, can be used as outcome measures in clinical trials, and might influence cognitive outcome. Fundació La Caixa.

Untargeted metabolomic, and proteomic analysis identifies metabolic biomarkers and pathway alterations in individuals with 22q11.2 deletion syndrome

IntroductionThe chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles.Objectives Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time.Methods In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression.ResultsWe observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P < 0.05) in 22q11.2DS as compared to TD, including those involved in 70 pathways such as gene expression, the PI3K-Akt signaling pathway and the complement system. Within participants with 22q11.2DS, no significant changes in those with and without medical or psychiatric conditions were observed.ConclusionTo our knowledge, this is the first report on plasma metabolic and proteomic profiling and on the identification of unique biomarkers in 22q11.2DS. These findings may suggest the potential role of the identified metabolites and proteins as biomarkers for the onset of comorbid conditions in 22q11.2DS. Ultimately, the altered protein pathways in 22q11.2DS may provide insights of the biological mechanisms underlying the neurodevelopmental phenotype and may provide missing molecular outcome measures in future clinical trials to assess early-diagnosis treatment and the efficacy of response to targeted treatment.

Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer’s Disease

BackgroundNovel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer’s disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain.MethodsNTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline.ResultsWe demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R2), while having very low contribution from Aβ pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R2 = 0.27), steeper atrophy (R2 ≥ 0.18) and steeper cognitive decline (R2 ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in Aβ positive cognitively unimpaired (βstd = 0.16) and impaired (βstd = 0.18) at baseline compared to their Aβ negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R2 = 0.21) and cognition (R2 = 0.20).ConclusionOur results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal.

Retinal ganglion cell and microvascular density loss in hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is characterized by progressive degeneration of distal axons in the long corticospinal tracts. Loss of retinal cells and microvascular networks has neither been suspected nor investigated. We concurrently examined the retinal microvasculature and retinal layer morphology in patients with HSP to assess whether retinal features may portray disease and its progression. Fifteen patients with HSP and 30 healthy controls were included in this cross-sectional case-control study. Disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Severity of ataxia was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Retinal microvasculature was measured by means of optical coherence tomography angiography (OCT-A) and morphology of retinal layers using structural OCT. Mixed-effects models were applied for data analysis. HSP patients showed significantly reduced vessel density of the superficial vascular plexus (SVP), reduced ganglion cell layer (GCL) volume, reduced inner plexiform layer (IPL) volume and reduced temporal-inferior peripapillary retinal nerve fiber layer (pRNFL) thickness versus healthy controls. GCL volume reduction correlated significantly with the worsening of visual acuity and higher SARA scores. These findings demonstrate that, in HSP both cells and vascular networks of the retina are compromised. Assessment of the retinal GCL, IPL and SVP may aid in diagnosis and monitoring of disease progression as well as provide novel structural outcome measures for clinical trials.

Auditory event-related potential differentiates girls with Rett syndrome from their typically-developing peers with high accuracy: Machine learning study

Rett Syndrome (RTT) is a rare neurodevelopmental disorder caused by mutation in the MECP2 gene. No cures are still available, but several clinical trials are ongoing. Here we examine neurophysiological correlates of auditory processing for ability to differentiate patients with RTT from typically developing (TD) peers applying standard machine learning (ML) methods and pipelines. Capitalized on the available event-related potential (ERP) data recorded in response to tone presented at different rates (stimulus onset asynchrony 900, 1800 and 3600 ms) from 24 patients with RTT and 27 their TD peer. We considered the most common ML models that are widely used for classification tasks. These include both linear models (logistic regression, support-vector machine with linear kernel) and tree-based nonlinear models (random forest, gradient boosting). Based on these methods we were able to differentiate RTT from TD children with high accuracy (with up to 0.94 ROC-AUC score), which was evidently higher at the fastest presentation rate. Importance analysis and perturbation importance pointed out that the most important feature for classification is P2-N2 peak-to-peak amplitude, consistently across the approaches and blocks with different presentation rate. The results suggest the unique pattern of ERP characteristics for RTT and points to features of importance. The results might be relevant for establishing outcome measures for clinical trials.

Validation of a modified version of the gross motor function measure in PPPR5D related neurodevelopmental disorder

BackgroundProtein phosphatase 2 regulatory subunit B’ Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder.ResultsThirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1–27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1–96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = −0.733; p < 0.001), TUG (rs= −0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains.ConclusionsThe GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.