Abnormal functional connectivity in radiologically isolated syndrome: A resting-state fMRI study.

BACKGROUND: Radiologically isolated syndrome (RIS) patients might have psychiatric and cognitive deficits, which suggests an involvement of major resting-state functional networks. Notwithstanding, very little is known about the neural networks involved in RIS. OBJECTIVE: To examine functional connectivity differences between RIS and healthy controls using resting-state functional magnetic resonance imaging (fMRI). METHODS: Resting-state fMRI data in 25 RIS patients and 28 healthy controls were analyzed using an independent component analysis; in addition, seed-based correlation analysis was used to obtain more information about specific differences in the functional connectivity of resting-state networks. Participants also underwent neuropsychological testing. RESULTS: RIS patients did not differ from the healthy controls regarding age, sex, and years of education. However, in memory (verbal and visuospatial) and executive functions, RIS patients' cognitive performance was significantly worse than the healthy controls. In addition, fluid intelligence was also affected. Twelve out of 25 (48%) RIS patients failed at least one cognitive test, and six (24.0%) had cognitive impairment. Compared to healthy controls, RIS patients showed higher functional connectivity between the default mode network and the right middle and superior frontal gyri and between the central executive network and the right thalamus (pFDR < 0.05; corrected). In addition, the seed-based correlation analysis revealed that RIS patients presented higher functional connectivity between the posterior cingulate cortex, an important hub in neural networks, and the right precuneus. CONCLUSION: RIS patients had abnormal brain connectivity in major resting-state neural networks and worse performance in neurocognitive tests. This entity should be considered not an "incidental finding" but an exclusively non-motor (neurocognitive) variant of multiple sclerosis.

Clinical exacerbation of SARS-CoV2 infection after fingolimod withdrawal.

The role of disease-modifying therapies in patients with autoimmune disorders during severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is controversial. Immunocompromised patients could have a more severe coronavirus disease-2019 (COVID-19) due to the absence of an adequate immune response against the SARS-CoV-2. However, therapies that act on immune response could play a protective role by dampening the cytokine-release syndrome. Fingolimod is a drug used for immune therapy in patients with multiple sclerosis (MS) through the sequestration of activated lymphocytes in the lymph nodes. We report the case of a 57-year-old man with relapsing-remitting MS treated with fingolimod that showed a reactivation of COVID-19 with signs of hyperinflammation syndrome after fingolimod withdrawal. Our case suggests that discontinuation of fingolimod during COVID-19 could imply a worsening of SARS-CoV2 infection.

ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain.

It has been suggested that some individuals may present genetic susceptibility to SARS-CoV-2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole-exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS-CoV-2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS-CoV-2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS-CoV-2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS-CoV-2 infection, some variants, especially in TMPRSS2, may be associated with COVID-19.

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System.

INTRODUCTION: AQP4 (aquaporin-4)-immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4-IgG in cell differentiation. MATERIAL AND METHODS: We included three groups-a group of patients with AQP4-IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. RESULTS AND CONCLUSIONS: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

Intranasal Administration of Undifferentiated Oligodendrocyte Lineage Cells as a Potential Approach to Deliver Oligodendrocyte Precursor Cells into Brain.

Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

Detecting Motor Impairment in Early Parkinson's Disease via Natural Typing Interaction With Keyboards: Validation of the neuroQWERTY Approach in an Uncontrolled At-Home Setting.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and one of the most common forms of movement disorder. Although there is no known cure for PD, existing therapies can provide effective symptomatic relief. However, optimal titration is crucial to avoid adverse effects. Today, decision making for PD management is challenging because it relies on subjective clinical evaluations that require a visit to the clinic. This challenge has motivated recent research initiatives to develop tools that can be used by nonspecialists to assess psychomotor impairment. Among these emerging solutions, we recently reported the neuroQWERTY index, a new digital marker able to detect motor impairment in an early PD cohort through the analysis of the key press and release timing data collected during a controlled in-clinic typing task. OBJECTIVE: The aim of this study was to extend the in-clinic implementation to an at-home implementation by validating the applicability of the neuroQWERTY approach in an uncontrolled at-home setting, using the typing data from subjects' natural interaction with their laptop to enable remote and unobtrusive assessment of PD signs. METHODS: We implemented the data-collection platform and software to enable access and storage of the typing data generated by users while using their computer at home. We recruited a total of 60 participants; of these participants 52 (25 people with Parkinson's and 27 healthy controls) provided enough data to complete the analysis. Finally, to evaluate whether our in-clinic-built algorithm could be used in an uncontrolled at-home setting, we compared its performance on the data collected during the controlled typing task in the clinic and the results of our method using the data passively collected at home. RESULTS: Despite the randomness and sparsity introduced by the uncontrolled setting, our algorithm performed nearly as well in the at-home data (area under the receiver operating characteristic curve [AUC] of 0.76 and sensitivity/specificity of 0.73/0.69) as it did when used to evaluate the in-clinic data (AUC 0.83 and sensitivity/specificity of 0.77/0.72). Moreover, the keystroke metrics presented a strong correlation between the 2 typing settings, which suggests a minimal influence of the in-clinic typing task in users' normal typing. CONCLUSIONS: The finding that an algorithm trained on data from an in-clinic setting has comparable performance with that tested on data collected through naturalistic at-home computer use reinforces the hypothesis that subtle differences in motor function can be detected from typing behavior. This work represents another step toward an objective, user-convenient, and quasi-continuous monitoring tool for PD.

Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy.

Post-COVID condition (PCC) and multiple sclerosis (MS) share some clinical and demographic features, including cognitive symptoms and fatigue. Some pathophysiological mechanisms well-known in MS, such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC. In this study, we aimed to compare the cognitive phenotypes of two large cohorts of patients with PCC and MS, and to evaluate the relationship between fatigue and cognitive performance. Cross-sectional study including 218 patients with PCC and 218 with MS matched by age, sex, and years of education. Patients were evaluated with a comprehensive neuropsychological protocol and were categorized according to the International Classification of Cognitive Disorders system. Fatigue and depression were also assessed. Cognitive profiles of PCC and MS largely overlapped, with a greater impairment in episodic memory in MS, but with small effect sizes. The most salient deficits in both disorders were in attention and processing speed. The severity of fatigue was greater in patients with PCC. Still, the correlations between fatigue severity and neuropsychological tests were more prominent in the case of MS. There were no differences in the severity of depression among groups. Our study found similar cognitive profiles in PCC and MS. Fatigue was more severe in PCC, but was more associated with cognitive performance in MS. Further comparative studies addressing the mechanisms related to cognitive dysfunction and fatigue may be of interest to advance the knowledge of these disorders and develop new therapies.

Cognitive dysfunction characteristics of multiple sclerosis with aging.

BACKGROUND: We aimed to investigate the characteristics of cognitive impairment in older people with multiple sclerosis (MS). METHODS: Cross-sectional study that included participants that were examined with a common and comprehensive neuropsychological protocol. The subjects were matched by sociodemographic variables and the following groups were generated for comparisons: young MS versus healthy controls (HC) (n = 246), old MS versus HC (n = 198), young MS vs old MS (n = 226), MS vs Alzheimer's disease (AD)(n = 70), and MS vs Parkinson's disease (PD) (n = 62). The ICCoDiMS criteria were used to define cognitive impairment in MS. RESULTS: Cognitive impairment was more frequent in young than old patients (70.8 % vs 52.2 %). Attention and speed processing is the most frequent cognitive domain impaired in MS (54.9 % of young MS vs 32.7 % of old MS). The frequency of impairment in attention/processing speed (54.9 % vs 32.7 %) and episodic memory (27.9 % vs 14.3) was higher in the young group than in the old group. There were no statistically significant differences in the distribution of impairment in executive function (46.0 % vs 35.3 %), visuospatial (17.9 % vs 9.5 %), and language (12.4 % vs 17.7 %). In those patients meeting the criteria for cognitive impairment, young MS patients showed lower performance in attention/processing speed tests. Conversely, old MS patients showed lower performance in episodic memory, verbal fluency, and planning. There were no differences in the correlations between SDMT and other neuropsychological tests in young and old patients, which suggests similar cognitive processes underlying SDMT performance in both groups. There were differences between old MS and prodromal AD, especially in episodic memory, while the cognitive profile of old MS was largely shared with PD. CONCLUSIONS: Our study found that the cognitive profile of MS is defined by a characteristic impairment in attention and processing speed, which is present during the lifespan. The impairment in processing speed is less prominent in old age, whereas the impairment of other cognitive functions becomes more relevant. These findings suggest potential differences in the pathophysiological processes associated with cognitive impairment between young and old ages that warrant further investigation.

European cross-cultural neuropsychological test battery (CNTB) for the assessment of cognitive impairment in multiple sclerosis: Cognitive phenotyping and classification supported by machine learning techniques.

BACKGROUND: The European Cross-Cultural Neuropsychological Test Battery (CNTB) has been proposed as a comprehensive battery for cognitive assessment, reducing the potential impact of cultural variables. In this validation study, we aimed to evaluate the diagnostic capacity of CNTB for the assessment of participants with multiple sclerosis (pwMS) compared to the Neuronorma battery (NN) according to the International Classification of Cognitive Disorders in MS criteria, and to develop machine learning (ML) algorithms to improve the diagnostic capacity of CNTB and to select the most relevant tests. METHODS: Sixty pwMS and 60 healthy controls (HC) with no differences in sex, age, or years of education were enrolled. All participants completed the CNTB and pwMS were also examined with NN, depression, and fatigue scales. Impaired domains and cognitive phenotypes were defined following ICCoDiMS based on CNTB scores and compared to NN, according to -1SD and -1.5SD cutoff scores. To select the most relevant tests, random forest (RF) was performed for different binary classifications. RESULTS: PwMS showed a lower performance compared to HC with medium-large effect sizes, in episodic memory, executive function, attention, and processing speed, in accordance with their characteristic cognitive profile. There were no differences in impaired domains or cognitive phenotypes between CNTB and NN, highlighting the role of episodic memory, executive function, attention, and processing speed tests. The most relevant tests identified by RF were consistent with inter-group comparisons and allowed a better classification than SD cutoff scores. CONCLUSION: CNTB is a valid test for cognitive diagnosis in pwMS, including key tests for the most frequently impaired cognitive domains in MS. The use of ML techniques may also be useful to improve diagnosis, especially in some tests with lower sensitivity.

Real-World Experience with Diroximel Fumarate in Patients with Multiple Sclerosis: A Prospective Multicenter Study.

BACKGROUND: Current literature and a real-world study suggest that diroximel fumarate (DRF) is safer than dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). However, no real-world study to date has significantly addressed the efficacy of this treatment. OBJECTIVES: This study aims to elucidate the safety, tolerability, and efficacy of DRF in a real-world setting, utilizing data from a Spanish national registry of patients commencing DRF therapy post-market introduction. METHODS: In this multicenter, prospective observational study, data were collected from MS patients who initiated DRF treatment. The study monitored demographic and clinical characteristics, safety outcomes (including adverse events, reasons for discontinuation, and lymphocyte counts), and efficacy outcomes (radiological and clinical activity). RESULTS: A total of 195 MS patients across 26 neurological departments were included, predominantly female (79.5%), with a mean age of 42.17 years, and a mean duration of treatment with DRF of 6.3 months. Most patients (70.3%) reported no adverse events, while gastrointestinal issues and flushing were the most common adverse events observed. The majority of patients (84.6%) continued with DRF treatment, with tolerability issues being the primary reason for discontinuation. Efficacy analysis showed low relapse rates post-DRF initiation, with most patients exhibiting stable or improved Expanded Disability Status Scale scores and radiological assessments demonstrating minimal activity. CONCLUSION: This comprehensive analysis provides valuable insights into the real-world application of DRF, confirming its safety and tolerability while offering preliminary evidence of its efficacy in managing MS.

Practical tool to identify Spasticity-Plus Syndrome amongst patients with multiple sclerosis. Algorithm development based on a conjoint analysis.

Introduction: The Spasticity-Plus Syndrome (SPS) in multiple sclerosis (MS) refers to a combination of spasticity and other signs/symptoms such as spasms, cramps, bladder dysfunction, tremor, sleep disorder, pain, and fatigue. The main purpose is to develop a user-friendly tool that could help neurologists to detect SPS in MS patients as soon as possible. Methods: A survey research based on a conjoint analysis approach was used. An orthogonal factorial design was employed to form 12 patient profiles combining, at random, the eight principal SPS signs/symptoms. Expert neurologists evaluated in a survey and a logistic regression model determined the weight of each SPS sign/symptom, classifying profiles as SPS or not. Results: 72 neurologists participated in the survey answering the conjoint exercise. Logistic regression results of the survey showed the relative contribution of each sign/symptom to the classification as SPS. Spasticity was the most influential sign, followed by spasms, tremor, cramps, and bladder dysfunction. The goodness of fit of the model was appropriate (AUC = 0.816). Concordance between the experts' evaluation vs. model estimation showed strong Pearson's (r = 0.936) and Spearman's (r = 0.893) correlation coefficients. The application of the algorithm provides with a probability of showing SPS and the following ranges are proposed to interpret the results: high (> 60%), moderate (30-60%), or low (< 30%) probability of SPS. Discussion: This study offers an algorithmic tool to help healthcare professionals to identify SPS in MS patients. The use of this tool could simplify the management of SPS, reducing side effects related with polypharmacotherapy.

Multi-Disease Validation of the RUDAS for Cognitive Screening in Alzheimer's Disease, Parkinson's Disease, and Multiple Sclerosis.

BACKGROUND: The Rowland Universal Dementia Assessment Scale (RUDAS) is a cognitive test with favorable diagnostic properties for detecting dementia and a low influence of education and cultural biases. OBJECTIVE: We aimed to validate the RUDAS in people with Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). METHODS: We enrolled one hundred and fifty participants (60 with AD, 30 with PD, 60 with MS, and 120 healthy controls (HC)). All clinical groups completed a comprehensive neuropsychological battery, RUDAS, and standard cognitive tests of each disorder: MMSE, SCOPA-COG, and Symbol Digit Modalities Test. Intergroup comparisons between clinical groups and HC and ROC curves were estimated. Random Forest algorithms were trained and validated to detect cognitive impairment using RUDAS and rank the most relevant scores. RESULTS: The RUDAS scores were lower in patients with AD, and patients with PD and MS showed cognitive impairment compared to healthy controls. Effect sizes were generally large. The total score was the most discriminative, followed by the memory score. Correlations with standardized neuropsychological tests were moderate to high. Random Forest algorithms obtained accuracies over 80-90% using the RUDAS for diagnosing AD and cognitive impairment associated with PD and MS. CONCLUSION: Our results suggest the RUDAS is a valid test candidate for multi-disease cognitive screening tool in AD, PD, and MS.

In Vitro Effects of Methylprednisolone over Oligodendroglial Cells: Foresight to Future Cell Therapies.

The implantation of oligodendrocyte precursor cells may be a useful therapeutic strategy for targeting remyelination. However, it is yet to be established how these cells behave after implantation and whether they retain the capacity to proliferate or differentiate into myelin-forming oligodendrocytes. One essential issue is the creation of administration protocols and determining which factors need to be well established. There is controversy around whether these cells may be implanted simultaneously with corticosteroid treatment, which is widely used in many clinical situations. This study assesses the influence of corticosteroids on the capacity for proliferation and differentiation and the survival of human oligodendroglioma cells. Our findings show that corticosteroids reduce the capacity of these cells to proliferate and to differentiate into oligodendrocytes and decrease cell survival. Thus, their effect does not favour remyelination; this is consistent with the results of studies with rodent cells. In conclusion, protocols for the administration of oligodendrocyte lineage cells with the aim of repopulating oligodendroglial niches or repairing demyelinated axons should not include corticosteroids, given the evidence that the effects of these drugs may undermine the objectives of cell transplantation.

Validation of a brief cross-cultural cognitive screening test in Multiple Sclerosis.

BACKGROUND: Several batteries have been developed for the cognitive assessment of people with multiple sclerosis (MS). However, all these tests have some limitations in general clinical practice and from a cross-cultural perspective. In this study, we aimed to validate a novel cognitive screening test, the Cross-Cultural Dementia screening test (CCD), in pwMS. METHODS: Seventy-five participants with relapsing-remitting MS and 75 healthy controls were enrolled and completed a comprehensive neuropsychological battery and the CCD. Intergroup comparisons, effect sizes, and correlations with previously validated tests were calculated for a majority and a pilot study of a minority sample. ROC curves were estimated, and random forest classification models were developed. RESULTS: There were statistically significant differences between cognitively impaired MS (MS-CI) group and healthy controls, and between MS-CI and non-cognitively impaired MS group in all subtests of CCD with medium to large effect sizes. Correlations with standardized neuropsychological tests were moderate to high, supporting concurrent validity. These results were replicated in the minority sample. The random forest models showed a very accurate classification using the CCD. This test showed good psychometric properties compared with SDMT. CONCLUSIONS: Our study validates the CCD for cognitive impairment screening in MS, showing advantages over other routinely used cognitive tests.

Validation of two new scales for the assessment of fatigue in Multiple Sclerosis: F-2-MS and FACIT-F.

BACKGROUND: Fatigue is one of the most common symptoms in neurology, especially in MS patients with a prevalence of 65%. It is described as the most disabling symptom by 40% of MS patients. This study aimed to validate the Functional Assessment of Chronic Illness Therapy fatigue version (FACIT-F) and the F-2-MS scale, a new tool to distinguish between fatigue and fatigability. METHODS: One hundred and fifteen patients with relapsing-remitting MS were enrolled. All patients completed a comprehensive neuropsychological battery, previously validated in MS. Fatigue was evaluated using the Fatigue Severity Scale (FSS), the Modified version of the Fatigue Impact Scale (MFIS), the Functional Assessment of Chronic Illness Therapy measure system (fatigue version) (FCIT-F), and a new tool for the assessment of fatigue and fatigability: the F-2-MS scale. Internal consistency was estimated with Cronbach's Alpha. For intergroup comparisons, Student's t-test and Pearson's chi-squared test were used. Pearson's correlation test was calculated for quantitative variables. Cohen's d was calculated to evaluate the effect size. Binary logistic regression was performed, considering the presence of fatigue as a criterion variable, and the FACIT-F and F-2-MS scores were added as predictor variables. ROC curves were also estimated. We conducted a confirmatory factor analysis for the F-2-MS scale, considering two latent factors. RESULTS: FACIT-F and F-2-MS showed high internal consistency. Both scales were highly correlated with MFIS and FSS, and showed a low correlation with Symbol Digit Modalities Test. There were significant differences between fatigued and non-fatigued patients on FACIT-F and F-2-MS scores with large effect sizes. Both scales showed AUC > 0.90 and achieved a correct classification >87%. Confirmatory factor analysis showed moderate evidence of two dimensions on the F-2-MS scale. CONCLUSIONS: The FACIT-F and F-2-MS scales showed appropriated psychometric properties to be used as fatigue measures in clinical and research settings, allowing a correct distinction between patients with and without fatigue, and contributing to the understanding of the complexities of fatigue in MS.

Nose-to-Brain: The Next Step for Stem Cell and Biomaterial Therapy in Neurological Disorders.

Neurological disorders are a leading cause of morbidity worldwide, giving rise to a growing need to develop treatments to revert their symptoms. This review highlights the great potential of recent advances in cell therapy for the treatment of neurological disorders. Through the administration of pluripotent or stem cells, this novel therapy may promote neuroprotection, neuroplasticity, and neuroregeneration in lesion areas. The review also addresses the administration of these therapeutic molecules by the intranasal route, a promising, non-conventional route that allows for direct access to the central nervous system without crossing the blood-brain barrier, avoiding potential adverse reactions and enabling the administration of large quantities of therapeutic molecules to the brain. Finally, we focus on the need to use biomaterials, which play an important role as nutrient carriers, scaffolds, and immune modulators in the administration of non-autologous cells. Little research has been conducted into the integration of biomaterials alongside intranasally administered cell therapy, a highly promising approach for the treatment of neurological disorders.

Development, Spanish Normative Data, and Validation of a Social Cognition Battery in Prodromal Alzheimer's Disease and Multiple Sclerosis.

OBJECTIVES: The assessment of social cognition changes may be challenging, especially in the earliest stages of some neurodegenerative diseases. Our objective was to validate a social cognition battery from a multidomain perspective. In this regard, we aimed to adapt several tests, collect normative data, and validate them in prodromal Alzheimer's disease (AD) and multiple sclerosis (MS). METHODS: A total of 92 healthy controls, 25 prodromal AD, and 39 MS patients were enrolled. Age-, gender-, and education-matched control groups were created for comparisons. Social cognition battery was composed of an emotion-labeling task developed from FACES database, the Story-based Empathy test (SET), the Faux Pas test, and the Interpersonal Reactivity Index. Patients were also evaluated with a comprehensive cognitive battery to evaluate the other cognitive domains. Automatic linear modeling was used to predict each social cognition test's performance using the neuropsychological tests examining other cognitive domains. RESULTS: The reliability of the battery was moderate-high. Significant intergroup differences were found with medium-large effect sizes. Moderate correlations were found between social cognition battery and neuropsychological tests. The emotion labeling task and SET showed moderate correlations with age and education, and age, respectively. Regression-based norms were created considering the relevant demographic variables. Linear regression models including other neuropsychological tests explained between 7.7% and 68.8% of the variance of the social cognition tests performance. CONCLUSIONS: Our study provides a battery for the assessment of social cognition in prodromal AD and MS with Spanish normative data to improve the evaluation in clinical and research settings.