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Background: Recently, subjective cognitive decline (SCD) was proposed as an early risk factor for future Alzheimer's disease (AD). Objective: In this study, we investigated whether accelerated long-term forgetting (ALF), assessed with extended testing intervals than those adopted in clinical practice, might be a cognitive feature of SCD. Using an explorative MRI analysis of the SCD sample, we attempted to investigate the areas most likely involved in the ALF pattern. Methods: We recruited 31 individuals with SCD from our memory clinic and subdivided them based on their rate of memory complaints into mild SCDs (nâ=â18) and severe SCDs (nâ=â13). A long-term forgetting procedure, involving the recall of verbal and visuo-spatial material at four testing delays (i.e., immediate, 30âmin, 24âh, and 7 days post-encoding) was used to compare the two sub-groups of SCDs with a healthy control group (HC; nâ=â16). Results: No significant between-group difference was found on the standard neuropsychological tests, nor in the immediate and 30âmin recall of the experimental procedure. By contrast, on the verbal test severe SCDs forgot significantly more than HCs in the prolonged intervals (i.e., 24âh and 7 days), with the greatest decline between 30âmin and 24âh. Finally, in the whole SCD sample, we found significant associations between functional connectivity values within some cortical networks involved in memory (default mode network, salience network, and fronto-parietal network) and verbal long-term measures. Conclusions: Our preliminary findings suggest that long-term forgetting procedures could be a sensitive neuropsychological tool for detecting memory concerns in SCDs, contributing to early AD detection.
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Disfunção Cognitiva , Imageamento por Ressonância Magnética , Transtornos da Memória , Testes Neuropsicológicos , Humanos , Masculino , Feminino , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/diagnóstico por imagem , Idoso , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Rememoração Mental/fisiologia , Encéfalo/diagnóstico por imagemRESUMO
We report on genetic and environmental modulation of social cognition abilities and brain volume correlates in two monozygotic twins (Twin1 and Twin2) with genetically confirmed myotonic dystrophy-type1 who grew up in different environmental settings. They both underwent neuropsychological assessment (i.e., Intelligent Quotient [IQ], theory of mind, emotion recognition tests), and MRI scanning to evaluate regional brain volumetrics compared to 10 gender and sex-matched healthy controls. Against a normal IQ level in both patients, Twin1 was more impaired in emotional processing and Twin2 in cognitive aspects of social cognition. Both patients showed grey matter (GM) atrophy in Brodmann Areas 23/31 (BA23/31) and BA7 bilaterally, while Twin2 showed additional GM loss in right BA46. Both patients showed a similar pattern of white matter atrophy involving the thalamus, basal ganglia, and uncinate fasciculus. White matter atrophy appeared to be mostly driven by genetics, while grey matter volumes appeared associated with different impairments in social cognition and possibly modulated by environment.
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Encéfalo , Imageamento por Ressonância Magnética , Distrofia Miotônica , Testes Neuropsicológicos , Fenótipo , Gêmeos Monozigóticos , Humanos , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Distrofia Miotônica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Masculino , Feminino , Adulto , Atrofia/patologia , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Cognição SocialRESUMO
Artificial intelligence (AI) is rapidly transforming the field of medicine, announcing a new era of innovation and efficiency. Among AI programs designed for general use, ChatGPT holds a prominent position, using an innovative language model developed by OpenAI. Thanks to the use of deep learning techniques, ChatGPT stands out as an exceptionally viable tool, renowned for generating human-like responses to queries. Various medical specialties, including rheumatology, oncology, psychiatry, internal medicine, and ophthalmology, have been explored for ChatGPT integration, with pilot studies and trials revealing each field's potential benefits and challenges. However, the field of genetics and genetic counseling, as well as that of rare disorders, represents an area suitable for exploration, with its complex datasets and the need for personalized patient care. In this review, we synthesize the wide range of potential applications for ChatGPT in the medical field, highlighting its benefits and limitations. We pay special attention to rare and genetic disorders, aiming to shed light on the future roles of AI-driven chatbots in healthcare. Our goal is to pave the way for a healthcare system that is more knowledgeable, efficient, and centered around patient needs.
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Inteligência Artificial , Doenças Raras , Humanos , Aprendizado Profundo , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Doenças Raras/terapiaRESUMO
In the original publication [...].
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Evidence in the literature indicates that aerobic physical activity may have a protective role in aging pathologies. However, it has not been clarified whether different types of aerobic exercise produce different effects. In particular, these potential differences have not been explored in patients with Alzheimer's disease (AD). The present narrative review has the specific aim of evaluating whether land (walking/running) and water (swimming) aerobic activities exert different effects on cognitive functions and neural correlates in AD patients. In particular, the investigation is carried out by comparing the evidence provided from studies on AD animal models and on patients. On the whole, we ascertained that both human and animal studies documented beneficial effects of land and water aerobic exercise on cognition in AD. Also, the modulation of numerous biological processes is documented in association with structural modifications. Remarkably, we found that aerobic activity appears to improve cognition per se, independently from the specific kind of exercise performed. Aerobic exercise promotes brain functioning through the secretion of molecular factors from skeletal muscles and liver. These molecular factors stimulate neuroplasticity, reduce neuroinflammation, and inhibit neurodegenerative processes leading to amyloid-ß accumulation. Additionally, aerobic exercise improves mitochondrial activity, reducing oxidative stress and enhancing ATP production. Aerobic activities protect against AD, but implementing exercise protocols for patients is challenging. We suggest that health policies and specialized institutions should direct increasing attention on aerobic activity as lifestyle modifiable factor for successful aging and age-related conditions.
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Doença de Alzheimer , Animais , Humanos , Doença de Alzheimer/patologia , Cognição , Exercício Físico/fisiologia , Terapia por Exercício/métodos , Peptídeos beta-AmiloidesRESUMO
Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.
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Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease, although 10%-30% of cases are sporadic. However, this percentage may include truly de novo patients (carrying a reduced D4Z4 allele that is not present in either of the parents) and patients with apparently sporadic disease resulting from mosaicism, non-penetrance, or complex genetic situations in either patients or parents. In this study, we characterized the D4Z4 Reduced Alleles (DRA) and evaluated the frequency of truly de novo cases in FSHD1 in a cohort of DNA samples received consecutively for FSHD-diagnostic from 100 Italian families. The D4Z4 testing revealed that 60 families reported a DRA compatible with FSHD1 (1-10 RU). The DRA co-segregated with the disease in most cases. Five families with truly de novo cases were identified, suggesting that this condition may be slightly lower (8%) than previously reported. In addition, D4Z4 characterization in the investigated families showed 4% of mosaic cases and 2% with translocations. This study further highlighted the importance of performing family studies for clarifying apparently sporadic FSHD cases, with significant implications for genetic counseling, diagnosis, clinical management, and procreative choices for patients and families.
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Distrofia Muscular Facioescapuloumeral , Humanos , Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/genética , Alelos , Mosaicismo , Itália/epidemiologia , Cromossomos Humanos Par 4/genéticaRESUMO
Introduction: Prospective memory (PM) impairments have been extensively documented in individuals with Parkinson's disease associated with mild cognitive impairment (PD-MCI) and in those with healthy aging. Considering how PM failure decreases individuals' quality of life and functional independence in the activities of daily living, training to enhance this ability could be a prior target of intervention. Objective: Here, we aimed to present the study protocol and preliminary results of a novel immersive virtual reality (IVR) and telemedicine-based (TM) cognitive intervention focused on executive abilities (i.e., planning, shifting, and updating) to improve PM functioning in PD-MCI patients and healthy elderly individuals. Methods: Outcome measures, collected before, immediately after and 2 months after the intervention, included: (1) pre-post training changes in objective cognitive functioning, evaluated with tests assessing executive functions and PM; (2) pre-post training changes in subjective perception of memory functioning, psychiatric symptoms, autonomy in daily living and quality of life, evaluated using the appropriate scales; (3) usability, feasibility and users' compliance with the proposed IVR and telemedicine program. The efficacy of this intervention compared to an active control condition is currently being evaluated in a randomized, double-blind controlled trial, which will be conducted on 30 eligible PD-MCI patients and 30 older adults. Results: Preliminary results concerning between-group comparisons of demographic and neuropsychological screening data show a good balance among the intervention groups considered in this study. The results also suggest good levels of usability, feasibility and acceptability, thus supporting the notion that our intervention can be used to promote cognitive functioning, even in people with cognitive decline. Conclusion: Considering the relatively low costs and easy accessibility to this program, it could prove valuable in primary prevention initiatives and early cognitive rehabilitation for dementia risk reduction.
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Breakthrough infections in SARS-CoV-2 vaccinated individuals are an ideal circumstance for the simultaneous exploration of both the vaccine-induced memory reaction to the spike (S) protein and the primary response to the membrane (M) and nucleocapsid (N) proteins generated by natural infection. We monitored 15 healthcare workers who had been vaccinated with two doses of Pfizer BioNTech BNT162b2 and were then later infected with the SARS-CoV-2 B.1.617.2. (Delta) variant, analysing the antiviral humoral and cellular immune responses. Natural infection determined an immediate and sharp rise in anti-RBD antibody titres and in the frequency of both S-specific antibody secreting cells (ASCs) and memory B lymphocytes. T cells responded promptly to infection by activating and expanding already at 2-5 days. S-specific memory and emerging M- and N-specific T cells both expressed high levels of activation markers and showed effector capacity with similar kinetics but with different magnitude. The results show that natural infection with SARS-CoV-2 in vaccinated individuals induces fully functional and rapidly expanding T and B lymphocytes in concert with the emergence of novel virus-specific T cells. This swift and punctual response also covers viral variants and captures a paradigmatic case of a healthy adaptive immune reaction to infection with a mutating virus.
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Introduction: Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a D4Z4 Reduced Allele (DRA). Methods: A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by D4Z4 sizing, methylation analysis and WES. Specific protocols were employed for D4Z4 sizing and methylation analysis, whereas the Illumina® Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer D4Z4 alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members. Results: The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (SMCHD1, DNMT3B and LRIF1) and 6 in candidate genes (CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1). Most of them were found together with a permissive short (4-7 RU) or borderline/long DRA (8-20 RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients. Discussion: Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (SMCHD1, DNMT3B, LRIF1) and possibly other candidate genes (CTCF, DNMT1, DNMT3A, EZH2, SUV39H1) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband's family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families.
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BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. OBJECTIVE: The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. METHODS: 23 SCD and 33 healthy subjects (HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. RESULTS: No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. CONCLUSIONS: SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term.
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The alteration of epigenetic modifications, including DNA methylation, can contribute to the etiopathogenesis and progression of many diseases. Among them, facioscapulohumeral dystrophy (FSHD) is a muscular disorder characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). As a consequence, these alterations are responsible for DNA hypomethylation and a transcriptional-active chromatin conformation change that, in turn, lead to the aberrant expression of DUX4 in muscle cells. In the present study, methylation levels of 29 CpG sites of the DR1 region (within each repeat unit of the D4Z4 macrosatellite) were assessed on 335 subjects by employing primers designed for enhancing the performance of the assay. First, the DR1 original primers were optimized by adding M13 oligonucleotide tails. Moreover, the DR1 reverse primer was replaced with a degenerate one. As a result, the protocol optimization allowed a better sequencing resolution and a more accurate evaluation of DR1 methylation levels. Moreover, the assessment of the repeatability of measurements proved the reliability and robustness of the assay. The optimized protocol emerges as an excellent method to detect methylation levels compatible with FSHD.
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The aim of this study was to shed light on the neural substrate of conceptual representations starting from the construct of higher-order convergence zones and trying to evaluate the unitary or non-unitary nature of this construct. We used the 'Thematic and Taxonomic Semantic (TTS) task' to investigate (a) the neural substrate of stimuli belonging to biological and artifact categories, (b) the format of stimuli presentation, i.e., verbal or pictorial, and (c) the relation between stimuli, i.e., categorial or contextual. We administered anodal transcranial direct current stimulation (tDCS) to different brain structures during the execution of the TTS task. Twenty healthy participants were enrolled and divided into two groups, one investigating the role of the anterior temporal lobes (ATL) and the other the temporo-parietal junctions (TPJ). Each participant underwent three sessions of stimulation to facilitate a control condition and to investigate the role of both hemispheres. Results showed that ATL stimulation influenced all conceptual representations in relation to the format of presentation (i.e., left-verbal and right-pictorial). Moreover, ATL stimulation modulated living categories and taxonomic relations specifically, whereas TPJ stimulation did not influence semantic task performances.
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Since the spinal cord has traditionally been considered a bundle of long fibers connecting the brain to all parts of the body, the study of its role has long been limited to peripheral sensory and motor control. However, in recent years, new studies have challenged this view pointing to the spinal cord's involvement not only in the acquisition and maintenance of new motor skills but also in the modulation of motor and cognitive functions dependent on cortical motor regions. Indeed, several reports to date, which have combined neurophysiological techniques with transpinal direct current stimulation (tsDCS), have shown that tsDCS is effective in promoting local and cortical neuroplasticity changes in animals and humans through the activation of ascending corticospinal pathways that modulate the sensorimotor cortical networks. The aim of this paper is first to report the most prominent tsDCS studies on neuroplasticity and its influence at the cortical level. Then, a comprehensive review of tsDCS literature on motor improvement in animals and healthy subjects and on motor and cognitive recovery in post-stroke populations is presented. We believe that these findings might have an important impact in the future making tsDCS a potential suitable adjunctive approach for post-stroke recovery.
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Córtex Motor , Acidente Vascular Cerebral , Animais , Humanos , Potencial Evocado Motor/fisiologia , Medula Espinal/fisiologia , Encéfalo , Acidente Vascular Cerebral/terapia , Córtex Motor/fisiologiaRESUMO
Here, we examined mechanisms that affect retrograde memory in amnestic mild cognitive impairment (a-MCI) as a function of longitudinal clinical outcome. 8 a-MCI who converted to Alzheimer's dementia (AD) during the subsequent 3-year follow-up (converter a-MCI) and 10 a-MCI who remained clinically stable during the same period (stable a-MCI) were compared at the baseline evaluation (i.e., when they were diagnosed as a-MCI) using a remote memory questionnaire for public events that allows disentangling the differential contribution of storage and retrieval mechanisms to performance accuracy. Results suggest that deficits in remote memory are primarily explained by impaired retrieval abilities in stable a-MCI and by impaired storage in converter-to-AD a-MCI. This distinction between retrograde amnesia due to defective trace utilisation in stable a-MCI and trace storage in converter a-MCI is consistent with the temporal unfolding of declining anterograde memory over the course of disease progression to AD.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Disfunção Cognitiva/psicologia , Doença de Alzheimer/psicologia , Progressão da Doença , Testes NeuropsicológicosRESUMO
BACKGROUND: At the moment, the possible options for the management of cognitive dysfunctions in patients with MS (pMS) are pharmacological interventions, cognitive rehabilitation (CR), and physical exercise. However, worldwide, multimodal programs are infrequently applied in pMS and CR is not easily accessible through the National Health System as MR. OBJECTIVE: The aim of the study is to explore if the combination of motor and cognitive rehabilitation may favor better outcomes on cognitive efficiency compared to separate trainings. METHODS: Forty-eight pMS were submitted to detailed neuropsychological and motor assessments, before (T0) and after (T1) having performed one of three rehabilitation conditions (two cognitive trainings/week-Reha1; one cognitive and one motor training/week-Reha2; two motor trainings/week-Reha3, for 12 weeks); they were randomly assigned to one condition or another. The CR was focused on memory functioning and performed with the Rehacom program. RESULTS: No significant differences in age, sex, education, and disease course were found between the three groups (sig. > .05). Reha1 patients increased only their cognitive performance, and Reha3 only increased their motor performance, while Reha2 increased both cognitive and motor performances. This benefit was also confirmed by the cognitive efficiency expressed by the Cognitive Impairment Index. CONCLUSIONS: These data confirm that to include cognitive training within rehabilitation programs may induce important benefits in pMS. Furthermore, pMS seem to benefit from a combined approach (cognitive and motor) more than from CR and motor rehabilitation separately (ClinicalTrial.gov ID: NCT05462678; 14 July 2022, retrospectively registered).
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Disfunção Cognitiva , Humanos , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/reabilitação , Terapia por Exercício , Memória/fisiologia , Resultado do TratamentoRESUMO
Prefrontal functions subserve inhibition control for retrieval of semantically related items inducing forgetting 19 a-MCI patients and 29 controls underwent neuropsychological evaluation and retrieval-practice paradigm (RPP) to estimate baseline remember (BR), retrieval-induced facilitation (FAC) and retrieval-induced forgetting (RIF). A-MCI patients underwent also 3 T-MRI to assess relationship between regional grey matter (rGM) volumes and RPP indexes Behaviourally, RIF and FAC were both observed controls, while RIF only was observed in a-MCI patients. In patients but not in controls, RIF was associated with cognitive efficiency and FAC with memory performance. Patients showed also associations between BR and rGM volumes in the precuneus, no association was found between rGM volumes and RIF and FAC. A-MCI patients did not benefit from repeated practice during retrieval of studied items, which is likely due to their memory disorder. In contrast, patient cognitive efficiency would drive retrieval suppression of interfering stimuli.
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Disfunção Cognitiva , Rememoração Mental , Humanos , Rememoração Mental/fisiologia , Testes Neuropsicológicos , Transtornos da Memória/etiologia , CogniçãoRESUMO
OBJECTIVE: Subjective cognitive decline (SCD) was recently proposed as an early risk factor for future mild cognitive impairment and Alzheimer's disease (AD). In this study, we investigated the sensitivity of novel neuropsychological testing paradigms (which have been proposed as potentially challenging tools for the identification of preclinical AD) in capturing the subtle cognitive changes leading to SCD but not objectively detected by traditional tests. METHOD: The performances of 18 patients with SCD and 15 healthy individuals with no worries of cognitive decline (healthy controls [HC]) was compared on demanding tasks that investigated, respectively, associative memory, memory binding, spatial pattern separation processes and semantic memory. The diagnostic utility of these tests in capturing the subtle cognitive changes associated with SCD and possible relationships with SCD-related worries were investigated. RESULTS: No significance between-group difference was found on the standard neuropsychological tests. Conversely, the performance of patients with SCD and HC differed significantly on specific indexes derived from experimental tasks assessing face-name associative memory and spatial pattern separation. Moreover, these measures correctly classified group membership with good overall accuracy (between 79% and 82%) and were significantly associated with self-perceived memory functioning. CONCLUSIONS: Our preliminary findings suggest that specific measures derived from demanding cognitive paradigms could be sensitive neuropsychological indexes for detecting the subtle cognitive impairment associated with SCD. These observations could be useful for further refining cognitive assessment aimed at early detection of AD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Testes Neuropsicológicos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , MemóriaRESUMO
The study describes a protocol for methylation analysis integrated with Machine Learning (ML) algorithms developed to classify Facio-Scapulo-Humeral Dystrophy (FSHD) subjects. The DNA methylation levels of two D4Z4 regions (DR1 and DUX4-PAS) were assessed by an in-house protocol based on bisulfite sequencing and capillary electrophoresis, followed by statistical and ML analyses. The study involved two independent cohorts, namely a training group of 133 patients with clinical signs of FSHD and 150 healthy controls (CTRL) and a testing set of 27 FSHD patients and 25 CTRL. As expected, FSHD patients showed significantly reduced methylation levels compared to CTRL. We utilized single CpG sites to develop a ML pipeline able to discriminate FSHD subjects. The model identified four CpGs sites as the most relevant for the discrimination of FSHD subjects and showed high metrics values (accuracy: 0.94, sensitivity: 0.93, specificity: 0.96). Two additional models were developed to differentiate patients with lower D4Z4 size and patients who might carry pathogenic variants in FSHD genes, respectively. Overall, the present model enables an accurate classification of FSHD patients, providing additional evidence for DNA methylation as a powerful disease biomarker that could be employed for prioritizing subjects to be tested for FSHD.