Brain Network Activation and Gait and Posture in FXTAS

Study Overview
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Brief Summary
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In this study the investigators aim to identify and characterize a potential neurophysiological biomarker by mapping functional networks of brain activity (Brain Network Activation, BNA) based on analysis of evoked response potential (ERP) signals in both asymptomatic FMR1 premutation carriers and in patients with various stages of FXTAS. Additionally correlations will be studied between these BNA scores and demographics (gender, age and disease duration) as well as genetic mutation and clinical scores.

Detailed Description
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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset (>50 years) multisystem neurodegenerative disorder, associated with an expansion in the 5ʹuntranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats, termed the FMR1 gene premutation. While the prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, the penetrance of FXTAS in male carriers is  40% compared to less than 20% in females. The mean age of onset of FXTAS is 60 years, presenting with intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonism, and psychiatric manifestations such as depression, anxiety and/or apathy. There are typical MRI findings in FXTAS patients, including increased T2-weighted signal intensity in the middle cerebellar peduncles, cerebellar and cerebral atrophy and volume loss of the corpus callosum. Currently, no definitive diagnostic tests exist for the symptomatic condition, FXTAS, in FMR1 premutation carriers, making it difficult to diagnose, particularly in the early stages of disease pathology. ElMindA, an Israeli company established in 2006, that focuses on the mapping of neuro-electrophysiological activity, has developed a novel method of mapping functional networks of brain activity (Brain Network Activation or BNA) based on analysis of evoked response potential (ERP) signals. Patients whose underlying disease involves impairment in brain circuitry and connectivity are expected to produce abnormal activity templates in response to the same paradigm, both as a result of failing to adhere to the normal pattern and of recruiting compensatory pathways and strategies to tackle the task. The essence of BNA analysis is the extraction of brain activity patterns common to a group of normal subjects, against which the brain activity of individual subjects may be compared. Patients with FXTAS have been found to exhibit executive and memory deficits along with altered prefrontal cortex activity in functional MRI studies and the investigators suspect that patients with FXTAS and also FMR1 premutation carriers in the early phase of neurodegeneration (even before exhibiting overt clinical symptoms of FXTAS) may display abnormal BNA patterns. Accordingly, at Sheba medical center the investigators have computed individual BNA scores for 30 healthy control subjects and thus defined the BNA patterns of healthy subjects to be used for comparison wit study subjects. The goal of the study is to identify and characterize a potential neurophysiological biomarker for early stage FXTAS and for disease progression by evaluating the electrophysiological activity in both asymptomatic FMR1 Premutation carriers and in patients with various stages (duration) of FXTAS. Additionally correlations will be studied between these BNA data and demographics (gender, age and disease duration). length of the pathological CGG repeat expansion as well as FXTAS score, gait and posture abnormalities (obtained by instrumental timed up and go evaluation) and neuropsychological status. Characterization of neuro-electrophysiological biomarkers may be important to detect early transformation from asymptomatic carriership to neurodegeneration and FXTAS and to enable early interventions and monitoring of response to treatment

Official Title
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Mapping Functional Networks of Brain Activity (Brain Network Activation) Based on Analysis of Evoked Response Potential (ERP) Signals and Registration of Posture and Gait-related Data in FMR1 Premutation Carriers and Patients With FXTAS.

Conditions
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Fragile X Associated Tremor-ataxia Syndrome, FXTAS

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: FMR1 premutation carriers (55-200 CGG repeats) symptomatic (with possible or probable FXTAS) or neurologically asymptomatic. Exclusion Criteria: Severe disability unable to perform tests treatment with neuroleptics other brain disease or pathology deafness or blindness

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| FXTAS<br>Patients positive for FMR1 premutation and meet diagnostic criteria for FXTAS | |
| FMR1 premutation asymptomatic<br>Patients positive for FMR1 premutation and do not meet diagnostic criteria for FXTAS | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BNA SCORE |  | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FXTAS SCORE | Clinical rating scale | 1 day | 
| Posture and gait data | Posture and gait data from Instrumental timed up and go test and items from the FXTAS rating scale. | 1 day | 
| NeuroTrax™ Computerized Cognitive Tests | Neuropsychological test | 1 day | 
| MoCA score | Neuropsychological test | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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evoked response potential, ERP, Brain Network Activation, BNA, Biomarker