Brain Network Activation and Gait and Posture in FXTAS (FXTAS-BNA)

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Fragile X Associated Tremor-ataxia Syndrome; FXTAS

Detailed Description

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

• Study Type: Observational
• Enrollment (Anticipated): 150

Contacts and Locations

• Study Contact: Name: Sharon Hassin, MD; Phone Number: 972547912020; Email: shassin@post.tau.ac.il
• Study Contact Backup: Name: Tsvia Fay-Karmon, MD; Email: tsviakar@gmail.com

Study Locations

• Israel
  • Ramat Gan, Israel, 5265601
    • Recruiting
    • Movement Disorders Institute, Sheba Medical Center
    • Contact: Ayelet Brill, Ms.; Phone Number: +972-3-5304931; Email: Ayelet.Brill@sheba.health.gov.il
    • Sub-Investigator: Tsvia Fay-Karmon, Dr.
    • Principal Investigator: Sharon Hassin-Baer, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Men and women above the age of 50, that are FMR1 premutation carriers (55-200 CGG repeats), both symptomatic (with possible or probable FXTAS) or neurologically asymptomatic.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
FXTAS; Patients positive for FMR1 premutation and meet diagnostic criteria for FXTAS
FMR1 premutation asymptomatic; Patients positive for FMR1 premutation and do not meet diagnostic criteria for FXTAS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Sheba Medical Center
• Collaborators: ElMindA Ltd
• Investigators: Principal Investigator: Sharon Hassin, MD, Movement Disorders Instuitute, Sheba Medical Center

Publications and helpful links

General Publications

• Leehey MA, Berry-Kravis E, Goetz CG, Zhang L, Hall DA, Li L, Rice CD, Lara R, Cogswell J, Reynolds A, Gane L, Jacquemont S, Tassone F, Grigsby J, Hagerman RJ, Hagerman PJ. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008 Apr 15;70(16 Pt 2):1397-402. doi: 10.1212/01.wnl.0000281692.98200.f5. Epub 2007 Dec 5.
• Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001 Jul 10;57(1):127-30. doi: 10.1212/wnl.57.1.127.
• Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective. Am J Hum Genet. 2004 May;74(5):805-16. doi: 10.1086/386296. Epub 2004 Mar 29. Erratum In: Am J Hum Genet. 2004 Aug;75(2):352.
• Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, Berry-Kravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet. 2003 Apr;72(4):869-78. doi: 10.1086/374321. Epub 2003 Mar 12.
• Jacquemont S, Farzin F, Hall D, Leehey M, Tassone F, Gane L, Zhang L, Grigsby J, Jardini T, Lewin F, Berry-Kravis E, Hagerman PJ, Hagerman RJ. Aging in individuals with the FMR1 mutation. Am J Ment Retard. 2004 Mar;109(2):154-64. doi: 10.1352/0895-8017(2004)1092.0.CO;2.
• Rogers C, Partington MW, Turner GM. Tremor, ataxia and dementia in older men may indicate a carrier of the fragile X syndrome. Clin Genet. 2003 Jul;64(1):54-6. doi: 10.1034/j.1399-0004.2003.00089.x.
• Hall DA, Howard K, Hagerman R, Leehey MA. Parkinsonism in FMR1 premutation carriers may be indistinguishable from Parkinson disease. Parkinsonism Relat Disord. 2009 Feb;15(2):156-9. doi: 10.1016/j.parkreldis.2008.04.037. Epub 2008 Jun 20.
• Brunberg JA, Jacquemont S, Hagerman RJ, Berry-Kravis EM, Grigsby J, Leehey MA, Tassone F, Brown WT, Greco CM, Hagerman PJ. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. AJNR Am J Neuroradiol. 2002 Nov-Dec;23(10):1757-66.
• Grigsby J, Brega AG, Leehey MA, Goodrich GK, Jacquemont S, Loesch DZ, Cogswell JB, Epstein J, Wilson R, Jardini T, Gould E, Bennett RE, Hessl D, Cohen S, Cook K, Tassone F, Hagerman PJ, Hagerman RJ. Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome. Mov Disord. 2007 Apr 15;22(5):645-50. doi: 10.1002/mds.21359.
• Ray S, Miller M, Karalunas S, Robertson C, Grayson DS, Cary RP, Hawkey E, Painter JG, Kriz D, Fombonne E, Nigg JT, Fair DA. Structural and functional connectivity of the human brain in autism spectrum disorders and attention-deficit/hyperactivity disorder: A rich club-organization study. Hum Brain Mapp. 2014 Dec;35(12):6032-48. doi: 10.1002/hbm.22603. Epub 2014 Aug 13.
• Karalunas SL, Fair D, Musser ED, Aykes K, Iyer SP, Nigg JT. Subtyping attention-deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria. JAMA Psychiatry. 2014 Sep;71(9):1015-24. doi: 10.1001/jamapsychiatry.2014.763.
• O'Keefe JA, Robertson-Dick E, Dunn EJ, Li Y, Deng Y, Fiutko AN, Berry-Kravis E, Hall DA. Characterization and Early Detection of Balance Deficits in Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). Cerebellum. 2015 Dec;14(6):650-62. doi: 10.1007/s12311-015-0659-7.
• Michel CM, Thut G, Morand S, Khateb A, Pegna AJ, Grave de Peralta R, Gonzalez S, Seeck M, Landis T. Electric source imaging of human brain functions. Brain Res Brain Res Rev. 2001 Oct;36(2-3):108-18. doi: 10.1016/s0165-0173(01)00086-8.
• Caviness JN, Adler CH, Hentz JG, Shill HA, Evidente VG, Driver-Dunckley ED, Sabbagh MN, Sue L, Beach TG. Incidental Lewy body disease: electrophysiological findings suggesting pre-clinical Lewy body disorders. Clin Neurophysiol. 2011 Dec;122(12):2426-32. doi: 10.1016/j.clinph.2011.03.033. Epub 2011 May 26.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: October 15, 2016
• First Submitted That Met QC Criteria: October 15, 2016
• First Posted (Estimate): October 18, 2016

Study Record Updates

• Last Update Posted (Actual): March 17, 2021
• Last Update Submitted That Met QC Criteria: March 16, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Biomarker; ERP; evoked response potential; Brain Network Activation; BNA
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Dyskinesias; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Chromosome Disorders; Sex Chromosome Disorders; Ataxia; Fragile X Syndrome; Tremor
• Other Study ID Numbers: SHEBA-3490-16-SMC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes