1. Esther Granell Hospital de la Santa Creu i Sant Pau Barcelona. Spain egranell@santpau.cat NEUROIMAGING IN FXTAS Can we predict conversion of premutation carriers?

2. BACKGROUND Fragile-X-associated Tremor/Ataxia Syndrome (FXTAS) is a late onset neurodegenerative disorder occurrying in carriers of a premutation expansion (55 to 200 repeats) of the Fragile X Mental Retardation (FMR1) gene

3. BACKGROUND NORMAL <54 CGG FULL MUTACION >200 CGG PREMUTATION 55-200 CGG Fragile X Syndrome (FXS) FMR1 gene RNAm absent protein (methylation) (no transcription) FMR1 gene RNAm translation FMR1protein Fragile X Tremor Ataxia Syndrome (FXTAS) FMR1 gene excess RNAm normal or low protein Toxic gain-of-function: inclusion formation and neurological dysfunction

4. Diagnostic criteria  Major Radiological: WM, MCP and brainstem hyperintensities  Minor Radiological: brain, WM lesions moderate/severe brain atrophy  Major Clinical: intentional tremor, gait distubances  Minor Clinical: parkinsonism, loss of short memory executive disturbances Some FXTAS develop cognitive decline and eventually dementia, this having been mainly described in men. Up to date, it remains unknown which carriers will develop FXTAS and cognitive decline late in life “Definitive” disease: 1 major radiological + 1 major clinical “Probable”disease: 1 major radiological + 1 minor or 2 major clinical “Possible disease”: 1 minor + 1 major radiological

5. PURPOSE  To investigate if 3T MRI markers can differentiate FXTAS from non-FXTAS subjects, which may be potentially useful in predicting conversion of premutation carriers to FXTAS  To evaluate the relationship between MRI markers and cognitive-neuropsychological disturbances

6. METHODS Prospective, cross-sectional study of 44 subjects (30 premutation carriers and 14 controls),aged 33-80, matched for age and sex  3T (Philips Intera 2.1) MRI included 3D FLAIR and 3D-T1 MPRAGE. Conventional, previously described MRI findings were assessed by two experienced neuroradiologists  Neurological and neuropsychological evaluations :executive, memory, attention, global intelligence, and conductual  Cortical thickness (Freesurfer) and hippocampal volume (FS) and hippocampal shape (SPHARM) were analyzed on 3D MPRAGE images searching for potential MR markers  Statistical analysis included group-comparisons (Student´s t-test and one-way ANOVA) and a General Lineal Model

7. MRI findings in FXTAS patients included:  Middle cerebellar peduncle, brainstem, and cerebral white matter hyperintensities  Cerebellar, brainstem and brain atrophy RESULTS

8. brain atrophylocationMTL a.brainstem a.HIcerebellar a.MCP HIWM HI premutated ++F,P,T++++ ++++/ cups,dots premutated +F--++++++ / cups,dots premutated +F,P--+++dots < 20 premutated +F,P---++6 dots premutated +F,T,P-+-+++cups,dots > 20 premutated ---++++2/3 dots premutated +F,P, ant. T-+++ +++ /dots, cups premutated +F,P--+++2 dots premutated ++F,T++ ++++++++ / cups,dots premutated +F,P-+++++ 3 dots premutated +---/+/- +F,P--+++2 dots premutated +Global F,P,T+-++Slight1 dot premutated ------+1, 2 dots premutated ++F,P-+-+++dots premutated -`----+-- premutated +F----+3dots premutated +++F,T,P++ +++++++++ premutated ++F,P-++++++ (few) premutated ++F,P,T++ - -- premutated ++F,P-++++++++-

9. brain atrophylocationMTL a.brainstem a.HIcerebellar a.MCP HIWM HI premutated ++F,P,T++++ ++++/ cups,dots premutated +F--++++++ / cups,dots premutated +F,P--+++dots < 20 premutated +F,P---++6 dots premutated +F,T,P-+-+++cups,dots > 20 premutated ---++++2/3 dots premutated +F,P, ant. T-+++ +++ /dots, cups premutated +F,P--+++2 dots premutated ++F,T++ ++++++++ / cups,dots premutated +F,P-+++++ 3 dots premutated +---/+/- +F,P--+++2 dots premutated +Global F,P,T+-++Slight1 dot premutated ------+1, 2 dots premutated ++F,P-+-+++dots premutated -`----+-- premutated +F----+3dots premutated +++F,T,P++ +++++++++ premutated ++F,P-++++++ (few) premutated ++F,P,T++ - -- premutated ++F,P-++++++++-

10. RESULTS 11 patients fulfilled FXTAS-criteria (women and men), 2 women having dementia: 1a1b 1c 2a 2b2c These 2 women having FXTAS and dementia showed predominant frontal and temporal lobe atrophy, and white matter hyperintensities

11. RESULTS-Cortical thickness  There was selective decrease in cortical thickness in frontal and temporal regions, already present in the premutation state FXTAS-Elder PreElder Pre-Elder Control Young Pre-Young Control

12. Young pre-Young conElder Pre–Elder conFXTAS-Elder Pre LH Rostralmiddlefrontal 0.000950.000270.00269 Superiorfrontal 0.008120.000467.24 × 10 -5 Precentral 0.00330.00250.007 Lateraloccipital 0.00140.00270.023 Parahippocampal 0.00140.00110.01 Anteriorcingulate 0.000950.0063 Posteriorcingulate 0.000790.00085 RH Superiorfrontal 0.000470.00028 Caudalmiddlefrontal 0.00040.0079 Inferiorparietal 0.00229 Insula 0.00970.00580.0097 Anteriorcingulate 0.00320.000700.0044 Posteriorcingulate 9.7 × 10 -6 0.005 Parahippocampal 0.0089 RESULTS-Cortical thickness

13. RESULTS- Hippocampal volume and shape  Additionally, there were changes in hippocampal volume and its shape in the premutated and FXTAS state, more profound in those patients with dementia. Hippocampal volume in D FTXAS <non D FXTAS<Elder Pre (p=0.015 and 0.037) Young pre-Young controlFXTAS-Elder preD FXTAS-non D FXTAS

14. On neuropsychology, there was evidence of prefrontal and temporal impairment in premutated patients along the disease process  (FrBSe) Frontal System Behavior Scale: Apathy, dishinibition and executive disfunction in premutated patients: Premutated vs Control (Total scale p= 0.021) FXTAS vs Elder pre (Apathy p=0.087) D FXTAS vs. Non-D FXTAS ( Apathy P=0.04)  Left hippocampal cognitive disturbances: AVLT (Auditory Verbal Learning Test) Immediate AVLT: FXTAS vs Premutated (p=0.042) Delayed AVLT: D FXTAS vs non-D FXTAS (p=0.074) RESULTS-Neuropsychology

15. CONCLUSION  There are MRI changes already present in the premutated state in the frontal and temporal brain regions  These reflect impairment of related brain functions. 3T MRI may provide biomarkers, which could be clinically useful

16. REFERENCES I 1) Jacquemont, S, et al.Fragile X Premutation Tremor/Ataxia Syndrome: Molecular, Clinical, and Neuroimaging Correlates. Am. J. Hum. Genet. 72:869–878, 2003 2) Rodriguez-Revenga L, et al. Motor and mental dysfunction in mother-daughter transmitted FXTAS. Neurology 2010 (in press) 3)A. Inagakia, A. Iidab, M. Matsubarac and H. Inagakid. Positron emission tomography and magnetic resonance imaging in spinocerebellar ataxia type 2: a study of symptomatic and asymptomatic individuals. European Journal of Neurology 2005, 12: 725–728 4)M.R.R. Gonçalves, L. P. Capelli, R. Nitrini, E. R. Barbosa, C. S. Porto, L. T. Lucato and A. M. Vianna-Morgante. Atypical clinical course of fxtas: rapidly progressive dementia as the major symptom. Neurology 2007;68;1864-1866 5)S. Jacquemont, R.J Hagerman, P.J Hagerman, M.A Leehey. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 2007 Jan; 6 (1): 45-55

17. REFERENCES II 5)S. Jacquemont, R.J Hagerman, P.J Hagerman, M.A Leehey. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 2007 Jan; 6 (1): 45-55 6) M. A. Leehey, E. Berry-Kravis, S. Min, D. A. Hall, C. D. Rice, L. Zhang, J. Grigsby, C. M. Greco, A.Reynolds, R. Lara, B J. Cogswell, S. Jacquemont, D.R. Hessl, F. Tassone, R. Hagerman. Progression of Tremor and Ataxia in Male Carriers of the FMR1 Premutation. Movement Disorders 2007; 22 (2): 203-206 7) M.A Leehey, R.P Munnhoz, A.E. Lang, J.A. Brunberg, J. Grigsby, C. Greco, S. Jacquemont, F. Tassone, A.M Lozano, P. Hagerman, RJ Hagerman. The Fragile X Premutation Presenting as Essential Tremor. Arch Neurol Vol 60, Jan 2003: 117-121 8)J. S. Adams, P. E. Adams, D. Nguyen, J. A. Brunberg, F. Tassone, W. Zhang, K. Koldewyn, S. M. Rivera, J. Grigsby, L. Zhang, C. DeCarli, P. J. Hagerman and R. J. Hagerman Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS) Neurology 2007;69;851-859

18. PIC, IFAE, UAB Genetics: M Mila L Rodriguez A Sanchez Neurology: J Pagonabarraga J Kulissevsky E Muñoz E Tolosa Neuroradiology: B Gómez J Ruscalleda M De Juan F Núñez Collaborators: O Lopez G Llebaria G Monté G Sanchez M Delfino Y Vives Patients and Controls Hospital Clinic/IDIBAPS H Santa Creu i Sant Pau MR technical staff Acknowledgements FIS 07/770