Esther Granell Hospital de la Santa Creu i Sant Pau Barcelona. Spain egranell@santpau.cat

Esther Granell Hospital de la Santa Creu i Sant PauBarcelona. Spainegranell@santpau.cat

NEUROIMAGING IN FXTAS Can we predict conversion of premutation carriers?

BACKGROUNDFragile-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

BACKGROUNDNORMAL<54 CGG

FULL MUTACION >200 CGG

PREMUTATION55-200 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 proteinToxic gain-of-function: inclusion formation and neurological dysfunction

Diagnostic criteriaMajor 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

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

METHODS Prospective, cross-sectional study of 44 subjects (30 premutationcarriers 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

MRI findings in FXTAS patients included:

Middle cerebellar peduncle, brainstem, and cerebral white matter hyperintensities

Cerebellar, brainstem and brain atrophy

RESULTS

brain atrophy location MTL a. brainstem a. HI cerebellar a. MCP HI WM HIpremutated ++ 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 + - - - / + / -

premutated + F,P - - + + + 2 dots

premutated + Global F,P,T + - + + Slight 1 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 - ++ + +++ ++ -

brain atrophy location MTL a. brainstem a. HI cerebellar a. MCP HI WM HIpremutated ++ 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 + - - - / + / -

premutated + F,P - - + + + 2 dots

premutated + Global F,P,T + - + + Slight 1 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 - ++ + +++ ++ -

RESULTS 11 patients fulfilled FXTAS-criteria (women and men), 2 women having dementia:

1a 1b 1c

2a 2b 2c

These 2 women having FXTAS and dementia showed predominant frontal and temporal lobe atrophy, and white matter hyperintensities

RESULTS-Cortical thickness There was selective decrease in cortical thickness in frontal and

temporal regions, already present in the premutation state

FXTAS-Elder Pre Elder Pre-Elder ControlYoung Pre-Young Control

Young pre-Young con Elder Pre–Elder con

FXTAS-Elder Pre

LH

Rostralmiddlefrontal 0.00095 0.00027 0.00269

Superiorfrontal 0.00812 0.00046 7.24 × 10-5

Precentral 0.0033 0.0025 0.007

Lateraloccipital 0.0014 0.0027 0.023

Parahippocampal 0.0014 0.0011 0.01

Anteriorcingulate 0.00095 0.0063

Posteriorcingulate 0.00079 0.00085

RH

Superiorfrontal 0.00047 0.00028

Caudalmiddlefrontal 0.0004 0.0079

Inferiorparietal 0.00229

Insula 0.0097 0.0058 0.0097

Anteriorcingulate 0.0032 0.00070 0.0044

Posteriorcingulate 9.7 × 10-6 0.005

Parahippocampal 0.0089

RESULTS-Cortical thickness

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 control FXTAS-Elder pre D FXTAS-non D FXTAS

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

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

REFERENCES I1) 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

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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

REFERENCES II5)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

PIC, IFAE, UAB

• Genetics:M MilaL RodriguezA Sanchez

• Neurology:J PagonabarragaJ KulissevskyE MuñozE Tolosa

• Neuroradiology:B GómezJ RuscalledaM De JuanF Núñez

• Collaborators:

O LopezG LlebariaG MontéG Sanchez M DelfinoY Vives

• Patients and Controls• Hospital Clinic/IDIBAPS• H Santa Creu i Sant Pau

• MR technical staff

Acknowledgements

FIS 07/770