slide1 n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Esther Granell Hospital de la Santa Creu i Sant Pau Barcelona. Spain egranell@santpau.cat PowerPoint Presentation
Download Presentation
Esther Granell Hospital de la Santa Creu i Sant Pau Barcelona. Spain egranell@santpau.cat

Loading in 2 Seconds...

play fullscreen
1 / 18

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


  • 174 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Esther Granell Hospital de la Santa Creu i Sant Pau Barcelona. Spain egranell@santpau.cat' - koto


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

NEUROIMAGING IN FXTAS

Can we predict conversion of premutation carriers?

Esther Granell

Hospital de la Santa Creu i Sant Pau

Barcelona. Spain

egranell@santpau.cat

background
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

background1
BACKGROUND

FMR1 gene RNAm translation FMR1protein

NORMAL

<54 CGG

Fragile X Syndrome (FXS)

FMR1 gene RNAm absent protein

(methylation) (no transcription)

FULL MUTACION

>200 CGG

Fragile X Tremor Ataxia Syndrome (FXTAS)

FMR1 gene excess RNAm normal or low protein

Toxic gain-of-function: inclusion formation and neurological dysfunction

PREMUTATION

55-200 CGG

diagnostic criteria

“Definitive” disease:

1 major radiological + 1major clinical

“Probable”disease:

1 major radiological + 1minor or

2 major clinical

“Possible disease”:

1 minor + 1 major radiological

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

purpose
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
METHODS

Prospective, cross-sectionalstudy of 44 subjects (30 premutation

carriers and 14 controls),aged 33-80, matched for age and sex

  • 3T (Philips Intera 2.1) MRI included3D FLAIR and 3D-T1

MPRAGE. Conventional, previouslydescribed MRI findingswere

assessedbytwoexperiencedneuroradiologists

  • Neurological and neuropsychologicalevaluations:executive, memory, attention, global intelligence, and conductual
  • Cortical thickness (Freesurfer) and hippocampalvolume (FS) and hippocampalshape (SPHARM) wereanalyzed on 3D MPRAGE imagessearching for potential MR markers
  • Statisticalanalysisincludedgroup-comparisons (Student´st-test and

one-way ANOVA) and a General Lineal Model

slide7

RESULTS

MRI findings in FXTAS patients included:

  • Middle cerebellar peduncle, brainstem, and cerebral white matter hyperintensities
  • Cerebellar, brainstem and brain atrophy
results
RESULTS

1b

1c

1a

11 patients fulfilled FXTAS-criteria (women and men),

2 women having dementia:

2a

2b

2c

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

results cortical thickness
RESULTS-Cortical thickness
  • There was selective decrease in cortical thickness in frontal and temporal regions, already present in the premutation state

Young Pre-Young Control

Elder Pre-Elder Control

FXTAS-Elder Pre

results hippocampal volume and shape
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

results neuropsychology
RESULTS-Neuropsychology

On neuropsychology, therewasevidence of prefrontal and temporal impairment in premutatedpatientsalongthediseaseprocess

  • (FrBSe) Frontal System Behavior Scale: Apathy, dishinibition and executive disfunction in premutated patients:

Premutatedvs 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 vsPremutated (p=0.042)

Delayed AVLT: D FXTAS vs non-D FXTAS (p=0.074)

conclusion
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 i
REFERENCES I

1)Jacquemont, S, et al.Fragile X Premutation Tremor/AtaxiaSyndrome: Molecular, Clinical, and NeuroimagingCorrelates. Am. J. Hum. Genet. 72:869–878, 2003

2) Rodriguez-Revenga L, et al. Motor and mental dysfunction in mother-daughtertransmittedFXTAS. 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

references ii
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

slide18

Acknowledgements

  • Collaborators:
  • O Lopez
  • G Llebaria
  • G Monté
  • G Sanchez
  • M Delfino
  • Y Vives
  • Genetics:
  • M Mila
  • L Rodriguez
  • A Sanchez
  • Neuroradiology:
  • B Gómez
  • J Ruscalleda
  • M De Juan
  • F Núñez
  • Patients and Controls
  • Hospital Clinic/IDIBAPS
  • H Santa Creu i Sant Pau
  • Neurology:
  • J Pagonabarraga
  • J Kulissevsky
  • E Muñoz
  • E Tolosa

PIC, IFAE, UAB

  • MR technical staff

FIS 07/770