The Effect of Cognitive Functioning,
Age, and Molecular Variables on
Brain Structure Among Carriers of the
Fragile X Premutation: Deformation
Based Morphometry Study
Naomi J. Goodrich-Hunsaker*, Ling M. Wong,
Yingratana McLennan, Flora Tassone, Danielle
Harvey, Johnson GadElkarim, Liang Zhan, Olusola
Ajilore, Alex Leow, Susan M. Rivera, Tony J. Simon
Funding: NIDCF UL1 DE019583, NIA RL1 AG032119, NINDS RL1
NS062412, NIDA TL1 DA024854.
13th International Fragile X Conference, Miami 2012
July 26, 2012
Talk Overview
1. Neurocognitive phenotype in fragile X
premutation carriers (fXPCs)
2. Deformation based morphometry analysis
3. Implications and future plans
FMR1 Gene Variation
Normal
< 45 CGG Repeats
Premutation
55 - 200 CGG Repeats
Full Mutation
> 200 CGG Repeats
Normal
Fragile X-associated tremor
ataxia syndrome (FXTAS)
Fragile X syndrome
FMR1 gene
mRNA
FMRP
Clinical
Psychomotor Speed
Adult
Males
Male Adult
‣
Male and female HCs
replicate published
population values, as do
male fXPCs1
Median RT (in ms) ± S.E.
Manual Motor
300
500
200
400
100
300
1
Adult female fXPCs show
faster psychomotor speed
compared to HCs2
HC (n = 17)
fXPC (n = 16)
Adult
Females
Female
Adult
Manual Motor
300
Median RT (in ms) ± S.E.
‣
Oral Motor
*
Oral Motor
500
*
200
400
100
300
Wong et al. Under Review, 2Goodrich-Hunsaker et al. J Int Neuropsychol Soc 2001:1-5
HC (n = 21)
fXPC (n = 40)
1
Wong et al. Under Review, 2Goodrich-Hunsaker et al. Front Hum Neurosci 2011;5:63, 3Goodrich-Hunsaker et al. Brain Cogn 2011;75:255-60
Numerical Spatial Attention
‣
‣
‣
Male fXPCs impaired compared to male HCs1
No difference between female fXPCs and HCs2
We see similar results on a magnitude1,3
comparison task!
Adult Males*
fXPC
6
100%
80%
4
40%
3
20%
2
1
1
2
3
4
5
Numerosity
6
7
8
0%
fXPC
100%
5
80%
4
60%
3
40%
2
20%
1
1
2
3
4
5
Numerosity
6
7
8
0%
Percent Error ± S.E.
60%
Percent Error ± S.E.
5
HC
6
Median RT / Oral Motor RT ± S.E.
HC
7
Median RT / Oral Motor RT ± S.E.
Adult Females
Aim of the Current Study
‣
We wanted to investigate structural brain deformation in
the same unaffected male and female fXPCs
‣
‣
Results might provide a bases for the aforementioned
cognitive impairments and/or be a biomarker for later
neurodegeneration
We also examined the possibility that genetic “dosage” (e.g.
CGG repeat length, FMR1 mRNA levels) might modulate
brain changes
Brain Features
‣
1
MRI studies have shown in older male fXPCs
‣
‣
T2 hyperintensities in the middle cerebellar peduncle1
‣
White matter abnormalities in the middle cerebellar
peduncle, superior cerebellar peduncle, and fornix / stria
terminalis4
Reduced volume in amygdala-hippocampal complex,
thalamus, caudate, insula, cerebellum, and brainstem2,3
‣
Female fXPCs with FXTAS demonstrate milder brain
changes than affected male fXPCs5,6
‣
Intranuclear inclusions are found throughout the CNS in
neurons and glial cells: cortex, basal ganglia, thalamus,
hippocampus, and cerebellum7,8
Leehey J Investig Med 2009;57:830-6, 2Moore et al. Brain 2004;127:2672-81, 3Hashimoto et al. Brain 2011;134:863-78, 4Hashimoto et al. Mov Disord
2001;26:1329-36, 5Murphy et al. J Am Acad Child Adolesc Psychiatry 1999;38:1294-301, 6Adams et al. Neurology 2007 28:851-9, 7Greco et al. Brain
2006;129:243-55, 8Tassone et al. J Med Genet 2004;41:e43
Study Design
‣
Participants included 102 adults (aged 18 - 45)
‣
‣
‣
48 HCs (24 males, 24 females)
34 female fXPCs
20 male fXPCs
‣
3T MRI using a Siemens Trio 3T scanner at the UCDIRC
‣
DBM analysis consisted of preprocessing, spatial
normalization, and Jacobian calculation
‣
‣
‣
ART acpcdetect (http://www.nitrc.org/projects/art/)
ANTs (http://www.picsl.upenn.edu/ANTS/)
VBM toolbox SPM8 (http://dbm.neuro.uni-jena.de/vbm/)
Deformation Based Morphometry
‣
Sensitive technique for investigating anatomical variations in
brain shape, because it provides an unbiased voxel-wise
comparison across the entire brain
Moving: Participant
Fixed: Template
Non-linear
Moving to Fixed
Jacobian Calculation
‣
Shown is the log of
Jacobian matrix from a
participant image with
respect to template
Volume decrease
Volume increase
Statistical Analyses
‣
Using SPM8, performed ANCOVA with age as covariate on
smoothed (4-mm Gaussian kernel) log Jacobian maps
‣
We report clusters exceed threshold of 100 voxels & FDRcorrected cluster level p < 0.05
‣
Contrasts:
‣
‣
‣
‣
Female fXPCs versus HCs
Male fXPCs versus HCs
Male fXPCs versus female fXPCs
Correlated the mean log Jacobian with:
‣
‣
‣
Age, IQ, CGG repeat length, FMR1 mRNA levels
Basic psychomotor speed performance
Enumeration & magnitude comparison task performance
Female fXPCs compared to HCs
‣
‣
Showed significant regional
volume enlargement in:
‣
Supplementary motor,
precentral & postcentral
gyrus
‣
‣
‣
Orbital part of frontal lobe
Anterior cingulate gyrus
Frontal lobe white matter
regions (e.g. anterior corona
radiata, superior longitudinal
fasciculus)
No significant clusters for
volume reduction in female
fXPCs compared to HCs
Male fXPCs compared to HCs
‣
Showed significant regional
volume reduction in:
‣
‣
‣
Cerebellar lobule VIIb
Middle cerebellar peduncle
Similar findings reported in
older male carriers with and
without FXTAS1,2
‣
1
No significant clusters for
volume enlargement in male
fXPCs compared to HCs
Moore et al. Brain 2004;127:2672-81, 2Hashimoto et al. Brain 2011;134:863-78
Male fXPCs compared to Female fXPCs
‣
Showed significant regional
volume reduction in:
‣
‣
‣
‣
‣
‣
Cerebellar lobule VIIb
‣
Thalamus
Middle cerebellar peduncle
Orbital part of frontal lobe
Middle temporal gyrus
Inferior parietal lobule
Superior longitudinal
fasciculus
‣
No significant clusters for
volume enlargement in male
fXPCs compared to female
fXPCs
Summary of Results
‣
Female and male fXPCs showed significant morphometric changes in OFC, ACC,
and thalamus, which are part of the network for decision-making and
emotional processing
‣
Relevant to clinical features of anxiety in female fXPCs and/or to the
psychiatric symptoms of FXTAS like disinhibition, obsessive-compulsiveness,
apathy
‣
Female fXPCs compared to HCs had enlarged volumes in sensory and motor
cortical areas, which may underlie enhanced basic psychomotor speed in
female fXPCs
‣
Male fXPCs compared to HCs and female fXPCs had reduced cerebellum and
MCP volume, regions implicated in the symptomology of FXTAS ‣
Male fXPCs compared to female fXPCs also showed reduced volume in IPL, a
region involved in processing cognitive domains like space, time, and number ‣
‣
Recall these same male fXPCs, but not female fXPCs were impaired on an
enumeration task & a magnitude comparison task
Correlation analyses revealed no significant associations
Implications & Future Plans
‣
First study to demonstrate brain deformation differences in
young adult male and female fXPCs using deformationbased morphometry
‣
Longitudinal studies needed to determine…
‣
Whether the morphological brain changes are present in
children with premutation allele (i.e., stable phenotype) ‣
Whether these anatomical variations relate to risk of
neurodegeneration (i.e., biomarker)
Thanks
‣
Thanks to all those that
participated in our study
‣
CABIL Lab members:
‣
‣
‣
‣
‣
Bella McLennan Ling Wong
Flora Tassone
‣
Thanks to: ‣
‣
‣
‣
‣
Susan Rivera
Paul Hagerman
Randi Hagerman
John Olichney
The rest of the NTRI
team
Danielle Harvey
Collaborators:
‣
‣
‣
‣
Johnson GadElkarim
Liang Zhan
Olusola Ajilore
Alex Leow
Funding: NIDCF UL1 DE019583, NIA
RL1 AG032119, NINDS RL1
NS062412, NIDA TL1 DA024854.
The Effect of Cognitive Functioning,
Age, and Molecular Variables on
Brain Structure Among Carriers of the
Fragile X Premutation: Deformation
Based Morphometry Study
Naomi J. Goodrich-Hunsaker*, Ling M. Wong,
Yingratana McLennan, Flora Tassone, Danielle
Harvey, Johnson GadElkarim, Liang Zhan, Olusola
Ajilore, Alex Leow, Susan M. Rivera, Tony J. Simon
Funding: NIDCF UL1 DE019583, NIA RL1 AG032119, NINDS RL1
NS062412, NIDA TL1 DA024854.
13th International Fragile X Conference, Miami 2012
July 26, 2012