Funding: NIDCF UL1 DE019583, NIA RL1 AG032119, NINDS RL1 NS062412, NIDA TL1 DA
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1 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 DA th International Fragile X Conference, Miami 2012 July 26, 2012
2 Talk Overview 1. Neurocognitive phenotype in fragile X premutation carriers (fxpcs) 2. Deformation based morphometry analysis 3. Implications and future plans
3 FMR1 Gene Variation Normal < 45 CGG Repeats Premutation CGG Repeats Full Mutation > 200 CGG Repeats FMR1 gene mrna FMRP Clinical Normal Fragile X-associated tremor ataxia syndrome (FXTAS) Fragile X syndrome
4 Psychomotor Speed Adult Males Male and female HCs replicate published population values, as do male fxpcs 1 Median RT (in ms) ± S.E Manual Motor Oral Motor HC (n = 17) fxpc (n = 16) Adult female fxpcs show faster psychomotor speed compared to HCs 2 Median RT (in ms) ± S.E Manual Motor Adult Females * Oral Motor HC (n = 21) fxpc (n = 40) * 1 Wong et al. Under Review, 2 Goodrich-Hunsaker et al. J Int Neuropsychol Soc 2001:1-5
5 Median RT / Oral Motor RT ± S.E. Percent Error ± S.E. 1 Wong et al. Under Review, 2 Goodrich-Hunsaker et al. Front Hum Neurosci 2011;5:63, 3 Goodrich-Hunsaker et al. Brain Cogn 2011;75: Numerical Spatial Attention Male fxpcs impaired compared to male HCs 1 No difference between female fxpcs and HCs 2 We see similar results on a magnitude 1,3 comparison task! Adult Males* Adult Females 7 HC fxpc 100% 6 HC fxpc 100% % 60% 40% 20% Median RT / Oral Motor RT ± S.E % 60% 40% 20% Percent Error ± S.E Numerosity 0% Numerosity 0%
6 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
7 Brain Features MRI studies have shown in older male fxpcs T2 hyperintensities in the middle cerebellar peduncle 1 Reduced volume in amygdala-hippocampal complex, thalamus, caudate, insula, cerebellum, and brainstem 2,3 White matter abnormalities in the middle cerebellar peduncle, superior cerebellar peduncle, and fornix / stria terminalis 4 Female fxpcs with FXTAS demonstrate milder brain changes than affected male fxpcs 5,6 Intranuclear inclusions are found throughout the CNS in neurons and glial cells: cortex, basal ganglia, thalamus, hippocampus, and cerebellum 7,8 1 Leehey J Investig Med 2009;57:830-6, 2 Moore et al. Brain 2004;127: , 3 Hashimoto et al. Brain 2011;134:863-78, 4 Hashimoto et al. Mov Disord 2001;26: , 5 Murphy et al. J Am Acad Child Adolesc Psychiatry 1999;38: , 6 Adams et al. Neurology :851-9, 7 Greco et al. Brain 2006;129:243-55, 8 Tassone et al. J Med Genet 2004;41:e43
8 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 ( ANTs ( VBM toolbox SPM8 (
9 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
10 Jacobian Calculation Shown is the log of Jacobian matrix from a participant image with respect to template Volume decrease Volume increase
11 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
12 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
13 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 FXTAS 1,2 No significant clusters for volume enlargement in male fxpcs compared to HCs 1 Moore et al. Brain 2004;127: , 2 Hashimoto et al. Brain 2011;134:863-78
14 Male fxpcs compared to Female fxpcs Showed significant regional volume reduction in: Cerebellar lobule VIIb Middle cerebellar peduncle Orbital part of frontal lobe Middle temporal gyrus Inferior parietal lobule Superior longitudinal fasciculus Thalamus No significant clusters for volume enlargement in male fxpcs compared to female fxpcs
15 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
16 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)
17 Thanks Thanks to all those that participated in our study CABIL Lab members: Bella McLennan Ling Wong Flora Tassone Danielle Harvey Collaborators: Johnson GadElkarim Liang Zhan Olusola Ajilore Alex Leow Thanks to: Susan Rivera Paul Hagerman Randi Hagerman John Olichney The rest of the NTRI team Funding: NIDCF UL1 DE019583, NIA RL1 AG032119, NINDS RL1 NS062412, NIDA TL1 DA
18 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 DA th International Fragile X Conference, Miami 2012 July 26, 2012
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