Fragile X is unique among neurogenetic conditions because it is the only such disorder with a dose-response mechanism based on a single gene (CGG-repeat-dependence of phenotypes). Also, it produces varying outcomes as a result of different pathogenic mechanisms related to FMR1 gene dysregulation - low/absent FMR1 protein (FMRP) in fragile X syndrome;elevated levels of """"""""toxic"""""""" FMR1 RNA. As a result of these characteristics, fragile X provides a unique model for developing a """"""""molecules to mind"""""""" explanation of a neurogenetic disorder that can then be used to generate hypotheses about the genetic bases of disorders with less clear molecular mechanisms. Thus, the overall objective of this component is to understand how variations in the mutation of a single gene (FMR1) produce a spectrum of cognitive dysfunction in both childhood and adulthood. To this end, we will generate the first detailed neurocognitive profile of an integrated set of cognitive domains that preliminary data suggest are highly vulnerable to changes in the expression of FMRP. The profile will consist of data derived from hypothesis-driven experimental cognitive processing tasks and magnetic resonance imaging (MRI) methods that will produce structural, functional and connectivity measures. We will refer to this profile as the FMR1 Sensitive Neurocognitive Profile (FSNP). It will focus on spatiotemporal, memory, numerical, and executive cognitive functions. It will be characterized in children and adults who have the fragile X full mutation and extended to smaller alleles in the premutation range, and to unaffected (normal repeat) controls. In our investigations we will consider the effect of two continuous variables: FMRP expression level and FMR1 mRNA level, and one categorical variable: phase of development (childhood or adulthood). There will be extensive interaction with other components. With Project 1 we will share the neurocognitive specification of phenotypes that will foster understanding of molecular mechanisms and treatment effects and we will be dependent on their molecular and cellular assessments. With Project 2 there will be a bidirectional feed of behavioral and MRI assessments, especially to drive investigations of the """"""""mixed phenotype"""""""" where FMRP and FMR1 RNA changes may interact. Data (and methods) shared between Projects 3 and 4 will extend lifespan analyses, clarify neurochemical mechanisms and neural progressions toward FXTAS, and drive novel MRI analysis method development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Linked Research project Grant (RL1)
Project #
3RL1NS062412-04S1
Application #
8128087
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Riddle, Robert D
Project Start
2007-09-30
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$74,181
Indirect Cost
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Wong, Ling M; Tassone, Flora; Rivera, Susan M et al. (2015) Temporal dynamics of attentional selection in adult male carriers of the fragile X premutation allele and adult controls. Front Hum Neurosci 9:37
Wong, Ling M; Goodrich-Hunsaker, Naomi J; McLennan, Yingratana et al. (2014) Eye movements reveal impaired inhibitory control in adult male fragile X premutation carriers asymptomatic for FXTAS. Neuropsychology 28:571-584
Kim, So-Yeon; Tassone, Flora; Simon, Tony J et al. (2014) Altered neural activity in the 'when' pathway during temporal processing in fragile X premutation carriers. Behav Brain Res 261:240-8
Leow, Alex; Harvey, Danielle; Goodrich-Hunsaker, Naomi J et al. (2014) Altered structural brain connectome in young adult fragile X premutation carriers. Hum Brain Mapp 35:4518-30
Kim, So-Yeon; Hashimoto, Ryu-ichiro; Tassone, Flora et al. (2013) Altered neural activity of magnitude estimation processing in adults with the fragile X premutation. J Psychiatr Res 47:1909-16
Wang, Jun Yi; Hessl, David; Schneider, Andrea et al. (2013) Fragile X-associated tremor/ataxia syndrome: influence of the FMR1 gene on motor fiber tracts in males with normal and premutation alleles. JAMA Neurol 70:1022-9
Wang, Jun Yi; Hagerman, Randi J; Rivera, Susan M (2013) A multimodal imaging analysis of subcortical gray matter in fragile X premutation carriers. Mov Disord 28:1278-84
Seritan, Andreea L; Bourgeois, James A; Schneider, Andrea et al. (2013) Ages of Onset of Mood and Anxiety Disorders in Fragile X Premutation Carriers. Curr Psychiatry Rev 9:65-71
Wang, Jun Yi; Hessl, David; Iwahashi, Christine et al. (2013) Influence of the fragile X mental retardation (FMR1) gene on the brain and working memory in men with normal FMR1 alleles. Neuroimage 65:288-98
Wang, Jun Yi; Hessl, David H; Hagerman, Randi J et al. (2012) Age-dependent structural connectivity effects in fragile x premutation. Arch Neurol 69:482-9

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