Carriers of the fragile X (FMR1) premutation have been shown to exhibit mild cognitive impairments and increased risk for psychiatric problems. Furthermore, they are at risk for developing a neurodegenerative disease, fragile X-associated tremor ataxia syndrome (FXTAS), characterized by neurological manifestations of progressive gait ataxia, intention tremor, Parkinsonism, dementia, autonomic dysfunction, and peripheral neuropathy. Neuropathological features of FXTAS include whole brain atrophy, ventricular enlargement, white matter disease, and neuronal and astrocytic intranuclear inclusion formation and neuropsychiatric symptoms include depression, anxiety, and executive dysfunction. The hypothesized molecular genetic pathogenic mechanism of FXTAS is toxic gain-of-function of FMR1 mRNA. The disease has a variable and age-related penetrance, affecting 75% of male premutation carriers by the eighth decade of life. While the features of FXTAS have been well-described, it is not known why some carriers become affected and others do not, and the variable rate of progression and risk factors associated with disease onset are poorly understood. In the first 5 years of this program of research ("Limbic System Function in Carriers of the Fragile X Premutation"), alongside other collaborative studies at our center, we have demonstrated that abnormal elevation of FMR1 mRNA is associated with reduced hippocampus, amygdala, and frontal lobe function, which in turn are correlated with psychological symptoms and social deficits, impaired memory recall and working memory in male premutation carriers at risk for FXTAS. Our other studies have shown brain white matter deterioration with age, reduced brain stem and increased ventricular volume, and high rates of mood and anxiety disorders in adult carriers without FXTAS compared to controls with normal FMR1 alleles. This work has provided important clues about potential genetic, brain and neuropsychological risk factors for disease progression, however no prospective longitudinal studies have been completed that provide critical data required to identify risk or protective factors for FXTAS. For the current project, we will examine the trajectory of key neuropsychological and neurological factors in adult male carriers of the FMR1 premutation between the ages of 40 and 69, in comparison to male controls without the premutation, using a longitudinal design. We will examine how several FMR1 molecular measures play a role in mediating the rate of progression of these key factors. The results of the study will provide critical information about the early markers of neurodegeneration that will aid in identification o patients most in need of preventive care and treatment as these interventions become available, and it may identify important measures to track response to interventions in the future.

Public Health Relevance

Carriers of the fragile X premutation have some mild cognitive impairment and increased risk for psychiatric problems. Furthermore, they are at increased risk for developing a late-onset neurological disease, Fragile X-Associated Tremor Ataxia Syndrome (FXTAS);however, it is not known why, how, and when some individuals become affected and others do not. This study will follow a group of men with the premutation and healthy controls in a longitudinal study to examine the trajectory of change of the structure and function of the brain and neuropsychological measures in an effort to determine factors explaining the early disease process that will occur in some of these men.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH078041-07
Application #
8649083
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gilotty, Lisa
Project Start
2006-07-01
Project End
2018-03-31
Budget Start
2014-06-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$573,506
Indirect Cost
$195,746
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Loesch, D Z; Bui, M Q; Hammersley, E et al. (2015) Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion. Clin Genet 87:173-8
Polussa, Jonathan; Schneider, Andrea; Hagerman, Randi (2014) Molecular Advances Leading to Treatment Implications for Fragile X Premutation Carriers. Brain Disord Ther 3:
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 28:571-84
Besterman, Aaron D; Wilke, Scott A; Mulligan, Tua-Elisabeth et al. (2014) Towards an Understanding of Neuropsychiatric Manifestations in Fragile X Premutation Carriers. Future Neurol 9:227-239
Lozano, Reymundo; Summers, Scott; Lozano, Cristina et al. (2014) Association between macroorchidism and intelligence in FMR1 premutation carriers. Am J Med Genet A 164A:2206-11
Iosif, Ana-Maria; Sciolla, Andres F; Brahmbhatt, Khyati et al. (2013) Caregiver Burden in Fragile X Families. Curr Psychiatry Rev 9:
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; 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
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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