Age-Dependent Structural Connectivity Effects in Fragile X Premutation

Abstract

Setting: Institutional practice.Patients: Fifteen younger (18-45 years old) carriers, 11 older (Ͼ45 years old) unaffected carriers, and 15 older carriers with fragile X-associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level.Main Outcome Measures: Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter.Results: In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, un-affected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum. Conclusions:The findings revealed widespread alterations in structural connectivity associated with fragile X-associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder.Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement.

Reduced Sensorimotor, Working Memory, and Episodic Memory Abilities in Aging Female FMR1 Premutation Carriers with and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

“…For example, it is possible that white matter degeneration may disrupt both movement speed and speed of information processing, but the extent to which these separate abilities are impacted in different individuals may vary as a function of localization or disease stage. This hypothesis is consistent with the well-documented white matter degeneration in males and females with FXTAS [ 6 , 37 , 38 ], including quantitative studies of white matter microstructural integrity [ 39 , 40 ]. These findings are also consistent with studies demonstrating that parkinsonian motor symptoms, including bradykinesia, are common in FXTAS, and suggest that tracking movement and cognitive slowing may be important for tracking FXTAS onset or progression in female premutation carriers [ 1 , 2 ].…”

Reduced Sensorimotor, Working Memory, and Episodic Memory Abilities in Aging Female FMR1 Premutation Carriers with and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

“…For example, it is possible that white matter degeneration may disrupt both movement speed and speed of information processing, but the extent to which these separate abilities are impacted in different individuals may vary as a function of localization or disease stage. This hypothesis is consistent with the well-documented white matter degeneration in males and females with FXTAS [ 6 , 37 , 38 ], including quantitative studies of white matter microstructural integrity [ 39 , 40 ]. These findings are also consistent with studies demonstrating that parkinsonian motor symptoms, including bradykinesia, are common in FXTAS, and suggest that tracking movement and cognitive slowing may be important for tracking FXTAS onset or progression in female premutation carriers [ 1 , 2 ].…”

Altered structural brain connectome in young adult fragile X premutation carriers

“…Lower local clustering coefficient (the degree to which neighboring nodes are interconnected) in the left hippocampus in male fXPCs relative to controls is consistent with the affective and cognitive differences that they manifest. While the translational implications of the directionality of this finding needs to be further studied in a future sample, such an involvement is consistent with several recent studies investigating a range of cognitive functions, including spatial processing, (MacLeod et al, 2010; Hocking et al, 2012; Wong et al, 2012) that have been theorized to be associated with hippocampus (Koldewyn et al, 2008; Wang et al, 2012) and with its role in affective processing by the limbic system (Jacquemont et al, 2004, Hessl et al, 2007). …”

Cerebellar volume mediates the relationship between FMR1 mRNA levels and voluntary step initiation in males with the premutation

“…The current findings revealed preliminary evidence that smaller cerebellar volume was a significant predictor of prolonged stepping times during single and dual-task conditions in PM males. These results are consistent with imaging evidence of structural alterations of the cerebellum in PM males with and without FXTAS [9][10][11]. There is growing evidence that the cerebellum, through its inflow and outflow tracts, is involved in integrating multiple sources of sensory information within extensive motor-and cognitive-related regions [20,21].…”

Reduced Sensorimotor, Working Memory, and Episodic Memory Abilities in Aging Female FMR1 Premutation Carriers with and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

“…For example, it is possible that white matter degeneration may disrupt both movement speed and speed of information processing, but the extent to which these separate abilities are impacted in different individuals may vary as a function of localization or disease stage. This hypothesis is consistent with the well-documented white matter degeneration in males and females with FXTAS [ 6 , 37 , 38 ], including quantitative studies of white matter microstructural integrity [ 39 , 40 ]. These findings are also consistent with studies demonstrating that parkinsonian motor symptoms, including bradykinesia, are common in FXTAS, and suggest that tracking movement and cognitive slowing may be important for tracking FXTAS onset or progression in female premutation carriers [ 1 , 2 ].…”

Altered structural brain connectome in young adult fragile X premutation carriers

“…Lower local clustering coefficient (the degree to which neighboring nodes are interconnected) in the left hippocampus in male fXPCs relative to controls is consistent with the affective and cognitive differences that they manifest. While the translational implications of the directionality of this finding needs to be further studied in a future sample, such an involvement is consistent with several recent studies investigating a range of cognitive functions, including spatial processing, (MacLeod et al, 2010; Hocking et al, 2012; Wong et al, 2012) that have been theorized to be associated with hippocampus (Koldewyn et al, 2008; Wang et al, 2012) and with its role in affective processing by the limbic system (Jacquemont et al, 2004, Hessl et al, 2007). …”

Cerebellar volume mediates the relationship between FMR1 mRNA levels and voluntary step initiation in males with the premutation

“…The current findings revealed preliminary evidence that smaller cerebellar volume was a significant predictor of prolonged stepping times during single and dual-task conditions in PM males. These results are consistent with imaging evidence of structural alterations of the cerebellum in PM males with and without FXTAS [9][10][11]. There is growing evidence that the cerebellum, through its inflow and outflow tracts, is involved in integrating multiple sources of sensory information within extensive motor-and cognitive-related regions [20,21].…”

Reduced Sensorimotor, Working Memory, and Episodic Memory Abilities in Aging Female FMR1 Premutation Carriers with and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

“…For example, it is possible that white matter degeneration may disrupt both movement speed and speed of information processing, but the extent to which these separate abilities are impacted in different individuals may vary as a function of localization or disease stage. This hypothesis is consistent with the well-documented white matter degeneration in males and females with FXTAS [ 6 , 37 , 38 ], including quantitative studies of white matter microstructural integrity [ 39 , 40 ]. These findings are also consistent with studies demonstrating that parkinsonian motor symptoms, including bradykinesia, are common in FXTAS, and suggest that tracking movement and cognitive slowing may be important for tracking FXTAS onset or progression in female premutation carriers [ 1 , 2 ].…”

Altered structural brain connectome in young adult fragile X premutation carriers

“…Lower local clustering coefficient (the degree to which neighboring nodes are interconnected) in the left hippocampus in male fXPCs relative to controls is consistent with the affective and cognitive differences that they manifest. While the translational implications of the directionality of this finding needs to be further studied in a future sample, such an involvement is consistent with several recent studies investigating a range of cognitive functions, including spatial processing, (MacLeod et al, 2010; Hocking et al, 2012; Wong et al, 2012) that have been theorized to be associated with hippocampus (Koldewyn et al, 2008; Wang et al, 2012) and with its role in affective processing by the limbic system (Jacquemont et al, 2004, Hessl et al, 2007). …”

Cerebellar volume mediates the relationship between FMR1 mRNA levels and voluntary step initiation in males with the premutation

“…The current findings revealed preliminary evidence that smaller cerebellar volume was a significant predictor of prolonged stepping times during single and dual-task conditions in PM males. These results are consistent with imaging evidence of structural alterations of the cerebellum in PM males with and without FXTAS [9][10][11]. There is growing evidence that the cerebellum, through its inflow and outflow tracts, is involved in integrating multiple sources of sensory information within extensive motor-and cognitive-related regions [20,21].…”