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.

Ventricular enlargement (VE) is commonly observed in aging and fragile X-associated tremor/ ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. VE may generate a mechanical force causing structural deformation. In this longitudinal study, we examined the relationships between VE and structural changes in the corpus callosum (CC) and putamen. MRI scans (2-7/person over 0.2-7.5 years) were acquired from 22 healthy controls, 26 unaffected premutation carriers (PFX−), and 39 carriers affected with FXTAS (PFX+). Compared with controls, PFX− demonstrated enlarged fourth ventricles whereas PFX+ displayed enlargement in both third and fourth ventricles, CC thinning, putamen atrophy/deformation (thinning and increased distance), and accelerated expansions in lateral ventricles. Common for all groups, baseline VE predicted accelerated CC thinning and putamen atrophy/deformation and conversely, baseline CC and putamen atrophy/deformation and enlarged third and fourth ventricles predicted accelerated lateral ventricular expansion. The results suggest a progressive VE within the four