Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients.

Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion-weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7-22 years; mean, 12 years) and 11 typically developing age-matched participants (age range, 8-23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel-based morphometry, whereas tract-based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral-postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum-localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early-stage white matter motor pathway degeneration within young patients.

Radiological imaging in ataxia telangiectasia: a review.

The human genetic disorder ataxia telangiectasia (A-T) is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition. Progressive cerebellar ataxia represents the most debilitating aspect of this disorder. At present, there is no therapy available to cure or prevent the progressive symptoms of A-T. While it is possible to alleviate some of the symptoms associated with immunodeficiency and deficient lung function, neither the predisposition to cancer nor the progressive neurodegeneration can be prevented. Significant effort has focused on improving our understanding of various clinical, genetic and immunological aspects of A-T; however, little attention has been directed towards identifying altered brain structure and function using MRI. To date, most imaging studies have reported radiological anomalies in A-T. This review outlines the clinical and biological features of A-T along with known radiological imaging anomalies. In addition, we briefly discuss the advent of high-resolution MRI in conjunction with diffusion-weighted imaging, which enables improved investigation of the microstructural tissue environment, giving insight into the loss in integrity of motor networks due to abnormal neurodevelopmental or progressive neurodegenerative processes. Such imaging approaches have yet to be applied in the study of A-T and could provide important new information regarding the relationship between mutation of the ataxia telangiectasia mutated (ATM) gene and the integrity of motor circuitry.

Antimalarial activity of the anticancer histone deacetylase inhibitor SB939.

Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC(50)], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC(50), ~150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study.

BACKGROUND: Our understanding of the effect of ataxia-telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. METHODS: Diffusion MRI were obtained from 12 patients (age range: 7-22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8-23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. RESULTS: Reduced fractional anisotropy along all analyzed patient tracts were observed (p < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. CONCLUSIONS: Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia-telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients.