Gray and white matter alterations in spinocerebellar ataxia type 7: An in vivo DTI and VBM study
Research Highlights
►Differences in gray matter volume between SCA7 patients and controls are presented. ►Differences in fractional anisotropy between SCA7 patients and controls are presented. ►Gray and white matter alterations in SCA7 patients go beyond the cerebellum and pons. ►Brodmann areas 2, 3, 6, 9, 13, 40 and the Claustrum are affected in SCA7 patients, previously unreported.
Introduction
Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disease. It is clinically characterized by ataxia, pyramidal syndrome and progressive macular dystrophy. It is the only type of spinocerebellar ataxia that manifests itself in progressive and irrevocable blindness (Paulson, 2009, Miller et al., 2009, Michalik et al., 2004).
SCA7 is caused by an abnormal repetition of the CAG trinucleotide in chromosome 3 (locus 3p12-p21.1), which recently led to the definition of a new gene, ataxin-7 (Garden and La Spada, 2008). Initial studies found that more than 36 CAG repetitions in the ataxin7 gene produce the SCA7 phenotype, while healthy subjects could have between 4 and 35. Additionally, there is a significant correlation between the amount of trinucleotide repetitions and the age at which the patients start showing the phenotype (David et al., 1998, Garden and La Spada, 2008, Johansson et al., 1998). It has also been described a correlation between the amount of repetitions and the clinical presentation of the disease; patients with up to 59 repetitions present the cerebellar symptoms first and those with higher than 59 repetitions typically present visual symptoms first (Johansson et al., 1998).
As mentioned earlier, SCA 7 patients develop blindness, which is the result of the degeneration of the photoreceptive cells, both cone and rod. The patients present diminished visual acuteness, achromatopsia and photosensitivity, followed by a progressive loss of peripheral vision and ending in blindness. The ophthalmological evaluations may show normal appearance of the macula at the beginning of the disease; nonetheless macular degeneration is progressively evident together with the degeneration of the photoreceptive cells. These become apparent through multifocal or full field electroretinograms depending on the stage of the disease (Manrique et al., 2009, Thurtell et al., 2009).
Most of what is known about the neural degeneration in SCA7 comes from postmortem neuropathological studies. Major atrophy has been reported in the cerebellum and the inferior olivary complex, including the cerebellar cortex and the spinocerebellar and olivocerebellar tracts (Enevoldson et al., 1994, Gouw et al., 1994, Martin et al., 1994). Degeneration has also been observed in the subthalamic nucleus, pallidum and the substantia nigra as well as the dorsal columns (Enevoldson et al., 1994, Martin et al., 1994).
Neuroimaging studies, mostly consisting of conventional magnetic resonance imaging, reveal a marked atrophy in the cerebellum and pons (Döhlinger et al., 2008). A previous MRI based study on the brainstem area showed atrophy in the cerebellum and pons, as well as degeneration in the transverse pontine fibers (Bang et al., 2003). A subsequent report by the same group used a semiautomatic process based on the area measurement of regions of interest in cerebellum and spine, normalized by the total area of the posterior fossa on the midsagittal plane, finding cerebellar atrophy as well as a large pontine atrophy compared to other SCAs (Bang et al., 2004).
Recent advances in neuroimaging, especially in magnetic resonance imaging, allow not only the acquisition of structural images in a millimetric resolution, but also of images that reflect the tissue microstructure through the measurement of water diffusion properties. The technique of voxel based morphometry (VBM) is a voxelwise analysis tool that is sensitive to the morphological differences of the gray matter and therefore, to changes in cortical density and volume due to the neurodegenerative processes (Ashburner and Friston, 2000, Good et al., 2001), including spinocerebellar ataxias type 1, 2, 3 and 6 (Brenneis et al., 2003, Lukas et al., 2006, Schulz et al., 2010). At the same time, images obtained through Diffusion Tensor Imaging (DTI) can be evaluated with a technique that quantifies the diffusion of water in the brain tissue, mostly in the white matter, where axonal membranes and myelin of the nervous tracts determine their diffusion properties through fractional anisotropy (FA) (Basser et al., 1994, Basser, 1995). Lower FA values could be the result of a decrement in axonal coherence, an axonal or myelin degeneration, axonal diameter reduction or glial cell genesis, all of which would reduce high orientated diffusion barriers turning the tissue into an isotropic medium (Beaulieu, 2002). For example, patterns of fractional anisotropy changes in white matter of cerebellar peduncles distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia syndromes (Prakash et al., 2009). Tract-based spatial statistics (TBSS) is a voxelwise analysis tool that aims to improve the sensitivity, objectivity and interpretability of analysis of multi-subject diffusion imaging studies (Smith et al., 2006).
Here we report changes across the brain found after comparing a group of SCA7 patients with a matched healthy control group using both VBM and DTI-TBSS. Results confirm earlier findings on cerebellar and pons degeneration, and show significant atrophy in previously undetected areas.
Section snippets
Subjects
Nine patients with a molecular diagnosis of Spinocerebellar Ataxia type 7 participated in this study (7 women, 2 men; 41.11 ± 16.18 years, ranging from 18 to 69 years old). The CAG repetition mean was 47.11 ± 4.08, ranging from 41 to 53. Nine control volunteers (7 women, 2 men; 41.22 ± 15.59 years, ranging from 19 to 65 years old) without any neurological or psychiatric affection participated as a control group. All participants gave their informed consent before entering the study. The research
Results
We used VBM on high resolution T1 weighted 3D images of the whole brain and cerebellum to compare gray matter volume between 9 SCA7 patients versus 9 matched controls. The regions with significant less gray matter volume (p < 0.05, corrected) in the patient group vs. the control group are summarized in Fig. 1, Fig. 2, while a complete list of all the areas with significant differences can be found in Table 1, where the coordinates of the local maximum of the 1-p value are shown for each voxels
Discussion
In this study we used two in vivo magnetic resonance imaging techniques to make a comprehensive analysis of gray and white matter changes occurring in SCA7 patients. Regarding gray matter, the results showed major changes in cerebellum, similar to those previously reported with both postmortem neuropathological brain tissue analysis, and earlier in vivo MRI technique (Enevoldson et al., 1994, Döhlinger et al., 2008). The analysis was also capable of detecting changes previously found only
Conclusions
In this article we present in vivo evidence of the structural changes that occur in gray and white matter in the brain and cerebellum of SCA7 patients that go beyond the reduction of cerebellar and pons volume as previously reported. These findings that identify SCA7 affected regions that previous methods could not detect can contribute to the better understanding of the symptomatology presented by patients in different stages of the disease.
Role of funding sources
This work was supported by the Doctoral Program in Biomedical Sciences at the Universidad Nacional Autónoma de México and a doctoral scholarship 206020 from the Consejo Nacional de Ciencia y Tecnología to S.A. and the Consejo Nacional de Ciencia y Tecnologia grant 102314 to J.F.R., and PAPIIT-DGAPA grant IN202810 to J.F.R.
The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the
Acknowledgments
We are grateful to the patients and their families for volunteering for this study with the only incentive being the advancement of the knowledge on this disease that affects them so profoundly.
We are grateful to Mr. Leopoldo Gonzalez-Santos and Mr. Juan José Ortiz for their technical support and systems administration.
References (44)
- et al.
Voxel-based morphometry—the methods
Neuroimage
(2000) - et al.
MR diffusion tensor spectroscopy and imaging
Biophys. J.
(1994) - et al.
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
Cell
(1997) - et al.
A voxel-based morphometric study of ageing in 465 normal adult human brains
Neuroimage
(2001) - et al.
Combining voxel intensity and cluster extent with permutation test framework
Neuroimage
(2004) - et al.
A global optimisation method for robust affine registration of brain images
Med. Image Anal.
(2001) - et al.
Improved optimization for the robust and accurate linear registration and motion correction of brain images
Neuroimage
(2002) - et al.
Dissociation of gray and white matter reduction in spinocerebellar ataxia type 3 and 6: a voxel-based morphometry study
Neurosci. Lett.
(2006) - et al.
Patterns of fractional anisotropy changes in white matter of cerebellar peduncles distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia syndromes
Neuroimage
(2009) - et al.
Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6
Neuroimage
(2010)
Advances in functional and structural MR image analysis and implementation as FSL
Neuroimage
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
Neuroimage
Current advances in lesion–symptom mapping of the human cerebellum
Neuroscience
Clinical and neuroradiological features of patients with spinocerebellar ataxias from Korean kindreds
Arch. Neurol.
Pontine atrophy precedes cerebellar degeneration in spinocerebellar ataxia 7: MRI-based volumetric analysis
J. Neurol. Neurosurg. Psychiatr.
Inferring microstructural features and the physiological state of tissues from diffusion-weighted images
NMR Biomed.
The basis of anisotropic water diffusion in the nervous system — a technical review
NMR Biomed.
Atrophy pattern in SCA2 determined by voxel-based morphometry
NeuroReport
Distribution of ataxin-7 in normal human brain and retina
Brain
Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7)
Hum. Mol. Genet.
Magnetic resonance imaging in spinocerebellar ataxias
Cerebellum
Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy: a clinical and genetic study of eight families
Brain
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