Widespread neuronal damage and cognitive dysfunction in spinocerebellar ataxia type 3

Abstract

Previous studies demonstrated cognitive impairments in spinocerebellar ataxia type 3 (SCA3/MJD); however, there is no consensus about the cognitive domains affected and the correlation with structural brain abnormalities. We investigated the neuropsychological profile and 3T-MRI findings, including high-resolution T1-images, diffusion tensor imaging and magnetic resonance spectroscopy of 32 patients with SCA3/MJD and 32 age-, gender- and educational level-matched healthy controls. We reviewed patients' clinical history and CAG repeat length, and performed assessment and rating of ataxia (SARA)-Brazilian version and the neuropsychiatric inventory. Patients presented worse performance in episodic and working memory and Beck inventories (depression and anxiety). SCA3/MJD patients had a reduction of gray matter volume (GM) in the cerebellum, putamen, cingulum, precentral and parietal lobe. A positive correlation was identified between the cognitive findings and GM of temporal, frontal, parietal, culmen and insula. We observed positive correlation between the brainstem's fractional anisotropy and digit span-forward. The following cerebellar metabolite groups (measured relative to creatine) were reduced in patients: N-acetyl-aspartate (NAA), NAA + N-acetyl-aspartate-glutamate and glutamate + glutamine (Glx). We found a positive correlation between Corsi's block-tapping task forward with Glx; semantic verbal fluency with phosphorylcholine and glycerophosphorylcholine; digits span-forward with NAA. The cognitive impairments in SCA3/MJD are associated not only with cerebellar and brainstem abnormalities, but also with neuroimaging evidence of diffuse neuronal and axonal dysfunction, particularly in temporal, frontal, parietal and insular areas.

Spinal Cord Damage in Machado-Joseph Disease

“…Pathological studies revealed severe neuronal loss predominantly in the cerebellum, brainstem, and basal ganglia [5]. This is indeed confirmed by recent quantitative neuroimaging data [6][7][8][9]. Damage to these regions accounts for the main clinical features in the disease, such as ataxia and movement disorders.…”

MR Imaging in Spinocerebellar Ataxias: A Systematic Review

“…20 A single study evaluated the NAA ϩ N-acetyl-aspartylglutamate/total Cr ratio in the left cerebellar white matter of patients with SCA3/MJD and found reduced ratios. 26 Reduced NAA levels in the cerebellar vermis and pons, with a strong inverse correlation between SARA scores and NAA levels in the pons, were reported in a single study. 19 Two studies evaluated the NAA/ choline ratio 20,21 ; NAA/Cho ratio was reduced in the cerebellar vermis in both studies, but one reported a direct 20 and the other an inverse correlation 21 with SARA.…”

“…20 One study evaluated the glutamate (Glu)/total Cr ratio in the left cerebellar white matter and found reductions in SCA3/MJD, but with no correlations with motor clinical or molecular data. 26 One study evaluated MR spectroscopy Glu levels and found reductions in the cerebellar vermis and pons, with no significant clinical or molecular correlations.…”

“…Only 1 study evaluated DTI in SCA3/ MJD, comprising 38 patients. 24 We excluded the DTI data in the study by Lopes et al 26 after contacting the study authors, because there was an overlap of patients and findings with the study by Guimarães et al 24 This study reported reduced fractional anisotropy (FA) in the bilateral cerebellum, including the dentate and other nuclei and cerebellar peduncles, and in the brain stem, including the midbrain and pons. Increased axial diffusivity (AD) and radial diffusivity (RD) were seen in different cerebellar and brain stem regions, while mean diffusivity did not differ from that in controls.…”

“…All 6 included MR spectroscopy studies evaluated only patients with SCA3/MJD, comprising 235 individuals. [19][20][21][22]25,26 Many of the studies evaluated different ROIs, which made it difficult to pool data.…”