CRISPR/sgRNA-directed synergistic activation mediator (SAM) as a therapeutic tool for Parkinson´s disease.

Parkinson`s disease (PD) is the second most prevalent neurodegenerative disease, and different gene therapy strategies have been used as experimental treatments. As a proof-of-concept for the treatment of PD, we used SAM, a CRISPR gene activation system, to activate the endogenous tyrosine hydroxylase gene (th) of astrocytes to produce dopamine (DA) in the striatum of 6-OHDA-lesioned rats. Potential sgRNAs within the rat th promoter region were tested, and the expression of the Th protein was determined in the C6 glial cell line. Employing pseudo-lentivirus, the SAM complex and the selected sgRNA were transferred into cultures of rat astrocytes, and gene expression and Th protein synthesis were ascertained; furthermore, DA release into the culture medium was determined by HPLC. The DA-producing astrocytes were implanted into the striatum of 6-OHDA hemiparkinsonian rats. We observed motor behavior improvement in the lesioned rats that received DA-astrocytes compared to lesioned rats receiving astrocytes that did not produce DA. Our data indicate that the SAM-induced expression of the astrocyte´s endogenous th gene can generate DA-producing astrocytes that effectively reduce the motor asymmetry induced by the lesion.

Longitudinal atrophy characterization of cortical and subcortical gray matter in Huntington's disease patients.

Huntington's disease (HD) is an inherited neurodegenerative disease with clinical manifestations that involve motor, cognitive and psychiatric deficits. Cross-sectional magnetic resonance imaging (MRI) studies have described the main cortical and subcortical macrostructural atrophy of HD. However, longitudinal studies characterizing progressive atrophy are lacking. This study aimed to describe the cortical and subcortical gray matter atrophy using complementary volumetric and surface-based MRI analyses in a cohort of seventeen early HD patients in a cross-sectional and longitudinal analysis and to correlate the longitudinal volumetric atrophy with the functional decline using several clinical measures. A group of seventeen healthy individuals was included as controls. After obtaining structural MRIs, volumetric analyses were performed in 36 cortical and 7 subcortical regions of interest per hemisphere and surface-based analyses were performed in the whole cortex, caudate, putamen and thalamus. Cross-sectional cortical surface-based and volumetric analyses showed significant decreases in frontoparietal and temporo-occipital cortices, while subcortical volumetric analysis showed significant decreases in all subcortical structures except the hippocampus. The longitudinal surface-based analysis showed widespread cortical thinning with volumetric decreases in the superior frontal lobe, while a subcortical volumetric decrease occurred in the caudate, putamen and thalamus with shape deformation on the anterior, medial and dorsal side. Functional capacity and motor status decline correlated with caudate progressive atrophy, while cognitive decline correlated with left superior frontal and right paracentral progressive atrophy. These results provide new insights into progressive volumetric and surface-based morphometric atrophy of gray matter in HD.

Cognitive Deficits Correlate with White Matter Deterioration in Spinocerebellar Ataxia Type 2.

OBJECTIVES: The aim of this study was to explore the relationship between cognitive and white matter deterioration in a group of participants with spinocerebellar ataxia type 2 (SCA2). METHODS: Fourteen genetically confirmed participants with SCA2 and 14 aged-matched controls participated in the study. Diffusion tensor imaging tract-based spatial statistics were performed to analyze structural white matter integrity. Significant group differences in the mean diffusivity were correlated with SCA2 cognitive deficits. RESULTS: Our analysis revealed higher mean diffusivity in the SCA2 group in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Cognitive scores correlated with white matter mean diffusivity in the parahippocampal area, inferior frontal and supramarginal gyri and the stria terminalis. CONCLUSIONS: Our findings show significant correlations between white matter microstructural damage in key areas affected in SCA2 and cognitive deficits. These findings result in a more comprehensive understanding of the effect of the neurodegenerative process in people with SCA2.

Establishment of induced pluripotent stem cell lines derived from Parkinson's disease Mexican patients: A sporadic (UNAMi002-A) and a familial (UNAMi003-A) case carrying a mutation in PINK1.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a prominent reduction of striatal dopamine levels leading to motor alterations. The mechanisms underlying neurodegeneration in PD remain unknown. Here, we generated an induced pluripotent stem cell line from dermal fibroblasts of a Mexican patient diagnosed with sporadic PD (UNAMi002-A) and another cell line from dermal fibroblasts of a patient carrying the point mutation c.1423delC in PINK1 (UNAMi003-A). These patient-derived iPS cell lines offer the possibility of modeling PD and understanding the mechanisms that contribute to dopamine neuron loss.

The effect of Parkinson's disease and Huntington's disease on human visuomotor learning.

Visuomotor adaptation is often driven by error-based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning-free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB-independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non-EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia.

Human Embryonic Stem Cell-Derived Immature Midbrain Dopaminergic Neurons Transplanted in Parkinsonian Monkeys.

Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.

Montreal Cognitive Assessment (MoCA) performance in Huntington's disease patients correlates with cortical and caudate atrophy.

Huntington's Disease (HD) is an autosomal neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Cognitive impairment develops gradually in HD patients, progressing later into a severe cognitive dysfunction. The Montreal Cognitive Assessment (MoCA) is a brief screening test commonly employed to detect mild cognitive impairment, which has also been useful to assess cognitive decline in HD patients. However, the relationship between MoCA performance and brain structural integrity in HD patients remains unclear. Therefore, to explore this relationship we analyzed if cortical thinning and subcortical nuclei volume differences correlated with HD patients' MoCA performance. Twenty-two HD patients and twenty-two healthy subjects participated in this study. T1-weighted images were acquired to analyze cortical thickness and subcortical nuclei volumes. Group comparison analysis showed a significantly lower score in the MoCA global performance of HD patients. Also, the MoCA total score correlated with cortical thinning of fronto-parietal and temporo-occipital cortices, as well as with bilateral caudate volume differences in HD patients. These results provide new insights into the effectiveness of using the MoCA test to detect cognitive impairment and the brain atrophy pattern associated with the cognitive status of prodromal/early HD patients.

Planning deficits in Huntington's disease: A brain structural correlation by voxel-based morphometry.

INTRODUCTION: Early Huntington's disease (HD) patients begin to show planning deficits even before motor alterations start to manifest. Generally, planning ability is associated with the functioning of anterior brain areas such as the medial prefrontal cortex. However, early HD neuropathology involves significant atrophy in the occipital and parietal cortex, suggesting that more posterior regions could also be involved in these planning deficits. OBJECTIVE: To identify brain regions associated with planning deficits in HD patients at an early clinical stage. MATERIALS AND METHODS: Twenty-two HD-subjects genetically confirmed with incipient clinical manifestation and twenty healthy subjects were recruited. All participants underwent MRI T1 image acquisition as well as testing in the Stockings of Cambridge (SOC) task to measure planning ability. First, group comparison of SOC measures were performed. Then, correlation voxel-based morphometry analyses were done between gray matter degeneration and SOC performance in the HD group. RESULTS: Accuracy and efficiency planning scores correlated with gray matter density in right lingual gyrus, middle temporal gyrus, anterior cingulate gyrus, and paracingulate gyrus. CONCLUSIONS: Our results suggest that planning deficits exhibited by early HD-subjects are related to occipital and temporal cortical degeneration in addition to the frontal areas deterioration.

Sex-related differences in motor learning and performance.

Gender differences have been shown across many domains, and motor skills are no exception. One of the most robust findings is a significant sex difference in throwing accuracy, which reflects the advantage of men in targeting abilities. However, little is known about the basis of this difference. To try to dissect possible mechanisms involved in this difference, here we tested for gender variations in a prism adaptation throwing task. We tested 154 subjects in a visuomotor prism adaptation task that discriminates between motor performance, visuomotor adaptation and negative aftereffects. Our results corroborate men's significant better throwing accuracy, although there were no adaptation differences between genders. In contrast, women showed significant larger negative aftereffects, which could be explained by a larger contribution of spatial alignment. These results suggest that different learning mechanisms, like strategic calibration and spatial alignment, may have different contributions in men and women.

Quantitative evaluation of MPTP-treated nonhuman parkinsonian primates in the HALLWAY task.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. An experimental model of this disease is produced in nonhuman primates by the administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this work, we put forward a new quantitative evaluation method that uses video recordings to measure the displacement, gate, gross and fine motor performance of freely moving subjects. Four Vervet monkeys (Cercopithecus aethiops) were trained in a behavioral observation hallway while being recorded with digital video cameras from four different angles. After MPTP intoxication the animals were tested without any drug and after 30 and 90 min of Levodopa/Carbidopa administration. Using a personal computer the following behaviors were measured and evaluated from the video recordings: displacement time across the hallway, reaching time towards rewards, ingestion time, number of attempts to obtain rewards, number of rewards obtained, and level of the highest shelf reached for rewards. Our results show that there was an overall behavioral deterioration after MPTP administration and an overall improvement after Levodopa/Carbidopa treatment. This demonstrates that the HALLWAY task is a sensitive and objective method that allows detailed behavioral evaluation of freely moving monkeys in the MPTP Parkinson's disease model.

Extensive cerebellar and thalamic degeneration in spinocerebellar ataxia type 10.

INTRODUCTION: Spinocerebellar ataxia type 10 (SCA10) is a hereditary neurodegenerative disorder caused by repeat expansions in the ATXN10 gene. Patients present with cerebellar ataxia frequently accompanied by seizures. Even though loss of cerebellar Purkinje neurons has been described, its brain degeneration pattern is unknown. Our aim was to characterize the gray and white matter degeneration patterns in SCA10 patients and the association with clinical features. METHODS: We enrolled 18 patients with molecular diagnosis of SCA10 and 18 healthy individuals matched for age and sex. All participants underwent brain MRI including high-resolution anatomical and diffusion images. Whole-brain Tract-Based Spatial Statistics (TBSS) and Voxel-Based Morphometry (VBM) were performed to identify white and grey matter degeneration respectively. A second analysis in the cerebellum identified the unbiased pattern of degeneration. Motor impairment was assessed using the SARA Scale. RESULTS: TBSS analysis in the patient group revealed white matter atrophy exclusively in the cerebellum. VBM analysis showed extensive grey matter degeneration in the cerebellum, brainstem, thalamus, and putamen. Significant associations between cerebellar degeneration and SARA scores were found. Additionally, degeneration in thalamic GM and WM in the cerebellar lobule VI were significantly associated with the presence of seizures. CONCLUSION: The results show that besides cerebellum and brainstem, brain degeneration in SCA10 includes predominantly the putamen and thalamus; involvement of the latter is strongly associated with seizures. Analysis of the unbiased degeneration pattern in the cerebellum suggests lobules VIIIb, IX, and X as the primary cerebellar targets of the disease, which expands to the anterior lobe in later stages.

Extrastriatal degeneration correlates with deficits in the motor domain subscales of the UHDRS.

INTRODUCTION: Striatal degeneration has significant behavioral effects in patients with Huntington's disease (HD). However, there is scant evidence of the possible contribution of extrastriatal regions to the motor alterations assessed within the different domains of the Unified Huntington's Disease Rating Scale (UHDRS). OBJECTIVE: Analyze if extrastriatal grey matter decrease in patients with HD correlates with motor performance assessed with the UHDRS and its different domains. METHOD: Twenty-two molecular diagnosed patients with incipient HD, and twenty-two control participants matched for sex and age participated in this study. Voxel-based morphometry (VBM) analyses were done to identify grey matter decrease in the HD patients, and its relationship with the motor deterioration measured with the UHDRS motor scale. To further explore this relationship, a principal component analysis (PCA) was done on the UHDRS domains scores. Then the average of each component was used as a covariate in a VBM analysis. Finally, individual sub-scores from each domain were also tested for correlations with the VBM results. RESULTS: In addition to the striatal degeneration, the VBM analysis showed significant negative correlations between the global UHDRS scores and the cerebellum, insula and precuneus atrophy. The UHDRS PCA showed component-related negative correlations suggesting a specific impact of individual degnerations. Further analyses with the individual sub-scores showed more specific corelations, including: chorea, with right caudate and left posterior cingulate gyrus; ocular pursuit, with left precentral gyrus, left superior temporal gyrus, cerebellum culmen and right temporal lobe. Saccadic movements with left postcentral gyrus and left middle occipital gyrus. CONCLUSION: In the early stages of HD, it is possible to find correlations between behavioral alterations as measured with the UHDRS motor domains, and extrastriatal regions, including specific areas of the cerebellum, and insular, parietal and frontal cortices. These areas could contribute to the HD related impairments along with the classical deficits associated with the striatal degeneration.

Rapid topographical plasticity of the visuomotor spatial transformation.

Information about the world is often encoded in the brain as topographic maps. These internal representations are not always static but can have a dynamic nature, allowing for constant adjustments that depend on factors like experience or injury. Recently, it has been shown that areas involved in visuomotor transformations also show topographical organization. These findings suggest that it could be possible to observe plastic modifications in specific parts of the representation in response to a local perturbation that affects only a part of the space that is represented. Here, we tested this hypothesis using an adaptation paradigm with hemiprisms. Our results suggest that, initially, the system tries to modify the visuomotor transformation in the whole spatial representation; however, if feedback is available from both hemifields, the system can perform specific regional topographical realignments. The results also suggest that access to the rearranged visuomotor transformation is independent of eye position, in contrast with previous studies that found a kind of conditional learning. Also, whereas prism adaptation experiments using ballistic movements do not show intermanual transfer of learning, the topographical modification found here is available to both hands. These results provide strong evidence for rapid topographical plasticity that can modify space transformations between two different modalities.

Neural correlates of ataxia severity in spinocerebellar ataxia type 3/Machado-Joseph disease.

BACKGROUND: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant inherited neurodegenerative disorder. Several post-mortem and imaging studies have shown cerebellar and brainstem atrophy. A number of studies have used volumetric regional information to investigate the relationship between neurodegeneration and the ataxia severity. However, regional analysis can obscure the specific location in which the degenerative process is affecting the brain tissue, which can be crucial for the development of new target treatments for this disease. Here we explored the relationship between the gray matter degeneration and the ataxia severity on a cohort of SCA3 patients using a voxel-wise approach. METHODS: Seventeen patients with molecular diagnose of SCA3 and 17 matched healthy controls participated in this study. Magnetic resonance imaging (MRI) brain images were acquired and voxel-based morphometry was used to obtain the grey matter volume of each participant. Ataxia severity in the patient group was evaluated using the scale for the assessment and rating of ataxia (SARA). RESULTS: Group comparison revealed significant atrophy in SCA3 including bilateral cerebellum, vermis, brainstem, and occipital cortex. Significant negative correlations between gray matter volume and SARA scores were found in the cerebellum and the cingulate gyrus. CONCLUSIONS: These findings highlight the specific contribution of the cerebellum and the cingulate cortex to the ataxia deficits among the other regions showing neurodegeneration in SCA3 patients.

Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease.

The ability to inhibit automatic versus voluntary saccade commands in demanding situations can be impaired in neurodegenerative diseases such as Huntington's disease (HD). These deficits could result from disruptions in the interaction between basal ganglia and the saccade control system. To investigate voluntary oculomotor control deficits related to the cortico-basal circuitry, we evaluated early HD patients using an interleaved pro- and anti-saccade task that requires flexible executive control to generate either an automatic response (look at a peripheral visual stimulus) or a voluntary response (look away from the stimulus in the opposite direction). The impairments of HD patients in this task are mainly attributed to degeneration in the striatal medium spiny neurons leading to an over-activation of the indirect-pathway thorough the basal ganglia. However, some studies have proposed that damage outside the indirect-pathway also contribute to executive and saccade deficits. We used the interleaved pro- and anti-saccade task to study voluntary saccade inhibition deficits, Voxel-based morphometry and Tract-based spatial statistic to map cortico-basal ganglia circuitry atrophy in HD. HD patients had voluntary saccade inhibition control deficits, including increased regular-latency anti-saccade errors and increased anticipatory saccades. These deficits correlated with white-matter atrophy in the inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior corona radiata and superior longitudinal fasciculus. These findings suggest that cortico-basal ganglia white-matter atrophy in HD, disrupts the normal connectivity in a network controlling voluntary saccade inhibitory behavior beyond the indirect-pathway. This suggests that in vivo measures of white-matter atrophy can be a reliable marker of the progression of cognitive deficits in HD.

Early Huntington's Disease: Impulse Control Deficits but Correct Judgment Regarding Risky Situations.

BACKGROUND: Huntington's disease (HD) patients show alterations in decision making tasks. However, it is still uncertain if these deficits are due to poor judgment regarding risky situations, or to impulse control deficits. OBJECTIVE: To elucidate whether decision-making in patients is related to genuine risk behavior or to impulse control deficits. METHODS: To test between these two alternative possibilities, we evaluated the performance of 19 prodromal HD patients and 19 matched healthy controls in the Cambridge Gambling Task (CGT). This task assesses decision-making while dissociating between genuine risk-taking behaviors (ascending condition) from impulsive behavior (descending condition). RESULTS: The results showed that patients and controls had the same performance during all trials in the ascending condition, reflecting a correct judgment regarding risky situations; however, during the descending condition, patients responded before the controls in all trials, making a significantly larger number of higher bets. Unlike the control group, they did not wait for more optimal subsequent options. CONCLUSION: These results suggest impulse control deficits in HD gene carriers, but unimpaired risk-taking judgment.

Semaphorin 3C Released from a Biocompatible Hydrogel Guides and Promotes Axonal Growth of Rodent and Human Dopaminergic Neurons.

Cell therapy in experimental models of Parkinson's disease replaces the lost dopamine neurons (DAN), but we still need improved methods to guide dopaminergic axons (DAx) of grafted neurons to make proper connections. The protein Semaphorin 3C (Sema3C) attracts DAN axons and enhances their growth. In this work, we show that the hydrogel PuraMatrix, a self-assembling peptide-based matrix, incorporates Sema3C and releases it steadily during 4 weeks. We also tested if hydrogel-delivered Sema3C attracts DAx using a system of rat midbrain explants embedded in collagen gels. We show that Sema3C released by this hydrogel attracts DAx, in a similar way to pretectum, which is known to attract growing DAN axons. We assessed the effect of Sema3C on the growth of DAx using microfluidic devices. DAN from rat midbrain or those differentiated from human embryonic stem cells showed enhanced axonal extension when exposed to hydrogel-released Sema3C, similar to soluble Sema3C. Notably, DAN of human origin express the cognate Sema3C receptors, Neuropilin1 and Neuropilin2. These results show that PuraMatrix is able to incorporate and release Sema3C, and such delivery guides and promotes the axonal growth of DAN. This biocompatible hydrogel might be useful as a Sema3C carrier for in vivo studies in parkinsonian animal models.

Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients.

BACKGROUND: Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo. METHODS: Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment. RESULTS: Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle. CONCLUSION: Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.

Olfactory performance in spinocerebellar ataxia type 7 patients.

A large body of evidence has shown olfactory deficits in many neurodegenerative diseases. However, the nature of the olfactory impairment remains poorly understood partly because the majority of studies have only explored smell identification capabilities. The purpose of the present study was twofold. First we wanted to test if patients with spinocerebellar ataxia type 7 (SCA7), a progressive neurodegenerative disorder characterized by cerebellar ataxia and visual loss, also have olfactory deficits. Secondly, we wanted to test the nature of the olfactory deficits by testing not only the identification level but also olfactory threshold and discrimination. Based on the olfactory dysfunction found in different neurodegenerative diseases and functional neuroimaging data showing cerebellar activation during olfaction, we hypothesized that SCA7 patients would show an olfactory impairment. To test this hypothesis we studied twenty-eight genetically confirmed SCA7 patients and twenty-seven matched controls using the Sniffing Sticks Test and the University of Pennsylvania Smell Identification Test (UPSIT). The results show that SCA7 patients' ability to discriminate and identify odors is significantly impaired, although their odor detection thresholds were at normal levels. These results suggest that SCA7 neurological damage affects olfactory perception but spares the patients' olfactory sensory capabilities.

Parahippocampal gray matter alterations in Spinocerebellar Ataxia Type 2 identified by voxel based morphometry.

Spinocerebellar Ataxia Type 2 (SCA2) is a genetic disorder causing cerebellar degeneration that result in motor and cognitive alterations. Voxel-based morphometry (VBM) analyses have found neurodegenerative patterns associated to SCA2, but they show some discrepancies. Moreover, behavioral deficits related to non-cerebellar functions are scarcely discussed in those reports. In this work we use behavioral and cognitive tests and VBM to identify and confirm cognitive and gray matter alterations in SCA2 patients compared with control subjects. Also, we discuss the cerebellar and non-cerebellar functions affected by this disease. Our results confirmed gray matter reduction in the cerebellar vermis, pons, and insular, frontal, parietal and temporal cortices. However, our analysis also found unreported loss of gray matter in the parahippocampal gyrus bilaterally. Motor performance test ratings correlated with total gray and white matter reductions, but executive performance and clinical features such as CAG repetitions and disease progression did not show any correlation. This pattern of cerebellar and non-cerebellar morphological alterations associated with SCA2 has to be considered to fully understand the motor and non-motor deficits that include language production and comprehension and some social skill changes that occur in these patients.