Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is the second-most common CAG repeat disease, caused by a glutamine-encoding expansion in the ATXN3 protein. SCA3 is characterized by spinocerebellar degeneration leading to progressive motor incoordination and early death. Previous studies suggest that potassium channel dysfunction underlies early abnormalities in cerebellar cortical Purkinje neuron firing in SCA3. However, cerebellar cortical degeneration is often modest both in the human disease and mouse models of SCA3, raising uncertainty about the role of cerebellar dysfunction in SCA3. Here, we address this question by investigating Purkinje neuron excitability in SCA3. In early-stage SCA3 mice, we confirm a previously identified increase in excitability of cerebellar Purkinje neurons and associate this excitability with reduced transcripts of two voltage-gated potassium (KV) channels, Kcna6 and Kcnc3, as well as motor impairment. Intracerebroventricular delivery of antisense oligonucleotides (ASO) to reduce mutant ATXN3 restores normal excitability to SCA3 Purkinje neurons and rescues transcript levels of Kcna6 and Kcnc3. Interestingly, while an even broader range of KV channel transcripts shows reduced levels in late-stage SCA3 mice, cerebellar Purkinje neuron physiology was not further altered despite continued worsening of motor impairment. These results suggest the progressive motor phenotype observed in SCA3 may not reflect ongoing changes in the cerebellar cortex but instead dysfunction of other neuronal structures within and beyond the cerebellum. Nevertheless, the early rescue of both KV channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.

'Staying strong on the inside and outside' to keep walking and moving around: Perspectives from Aboriginal people with Machado Joseph Disease and their families from the Groote Eylandt Archipelago, Australia.

Machado Joseph Disease (MJD) (spinocerebellar ataxia 3) is a hereditary neurodegenerative disease causing progressive ataxia and loss of mobility. It is the most common spinocerebellar ataxia worldwide. Among Aboriginal families of Groote Eylandt and related communities across Australia's Top End, MJD is estimated to be more prevalent than anywhere else in the world. This study explored lived experiences of individuals and families with MJD to determine what is important and what works best to keep walking and moving around. A collaborative qualitative exploratory study, drawing from constructivist grounded theory methods, was undertaken for data collection and analysis. Semi-structured in-depth interviews were conducted with individuals with MJD (n = 8) and their family members (n = 4) from the Groote Eylandt Archipelago where ~1500 Aboriginal people (Warnumamalya) live. Interviews were led by Warnumamalya community research partners in participants' preferred language(s). Participants described their experience of living with MJD, from 'knowing about MJD', 'protecting yourself from MJD' and 'adjusting to life with MJD'. While the specific importance of walking and moving around differed widely between participants, all perceived that walking and moving around enabled them to do what mattered most to them in life. 'Staying strong on the inside and outside' (physically, mentally, emotionally, spiritually) was perceived to work best to keep walking and moving around as long as possible. A framework that included personal and environmental strategies for staying strong emerged: 'Exercising your body', 'having something important to do', 'keeping yourself happy', 'searching for good medicine', 'families helping each other' and 'going country'. This study, the first to explore lived experiences of MJD in Australia, highlights the importance of maintaining mobility as long as possible. Strategies perceived to work best address physical and psychosocial needs in an integrated manner. Services supporting families with MJD need flexibility to provide individualised, responsive and holistic care.

Choosing not to know: accounts of non-engagement with pre-symptomatic testing for Machado-Joseph disease.

This paper reports accounts from people at-risk for, or affected by, Machado-Joseph disease, and their family members, about their decisions not to seek pre-symptomatic testing, therefore remaining (for the time) uninformed about their genetic status. We draw on individual and family semi-structured interviews with participants recruited through a national patient's association (n = 25). Qualitative thematic analysis revealed three main categories of accounts: (1) justifying the decision "not to know", because either no clinical benefit was expected or predictive knowledge was anticipated as psychologically burdensome; (2) prioritizing everyday life, maintaining hope and the goal of living a valid life; and (3) the wish to know: ambivalence and conflict within the family. Findings suggest the value of genetic information is often questioned when no effective treatment or cure is available; and that people have different tolerance thresholds for predictive information, and this impacts individuals within the family differently. We discuss this in the context of the making of "responsible" decisions, and of the tensions that may arise within families between the best interests or wishes of a person and those of other family members. We hope this will clarify the reasoning of those who opt for non-engagement with medical genetic services and, more specifically, pre-symptomatic testing. Further, we hope it will be relevant for the provision of genetic counselling and psychosocial support to such families.

Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. METHODS: The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly confirmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. RESULTS: The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. CONCLUSIONS: The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients.

Pre-symptomatic testing for neurodegenerative disorders: Middle- to long-term psychopathological impact.

BACKGROUND: Over the past 20 years, studies have revealed that the communication of a pre-symptomatic test (PST) result for late-onset diseases, such as Huntington’s disease (HD), doesn’t cause psychological disturbance. This cross-sectional study investigated the middle- (4 years) to long-term (7 and 10 years) psychological impact of PST for 3 autosomal dominant late-onset diseases: HD, Machado-Joseph disease (DMJ) and familial amyloid polyneuropathy (FAP). METHOD: The study included 203 subjects: 170 (84%) agreed to make the PST for FAP, 29 (14%) for HD and 4 (2%) for MJD. They were mostly women (58%) and married (67%). It was considered the cutoffs points: 4 years (middle-term) and 7 and 10 years (long-term) indicating the time after receiving the TPS results. RESULTS: women and widows (oldest) presented the highest mean values for almost all BSI dimensions and the highest values correspond to the obsessive-compulsive dimension. MJD participants presented the highest mean values. No differences were found concerning the PST test results while participants are still asymptomatic. Psychopathology was only present in symptomatic carriers. CONCLUSIONS: The onset of the disease seems to assume the trigger for psychological disturbance, regardless the time that has elapsed since the PST result communication or the individual carrier/non-carrier condition.

Subjects at Risk for Genetic Late-Onset Neurological Diseases: Objective Knowledge.

BACKGROUND/AIMS: This study addresses the objective knowledge about the disease of subjects at risk for 3 genetic late-onset neurological diseases (LOND): familial amyloid polyneuropathy (FAP) TTR V30M, Huntington disease (HD), and Machado-Joseph disease (MJD). METHODS: Subjects at risk for FAP, HD, and MJD submitted to genetic counseling to know their status (carrier or non-carrier) and subjects at risk for hereditary hemochromatosis (HH), the control group, completed a sociodemographic questionnaire and answered the open-ended question: "What do you know about this disease?." RESULTS: From 10 categories of answers, references to the disease, quantitative answers, references to the family, and metaphors stood out. References to the disease, references to the family, and metaphors were mentioned more often by subjects at risk for LOND than by subjects at risk for HH (control group). CONCLUSION: The disease itself and its meaning as well as sick relatives play a key role in the objective knowledge about LOND. Thus, genetic counseling protocols of subjects at risk for LOND should include questions concerning family knowledge and disease experience.

Nonmotor Symptoms in Patients with Spinocerebellar Ataxia Type 10.

Nonmotor symptoms (NMS) have been described in several neurodegenerative diseases but have not been systematically evaluated in spinocerebellar ataxia type 10 (SCA10). The objective of the study is to compare the frequency of NMS in patients with SCA10, Machado-Joseph disease (MJD), and healthy controls. Twenty-eight SCA10, 28 MJD, and 28 healthy subjects were prospectively assessed using validated screening tools for chronic pain, autonomic symptoms, fatigue, sleep disturbances, psychiatric disorders, and cognitive function. Chronic pain was present with similar prevalence among SCA10 patients and healthy controls but was more frequent in MJD. Similarly, autonomic symptoms were found in SCA10 in the same proportion of healthy individuals, while the MJD group had higher frequencies. Restless legs syndrome and REM sleep behavior disorder were uncommon in SCA10. The mean scores of excessive daytime sleepiness were worse in the SCA10 group. Scores of fatigue were higher in the SCA10 sample compared to healthy individuals, but better than in the MJD. Psychiatric disorders were generally more prevalent in both spinocerebellar ataxias than among healthy controls. The cognitive performance of healthy controls was better compared with SCA10 patients and MJD, which showed the worst scores. Although NMS were present among SCA10 patients in a higher proportion compared to healthy controls, they were more frequent and severe in MJD. In spite of these comparisons, we were able to identify NMS with significant functional impact in patients with SCA10, indicating the need for their systematic screening aiming at optimal treatment and improvement in quality of life.

Arginine vasopressin relates with spatial learning and memory in a mouse model of spinocerebellar ataxia type 3.

Spinocerebellar ataxia is an inherited neurodegenerative disorder that the most prevalent type is type 3 (SCA3). Arginine vasopressin (AVP) is released within the lateral septum for controlling the learning and memory. This communication studied the effect of AVP on the spatial learning and memory of SCA3 mice. The spatial learning and memory were analyzed by Morris water maze test (MWM), and AVP concentration was measured by radioimmunoassay. The results showed that (Alves et al., 2010) the swimming velocity, distance traveled and latency to the platform of MWM in SCA3 mice were reduced slower than those in WT mice over 4 training days (p<0.05, 0.01 or 0.001); (Antunes and Zimmerman, 1978) SCA3 mice showed a lower performance of spatial learning and memory of MWM during the fifth day (test day) compared to WT mice; (Bao et al., 2014) SCA3 mice had a decrease of AVP concentration in cerebral cortex (6.3±0.6pg/mg vs. 11.4±1.0pg/mg, p<0.01), hypothalamus (6.1±1.3ng/mg vs. 10.3±2.1ng/mg, p<0.05), hippocampus (3.2±0.5pg/mg vs. 5.2±1.0pg/mg, p<0.01) and cerebellum (4.7±0.9pg/mg vs. 8.3±1.1pg/mg, p<0.01), not in spinal cord, pituitary and serum; and (Barberies and Tribollet, 1996) intraventricular AVP could significantly quicken swimming velocity, cut down distance traveled and reduce latency to the platform of MWM in a dose-dependent manner, but intraventricular AVP receptor antagonist weakened the spatial learning and memory of MWM in SCA3 mice during the fifth day. The data suggested that AVP in the brain, not spinal cord and peripheral system of SCA3 mice related with the change of the spatial learning and memory of MWM.

Fatigue and Its Associated Factors in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

Fatigue has been described in several neurodegenerative diseases, reducing quality of life. A systematic evaluation of this clinical feature is lacking in SCA3/MJD. The aim of this study was to evaluate the frequency and the factors associated with fatigue in SCA3/MJD. Patients with SCA3/MJD and matched healthy controls answered the Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Scale for the assessment and rating of ataxia (SARA) was used to determine ataxia severity. We used Mann-Whitney and Fisher exact tests to compare mean scores and proportions between groups. Linear regression analyses were employed to investigate factors associated with fatigue in SCA3/MJD. Seventy-four patients were included with a mean age and disease duration of 47.2 ± 12.8 and 9.5 ± 6.37 years, respectively. There were 38 men and 36 women. Mean (CAG)n was 72.2 ± 3.8. Mean MFIS score was higher in patients with SCA3/MJD (41.4 ± 16.2 vs 18.4 ± 12.9, p < 0.001). According to BDI scores, relevant depressive symptoms were found in 69.4 % of patients but only in 10.4 % of controls (p < 0.001). The proportion of patients with ESS scores indicating excessive daytime somnolence was also higher than controls (37.5 vs 22.3 %, p = 0.05). In the multiple regression analysis, both BDI and ESS scores were associated with fatigue (r = 0.67, p < 0.001 and p = 0.01). Fatigue is frequent and strongly associated with depression and excessive daytime somnolence in SCA3/MJD.

Mid- and long-term anxiety levels associated with presymptomatic testing of Huntington's Disease, Machado-Joseph Disease, Machado-Joseph disease, and familial amyloid polyneuropathy

Objective: To study anxiety as a variable of the mid- and long-term psychological impact of pre-symptomatic testing for three autosomal dominant late-onset disorders – Huntington’s disease (HD), Machado-Joseph disease (MJD) and familial amyloid polyneuropathy (FAP) TTR V30M – in a Portuguese sample. Methods: This cross-sectional study included 203 participants: 170 (83.7%) underwent pre-symptomatic testing for FAP, 29 (14.3%) for HD, and 4 (2%) for MJD. Of the 203 participants, 73 (36.0%) were asymptomatic carriers, 29 (14.5%) were symptomatic carriers, 9 (4.5%) were diagnosed with FAP and had a liver transplant, and 89 (44.5%) were non-carriers. Most were women (58.1%) and married (66.5%). The anxiety variable was assessed using the Zung Self-Rating Anxiety Scale (SAS). Results: The anxiety scores were higher for symptomatic carriers and for those who underwent psychological support consultations over the years. For symptomatic carriers, the mean scores were superior to 40 points, which reflects clinical anxiety. Conclusion: Although it was not possible to differentiate between the mid- and long-term psychological impacts, this study supports the conclusion that the proximity to the age of symptoms onset might be a trigger for anxiety.

Mid- and long-term anxiety levels associated with presymptomatic testing of Huntington's disease, Machado-Joseph disease, and familial amyloid polyneuropathy.

OBJECTIVE: To study anxiety as a variable of the mid- and long-term psychological impact of pre-symptomatic testing for three autosomal dominant late-onset disorders - Huntington's disease (HD), Machado-Joseph disease (MJD) and familial amyloid polyneuropathy (FAP) TTR V30M - in a Portuguese sample. METHODS: This cross-sectional study included 203 participants: 170 (83.7%) underwent pre-symptomatic testing for FAP, 29 (14.3%) for HD, and 4 (2%) for MJD. Of the 203 participants, 73 (36.0%) were asymptomatic carriers, 29 (14.5%) were symptomatic carriers, 9 (4.5%) were diagnosed with FAP and had a liver transplant, and 89 (44.5%) were non-carriers. Most were women (58.1%) and married (66.5%). The anxiety variable was assessed using the Zung Self-Rating Anxiety Scale (SAS). RESULTS: The anxiety scores were higher for symptomatic carriers and for those who underwent psychological support consultations over the years. For symptomatic carriers, the mean scores were superior to 40 points, which reflects clinical anxiety. CONCLUSION: Although it was not possible to differentiate between the mid- and long-term psychological impacts, this study supports the conclusion that the proximity to the age of symptoms onset might be a trigger for anxiety.

Depression and clinical progression in spinocerebellar ataxias.

BACKGROUND: Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood. OBJECTIVES: To study the prevalence and influence of depressive symptoms in SCAs. METHODS: We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years. We employed regression models to study the effects of depressive symptoms on clinical progression indexed by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington's Disease Rating Scale Part IV (UHDRS-IV) and EQ5D after adjusting for age, sex and pathological CAG repeats. RESULTS: Comorbid depression is common in SCAs (26%). Although the baseline prevalence of depression was similar among different SCA types, suicidal ideation was more frequently reported in SCA3 (65%). Depressive symptoms were associated with SARA scores but did not significantly progress over time within 2 years or deteriorate by increased numbers of pathological CAG repeats. The effects of depression on ataxia progression varied across different SCA types. Nevertheless, depression had consistently negative and significant impact on functional status and quality of life in all SCAs, even after accounting for ataxia progression. CONCLUSIONS: Depressive symptoms are not simply the consequence of motor disability in SCAs. Comorbid depression per se contributes to different health outcomes and deserves more attention when caring patients with SCAs.

Progressive cognitive dysfunction in spinocerebellar ataxia type 3.

BACKGROUND: Although it is well established that there is cognitive dysfunction in spinocerebellar ataxia type 3 (SCA3), it is unknown whether cognition deteriorates with disease progression. We therefore prospectively studied cognitive function in patients with SCA3. METHODS: Eleven patients with SCA3 were assessed using an extensive neuropsychological test battery and retested after 3.5 ± 0.4 years. RESULTS: In addition to ataxia and motor control, verbal learning and verbal and figural memory deteriorated significantly during the follow-up period. An increase in depressive symptoms was not observed. CONCLUSIONS: The observation that memory and learning abilities deteriorated with disease progression suggests that cognitive dysfunction is an integral part of SCA3. Because the applied tests for memory function did not require motor responses, cognitive decline cannot be attributed to progressive cerebellar ataxia. The deterioration of verbal and figural memory can be explained either by extracerebellar pathology or by disruption of cerebellar-cerebral circuitries.

Psychological well-being and family satisfaction levels five years after being confirmed as a carrier of the Machado-Joseph disease mutation.

The present study on long-term outcome of presymptomatic testing for Machado-Joseph disease (MJD) aimed to evaluate the psychological well-being and the familial satisfaction of subjects that 5 years prior received an unfavorable result in the predictive testing (PT). The study included 47 testees of Azorean origin (23 from the island of Flores and 24 from S. Miguel) that completed the fourth evaluation session of the MJD protocol, and undertook a neurological examination at the moment of participation in the study. Nearly 50% of testees were symptomatic at the time of the study. Psychological well-being of the 47 participants was evaluated using the Psychological General Well-Being Index (PGWB). The family satisfaction scale by adjectives was applied to obtain information on family dynamics. The average PGWB score of the total participants was of 73.3, a value indicative of psychological well-being. Nearly half of the testees presented scores indicating psychological well-being, whereas scores indicating moderate (28.9%) or severe (23.7%) stress were found in the remaining. The average score in the PGWB scale was lower in symptomatic than in asymptomatic subjects; moreover, the distinct distribution of the well-being categories seen in the two groups shows an impact of the appearance of first symptoms on the psychological state. Motives for undertaking the test, provided 5 years prior, failed to show an impact in well-being. The average score for familial satisfaction was of 134, a value compatible with high familial satisfaction, which represented the most frequent category (59.6%). Results demonstrate that well-being and family satisfaction need to be monitored in confirmed carriers of the MJD mutation. The inclusion of acceptance studies, after PT, as well as the development of acceptance training actions, should be of major importance to anticipate the possibility of psychological damage.

Cerebellar cognitive affective syndrome in Machado Joseph disease: core clinical features.

The cerebellum is no longer considered a purely motor control device, and convincing evidence has demonstrated its relationship to cognitive and emotional neural circuits. The aims of the present study were to establish the core cognitive features in our patient population and to determine the presence of Cerebellar Cognitive Affective Syndrome (CCAS) in this group. We recruited 38 patients with spinocerebellar ataxia type 3 (SCA3) or Machado­Joseph disease (MJD)-SCA3/MJD and 31 controls. Data on disease status were recorded (disease duration, age, age at onset, ataxia severity, and CAG repeat length). The severity of cerebellar symptoms was measured using the International Cooperative Ataxia Rating Scale and the Scale for the Assessment and Rating of Ataxia. The neuropsychological assessment consisted of the Mini-Mental State Examination, Clock Drawing Test, Wechsler Adult Intelligence Scale, Rey­Osterrieth Complex Figure, Wisconsin Card Sorting Test, Stroop Color­Word Test, Trail-Making Test, Verbal Paired Associates, and verbal fluency tests. All subjects were also submitted to the Hamilton Anxiety Scale and Beck Depression Inventory. After controlling for multiple comparisons, spatial span, picture completion, symbol search, Stroop Color­Word Test, phonemic verbal fluency, and Trail-Making Tests A and B were significantly more impaired in patients with SCA3/MJD than in controls. Executive and visuospatial functions are impaired in patients with SCA3/MJD, consistent with the symptoms reported in the CCAS. We speculate on a possible role in visual cortical processing degeneration and executive dysfunction in our patients as a model to explain their main cognitive deficit.

Sleep disorders in machado-joseph disease: frequency, discriminative thresholds, predictive values, and correlation with ataxia-related motor and non-motor features.

Sleep disorders are common complaints in patients with neurodegenerative diseases such as spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD)--SCA3/MJD. We evaluated the frequency of sleep disorders in SCA3/MJD patients against controls matched by age and gender, and correlated data with demographic and clinical variables. The main sleep disorders evaluated were rapid eye movement (REM) sleep behavior disorder (RBD), restless leg syndrome (RLS), and excessive daytime sleepiness (EDS). We recruited 40 patients with clinical and molecular-proven SCA3/MJD and 38 controls. We used the following clinical scales to evaluate our primary outcome measures: RBD Screening Questionnaire, International RLS Rating Scale, and Epworth Sleepiness Scale. To evaluate ataxia-related motor and non-motor features, we applied the International Cooperative Ataxia Rating Scale, the Scale for the Assessment and Rating of Ataxia, and the Unified Parkinson's Disease Rating Scale part III. Psychiatric manifestations were tested with the Hamilton Anxiety Scale, and Beck Depression Inventory. The frequency of RBD and RLS were significantly higher in the SCA3/MJD group than in the control group (p < 0.001). There was no difference between both groups with regard to EDS. The accuracy of RDBSQ to discriminate between cases and controls was considered the best area under the ROC curve (0.86). Within-SCA3/MJD group analysis showed that anxiety and depression were significantly correlated with RDB, but not with RLS. Additionally, depression was considered the best predictive clinical feature for RDB and EDS.

Occupational therapy in spinocerebellar ataxia type 3: an open-label trial

Occupational therapy (OT) is a profession concerned with promoting health and well-being through occupation, by enabling handicapped people to participate in the activities of everyday life. OT is part of the clinical rehabilitation of progressive genetic neurodegenerative diseases such as spinocerebellar ataxias; however, its effects have never been determined in these diseases. Our aim was to investigate the effect of OT on both physical disabilities and depressive symptoms of spinocerebellar ataxia type 3 (SCA3) patients. Genomically diagnosed SCA3 patients older than 18 years were invited to participate in the study. Disability, as evaluated by functional independence measurement and Barthel incapacitation score, Hamilton Rating Scale for Depression, and World Health Organization Quality of Life questionnaire (WHOQOL-BREF), was determined at baseline and after 3 and 6 months of treatment. Twenty-six patients agreed to participate in the study. All were treated because OT prevents blinding of a control group. Fifteen sessions of rehabilitative OT were applied over a period of 6 months. Difficult access to food, clothing, personal hygiene, and leisure were some of the main disabilities focused by these patients. After this treatment, disability scores and quality of life were stable, and the Hamilton scores for depression improved. Since no medication was started up to 6 months before or during OT, this improvement was related to our intervention. No association was found between these endpoints and a CAG tract of the MJD1 gene (CAGn), age, age of onset, or neurological scores at baseline (Spearman test). Although the possibly temporary stabilization of the downhill disabilities as an effect of OT remains to be established, its clear effect on depressive symptoms confirms the recommendation of OT to any patient with SCA3 or spinocerebellar ataxia.