Stages Of Huntington's Disease Research Articles

Modulation of adenosine signaling reverses 3-nitropropionic acid-induced bradykinesia and memory impairment in adult zebrafish

Huntington's disease (HD) is a neurodegenerative disorder, characterized by motor dysfunction, psychiatric disturbance, and cognitive decline. In the early stage of HD, occurs a decrease in dopamine D2 receptors and adenosine A2A receptors (A2AR), while in the late stage also occurs a decrease in dopamine D1 receptors and adenosine A1 receptors (A1R). Adenosine exhibits neuromodulatory and neuroprotective effects in the brain and is involved in motor control and memory function. 3-Nitropropionic acid (3-NPA), a toxin derived from plants and fungi, may reproduce HD behavioral phenotypes and biochemical characteristics. This study investigated the effects of acute exposure to CPA (A1R agonist), CGS 21680 (A2AR agonist), caffeine (non-selective of A1R and A2AR antagonist), ZM 241385 (A2AR antagonist), DPCPX (A1R antagonist), dipyridamole (inhibitor of nucleoside transporters) and EHNA (inhibitor of adenosine deaminase) in an HD pharmacological model induced by 3-NPA in adult zebrafish. CPA, CGS 21680, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA were acutely administered via i.p. in zebrafish after 3-NPA (at dose 60 mg/kg) chronic treatment. Caffeine and ZM 241385 reversed the bradykinesia induced by 3-NPA, while CGS 21680 potentiated the bradykinesia caused by 3-NPA. Moreover, CPA, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA reversed the 3-NPA-induced memory impairment. Together, these data support the hypothesis that A2AR antagonists have an essential role in modulating locomotor function, whereas the activation of A1R and blockade of A2AR and A1R and modulation of adenosine levels may reduce the memory impairment, which could be a potential pharmacological strategy against late-stage symptoms HD.

EE451 Healthcare Resource Use, Concomitant Conditions, and Treatment Patterns in Huntington's Disease: A Commercial Claims Analysis

Cognitive and behavioral symptoms of Huntington’s disease (HD) impose a significant burden in the early stages of HD alongside or before the motor manifestations. Limited data exists on the treatment options for these symptoms, and respective quantitative burden and costs. Using US commercial claims data, this study aims to explore the treatment patterns and healthcare resource utilization (HCRU) among those with HD.

Hyperactive Striatal Dopamine Signaling Observed in Huntington’s Disease Mouse Models Prior to Motor Symptom Onset Can be Attenuated via Activation of M4 Receptors

Almost all Huntington’s Disease (HD) patients die within 10‐30 years after symptom onset and currently there are no available treatments to slow, stop, or reverse its progression. HD is a neurodegenerative disease that causes a biphasic signaling pattern in the striatum in which there is hyperactive signaling during the early stages, followed by hypoactive signaling later on. Among the many neurotransmitters shown to follow the biphasic signaling pattern found in HD, dopamine (DA) and its inputs from the mid‐brain to the striatum are thought to be critical for motor and action planning. However, there is currently a lack of studies that directly examine DA signaling in animal models before symptom onset, leaving room for investigation in a critical area of the disease. Here we use a combination of techniques to assess dopamine signaling and its regulation during pre‐symptomatic disease stages. We hypothesized that we would observe increased dopamine transients in YAC128 positive mice when compared to littermate controls at this time point, and that activation of the M4 receptor with the M4 selective positive allosteric modulator (PAM) VU’154 would normalize transient amplitude in YAC128 mice. Using fast scanning cyclic voltammetry (FSCV), we recorded dopamine signaling in pre‐symptomatic YAC128 mice via ex vivo preparations. We also used, fiber photometry to record dopamine signaling in vivo, in the same mouse strain. We found that indeed, DA transient amplitudes are increased in pre‐symptomatic YAC128 mice when compared to littermate controls in both ex vivo and in vivo settings. Additionally, we report that activation of the M4 receptor is able to normalize the enhanced DA signaling in HD mice. These findings are some of the first to directly show increased DA signaling in the basal ganglia in early stage HD rodent models and support previous evidence that M4 ­­­­­­­is potentially an exciting target for normalizing aberrant neurotransmission in HD.

Classification of Huntington's Disease Stage with Features Derived from Structural and Diffusion-Weighted Imaging.

The purpose of this study was to classify Huntington’s disease (HD) stage using support vector machines and measures derived from T1- and diffusion-weighted imaging. The effects of feature selection approach and combination of imaging modalities are assessed. Fourteen premanifest-HD individuals (Pre-HD; on average > 20 years from estimated disease onset), eleven early-manifest HD (Early-HD) patients, and eighteen healthy controls (HC) participated in the study. We compared three feature selection approaches: (i) whole-brain segmented grey matter (GM; voxel-based measure) or fractional anisotropy (FA) values; (ii) GM or FA values from subcortical regions-of-interest (caudate, putamen, pallidum); and (iii) automated selection of GM or FA values with the algorithm Relief-F. We assessed single- and multi-kernel approaches to classify combined GM and FA measures. Significant classifications were achieved between Early-HD and Pre-HD or HC individuals (accuracy: generally, 85% to 95%), and between Pre-HD and controls for the feature FA of the caudate ROI (74% accuracy). The combination of GM and FA measures did not result in higher performances. We demonstrate evidence on the high sensitivity of FA for the classification of the earliest Pre-HD stages, and successful distinction between HD stages.

Posterior reversible encephalopathy syndrome due to arterial hypertension may mark the onset of the symptomatic phase in Huntington's disease.

Autonomic dysregulation of cardiovascular functions marks early Huntingtons disease (HD). Blood-brain barrier (BBB) is dysfunctional in HD. A 37-year-old female carrying 41 CAG triplets in the huntingtin gene acutely presented with a multifaceted syndrome attributable to posterior reversible encephalopathy syndrome (PRES). Syndrome was associated with arterial hypertension (AHT). The syndrome fully recovered both by imaging and clinical signs after normalization of arterial pressure during hospitalization. Immediately after hospital discharge, the patient developed a complex psychiatric syndrome and choreic movements that represented conversion to the symptomatic phase of HD. A one-year later follow up clearly showed the patient had developed the symptomatic stage of HD by presenting both psychiatric symptoms and choreic movements. Onset of AHT may represent an early premonitory signal of HD becoming manifested. Induction of PRES might be associated with BBB impairment in HD.

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment.

In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5–3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.

Does physical activity improve motor function and gait in huntington disease? A systematic review and meta-analysis.

Huntington's disease (HD) is a degeneration of the brain. To assess the evidence of the physical activity (PA) to improve motor function, gait speed, and walking endurance in individuals with HD. Two reviewers independently screened references and selected relevant studies to identify randomized controlled trials (RCT), from MEDLINE/PubMed, CENTRAL, PEDro, Scopus, CINAHL, Web of Science databases from inception to September 2021. Two reviewers evaluated risk of bias by the PEDro scale. The primary outcome was assessed motor function, gait speed and walking endurance as a secondary outcome was evaluated activities of daily living (ADL), lower limb functionality strenght, balance, mobility and cognition function in HD. Eight RCT were finally included (231 individuals). Forest plots showed a positive effect for gait endurance, the mean difference (MD) was 17.40 (95% CI from 5.40 to 29.35; p = 0.004), the MD lower limb functionality strength was 1.76 (95% CI from 0.18 to 3.33; p = 0.03) favoring PA group and the MD cognition function was 1.83 (95% CI from 0.50 to 3.16; p = 0.007). No benefits were found for motor function, gait speed, ADL, balance and mobility. Positive effects of programs PA were observed for walking endurance lower limb functionality strenght and cognition function in low and moderate stage of HD. However, no benefits were found for motor function, gait speed, ADL, balance and mobility. All authors included aerobic exercises in their programs but is unclear if vigorous and intensive PA is optimal for individuals with HD.

Huntington's Disease Gene Hunters: An Expanding Tale.

Huntington's Disease Gene Hunters: An Expanding Tale.

Cognition in Huntington's disease

Cognitive impairment is a well-known feature of Huntington's disease (HD). Generalized cognitive impairment is evident in various stages of HD including prodromal period of the disease. Cognitive and behavioral symptoms emerge many years before the onset of motor symptoms and are associated with functional decline in HD. Cognitive deficits in HD are widespread including abnormalities in processing speed, memory and executive functions. A substantial subset of patients with HD met criteria for mild cognitive impairment (MCI) in pre-HD stage.

Real-time three-dimensional tracking of single vesicles reveals abnormal motion and pools of synaptic vesicles in neurons of Huntington's disease mice

SummaryAlthough defective synaptic transmission was suggested to play a role in neurodegenerative diseases, the dynamics and vesicle pools of synaptic vesicles during neurodegeneration remain elusive. Here, we performed real-time three-dimensional tracking of single synaptic vesicles in cortical neurons from a mouse model of Huntington's disease (HD). Vesicles in HD neurons had a larger net displacement and radius of gyration compared with wild-type neurons. Vesicles with high release probability (Pr) were interspersed with low-Pr vesicles in HD neurons, whereas high-Pr vesicles were closer to fusion sites than low-Pr in wild-type neurons. Non-releasing vesicles in HD neurons had an abnormally high prevalence of irregular oscillatory motion. These abnormal dynamics and vesicle pools were rescued by overexpressing Rab11, and the abnormal irregular oscillatory motion was rescued by jasplakinolide. Our studies reveal the abnormal dynamics and pools of synaptic vesicles in the early stages of HD, suggesting a possible pathogenic mechanism of neurodegenerative diseases.

The experience of a sample of individuals in the United Kingdom living in the pre-manifest stage of Huntington's disease: An interpretative phenomenological analysis.

This paper explores the experience of ten individuals living in the UK who were in the pre-manifest stage of Huntington's disease (HD), a genetic neurodegenerative condition. Data were gathered using semi-structured interviews and analyzed using interpretative phenomenological analysis. Three themes were reported from the data: 'feeling limited by time', 'the perception of stalling time', and 'making the most of time', all highlighting the way in which time holds significant meaning when living in the pre-manifest stage of HD. This study has highlighted the difficulties experienced by individuals when adjusting to the pre-manifest stage of HD. Feeling able to manage their anxieties and dealing with ongoing uncertainty related to future deterioration was key to supporting their wellbeing, facilitated by factors such as positivity and hope. Individuals may benefit from counseling which supports them to develop proactive coping strategies to manage their anxieties and acceptance of an uncertain future.

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington's disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

Visual hallucinations in Gentington's disease: ophthalmic validation of ‘North-East Visual Hallucinations Interview

Huntington's disease (HD) is a steadily progressive neurodegenerative disease caused by a mutation in the huntingtin gene, with progressive motor, cognitive and mental impairments.The aim of the study is to determine the validity of the North‑East Visual Hallucinations Interview (NEVHI) in a Russian sample of patients.Materials and methods. 78 subjects were examined: 26 patients at the manifest stage of HD, 21 pre‑manifest carriers of the HD gene and 31 volunteers of the control group.Results. The low incidence of visual hallucinations according to the NEVHI does not allow us to conclude about their specificity for HD. Failure to achieve the level of statistical significance in this case suggests a high risk of type II error associated with the low occurrence of the symptom and the relatively small group size.Conclusion. The study showed that the NEVHI questionnaire can serve as an adequate method for the diagnosis of visual hallucinations in HD.

The prevalence of pain in Huntington's disease in a large worldwide cohort

IntroductionPain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers. MethodsA cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons. ResultsIn the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%–35%), of painful conditions 17% (95% CI 15%–19%) and analgesic use 13% (95% CI 11%–15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%–35%] vs 42% [95% CI 39%–45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%–18%] vs 12% [95% CI 10%–14%], 15% [95% CI 13%–17%], P < 0,01]. No significant group difference was present in analgesic use. ConclusionsThe prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain.

Prolong psychosis preceding cognitive and motor symptoms; an unusual presentation in Huntington's disease

ObjectiveTo describe an unusual clinical presentation of Huntington's disease.Case reportA 39-years-old married female, a homemaker, presented to the psychiatry clinic with her husband, with over a nine-year history of decreased sleep, suspiciousness, self-talking, agitation, anger outbursts, aggression, and social isolation. The patient was diagnosed with schizophrenia. Previously, she received various antipsychotics and Electroconvulsive therapy (ECT). The patient showed a partial response to treatment. Over the last 2-3 years, the patient had a progressive decline and later required supervision in her Activities of Daily Living (ADLs). She developed slurred speech limited to 1-2 worded answers, gait disturbance, falls, involuntary movements of the trunk and distal extremities, bowel and bladder incontinence, and severe weight loss. The patient's mother and older brother had a history of death in their early 40s due to an unknown cause.At presentation, the patient was restless, irritable, self-talking incoherently, neither made nor maintained eye contact and tried hitting and biting upon approaching closely. She did not respond to any queries or followed commands. The patient showed poor personal hygiene. On examination, the patient was hemodynamically stable, had a loss of muscle bulk, broad-based gait, and choreiform movements of the trunk and distal extremities. We admitted the patient to the psychiatry ward and also consulted the neurology team. Her blood investigations showed ASMA antibodies positive, MRI brain was suggestive of Huntington's disease (HD), and her genetic test for Huntington gene confirmed the diagnosis of HD. We started the patient on Fluoxetine, Clonazepam, and Olanzapine. The patient showed a decrease in agitation, and her self-talking stopped.DiscussionHD is a rare genetic disease that has well-characterized symptoms. However, as seen in our patient, these symptoms can evolve and progress unusually in the early and middle stages. Psychosis in HD patients is rare but known. Psychosis is rare in HD and usually presents after a clear clinical picture of HD is apparent. Our case discussed psychotic symptoms in the pre-choreic stage of HD which adds to the existing evidence on challenging presentations and management of HD. Further research can help increase confidence in these outcomes and treatment guidelines.ConclusionOur case highlights an unusual clinical presentation of HD, which can be challenging and lead to diagnostic delays. We recommend a thorough approach to history and revision of diagnosis in case of atypical presentations.

Abnormal patterns of sleep and EEG power distribution during non-rapid eye movement sleep in the sheep model of Huntington's disease

Sleep disruption is a common invisible symptom of neurological dysfunction in Huntington's disease (HD) that takes an insidious toll on well-being of patients. Here we used electroencephalography (EEG) to examine sleep in 6 year old OVT73 transgenic sheep (Ovis aries) that we used as a presymptomatic model of HD. We hypothesized that despite the lack of overt symptoms of HD at this age, early alterations of the sleep-wake pattern and EEG powers may already be present. We recorded EEG from female transgenic and normal sheep (5/group) during two undisturbed ‘baseline’ nights with different lighting conditions. We then recorded continuously through a night of sleep disruption and the following 24 h (recovery day and night). On baseline nights, regardless of whether the lights were on or off, transgenic sheep spent more time awake than normal sheep particularly at the beginning of the night. Furthermore, there were significant differences between transgenic and normal sheep in both EEG power and its pattern of distribution during non-rapid eye movement (NREM) sleep. In particular, there was a significant decrease in delta (0.5–4 Hz) power across the night in transgenic compared to normal sheep, and the distributions of delta, theta and alpha oscillations that typically dominate the EEG in the first half of the night of normal sheep were skewed so they were predominant in the second, rather than the first half of the night in transgenic sheep. Interestingly, the effect of sleep disruption on normal sheep was also to skew the pattern of distribution of EEG powers so they looked more like that of transgenic sheep under baseline conditions. Thus it is possible that transgenic sheep exist in a state that resemble a chronic state of physiological sleep deprivation. During the sleep recovery period, normal sheep showed a significant ‘rebound’ increase in delta power with frontal dominance. A similar rebound was not seen in transgenic sheep, suggesting that their homeostatic response to sleep deprivation is abnormal. Although sleep abnormalities in early stage HD patients are subtle, with patients often unaware of their existence, they may contribute to impairment of neurological function that herald the onset of disease. A better understanding of the mechanisms underlying EEG abnormalities in early stage HD would give insight into how, and when, they progress into the sleep disorder. The transgenic sheep model is ideally positioned for studies of the earliest phase of disease when sleep abnormalities first emerge.

Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology.

ObjectiveTo define the role played by microglia in different stages of Huntington disease (HD), we used the TSPO radioligand [11C]-ER176 and PET to evaluate microglial activation in relation to neurodegeneration and in relation to the clinical features seen at premanifest and manifest stages of the disease.MethodsThis is a cross-sectional study in which 18 subjects (6 controls, 6 premanifest, and 6 manifest HD gene carriers) underwent a [11C]-ER176 PET scan and an MRI for anatomic localization. Segmentation of regions of interest (ROIs) was performed, and group differences in [11C]-ER176 binding (used to evaluate the extent of microglial activation) were assessed by the standardized uptake value ratio (SUVR). Microglial activation was correlated with ROIs volumes, disease burden, and the scores obtained in the clinical scales. As an exploratory aim, we evaluated the dynamic functions of microglia in vitro, by using induced microglia-like (iMG) cells from peripheral blood monocytes.ResultsIndividuals with manifest HD present higher [11C]-ER176 SUVR in both globi pallidi and putamina in comparison with controls. No differences were observed when we compared premanifest HD with controls or with manifest HD. We also found a significant correlation between increased microglial activation and cumulative disease burden, and with reduced volumes. iMG from controls, premanifest HD, and manifest HD patients showed similar phagocytic capacity.ConclusionsAltogether, our data demonstrate that microglial activation is involved in HD pathophysiology and is associated with disease progression.

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.

High-Throughput Sequencing of BACHD Mice Reveals Upregulation of Neuroprotective miRNAs at the Pre-Symptomatic Stage of Huntington's Disease.

Huntington’s disease (HD) is a genetic disorder marked by transcriptional alterations that result in neuronal impairment and death. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and fine-tuning of gene expression. Several studies identified altered miRNA expression in HD and other neurodegenerative diseases, however their roles in early stages of HD remain elusive. Here, we deep-sequenced miRNAs from the striatum of the HD mouse model, BACHD, at the age of 2 and 8 months, representing the pre-symptomatic and symptomatic stages of the disease. Our results show that 44 and 26 miRNAs were differentially expressed in 2- and 8-month-old BACHD mice, respectively, as compared to wild-type controls. Over-representation analysis suggested that miRNAs up-regulated in 2-month-old mice control the expression of genes crucial for PI3K-Akt and mTOR cell signaling pathways. Conversely, miRNAs regulating genes involved in neuronal disorders were down-regulated in 2-month-old BACHD mice. Interestingly, primary striatal neurons treated with anti-miRs targeting two up-regulated miRNAs, miR-449c-5p and miR-146b-5p, showed higher levels of cell death. Therefore, our results suggest that the miRNAs altered in 2-month-old BACHD mice regulate genes involved in the promotion of cell survival. Notably, over-representation suggested that targets of differentially expressed miRNAs at the age of 8 months were not significantly enriched for the same pathways. Together, our data shed light on the role of miRNAs in the initial stages of HD, suggesting a neuroprotective role as an attempt to maintain or reestablish cellular homeostasis.

Is Ataxia an Underestimated Symptom of Huntington's Disease?

Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum.Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD.Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity.Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001).Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.