Huntington's Chorea Research Articles

Rational approaches for the design of various GABA modulators and their clinical progression.

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

The impact of proteostasis dysfunction secondary to environmental and genetic causes on neurodegenerative diseases progression and potential therapeutic intervention.

Aggregation of particular proteins in the form of inclusion bodies or plaques followed by neuronal death is a hallmark of neurodegenerative proteopathies such as primary Parkinsonism, Alzheimer's disease, Lou Gehrig's disease, and Huntington's chorea. Complex polygenic and environmental factors implicated in these proteopathies. Accumulation of proteins in these disorders indicates a substantial disruption in protein homeostasis (proteostasis). Proteostasis or cellular proteome homeostasis is attained by the synchronization of a group of cellular mechanisms called the proteostasis network (PN), which is responsible for the stability of the proteome and achieves the equilibrium between synthesis, folding, and degradation of proteins. In this review, we will discuss the different types of PN and the impact of PN component dysfunction on the four major neurodegenerative diseases mentioned earlier. Graphical abstract.

Apathy as a non-motor symptom of Parkinson's disease and Huntington's chorea

Apathy as a non-motor symptom of Parkinson's disease and Huntington's chorea

Evolutionary Medicine – A Great Way to Teach Biology

Great teaching is often all about the questions posed to students. When learners get their teeth into an interesting question, they grow as they chew on it. As physicians, we have discovered that disease makes more sense if you ask evolutionary questions, and these questions make a great starting point for science education. One of Darwin's two main questions was how species are related to each other. His answer was that all organisms have common ancestors. This is the foundation for studies of phylogeny. To teach phylogenetic trees, you can use canids or birds, but students are particularly interested if they are tracing the origins of HIV or tuberculosis, or the history of human traits, such as the appendix. Darwin's other question was about why bodies work so well. His answer was natural selection. The characteristics of individuals who have more offspring than others become more common over the generations. This explains why kidneys, hearts, eyes, and brains are so astoundingly well suited to their purposes. As physicians, we constantly confront a very different question. If natural selection is so …

Why Did the Nazis Sterilize the Blind? Genetics and the Shaping of the Sterilization Law of 1933

AbstractThe introduction of blindness into the Sterilization Law passed by the Nazis in July 1933, was exceptional, even by the standards of the time. Prior sterilization bills had focused on mental and nervous disorders, and they almost always excluded blindness as a category. The wish to sterilize the blind cannot be explained solely as stemming from the eugenic or economic threat that they allegedly posed to German society; such threats were acknowledged to be marginal, and they paled in comparison to the perceived menace attributed to the so-called feeble-minded and mentally ill. What made blindness of special significance for Nazi lawmakers was its disciplinary status among geneticists as an indisputable demonstration of the validity of the laws of heredity to human maladies. Together with two additional disease categories—deafness and Huntington's chorea—blindness provided Nazi legislators with scientific legitimization that helped pave the way for the sterilization of the mentally ill. For the blind, it was therefore not the fanaticism of the Nazis but rather their aspiration to ground their policy in biological teaching that ultimately proved fateful.

Quinoline analogs of 2-aminoindane as potential central dopaminergic agents

Neurodegenerative disorders such as Parkinson and Huntington Chorea are related with damage to the central dopaminergic system. On the purpose to find new drugs able to re-establish the imbalance on the dopaminergic neurotransmission in the central nervous system and counteract some of the neurodegenerative sicknesses, we have designed, synthesized, pharmacologically evaluated, and studied through molecular modeling,2-aminoindane-quinoline analog derivatives (1–5). Pharmacological studies made on the central nervous system through ICV (intracerebroventricular) and IS (intrastriatal), of compounds (1–5) showed agonistic activity by the activation of dopaminergic mechanisms on the central nervous system. The corresponding molecular modeling study permitted us not only to explain the differential behavior of studied compounds, but also to understand whichmolecular interactions are responsible to stabilize the different complexes formed between those compounds and the D2 receptor. These results validate our medicinal chemical approach in different aspects: the receptor model used, the responsible fragment inserted within the structure of the compounds capable of interacting with the receptor, the complementary functional groups that facilitate the expected response and the pharmacological administration routes. All these aspects are important for the design of this type of compounds as potential anti-Parkinson and/or anti-Huntington agents.

Huntington's chorea in a child. The first description of the disease in Ukraine. Proper observation

Huntington's chorea in a child. The first description of the disease in Ukraine. Proper observation

Cancer-Related Fatigue: Perception of Effort or Task Failure?

Patient's rating of perceived effort (RPE) is used to assess central fatigue. Cancer-related fatigue (CRF) is believed to be of central origin. The increased RPE with a motor task, such as the Finger-Tapping Test (FTT), can easily be measured in the clinical setting. To correlate the FTT, RPE and the Brief Fatigue Inventory (BFI) rated fatigue severity in patients with cancer. Subjective fatigue was assessed in adult patients with cancer by the BFI. Participants performed a modified FTT with the index finger of the dominant hand: 15 seconds × 2, 30 seconds × 2, and 60 seconds × 2 with 1 minute of rest between each time trial. Rating of perceived effort at the end of task was measured by the Borg 10 scale. Brain metastasis, history of brain radiation, Parkinson disease, Huntington Chorea, multiple sclerosis, delirium, and depression. Pearson correlation coefficients were used to describe the relationships between BFI, FTT, and Borg 10 scale. Thirty patients participated. Mean age was 56.2. Sixteen were females (53.3%). The mean BFI mean was 4.1, median 4.4. Tapping rate did not correlate with fatigue severity. The RPE correlated with the mean BFI: r s 0.438, P = .0155. These correlations persisted after adjustment for age. An increased RPE in the absence of task failure suggests that the origin of CRF is central. The performance of an FTT with RPE helps to improve our understanding of fatigue in the clinical setting.

Alternative Routes of Administration of the Neuroprotective Pituitary Adenylate Cyclase Activating Polypeptide.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with diverse actions, including strong neurotrophic and neuroprotective effects. The aim of our present review is to provide a summary of the different approaches how in vivo neuroprotective effects can be achieved, emphasizing the potential translational values for future therapeutic applications. In the central nervous system, PACAP has been shown to have in vivo protective effects in models of cerebral ischemia, Parkinson's and Alzheimer's disease, Huntington chorea, traumatic brain and spinal cord injury and different retinal pathologies. PACAP passes through the bloodbrain barrier and therefore, systemic administration can affect the nervous system and lead to neuroprotective effects. This review summarizes results obtained in neuronal injury studies via local, such as intracerebral, intrathecal, intracerebroventricular, intravitreal and systemic treatments, such as intravenous, intraperitoneal and subcutaneous administration of PACAP. A few other options are summarized, like intranasal and eye drops treatments, as well as difficulties and side effects of different treatments are also discussed.

Enzymatic and non-enzymatic pathways of kynurenines' dimerization: the molecular factors for oxidative stress development.

Kynurenines, the products of tryptophan oxidative degradation, are involved in multiple neuropathologies, such as Huntington's chorea, Parkinson's disease, senile dementia, etc. The major cause for hydroxykynurenines's neurotoxicity is the oxidative stress induced by the reactive oxygen species (ROS), the by-products of L-3-hydroxykynurenine (L-3HOK) and 3-hydroxyanthranilic acid (3HAA) oxidative self-dimerization. 2-aminophenol (2AP), a structural precursor of L-3HOK and 3HAA, undergoes the oxidative conjugation to form 2-aminophenoxazinone. There are several modes of 2AP dimerization, including both enzymatic and non-enzymatic stages. In this study, the free energies for 2AP, L-3HOK and 3HAA dimerization stages have been calculated at B3LYP/6-311G(d,p)//6-311+(O)+G(d) level, both in the gas phase and in heptane or water solution. For the intermediates, ionization potentials and electron affinities were calculated, as well as free energy and kinetics of molecular oxygen interaction with several non-enzymatically formed dimers. H-atom donating power of the intermediates increases upon the progress of the oxidation, making possible generation of hydroperoxyl radical or hydrogen peroxide from O2 at the last stages. Among the dimerization intermediates, 2-aminophenoxazinole derivatives have the lowest ionization potential and can reduce O2 to superoxide anion. The rate for O-H homolytic bond dissociation is significantly higher than that for C-H bond in non-enzymatic quinoneimine conjugate. However, the last reaction passes irreversibly, reducing O2 to hydroperoxyl radical. The inorganic ferrous iron and the heme group of Drosophila phenoxazinone synthase significantly reduce the energy cost of 2AP H-atom abstraction by O2. We have also shown experimentally that total antioxidant capacity decreases in Drosophila mutant cardinal with L-3HOK excess relative to the wild type Canton-S, and lipid peroxidation decreases in aged cardinal. Taken together, our data supports the conception of hydroxykynurenines' dual role in neurotoxicity: serving as antioxidants themselves, blocking lipid peroxidation by H-atom donation, they also can easily generate ROS upon dimerization, leading to the oxidative stress development.

Comparing Risperidone and Olanzapine to Tetrabenazine for the Management of Chorea in Huntington Disease: An Analysis from the Enroll-HD Database.

Huntington's chorea (HC) is commonly managed with neuroleptic medications, though there is little evidence to support their use. This study aimed to perform a real-world comparison of the efficacy of risperidone and olanzapine to tetrabenazine (TBZ) for HC. The Enroll-HD database was used to perform a propensity score-matched comparison of risperidone and olanzapine to TBZ, regarding their efficacy in controlling chorea. Participants with motor manifest Huntington's disease (HD) were grouped according to their use of risperidone, olanzapine, or TBZ. For the three groups, independent propensity score matching was performed on participants' baseline total functional score (TFC), baseline total motor score (TMS), disease burden score, CAG repeat length, baseline age, region, sex, and body mass index. Independent samples t test was used to calculate the differences between the groups in the annual rate of change of the TMS from the baseline to the second available visit. The risperidone (n = 72) and olanzapine groups (n = 77) had annualized increases (worsening) in the TMS of only 1.47 points and 3.20 points, respectively, compared to 5.70 points in the two matched TBZ groups (n = 72) (P = 0.019) and (n = 77) (P = 0.143), respectively. In the absence of prospective data, this analysis of the Enroll-HD database found that the neuroleptics risperidone and olanzapine seemed to at least be comparable to TBZ at controlling HC. These results demonstrate that neuroleptics may have comparable efficacy to TBZ for the treatment of HC. Further prospective studies are needed to confirm these findings.

Changes in recruitment of motor cortex excitation and inhibition in patients with drug-induced tardive syndromes

It has recently been suggested that drug-induced tardive syndromes (TS) might be due to maladaptive plasticity, which increases motor excitability in cerebral cortex and basal ganglia. In order to test this hypothesis, we performed the first measurements of cortical excitability in TS. Motor cortex excitability was examined using transcranial magnetic stimulation (TMS) in 22 TS patients and compared with that in 20 age and sex-matched healthy individuals. Resting and active motor threshold (RMT, AMT) and input-output curves (I/O curves) assessed corticospinal excitability. The duration of the contralateral silent period (cSP) at a range of stimulation intensities and ipsilateral silent period (iSP) were used as measures of inhibition. There were no significant differences in RMT and AMT between patients and controls, although the input-output curves were significantly steeper in patients. The cSP (at different stimulus intensities) and iSP were both longer in the patients compared to the control group. However, most of this difference could be accounted for by increased recruitment of motor evoked potentials (MEPs) in patients. TS is characterized by hyperexcitability of corticospinal output that might contribute to the lack of selectivity in muscle recruitment and contribute to excess involuntary movement. The findings are opposite to those in naturally-occurring hyperkinesia such as Sydenham's and Huntington's chorea, suggesting a fundamental difference in the pathophysiology.

Oxidative stress and neurodegeneration: the involvement of iron

Many evidences indicate that oxidative stress plays a significant role in a variety of human disease states, including neurodegenerative diseases. Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing proteins and enzymes, though it could be also toxic. Actually, free iron excess generates oxidative stress, particularly in brain, where anti-oxidative defences are relatively low. Its accumulation in specific regions is associated with pathogenesis in a variety of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis and Neurodegeneration with Brain Iron Accumulation). Anyway, the extent of toxicity is dictated, in part, by the localization of the iron complex within the cell (cytosolic, lysosomal and mitochondrial), its biochemical form, i.e., ferritin or hemosiderin, as well as the ability of the cell to prevent the generation and propagation of free radical by the wide range of antioxidants and cytoprotective enzymes in the cell. Particularly, ferrous iron can act as a catalyst in the Fenton reaction that potentiates oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals (·OH). The observation that patients with neurodegenerative diseases show a dramatic increase in their brain iron content, correlated with the production of reactive oxigen species in these areas of the brain, conceivably suggests that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. The aim of this review is to describe the chemical features of iron in human beings and iron induced toxicity in neurodegenerative diseases. Furthermore, the attention is focused on metal chelating drugs therapeutic strategies.

Reliability of the bicaudate parameter in the revealing of the enlarged lateral Ventricles in schizophrenia patients.

In schizophrenia patients the lateral ventricle enlargement has mostly been reported in relationship with smaller cortical and/or subcortical brain volumes; and it has been observed that ventricular system growth may be a consequence of the smaller caudate nucleus volume. Bicaudate parameters have been used in the Alzheimer dementia and Huntington's chorea diagnosing in order to evaluate brain changes and the enlargement of the lateral ventricles. This study has been carried out on 140 patients out of which 70 patients (30 men and 40 women) who met the ICD 10 criteria for schizophrenia and 70 healthy controls (30 men and 40 women) matched on sex and age with the studied group. All of them underwent direct caudatometry and volume computation based on MRI scans. Except for the bicorporal line, for all the parameters were obtained the statistically highly significant differences between the examined and control groups. Significant correlation was established for the majority of bicaudate parameters and volumes of the caudate nuclei and lateral ventricles. Enlargement of the lateral ventricles is one of the most frequent MRI finding in schizophrenia patients. Ventricles are enlarging gradually and frontal horns are more affected than other parts. The increased volumes of the caudate nuclei signalized that ventricular enlargement is not the consequence of the caudate atrophy. Bicaudate parameters are reliable parameters for the quick orientation in order to assess the enlarged ventricles in schizophrenia patients.

HTT Gene Premutation Allele Frequencies in the Russian Federation

Huntington disease (Huntington chorea, HD) is a severe neurodegenerative disease determined by polyglutamine. Polyglutamine expansion in exon 1 of the HTT gene causes Huntington disease. To date, less than 35 CAG triplets are suggested to be present in normal alleles. Alleles bearing from 27 to 35 CAG repeats are generally considered as intermediate or premutation. Alleles with the number of CAG repeats varying from 36 to 39 demonstrate reduced penetrance and result in late manifestation of the disease. To date, no studies based on representative samples of Russian residents estimating the frequencies of premutation and alleles with reduced penetrance have been published. Meanwhile, this is extremely important for genetic counseling of patients bearing such alleles and for the calculation of risks for their offspring. In the present study, the analysis of samples of Russian patients with incoming diagnoses of Huntington chorea (N = 1092), Wilson–Konovalov disease (N = 333), Hallervorden–Spatz disease (N = 33) and a control group consisting of 230 unexamined individuals from the Russian Federation under 45 years of age was carried out. A spectrum of CAG repeat length in the HTT gene in patients with HD was obtained. Patients with HD were detected in the samples of patients with incoming diagnoses of Wilson–Konovalov disease and Hallervorden–Spatz disease. This observation indicates the complexity of differential diagnosis of these diseases. An assumption was made that an allele with 36 CAG repeats should be classified as premutation. We confirmed the previously observed trend for the increased number of CAG repeats in the case of paternal transmission of the mutant allele. The frequency of premutation allele of 2.6% in Russian residents was established.

Experience of Individuals With Huntington Disease and Chorea (P4.050)

Experience of Individuals With Huntington Disease and Chorea (P4.050)

Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings.

The principal symptoms of Huntington's disease (HD), chorea, cognitive deficits, and psychiatric symptoms are associated with the massive loss of striatal and cortical projection neurons. As current drug therapies only partially alleviate symptoms, finding alternative treatments has become peremptory. Cell replacement using stem cells is a rapidly expanding field that offers such an alternative. In this review, we examine recent studies that use mesenchymal cells, as well as pluripotent, cell-derived products in animal models of HD. Additionally, we provide further electrophysiological characterization of a human neural stem cell line, ESI-017, which has already demonstrated disease-modifying properties in two mouse models of HD. Overall, the field of regenerative medicine represents a viable and promising avenue for the treatment of neurodegenerative disorders including HD.

Neurodegenerative diseases

Neurodegenerative diseases are sporadic and rare hereditary disorders of the central nervous system, which cause a slowly progressive loss of function of specific neuron populations and their connections. Severe impairments and care dependency can be the sequelae. Neurodegenerative disorders are diseases of older people; therefore, the demographic shift leads to an increase in the number of affected patients. Radiologists will also become more involved. For this reason important neurodegenerative diseases are presented in this article. In addition to Alzheimer's and Parkinson's diseases these also include frontotemporal lobar degeneration, Lewy body dementia, vascular dementia, Creutzfeldt-Jakob disease and Huntington's chorea. The clinical symptoms and diagnostics are described, whereby the focus lies on typical results of morphological imaging.

Interrelationships Among Gut Microbiota and Host: Paradigms, Role in Neurodegenerative Diseases and Future Prospects.

Advances in the knowledge of the microbiota and concepts related to it have triggered a wake-up call in biomedicine. The development in various scientific areas has enabled a better and broader approach to everything concerning the set of families of microorganisms that coexist with an individual and are able to function as one or more organs in its body. Among the aforementioned scientific areas, those worth mentioning are the advances/progress in biotechnological resources and, in particular, molecular biology and related areas. This has given rise to the era of "omics", marking a turning point in the understanding of numerous physiologic and pathophysiologic processes of the organism. The current theory is that the microbiota and the host maintain an intimate relationship that is of a markedly bilateral nature. This continuous feedback has different connotations between one individual and another, but also within the same individual throughout its life span, which is determined by its own conditioning factors (such as its genetic profile), and environmental ones (mainly diet and lifestyles). Both elements (microbiota and host) coexist harmoniously, maintaining a balance, which can be altered and give rise to different morbid entities. Among these is its relation to chronic processes, and especially those of an autoimmune origin. Such may be neurological diseases situations and, specifically, those of a neurodegenerative nature. In disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and Alzheimer's disease, among others, it has been found that a disharmonic coexistence between microbiota and host may have implications in their etiology and pathogenesis. A better understanding of those implications has led to the development of actions on the gut microbiota as a target to slow down the advancement or establishment of neurodegeneration. In this scenario, several treatment strategies have emerged, such as probiotic food intake and stool transplantation. Their real potentialities remain to be elucidated, although current scientific evidence infers that the development of those therapeutic approaches could offer a ray of hope in the prospects of tackling neurodegenerative diseases.

A reversible liquid drop aggregation controls glucose response in yeast.

Glucose is the preferred carbon of the yeast Saccharomyces cerevisiae. Depletion of glucose activates SNF1 (yeast AMP-activated protein kinase-AMPK), allowing cells to switch from fermentation to respiration. We have recently characterized the mechanism by which SNF1 activity is regulated by the Std1 protein, and its regulator Sip5. The hitherto uncharacterized protein kinase Vhs1 phosphorylates Sip5 in response to glucose availability, disengaging it from Std1 and promoting the sequestering of the SNF1 activator out of the nucleus into cytoplasmic puncta. These aggregates, which have the properties of liquid drops, and not of amyloids, reside in the nucleus-vacuole junction. The process is reversible, and Std1 puncta dissolve when glucose becomes scarce again. This reversible process requires protein chaperones, similar to the aggregation of toxic or misfolded proteins such as those associated with Huntington's Chorea, Alzheimer's and CJD diseases. Our results thus reveal a regulated, non-pathological, physiological role of protein aggregation that controls a major metabolic cellular pathway.