Is brain lactate increased in Huntington's disease?

Impaired brain energy metabolism with increased regional brain lactate may play a role in the pathogenesis of Huntington's disease (HD). Magnetic resonance spectroscopy (MRS) has provided conflicting evidence, however, regarding metabolic changes. Our objective was to evaluate the potential contribution of CSF lactate to the changes observed with MRS in HD. We performed single voxel MRS at 3 T in 23 patients with HD and 28 age-matched control subjects using a method to segment voxels into grey matter, white matter, and CSF, and to extrapolate regional lactate content to a hypothetical voxel containing 100% brain in order to control for differences in CSF lactate. Lactate/creatine and lactate/N-acetyl aspartate (Lac/NAA) ratios were significantly increased in parieto-occipital (p<0.05) and cerebellar (p<0.01) voxels in HD patients. After extrapolating group Lac/NAA results to a theoretical voxel containing 100% brain, this ratio was greater in the HD group than the control group, suggesting possibly increased lactate in this predicted voxel, although the difference between groups did not reach statistical significance. These results suggest an increase in brain lactate content in manifest HD, in a regionally non-specific fashion, although the possibility of a CSF contribution to this increase cannot be ruled out. Regardless, this supports the possibility of impaired mitochondrial function resulting in abnormal brain energy metabolism in HD.     

Huntington's disease: effect of memantine on FDG-PET brain metabolism?

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.     

Can directed activity improve mobility in Huntington's disease?

Huntington's disease is an inherited disorder of the CNS that results in progressive deterioration of mobility and cognition and also affects behaviour. There are no disease-modifying interventions available to date, although there has been considerable progress in research directed at understanding the pathological basis of the disease with a view to identifying potential treatments. It is however important not to overlook currently available treatment strategies, including rehabilitation approaches. There has been little work to date to explore the potential of such approaches and here we highlight the need for more systematic studies in this area as well as the need for good objective assessment tools and the potential role that rehabilitation and training may have in the application of novel treatment options.     

Cerebellar abnormalities in Huntington's disease: A role in motor and psychiatric impairment?

The cerebellum has received limited attention in Huntington's disease (HD), despite signs of possible cerebellar dysfunction, including motor incoordination and impaired gait, which are currently attributed to basal ganglia atrophy and disrupted fronto‐striatal circuits. This study is the first to investigate a potential contribution of macro‐ and microstructural cerebellar damage to clinical manifestations of HD. T1‐ and diffusion‐weighted 3T magnetic resonance imaging (MRI) scans were obtained from 12 controls and 22 early‐stage HD participants. Manual delineation and voxel‐based morphometry were used to assess between‐group differences in cerebellar volume, and diffusion metrics were compared between groups within the cerebellar gray and white matter. Associations between these imaging measures and clinical scores were examined within the HD group. Reduced paravermal volume was detected in HD compared with controls using voxel‐based morphometry (P < 0.05), but no significant volumetric differences were found using manual delineation. Diffusion abnormalities were detected in both cerebellar gray matter and white matter. Smaller cerebellar volumes, although not significantly reduced, were significantly associated with impaired gait and psychiatric morbidity and of borderline significance with pronate/supinate‐hand task performance. Abnormal cerebellar diffusion was associated with increased total motor score, impaired saccade initiation, tandem walking, and timed finger tapping. In conclusion, atrophy of the paravermis, possibly encompassing the cerebellar nuclei, and microstructural abnormalities within the cerebellum may contribute to HD neuropathology. Aberrant cerebellar diffusion and reduced cerebellar volume together associate with impaired motor function and increased psychiatric symptoms in stage I HD, potentially implicating the cerebellum more centrally in HD presentation than previously recognized. © 2014 International Parkinson and Movement Disorder Society     

Histone methylation in Huntington's disease:are bivalent promoters the critical targets?

正Huntington’s disease(HD)is a currently incurable,late onset,progressive,ultimately fatal neurological disorder(Bates et al.,2015).We have recently published the results of comprehensive genetic interaction tests aimed at identification of histone methyltransferases and demethylases involved in HD pathogenesis in a Drosophila model of the disease(Song et al.,2018).The methylation state of histone proteins regulates the accessibility of     

Experimental therapeutics in Huntington's disease: are models useful for therapeutic trials?

PURPOSE OF REVIEW: Research conducted over the past 10 years has uncovered molecular mechanisms that are likely to be important in the early stages of Huntington's disease pathogenesis. This review summarizes the resources and strategies that are in place in order to exploit these new findings and use them to develop novel Huntington's disease therapeutics. The role that disease models will play in this process is discussed. RECENT FINDINGS: A wide variety of models of Huntington's disease have been developed including yeast, Caenorhabditis elegans, Drosophila melanogaster and mouse. These can be developed as screening assays for the identification of chemical compounds that show beneficial effects against a specific phenotype and for the cross validation of potential therapeutics. The first compounds arising through this drug development pipeline have been reported. Similarly, the preclinical screening of compounds in mouse models is being developed in a coordinated manner. SUMMARY: Our understanding of the molecular basis of Huntington's disease is increasing at an exponential rate. Over the next few years an increasing number of potential therapeutic compounds will have been identified. It will only be possible to take a small number of these through to phase III clinical trials. The challenge will be to use the in-vivo models of Huntington's disease to best predict which of these compounds should be pursued in the clinic, to avoid depleting the patient population willing to enter into trials, and demoralizing them by conducting repeated unsuccessful trials.     

What is the impact of education on Huntington's disease?

Huntington's disease (HD) is a neurodegenerative disease caused by a cytosine adenosine guanine (CAG) expansion in the huntingtin gene. The length of the triplet repeat is the most important factor in determining age of onset and the severity of the disease, but substantial variability of these parameters is attributed to other factors. To investigate the relationship between the years of education and the age at onset and the severity of the phenotype in patients with HD, we applied multiple linear regression analysis to examine the impact of education on the age at onset and the severity of the clinical scores assessed by the Unified Huntington's Disease Rating Scale (UHDRS) of 891 patients with HD from the multinational observational study “Registry” conducted by the European Huntintgton's Disease Network. The model was adjusted for CAG repeat length and age at the time of assessment. Patients with lengthier education exhibited earlier estimated age at onset but less severe clinical scores (motor = ?3.6, P = 0.006; cognitive = 27.0, P < 0.001; behavioral = ?3.0, P < 0.001; and functional capacity = 1.1 points, P < 0.001) than those with shorter education, after controlling for age and number of CAG repeats. These differences persisted throughout all quartiles of disease severity. An earlier recognition of symptoms and manifestations among the more educated patients could explain the earlier estimated age at onset in this group. The link between better clinical UHDRS scores and higher education might reflect a beneficial effect of education or its covariates on the course of HD. © 2011 Movement Disorder Society     

Aquaporins in cerebrovascular disease: a target for treatment of brain edema?

In cerebrovascular disease, edema formation is frequently observed within the first 7 days and is characterized by molecular and cellular changes in the neurovascular unit. The presence of water channels, aquaporins (AQPs), within the neurovascular unit has led to intensive research in understanding the underlying roles of each of the AQPs under normal conditions and in different diseases. In this review, we summarize some of the recent knowledge on AQPs, focusing on AQP4, the most abundant AQP in the central nervous system. Several experimental models illustrate that AQPs have dual, complex regulatory roles in edema formation and resolution. To date, no specific therapeutic agents have been developed to inhibit water flux through these channels. However, experimental results strongly suggest that this is an important area for future investigation. In fact, early inhibition of water channels may have positive effects in the prevention of edema formation. At later time points during the course of disease, AQP is important for the clearance of water from the brain into blood vessels. Thus, AQPs, and in particular AQP4, have important roles in the resolution of edema after brain injury. The function of these water channel proteins makes them an excellent therapeutic target.     

Pathologic gambling in Parkinson's disease: a behavioral manifestation of pharmacologic treatment?

We describe 12 patients with Parkinson's disease and pathologic gambling. This association has apparently never been reported. The patients were selected from a Parkinson's disease unit of 250 patients. They met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for pathologic gambling. All patients underwent a neurologic, psychiatric, and psychologic examination, specifically noting the presence or absence of psychopathology in the spectrum of impulse control disorder and the nature of the gambling. Ten patients started gambling after the onset of Parkinson's disease and treatment with levodopa. The pathologic behavior was exclusively present or was markedly increased in "on" periods in 11 patients. All patients had motor fluctuations at the time of the study. Slot machines were the preferred source of gambling for 10 patients, similar to the Spanish gambling population. That the gambling behavior appears more often in the "on" periods of motor fluctuations and that it begins after the onset of Parkinson's disease in most patients and worsens with levodopa therapy suggest that it could be related to the dopaminergic tone in patients with Parkinson's disease and motor fluctuations (that is, it could represent a behavioral manifestation of pharmacologic treatment).     

Huntington's disease: How intermediate are intermediate repeat lengths?

Background: Huntington's disease (HD) is a devastating heredoneurodegenerative disorder associated with a wide variety of neurological and psychiatric symptoms caused by an expanded CAG repeat in the HTT gene. The expansion mutation in HTT is dominantly transmitted and codes for a protein named huntingtin (htt). Hypothesis: One hypothesis, according to a multistep mechanism, is that the intergenerational transmission of the normal repeat size causes small, progressive CAG stretch elongations in the general population from one generation to another, until a critical pathological CAG repeat threshold is reached. Mutations may originate in the offspring from paternally transmitted CAG repeats, falling within an intermediate alleles (IA) range of 27 to 35 in repeat length. Conclusions: There has been emerging evidence that some individuals with IAs might develop an HD phenotype. This presents a challenge for genetic counseling, because these individuals are often reassured that they are “disease free.” However, there are many unanswered questions related to the role of IAs in the development of the HD phenotype and in the pathogenesis of HD. © 2012 Movement Disorder Society © 2012 Movement Disorder Society     

Is Huntington's a glutamine storage disease?

Huntington's disease is a neurological disorder caused by the expansion of a polyglutamine tract in the protein huntingtin. Several other neurological diseases also result from the expansion of polyglutamine regions in different proteins. Despite intense efforts, no definitive biochemical or physiological role for huntingtin has been described, nor has a function been assigned to the polyglutamine region in unaffected individuals. This article presents the hypothesis that polyglutamine expansions within huntingtin and other polyglutamine proteins provide a function in and of themselves. Incorporating multiple glutamine residues into a protein during synthesis, and releasing them during protein turnover, may represent a means of minimizing interruptions in brain levels of glutamine and glutamate during periods of malnutrition. The number and variety of different proteins containing polyglutamine expansions can be interpreted as a series of evolutionary "experiments" toward a nontoxic form for glutamine storage.     

A case of neuro-Beh?et's disease presenting with chorea]

A 46-year-old man was admitted to our hospital because of emotional instability and involuntary movement of the right upper limb. Neurological examination revealed inability to concentrate, emotional incontinence, recent memory disturbance, chorea of bilateral upper limbs and neck, and bilateral pyramidal signs. Brain MRI showed atrophy of bilateral caudate nucleus and diffuse abnormal intensity area with low intensity on T1-weighted images and high intensity on T2-weighted images in cerebral white matter around the lateral ventricles. Huntington's disease was suspected at first, but it was ruled out by DNA analysis. After admission, oral and genital aphthae developed and the CSF examination showed pleocytosis (273 leukocytes/mm3; 39 polymorphonuclear leukocytes and 234 lymphocytes), so we diagnosed this case as neuro-Beh?et's disease. Although basal ganglia is occasionally involved in neuro-Beh?et's disease, chorea is rare. Neuro-Beh?et's disease should be considered as a cause of chorea.     

Functional compensation or pathology in cortico-subcortical interactions in preclinical Huntington's disease?

Huntington's disease (HD) is an autosomal dominant neurological disorder, with degeneration amongst others affecting the basal ganglia dopaminergic system. Recent findings suggest compensatory as well as pathogenetic mechanisms mediated via the adenosine receptor system in the presymptomatic stage (pHD) of HD. The adenosine receptor system is functionally related to the dopaminergic system. In this study, we assessed error processing, a dopamine-dependent cognitive function, using an event-related potential the error negativity (Ne/ERN) in pHD and controls. This was done by means of a flanker task. The Ne consists of a cognitive and a motor component, expressed via different frequency bands. Time-frequency decomposition of the Ne into delta and theta sub-components was applied to assess if degeneration or compensation predominantly involve cognitive or motor processes. No parameter of the behavioral data (reaction times, error frequency, corrections, post-error slowing) differed between the groups. A selective increase in the power of the cognitive delta-Ne component was found in pHD relative to controls inversely related to the estimated age of onset (eAO). Thus, the increase in the power of the cognitive delta-Ne component was stronger in pHD with an earlier eAO. An earlier eAO implies stronger pathogenetic mechanisms. Due to the behavioral data our results speak for a solely cognitive compensating-mechanism controlling performance monitoring in pHD. In contrast, correlations with eAO suggest that the increase in delta-Ne activity is also related to pathogenesis. It is proposed that compensation is a transient effect of the whole pathogenetic dynamics of HD, with these two processes not foreclosing each other.     

Hereditary chorea – what else to consider when the Huntington's disease genetics test is negative?

Chorea, cognitive, behavioural and psychiatric disturbance occur in varying combinations in Huntington's disease (HD). This is often easy to recognise particularly in the presence of an autosomal dominant history. Whilst HD may be the most common aetiology of such a presentation, several HD phenocopies should be considered if genetic testing for HD is negative. We searched PubMed and the Cochrane Database from January 1, 1946 up to January 1, 2016, combining the search terms: ‘chorea’, ‘Huntington's disease’, ‘HDL’ and ‘phenocopies’. HD phenocopies frequently display additional movement disorders such as myoclonus, dystonia, parkinsonism and tics. Here, we discuss the phenotypes, and investigations of HD‐like disorders where the combination of progressive chorea and cognitive impairment is obvious, but HD gene test result is negative. Conditions presenting with sudden onset chorea such as vascular, infectious and autoimmune causes are not the primary focus of our discussion, but we will make a passing reference to these as some of these conditions are potentially treatable. Hereditary forms of chorea are a heterogeneous group of conditions and this number is increasing. While most of these conditions are not curable, molecular genetic testing has enabled many of these disorders to be distinguished from HD. Getting a precise diagnosis may enable patients and their families to better understand the nature of their condition.     

Pharmacological treatment of Parkinson’s disease: life beyond dopamine D2/D3 receptors?

Summary. Parkinson’s disease (PD) is a multisystemic disorder in which several neurotransmitters other than dopamine are affected. Drugs acting on non-dopaminergic systems are envisaged as promising agents to treat PD and levodopa-induced dyskinesias (LID). However, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed in human studies showing negative, inconsistent or unsatisfactory results. Most of these drugs had been tested previously in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, as well as in the classic 6-hydroxydopamine-lesioned rat model. These failures raise several questions and concerns about the true reliability of animal studies, the adequacy of the working hypotheses and design of clinical trials, the validity of tools in current use to evaluate a particular effect, and the selectivity of the drugs used. More importantly, observed discrepancies between the results in models and patients, could challenge the validity of current ideas about the pathophysiology of parkinsonism and LID. Correspondence: Gurutz Linazasoro, Centro Investigación Parkinson, Policlínica Gipuzkoa, Parque Tecnológico Miramón, 20009 San Sebastián (Gipuzkoa), Spain