Huntington disease research
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"Recent Huntington disease publications are scanned daily from major neurology journals and updated here" Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. Related Articles
Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.
J Clin Invest. 2007 Nov;117(11):3258-70
Huntington disease research Authors: Zinnanti WJ, Lazovic J, Housman C, LaNoue K, O'Callaghan JP, Simpson I, Woontner M, Goodman SI, Connor JR, Jacobs RE, Cheng KC
Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA- I.
Huntington disease research PMID: 17932566 [PubMed - in process]Thalamic metabolism and symptom onset in preclinical Huntington's disease. Related Articles
Thalamic metabolism and symptom onset in preclinical Huntington's disease.
Brain. 2007 Nov;130(Pt 11):2858-67
Huntington disease research Authors: Feigin A, Tang C, Ma Y, Mattis P, Zgaljardic D, Guttman M, Paulsen JS, Dhawan V, Eidelberg D
The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]- fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD- related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.
Huntington disease research PMID: 17893097 [PubMed - indexed for MEDLINE]Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. Related Articles
Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease.
J Clin Invest. 2007 Oct;117(10):2889-902
Huntington disease research Authors: Cho SR, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman SA
Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU(+) betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease.
Huntington disease research PMID: 17885687 [PubMed - indexed for MEDLINE]Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington's disease: evidence from event-related fMRI. Related Articles
Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington's disease: evidence from event-related fMRI.
Brain. 2007 Nov;130(Pt 11):2845-57
Huntington disease research Authors: Wolf RC, Vasic N, Schönfeldt-Lecuona C, Landwehrmeyer GB, Ecker D
Evidence from magnetic resonance imaging (MRI) suggests early structural and functional brain changes in individuals with the Huntington's disease (HD) gene mutation who are presymptomatic for the motor symptoms of the disorder (pre-HD subjects). The objective of this study was to investigate the functional neuroanatomy of verbal working memory (WM) in pre-HD subjects. By means of event-related functional MRI, we studied healthy controls (n = 16) and pre-HD subjects (n = 16) with a parametric WM paradigm comprising three different WM load levels. Voxel-based morphometry (VBM) was used to control potentially confounding brain atrophy. Although WM performance did not significantly differ between pre-HD subjects and healthy controls, pre-HD subjects showed a significantly decreased activation of the left dorsolateral prefrontal cortex (DLPFC) at intermediate and high WM load levels only. This region was not affected by early cortical atrophy, as revealed by VBM. Pre-HD individuals close to the onset of motor symptoms showed an increased activation of the left inferior parietal lobule and the right superior frontal gyrus compared with both pre-HD subjects far from symptom onset and healthy controls. In addition, the activation level in the left DLPFC was positively correlated with the UHDRS cognitive subscore in pre-HD subjects. Our findings demonstrate that early functional brain changes in pre-HD subjects may occur in the DLPFC before manifest cortical atrophy, and support a role of this region in the expression of clinical symptoms. Compensatory brain responses in pre-HD individuals may occur with closer proximity to the onset of manifest clinical symptoms.
Huntington disease research PMID: 17855375 [PubMed - indexed for MEDLINE]Morphology of the cerebral cortex in preclinical Huntington's disease. Related Articles
Morphology of the cerebral cortex in preclinical Huntington's disease.
Am J Psychiatry. 2007 Sep;164(9):1428-34
Huntington disease research Authors: Nopoulos P, Magnotta VA, Mikos A, Paulson H, Andreasen NC, Paulsen JS
OBJECTIVE: Cortical morphology was evaluated in subjects with known gene expansion for Huntington's disease and no manifest disease. METHOD: Magnetic resonance imaging scans were obtained for 24 subjects with preclinical Huntington's disease and were compared to those for 24 matched healthy subjects by means of novel imaging methods to quantify aspects of cortical structure. RESULTS: In relation to the comparison subjects, those with preclinical Huntington's disease showed altered cortex morphology with enlargement of gyral crowns and abnormally thin sulci. These changes were manifested in global alterations of gyral and sulcal shape. CONCLUSION: These findings lend support to the notion that, in addition to the degenerative process, abnormal neural development may also be an important process in the pathoetiology of Huntington's disease.
Huntington disease research PMID: 17728429 [PubMed - indexed for MEDLINE]Huntington's disease: getting closer. Related Articles
Huntington's disease: getting closer.
Am J Psychiatry. 2007 Sep;164(9):1318
Huntington disease research Authors: Greenamyre JT
Huntington disease research PMID: 17728414 [PubMed - indexed for MEDLINE]Disease targets and strategies for the therapeutic modulation of endogenous neural stem and progenitor cells. Related Articles
Disease targets and strategies for the therapeutic modulation of endogenous neural stem and progenitor cells.
Clin Pharmacol Ther. 2007 Oct;82(4):453-60
Huntington disease research Authors: Goldman SA
Neural stem cells, able to self-renew and give rise to both neurons and glia, line the cerebral ventricles of the adult human brain. Humans also harbor lineage-restricted neuronal progenitors in the hippocampus and glial progenitor cells in both the gray and white matter of the forebrain. These various stem and progenitor cell types may provide targets for pharmacotherapy for a variety of disorders of the central nervous system. Each resident progenitor phenotype may be mobilized and induced to differentiate in vivo by the actions of both exogenous growth factors and small molecule modulators of progenitor-selective signaling pathways. This strategy may be particularly efficacious in neurodegenerations such as Huntington's disease, in which lost neurons may be replenished through the directed induction of progenitor cells lining the ventricular wall of the affected striatum. Similarly, the mobilization of glial progenitor cells may permit the introduction of new oligodendrocytes to demyelinated regions of adult white matter. Our rapidly increasing understanding of the molecular control of progenitor cell mobilization and differentiation should provide a wealth of new opportunities for recruiting endogenous progenitors as a means of treating neurological disease.
Huntington disease research PMID: 17713467 [PubMed - indexed for MEDLINE]Beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington's disease. Related Articles
Beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington's disease.
Brain. 2007 Jul;130(Pt 7):1732-44
Huntington disease research Authors: Johnson SA, Stout JC, Solomon AC, Langbehn DR, Aylward EH, Cruce CB, Ross CA, Nance M, Kayson E, Julian-Baros E, Hayden MR, Kieburtz K, Guttman M, Oakes D, Shoulson I, Beglinger L, Duff K, Penziner E, Paulsen JS,
Previous studies of emotion recognition suggest that detection of disgust relies on processing within the basal ganglia and insula. Research involving individuals with symptomatic and pre-diagnostic Huntington's disease (HD), a disease with known basal ganglia atrophy, has generally indicated a relative impairment in recognizing disgust. However, some data have suggested that recognition of other emotions (particularly fear and anger) may also be affected in HD, and a recent study found fear recognition deficits in the absence of other emotion-recognition impairments, including disgust. To further examine emotion recognition in HD, we administered a computerized facial emotion recognition task to 475 individuals with the HD CAG expansion and 57 individuals without. Logistic regression was used to examine associations of emotion recognition performance with estimated proximity to clinical diagnosis (based on CAG repeat length and current age) and striatal volumes. Recognition of anger, disgust, fear, sadness and surprise (but not happiness) was associated with estimated years to clinical diagnosis; performance was unrelated to striatal volumes. Compared to a CAG-normal control group, the CAG-expanded group demonstrated significantly less accurate recognition of all negative emotions (anger, disgust, fear, sadness). Additionally, participants with more pronounced motor signs of HD were significantly less accurate at recognizing negative emotions than were individuals with fewer motor signs. Findings indicate that recognition of all negative emotions declines early in the disease process, and poorer performance is associated with closer proximity to clinical diagnosis. In contrast to previous results, we found no evidence of relative impairments in recognizing disgust or fear, and no evidence to support a link between the striatum and disgust recognition.
Huntington disease research PMID: 17584778 [PubMed - indexed for MEDLINE]Psychiatric and cognitive difficulties as indicators of juvenile huntington disease onset in 29 patients. Related Articles
Psychiatric and cognitive difficulties as indicators of juvenile huntington disease onset in 29 patients.
Arch Neurol. 2007 Jun;64(6):813-9
Huntington disease research Authors: Ribaï P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, Legout A, Dodé C, Brice A, Dürr A
BACKGROUND: Juvenile Huntington disease (JHD) is a rare clinical entity characterized by an age at onset younger than 20 years. Patients usually have an expansion of more than 60 CAG repeats in the Huntington disease (HD) gene, and the disease is usually inherited from the father. In general, precise age at onset is difficult to assess in HD because of insidious onset and anosognosia. Onset of motor difficulty signs is usually used to define age at onset. OBJECTIVES: To evaluate diagnosis delay in patients with JHD and to analyze the clinical and genetic features of JHD. DESIGN: Retrospective clinical and genetic review. SETTING: Referral center for HD at Salpêtrière Hospital, Paris, France. PATIENTS: Twenty-nine patients with HD with onset before or at age 20 years who carried an abnormal CAG repeat expansion in the HD gene. RESULTS: The mean +/- SD delay before diagnosis was 9 +/- 6 years (range, 0-21 years). The most remarkable signs at onset were severe psychiatric and cognitive disturbances (19 of 29 [65.5%]); rigidity was absent. Unusual signs at onset included myoclonic head tremor in 3 patients, severe isolated drug or alcohol addiction in 2, psychotic disorder in 1, and difficulty writing in 1. One patient had progressive cerebellar signs associated with cerebellar atrophy on cerebral magnetic resonance imaging before signs suggestive of HD appeared. During the course of the disease, psychiatric disturbances were severe, with at least 1 suicide attempt in 7 of 29 patients. Transmission was maternal in 25% of patients. Forty-six percent of patients with JHD had fewer than 60 CAG repeats; 6 of these patients inherited the disease from their father. Anticipation (mean +/- SD, 18 +/- 9 vs 25 +/- 11 years; P = .27) and age at onset (mean +/- SD, 17.14 +/- 2.2 vs 13.29 +/- 5.5 years; P = .09) was similar in patients with maternal compared with paternal transmission, respectively. CONCLUSIONS: Patients with JHD started showing disease symptoms through nonspecific features, mostly psychiatric and cognitive difficulties. This led to misdiagnosis or diagnosis delay, especially in cases without a familial history of HD. Maternal transmissions and expansions of fewer than 60 CAG repeats were unexpectedly frequent in this series and should not be considered exceptional.
Huntington disease research PMID: 17562929 [PubMed - indexed for MEDLINE]Juvenile-onset huntington disease: a matter of perspective.
Juvenile-onset huntington disease: a matter of perspective.
Arch Neurol. 2007 Jun;64(6):783-4
Huntington disease research Authors: Biglan K, Shoulson I
Huntington disease research PMID: 17562925 [PubMed - indexed for MEDLINE]Neural transplantation in Huntington disease: long-term grafts in two patients. Related Articles
Neural transplantation in Huntington disease: long-term grafts in two patients.
Neurology. 2007 Jun 12;68(24):2093-8
Huntington disease research Authors: Keene CD, Sonnen JA, Swanson PD, Kopyov O, Leverenz JB, Bird TD, Montine TJ
OBJECTIVE: Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation. METHODS: Methods used were pathologic examination, histochemistry, and immunohistochemistry. RESULTS: Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells. CONCLUSIONS: These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.
Huntington disease research PMID: 17562830 [PubMed - indexed for MEDLINE]Long-term fetal cell transplant in Huntington disease: stayin' alive.
Long-term fetal cell transplant in Huntington disease: stayin' alive.
Neurology. 2007 Jun 12;68(24):2055-6
Huntington disease research Authors: Frank S, Biglan K
Huntington disease research PMID: 17562824 [PubMed - indexed for MEDLINE]The neurology of disgust.
The neurology of disgust.
Brain. 2007 Jul;130(Pt 7):1715-7
Huntington disease research Authors: Sprengelmeyer R
Huntington disease research PMID: 17550907 [PubMed - indexed for MEDLINE]Individual dopaminergic neurons show raised iron levels in Parkinson disease. Related Articles
Individual dopaminergic neurons show raised iron levels in Parkinson disease.
Neurology. 2007 May 22;68(21):1820-5
Huntington disease research Authors: Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM
OBJECTIVE: Evidence suggests that abnormal iron metabolism is associated with Parkinson disease (PD), with raised iron levels found in pathologically affected areas in PD. It is unknown if this elevated iron is actually associated with neurons or reactive glia, and we therefore addressed this issue by determining if raised iron was present in single dopaminergic neurons. METHODS: We used unfixed frozen sections from postmortem tissue of PD patients and elderly normal individuals to avoid metal contamination and translocation. Levels of iron and other elements were measured using sensitive and specific wavelength dispersive electron probe x-ray microanalysis coupled with cathodoluminescence spectroscopy in individual substantia nigra dopaminergic neurons. RESULTS: We identified raised intraneuronal iron in single defined substantia nigra neurons in PD (mean neuronal iron 2,838 vs 1,611, p < 0.0001) but not in other movement disorders such as Huntington disease. These findings were unrelated to the density of remaining neurons. CONCLUSIONS: Primary changes in neuronal iron could lead to neurodegeneration in Parkinson disease.
Huntington disease research PMID: 17515544 [PubMed - indexed for MEDLINE]Predictors of diagnosis in Huntington disease. Related Articles
Predictors of diagnosis in Huntington disease.
Neurology. 2007 May 15;68(20):1710-7
Huntington disease research Authors: Langbehn DR, Paulsen JS,
OBJECTIVE: Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. METHODS: We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. RESULTS: Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington's Disease Rating Scale. When a movement disorder specialist initially had a global impression of "soft signs" present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. CONCLUSIONS: Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.
Huntington disease research PMID: 17502553 [PubMed - indexed for MEDLINE]Speech and language delay are early manifestations of juvenile-onset Huntington disease. Related Articles
Speech and language delay are early manifestations of juvenile-onset Huntington disease.
Neurology. 2007 Apr 17;68(16):1325; author reply 1325
Huntington disease research Authors: Rosenberger PB
Huntington disease research PMID: 17438232 [PubMed - indexed for MEDLINE]Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. Related Articles
Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3.
Brain. 2007 Sep;130(Pt 9):2302-9
Huntington disease research Authors: Shimohata T, Hara K, Sanpei K, Nunomura J, Maeda T, Kawachi I, Kanazawa M, Kasuga K, Miyashita A, Kuwano R, Hirota K, Tsuji S, Onodera O, Nishizawa M, Honma Y
Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.
Huntington disease research PMID: 17405764 [PubMed - indexed for MEDLINE]Microglial activation in presymptomatic Huntington's disease gene carriers. Related Articles
Microglial activation in presymptomatic Huntington's disease gene carriers.
Brain. 2007 Jul;130(Pt 7):1759-66
Huntington disease research Authors: Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P
Microglial activation may play a role in the pathogenesis of Huntington's disease (HD). Using 11C-(R)-PK11195 (PK) positron emission tomography (PET), we investigated microglial activation in HD presymptomatic gene carriers (PGCs), its relationship with striatal neuronal dysfunction measured with 11C-raclopride (RAC) PET, and the role of PK PET as a possible marker of subclinical disease progression in PGCs. Eleven HD PGCs underwent PK and RAC PET. Their results were compared with those of healthy controls. PK and RAC binding was measured using region-of-interest analysis. Regional increases in PK binding were also localized with voxel-based statistical parametric mapping. HD PGCs had lower striatal RAC binding than the controls but significantly higher striatal and cortical PK binding. Individual levels of higher striatal PK binding in PGCs correlated with lower striatal RAC binding and, after excluding one outlier, with a higher probability of developing HD in 5 years. The inverse association between striatal PK and RAC binding in PGCs continues into early to moderate stages of HD. This study demonstrated for the first time in vivo widespread microglial activation in preclinical HD which correlated with striatal neuronal dysfunction. These findings indicate that microglial activation is an early event in the pathogenic processes of HD and is associated with subclinical progression of disease. PK PET may be a useful marker of active subclinical disease and a means of investigating the efficacy of neuroprotection strategies in PGCs.
Huntington disease research PMID: 17400599 [PubMed - indexed for MEDLINE]Striatal graft projections are influenced by donor cell type and not the immunogenic background. Related Articles
Striatal graft projections are influenced by donor cell type and not the immunogenic background.
Brain. 2007 May;130(Pt 5):1317-29
Huntington disease research Authors: Kelly CM, Precious SV, Penketh R, Amso N, Dunnett SB, Rosser AE
Reconstruction of CNS circuitry is a major aim of neural transplantation, and is currently being assessed clinically using foetal striatal tissue in Huntington's disease. Recent work suggests that neuronal precursors derived from foetal striatum may have a greater capacity than primary foetal striatum to project to the usual striatal target areas such as the globus pallidus and substantia nigra, raising the possibility that they have a greater potential for circuit reconstruction. However, comparing the reconstructive capacity of the two donor cells types is confounded by the fact that many precursor experiments have been carried out in a xenogeneic background in order to utilize species-specific markers for tracking the donor cells, whereas most primary foetal transplant studies have utilized an allograft paradigm. Thus, differences in immunogenic background could influence the findings; for example, xenogeneic grafts may not recognize host inhibitory signals, thereby encouraging more profuse and extensive projections. We have addressed this issue directly by comparing foetal neural precursor and primary foetal grafts in both allo- and xenograft environments using several labelling techniques, including GFP-transgenic mice and LacZ-labelled cells as donor tissue and iontophoretic injection of the anterograde tracers BDA, neurobiotin and PHA-L in the host. We present clear evidence that foetal neural precursors produce grafts with richer axonal outgrowth than primary foetal grafts, and that this is independent of the immunogenic background. Furthermore, both neural precursor and primary grafts derived from human foetal tissue produced a significantly richer outgrowth than do grafts of mouse donor tissue, which may relate to their large final graft volume and the greater intrinsic potential of human CNS neurons for greater axon elongation.
Huntington disease research PMID: 17395612 [PubMed - indexed for MEDLINE]Decreased frontal choline and neuropsychological performance in preclinical Huntington disease. Related Articles
Decreased frontal choline and neuropsychological performance in preclinical Huntington disease.
Neurology. 2007 Mar 20;68(12):906-10
Huntington disease research Authors: Gómez-Ansón B, Alegret M, Muñoz E, Sainz A, Monte GC, Tolosa E
OBJECTIVES: To study metabolic brain changes in preclinical carriers of Huntington disease (PreHD) using proton magnetic resonance spectroscopy (1H -MRS) and to examine their relationship to neuropsychological performance. METHODS: Seventeen subjects with PreHD and 17 controls, matched for age and education, were studied. Frontal cortex and basal ganglia 1H-MRS, and a detailed neuropsychological battery, including visuomotor integration and speed, and memory, frontal, and visuospatial tests were performed. Statistical analysis included Student t-test and Pearson correlations (significance p < 0.05). RESULTS: Frontal choline-containing compounds (CHO) were decreased in PreHD [t (32) = -2.834, p = 0.008]. Subjects with PreHD performed worse than controls in the 15-Objects test [t (32) = 4.077, p = 0.000], Luria motor alternances [t (32) = -2.094, p = 0.044], and Symbol Digit tests [t (32) = -2.136, p = 0.040]. Decreased frontal CHO in PreHD correlated to slowing in visuomotor tasks (the 15-Objects test: r = -0.60, p = 0.000, and the Symbol Digit: r = 0.37, p = 0.047). CONCLUSION: As choline -containing compounds relate to membrane turnover, membrane dysfunction antedating neuronal death is suggested to occur in the frontal cortex in preclinical carriers of Huntington disease. This dysfunction may be responsible for some of the neuropsychological deficits observed.
Huntington disease research PMID: 17372125 [PubMed - indexed for MEDLINE]Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Related Articles
Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial.
Neurology. 2007 Mar 6;68(10):797; author reply 797
Huntington disease research Authors: Savani AA, Login IS
Huntington disease research PMID: 17339599 [PubMed - indexed for MEDLINE]Huntington's disease--making connections. Related Articles
Huntington's disease--making connections.
N Engl J Med. 2007 Feb 1;356(5):518-20
Huntington disease research Authors: Greenamyre JT
Huntington disease research PMID: 17267914 [PubMed - indexed for MEDLINE]Huntington's disease. Related Articles
Huntington's disease.
Lancet. 2007 Jan 20;369(9557):218-28
Huntington disease research Authors: Walker FO
Huntington's disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties. Typically, onset of symptoms is in middle-age after affected individuals have had children, but the disorder can manifest at any time between infancy and senescence. The mutant protein in Huntington's disease--huntingtin--results from an expanded CAG repeat leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function. The precise pathophysiological mechanisms of Huntington's disease are poorly understood, but research in transgenic animal models of the disorder is providing insight into causative factors and potential treatments.
Huntington disease research PMID: 17240289 [PubMed - indexed for MEDLINE]Neurologic phenotypes associated with acanthocytosis. Related Articles
Neurologic phenotypes associated with acanthocytosis.
Neurology. 2007 Jan 9;68(2):92-8
Huntington disease research Authors: Walker RH, Jung HH, Dobson-Stone C, Rampoldi L, Sano A, Tison F, Danek A
The term "neuroacanthocytosis" is normally used to refer to autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome, but there are other movement disorders in which erythrocyte acanthocytosis may also be seen, such as Huntington disease-like 2 and pantothenate kinase-associated neurodegeneration. Disorders of serum lipoproteins such as Bassen-Kornzweig disease form a distinct group of neuroacanthocytosis syndromes in which ataxia is observed, but movement disorders are not seen. Genetic testing has enabled us to distinguish between these disorders, even when there are considerable similarities between phenotypes. Improved detection is important for accurate genetic counseling, for monitoring for complications, and, it is hoped, for implementing causal treatments, once these become available. As in other neurodegenerative conditions, animal models are a promising strategy for the development of such therapies.
Huntington disease research PMID: 17210889 [PubMed - indexed for MEDLINE]Specific psychiatric manifestations among preclinical Huntington disease mutation carriers. Related Articles
Specific psychiatric manifestations among preclinical Huntington disease mutation carriers.
Arch Neurol. 2007 Jan;64(1):116-21
Huntington disease research Authors: Marshall J, White K, Weaver M, Flury Wetherill L, Hui S, Stout JC, Johnson SA, Beristain X, Gray J, Wojcieszek J, Foroud T
BACKGROUND: Despite the need for significant clinical intervention owing to the psychiatric manifestations of Huntington disease (HD), there has been a paucity of studies specifically designed to evaluate these symptoms prior to disease diagnosis. OBJECTIVES: To investigate whether the Symptom Checklist 90-Revised (SCL-90-R) and the Center for Epidemiological Studies Depression Scale can be used to detect psychiatric manifestations among preclinical mutation carriers with absent or minimal motor signs of HD. DESIGN, SETTING, AND PARTICIPANTS: Individuals at risk for or recently diagnosed with HD were recruited and then evaluated at Indiana University School of Medicine, Indianapolis. All of the subjects completed a uniform clinical evaluation that included the Unified Huntington's Disease Rating Scale-99, molecular testing to determine HD mutation status, the SCL-90-R, and the Center for Epidemiological Studies Depression Scale. The sample was divided into 4 study groups: 171 individuals in the nonmutation carrier group; 29 with minimal, if any, motor signs of HD in the preclinical mutation carrier group 1; 20 with motor abnormalities suggestive of HD in the preclinical mutation carrier group 2; and 34 in the manifest HD group. MAIN OUTCOME MEASURES: Scores on the SCL-90-R and Center for Epidemiological Studies Depression Scale were compared. RESULTS: Five SCL-90-R symptom dimensions (obsessive- compulsive, interpersonal sensitivity, anxiety, paranoid ideation, and psychoticism) demonstrated a significant group effect (P < or = .04). The preclinical mutation carrier group 2 and the manifest HD group scored significantly higher on all 5 dimensions as compared with the nonmutation carrier group. The preclinical mutation carrier group 2 scored significantly higher than the nonmutation carrier group for 3 of the SCL-90-R symptom dimensions (anxiety, paranoid ideation, and psychoticism). A significant group effect was found on the Center for Epidemiological Studies Depression Scale (P = .04). The frequency of depressive symptoms was significantly higher in the manifest HD group and the preclinical mutation carrier group 2 as compared with the nonmutation carrier group. CONCLUSION: This study identified specific psychiatric symptom dimensions that differentiate nonmutation carriers from individuals in the early preclinical stages of HD who are either symptom free or have minor nonspecific motor abnormalities.
Huntington disease research PMID: 17210818 [PubMed - indexed for MEDLINE]The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea. Related Articles
The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea.
Brain. 2007 Jan;130(Pt 1):222-32
Huntington disease research Authors: Huot P, Lévesque M, Parent A
The striatum harbours a population of dopaminergic neurons that is thought to act as a local source of dopamine (DA). This neuronal population increases in size in animal models of Parkinson's disease, where striatal DA levels are low, but its fate in idiopathic Parkinson's disease and Huntington's chorea is poorly known. In this study, we used antibodies raised against the enzyme tyrosine hydroxylase (TH), a faithful marker of dopaminergic neurons, to compare, by means of stereological counting methods, the number of striatal TH+ neurons on post-mortem brain sections from Parkinson's disease patients, Huntington's disease patients and age- matched controls. Propidium iodide nuclear staining was also performed to avoid counting short TH+ axonal segments that bear a large swollen varicosity and resemble small bipolar neurons. In normal subjects, TH+ neurons were scattered throughout the striatum, but they abounded preferentially in the ventral portion of the structure and were more numerous in the putamen than in the caudate nucleus. They displayed a multipolar cell body of medium size (10-20 mum in diameter) that emitted 3-5 smooth dendrites, a typical characteristic of striatal interneurons. These TH+ cells were rarely found in the small TH-poor striosomes, most of them being embedded in the large TH-rich extrastriosomal matrix. The number of striatal TH+ neurons was also found to vary according to an inverse relation with the age of the subjects. In pathological brains, the morphological characteristics of the striatal TH+ neurons were relatively unaltered, but the number of such neurons was markedly reduced compared with controls. The striatum of Parkinson's disease patients was found to contain six times less TH+ neurons than that of controls, whereas the striatum of Huntington's disease patients was largely devoid of such neurons. These findings are at odds with the results obtained in rodent and monkey models of Parkinson's disease, in which the number of striatal TH+ neurons is reported to increase markedly following DA denervation. Since Parkinson's disease patients examined in this study were all treated with l-3,4-dihydroxyphenylalanine to compensate for the loss of striatal DA and that levels of striatal DA are reportedly higher in the striatum of Huntington's disease patients compared with controls, we hypothesize that local DA concentrations exert a negative feedback on the expression of TH phenotype by striatal interneurons. A better knowledge of factors governing the in vivo state of this ectopic neuronal population could open new therapeutic avenues for the treatment of Parkinson's disease and Huntington's chorea.
Huntington disease research PMID: 17142832 [PubMed - indexed for MEDLINE]Refusing to provide a prenatal test: can it ever be ethical? Related Articles
Refusing to provide a prenatal test: can it ever be ethical?
BMJ. 2006 Nov 18;333(7577):1066-8
Huntington disease research Authors: Duncan RE, Foddy B, Delatycki MB
Huntington disease research PMID: 17110726 [PubMed - indexed for MEDLINE]Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family. Related Articles
Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family.
Neurology. 2006 Nov 14;67(9):1701-3
Huntington disease research Authors: Schneider SA, van de Warrenburg BP, Hughes TD, Davis M, Sweeney M, Wood N, Quinn NP, Bhatia KP
We describe clinical and genetic analysis of a family with spinocerebellar ataxia 17 (SCA17) presenting with a Huntington disease-like (HDL) syndrome. Clinically diagnosed, HD is genetically heterogeneous. Differential diagnosis includes SCA17. However, SCA17 HDL presentation has been observed only sporadically or in solitary individuals within a family. HDL phenotypic homogeneity in SCA17 has not been described. SCA17 can present with a HDL syndrome in multiple family members.
Huntington disease research PMID: 17101913 [PubMed - indexed for MEDLINE]The future of genomic profiling of neurological diseases using blood. Related Articles
The future of genomic profiling of neurological diseases using blood.
Arch Neurol. 2006 Nov;63(11):1529-36
Huntington disease research Authors: Sharp FR, Xu H, Lit L, Walker W, Apperson M, Gilbert DL, Glauser TA, Wong B, Hershey A, Liu DZ, Pinter J, Zhan X, Liu X, Ran R
Sequencing of the human genome and new microarray technology make it possible to assess all genes on a single chip or array. Recent studies show different patterns of gene expression related to different tissues and diseases, and these patterns of gene expression are beginning to be used for diagnosis and treatment decisions in various types of lymphoid and solid malignancies. Because of obvious problems obtaining brain tissue, progress in genomics of neurological diseases has been slow. To address this, we demonstrated that different types of acute injury in rodent brain produced different patterns of gene expression in peripheral blood. These animal studies have now been extended to human studies. Two groups have shown that there are specific genomic profiles in the blood of patients after ischemic stroke that are highly sensitive and specific for predicting stroke. Other recent studies demonstrate specific genomic profiles in the blood of patients with Down syndrome, neurofibromatosis, tuberous sclerosis, Huntington disease, multiple sclerosis, Tourette syndrome, and others. In addition, data demonstrate specific profiles of gene expression in the blood related to different drugs, toxins, and infections. Although all of these studies are still preliminary basic scientific endeavors, they suggest that this approach will have clinical applications to neurological diseases in humans.
Huntington disease research PMID: 17101821 [PubMed - indexed for MEDLINE]Striosomes and mood dysfunction in Huntington's disease. Related Articles
Striosomes and mood dysfunction in Huntington's disease.
Brain. 2007 Jan;130(Pt 1):206-21
Huntington disease research Authors: Tippett LJ, Waldvogel HJ, Thomas SJ, Hogg VM, van Roon-Mom W, Synek BJ, Graybiel AM, Faull RL
Variable phenotype is common in neurological disorders with single-gene inheritance patterns. In Huntington's disease, mood and cognitive symptoms are variably co-expressed with motor symptoms. There is also variable degeneration of neurons in the two major neurochemical compartments of the striatum, the striosomes and the extrastriosomal matrix. To determine whether the phenotypic variability in Huntington's disease is related to this compartmental organization, we carried out a double-blind study in which we used GABA(A) receptor immunohistochemistry to analyse the status of striosomes and matrix in the brains of 35 Huntington's disease cases and 13 control cases, and collected detailed data on the clinical symptomatology expressed by the patients from family members and records. We report here a significant association between pronounced mood dysfunction in Huntington's disease patients and differential loss of the GABA(A) receptor marker in striosomes of the striatum. This association held for both clinical onset and end-stage assessments of symptoms. The cases with accentuated striosome abnormality further exhibited later onset age, lower disease grade and lower CAG repeat length in the HD gene. We found no independent association, however, between CAG repeat length or age of onset and mood dysfunction. We suggest that variation in clinical symptomatology in Huntington's disease is associated with variation in the relative abnormality of GABA(A) receptor expression in the striosome and matrix compartments of the striatum, and that striosome-related circuits may modulate mood functioning.
Huntington disease research PMID: 17040921 [PubMed - indexed for MEDLINE]Effect of donepezil on motor and cognitive function in Huntington disease. Related Articles
Effect of donepezil on motor and cognitive function in Huntington disease.
Neurology. 2006 Oct 10;67(7):1268-71
Huntington disease research Authors: Cubo E, Shannon KM, Tracy D, Jaglin JA, Bernard BA, Wuu J, Leurgans SE
Striatal cholinergic dysfunction may be important in Huntington disease (HD). We studied whether donepezil improves chorea, cognition, and quality of life (QoL) in HD. Thirty patients were randomly assigned to treatment with donepezil or placebo. At the doses studied, donepezil did not improve chorea, cognition, or QoL. Adverse events were similar between both groups. Based on this small sample study, donepezil was not an effective treatment for HD.
Huntington disease research PMID: 17030764 [PubMed - indexed for MEDLINE]Speech and language delay are early manifestations of juvenile-onset Huntington disease.
Speech and language delay are early manifestations of juvenile-onset Huntington disease.
Neurology. 2006 Oct 10;67(7):1265-7
Huntington disease research Authors: Yoon G, Kramer J, Zanko A, Guzijan M, Lin S, Foster-Barber A, Boxer AL
The neurocognitive features of juvenile-onset Huntington disease (HD) are not well understood. We present three patients with onset of HD symptoms before age 10 years in whom speech delay was the first symptom. Speech delay predated motor symptoms by at least 2 years, and language function was consistently impaired on formal testing. Screening for speech delay is particularly important in children with a family history of HD.
Huntington disease research PMID: 17030763 [PubMed - indexed for MEDLINE]Increased rate of whole-brain atrophy over 6 months in early Huntington disease. Related Articles
Increased rate of whole-brain atrophy over 6 months in early Huntington disease.
Neurology. 2006 Aug 22;67(4):694-6
Huntington disease research Authors: Henley SM, Frost C, MacManus DG, Warner TT, Fox NC, Tabrizi SJ
The authors measured the rate of whole-brain atrophy over 6 months in 13 patients with early Huntington disease (HD) and seven matched controls. Patients with early HD had significantly increased rates of whole-brain atrophy vs controls (mean [SD] HD, 1.10 [0.88]%/year; controls, 0.26 [0.54]%/year). The measurement of cerebral change over short time periods (e.g., 6 months) may be relevant for trials designed to assess effects on neurodegeneration or atrophy.
Huntington disease research PMID: 16924028 [PubMed - indexed for MEDLINE]Successful spinal anesthesia in a patient with Huntington's chorea. Related Articles
Successful spinal anesthesia in a patient with Huntington's chorea.
Anesth Analg. 2006 Aug;103(2):512-3
Huntington disease research Authors: Esen A, Karaaslan P, Can Akgün R, Arslan G
Huntington disease research PMID: 16861472 [PubMed - indexed for MEDLINE]Saccades in presymptomatic and early stages of Huntington disease. Related Articles
Saccades in presymptomatic and early stages of Huntington disease.
Neurology. 2006 Aug 8;67(3):394-9
Huntington disease research Authors: Blekher T, Johnson SA, Marshall J, White K, Hui S, Weaver M, Gray J, Yee R, Stout JC, Beristain X, Wojcieszek J, Foroud T
OBJECTIVE: To evaluate quantitative measures of eye movements as possible biomarkers in prediagnostic and early stages of Huntington disease (HD). METHODS: The study sample (n = 215) included individuals both at risk and recently diagnosed with HD. All participants completed a uniform clinical evaluation which included administration of the Unified Huntington's Disease Rating Scale (UHDRS) by a movement disorder neurologist and molecular testing to determine HD gene status. A high resolution, video-based eye tracking system was employed to quantify measures of eye movement (error rates, latencies, SD of latencies, velocities, and accuracies) during a computerized battery of saccadic and steady fixation tasks. RESULTS: Prediagnostic HD gene carriers and individuals with early HD demonstrated three types of significant abnormalities while performing memory guided and anti-saccade tasks: increased error rate, increased saccade latency, and increased variability of saccade latency. The eye movement abnormalities increased with advancing motor signs of HD. CONCLUSIONS: Abnormalities in eye movement measures are a sensitive biomarker in the prediagnostic and early stages of Huntington disease (HD). These measures may be more sensitive to prediagnostic changes in HD than the currently employed neurologic motor assessment.
Huntington disease research PMID: 16855205 [PubMed - indexed for MEDLINE]At risk for Huntington disease: The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled. Related Articles
At risk for Huntington disease: The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled.
Arch Neurol. 2006 Jul;63(7):991-6
Huntington disease research Authors:
OBJECTIVE: To identify the emerging clinical precursors that indicate the early onset of Huntington disease (HD) in a reliable and gene-specific manner. This information is critical for the development of therapeutic trials aimed at postponing clinical onset in HD gene carriers. METHODS: Between July 1999 and January 2004, 1001 adults at 50-50 risk for HD agreed to provide longitudinal clinical data and a blood DNA sample under consent provisions that require their individual clinical and genetic information to never be revealed. RESULTS: The Prospective Huntington At Risk Observational Study (PHAROS) cohort is characterized by a 2:1 predominance of women to men, high educational attainment, and gainful employment. Despite the gender disparity, the demographic, hereditary, and clinical characteristics of the female and male participants were similar. Investigators, who are unaware of individual gene status, characterized the baseline cohort to be highly functional with minimal motor or cognitive impairment; 92.3% of participants were judged to have no or nonspecific motor abnormalities; 6.7%, to have possible or probable motor signs; and only 1.0%, to have unequivocal HD. CONCLUSION: The baseline characteristics of the PHAROS cohort make it well suited to generate objective and prospective data about gene-specific clinical precursors that can be used as outcomes in controlled trials aimed at postponing the onset of HD.
Huntington disease research PMID: 16831969 [PubMed - indexed for MEDLINE]Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Related Articles
Microglial activation correlates with severity in Huntington disease: a clinical and PET study.
Neurology. 2006 Jun 13;66(11):1638-43
Huntington disease research Authors: Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, Brooks DJ, Piccini P
BACKGROUND: Huntington disease (HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas of neuronal loss has recently been described in postmortem studies. Activated microglia are known to release neurotoxic cytokines, and these may contribute to the pathologic process. METHODS: To evaluate in vivo the involvement of microglia activation in HD, the authors studied patients at different stages of the disease using [(11)C](R)-PK11195 PET, a marker of microglia activation, and [(11)C]raclopride PET, a marker of dopamine D2 receptor binding and hence striatal GABAergic cell function. RESULTS: In HD patients, a significant increase in striatal [(11)C](R)-PK11195 binding was observed, which significantly correlated with disease severity as reflected by the striatal reduction in [(11)C]raclopride binding, the Unified Huntington's Disease Rating Scale score, and the patients' CAG index. Also detected were significant increases in microglia activation in cortical regions including prefrontal cortex and anterior cingulate. CONCLUSIONS: These [(11)C](R)- PK11195 PET findings show that the level of microglial activation correlates with Huntington disease (HD) severity. They lend support to the view that microglia contribute to the ongoing neuronal degeneration in HD and indicate that [(11)C](R)-PK11195 PET provides a valuable marker when monitoring the efficacy of putative neuroprotecting agents in this relentlessly progressive genetic disorder.
Huntington disease research PMID: 16769933 [PubMed - indexed for MEDLINE]Preparing for preventive clinical trials: the Predict-HD study. Related Articles
Preparing for preventive clinical trials: the Predict-HD study.
Arch Neurol. 2006 Jun;63(6):883-90
Huntington disease research Authors: Paulsen JS, Hayden M, Stout JC, Langbehn DR, Aylward E, Ross CA, Guttman M, Nance M, Kieburtz K, Oakes D, Shoulson I, Kayson E, Johnson S, Penziner E,
BACKGROUND: The optimal design and outcome measures for preventive clinical trials in neurodegenerative diseases are unknown. OBJECTIVE: To examine measures that may be associated with disease in the largest cohort ever recruited of prediagnosed individuals carrying the gene expansion for Huntington disease (HD). DESIGN: The Predict-HD study is a multicenter observational research study in progress at 17 sites in the United States, 4 in Canada, and 3 in Australia. SETTING: Genetics and HD outpatient clinics. PARTICIPANTS: Five hundred five at-risk individuals who had previously undergone elective DNA analyses for the CAG expansion in the HD gene (predictive testing) and did not currently have a clinical diagnosis of HD. MAIN OUTCOME MEASURES: Basal ganglia volumes on magnetic resonance images, estimated probability of diagnosis (based on CAG repeat length), performances on 21 standardized cognitive tasks, total scores on 3 scales of psychiatric distress, and motor diagnosis based on the Unified Huntington's Disease Rating Scale. RESULTS: Several variables showed progressive decline as the diagnostic ratings advanced toward manifest disease. Estimated probability of diagnosis was associated with Unified Huntington's Disease Rating Scale prediagnostic stages and varied from 15% in persons with no motor abnormalities to nearly 40% in those with abnormalities suggestive of probable disease. Striatal volumes, cognitive performances, and even psychiatric ratings declined significantly with motor manifestations of disease. CONCLUSIONS: The documentation of biological and refined clinical markers suggests several clinical end points for preventive clinical trials. Longitudinal study is critical to further validate possible markers for prediagnosed HD.
Huntington disease research PMID: 16769871 [PubMed - indexed for MEDLINE]Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study. Related Articles
Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study.
Arch Neurol. 2006 May;63(5):729-35
Huntington disease research Authors: Okun MS, Fernandez HH, Rodriguez RL, Romrell J, Suelter M, Munson S, Louis ED, Mulligan T, Foster PS, Shenal BV, Armaghani SJ, Jacobson C, Wu S, Crucian G
BACKGROUND: Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. OBJECTIVE: To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. DESIGN: Double-masked, placebo-controlled, parallel-group, single-center trial. PATIENTS: Two experimental groups: patients with PD who were receiving either TT or placebo. INTERVENTIONS: Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. MAIN OUTCOME MEASURES: The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. RESULTS: Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). CONCLUSIONS: Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.
Huntington disease research PMID: 16682542 [PubMed - indexed for MEDLINE]Identification of an oculomotor biomarker of preclinical Huntington disease. Related Articles
Identification of an oculomotor biomarker of preclinical Huntington disease.
Neurology. 2006 Aug 8;67(3):485-7
Huntington disease research Authors: Golding CV, Danchaivijitr C, Hodgson TL, Tabrizi SJ, Kennard C
The authors examined oculomotor function to identify a biomarker of disease progression in genetically confirmed preclinical and early clinical Huntington disease (HD). Initiation deficits of voluntary-guided, but not reflexive, saccades were characteristic of preclinical HD. Saccadic slowing and delayed reflexive saccades were demonstrated in clinical but not preclinical HD. Saccadic measures provide biomarkers of disease progression in both preclinical and early clinical stages of HD.
Huntington disease research PMID: 16625001 [PubMed - indexed for MEDLINE]Delayed amnesic syndrome after riluzole autointoxication in Huntington disease. Related Articles
Delayed amnesic syndrome after riluzole autointoxication in Huntington disease.
Neurology. 2006 Apr 11;66(7):1123-4
Huntington disease research Authors: Haaxma CA, Kremer HP, van de Warrenburg BP
Huntington disease research PMID: 16606937 [PubMed - indexed for MEDLINE]The association of CAG repeat length with clinical progression in Huntington disease. Related Articles
The association of CAG repeat length with clinical progression in Huntington disease.
Neurology. 2006 Apr 11;66(7):1016-20
Huntington disease research Authors: Rosenblatt A, Liang KY, Zhou H, Abbott MH, Gourley LM, Margolis RL, Brandt J, Ross CA
OBJECTIVE: To determine whether the rate of clinical progression in Huntington disease (HD) is influenced by the size of the CAG expansion. METHODS: The dataset consisted of 3,402 examinations of 512 subjects seen through the Baltimore Huntington's Disease Center. Subjects were seen for a mean of 6.64 visits, with mean follow-up of 6.74 years. Subjects were administered the Quantified Neurological Examination, with its subsets the Motor Impairment and Chorea Scores, the Mini-Mental State Examination, and the HD Activities of Daily Living (ADL) Scale. RESULTS: In an analysis based on the Random Effects Model, CAG length was significantly associated with the rate of progression of all measures except chorea and ADL. There was a significant interaction term between CAG length and disease duration for all measures except chorea. Further graphical exploration of the data supported these linear models and suggested that subjects at the low end of the expanded CAG repeat range may experience a more benign late course. CONCLUSIONS: CAG repeat length has a small effect on rate of progression that may be clinically important over time. Individuals with the shortest expansions appear to have the best prognosis. These effects of the CAG length may be relevant in the analysis of clinical trials.
Huntington disease research PMID: 16606912 [PubMed - indexed for MEDLINE]Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. Related Articles
Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase.
J Clin Invest. 2006 May;116(5):1410-24
Huntington disease research Authors: Borrell-Pagès M, Canals JM, Cordelières FP, Parker JA, Pineda JR, Grange G, Bryson EA, Guillermier M, Hirsch E, Hantraye P, Cheetham ME, Néri C, Alberch J, Brouillet E, Saudou F, Humbert S
There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin-induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through formation of clathrin -coated vesicles containing brain-derived neurotrophic factor (BDNF). Cystamine increases BDNF secretion from the Golgi region that is blocked by reducing HSJ1b levels or by overexpressing transglutaminase. We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain. Finally, cysteamine increases serum levels of BDNF in mouse and primate models of HD. Therefore, cysteamine is a potential treatment for HD, and serum BDNF levels can be used as a biomarker for drug efficacy.
Huntington disease research PMID: 16604191 [PubMed - indexed for MEDLINE]Parameter-based assessment of spatial and non-spatial attentional deficits in Huntington's disease. Related Articles
Parameter-based assessment of spatial and non-spatial attentional deficits in Huntington's disease.
Brain. 2006 May;129(Pt 5):1137-51
Huntington disease research Authors: Finke K, Bublak P, Dose M, Müller HJ, Schneider WX
A major challenge for neuropsychological research on Huntington's disease is the identification of biomarkers for the disease at the level of cognitive functions. Given that cortical-striatal-thalamic circuits are particularly vulnerable, possible markers loading functionally on these brain regions should be particularly significant. We investigated whether parametric values derived from a 'theory of visual attention' (TVA) can serve that purpose. They are derived as mathematically independent, quantitative measures of attentional components, and the tasks require only non-speeded vocal responses. As such, the methodology seems well suited for testing patients with motor problems and general cognitive decline. Accumulating neuroanatomical evidence suggests that striatal atrophy in Huntington's disease is asymmetrical with a more pronounced left-sided degeneration. We applied a partial-report paradigm to analyse whether this results in a pathological (leftward) bias of the spatial distribution of attention. In partial report, red target letters are presented either alone or accompanied by either a second target or a green distractor letter presented in the same or in the opposite hemi-field. Since basal ganglia lesions have also been shown to cause spatially non-lateralized impairments, that is, reduced perceptual processing speed and visual working memory (WM) storage capacity within both hemi-fields, we tested possible reductions in these parameters with a whole-report paradigm. Here, columns of five red or green letters are briefly presented and the subject has to report as many as possible. Eighteen patients and 18 matched control subjects performed a partial- and a whole-report task with briefly presented letter displays. In partial report, Huntington's disease patients demonstrated a pathological bias, indicating increased attentional weighting to the left hemi-field. The extent of lateralization was strongly related to age at onset and to the number of cytosine-adenine-guanine (CAG) triplet repeats on gene IT15. In contrast, the extent of lateralization was not related to disease progression as reflected by the duration of the disease since onset of the first symptoms. In whole report, the non-lateralized attentional parameters processing speed and visual WM storage capacity were reduced bilaterally in both hemi-fields. The extent of the reduction was related to the disease duration since onset, whereas no significant correlation with CAG repeats or age at onset was found. Laterality of attentional weighting may, therefore, represent a possible trait marker reflecting the intensity of the pathogenic mechanisms, while the reduction of visual processing speed and storage capacity may be state markers for the stage of disease progression.
Huntington disease research PMID: 16504973 [PubMed - indexed for MEDLINE]Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial.
Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial.
Neurology. 2006 Feb 14;66(3):366-72
Huntington disease research Authors:
BACKGROUND: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type 2 vesicular monoamine transporter. Open-label reports indicate TBZ is effective in treating chorea. OBJECTIVE: To examine the safety, efficacy, and dose tolerability of TBZ for treating chorea in Huntington disease (HD). METHODS: The authors randomized 84 ambulatory patients with HD to receive TBZ (n = 54) or placebo (n = 30) for 12 weeks. TBZ was increased over 7 weeks up to a maximum of 100 mg/day or until the desired antichoreic effect occurred or intolerable adverse effects supervened. The primary outcome was the change from baseline in the chorea score of the Unified Huntington's Disease Rating Scale (UHDRS) RESULTS: TBZ treatment resulted in a reduction of 5.0 units in chorea severity compared with a reduction of 1.5 units on placebo treatment (adjusted mean effect size = -3.5 +/- 0.8 UHDRS units [mean +/- SE]; 95% CI: -5.2, -1.9; p < 0.0001). There was also a significant benefit on ratings of clinical global improvement. There were five study withdrawals in the TBZ group and five serious adverse events (SAEs) in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer) compared with one withdrawal and no SAEs in the placebo group. CONCLUSION: Tetrabenazine (TBZ), at adjusted dosages of up to 100 mg/day, effectively lessens chorea in ambulatory patients with Huntington disease. TBZ should be dosed individually based on ongoing assessment of possible adverse side effects.
Huntington disease research PMID: 16476934 [PubMed - indexed for MEDLINE]Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles. Related Articles
Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles.
Brain. 2006 Apr;129(Pt 4):877-86
Huntington disease research Authors: Underwood BR, Broadhurst D, Dunn WB, Ellis DI, Michell AW, Vacher C, Mosedale DE, Kell DB, Barker RA, Grainger DJ, Rubinsztein DC
There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time- of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.
Huntington disease research PMID: 16464959 [PubMed - indexed for MEDLINE]Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Related Articles
Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG.
Neurology. 2006 Jan 24;66(2):250-2
Huntington disease research Authors: Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD
In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.
Huntington disease research PMID: 16434666 [PubMed - indexed for MEDLINE]Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Related Articles
Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis.
Neurology. 2006 Jan 24;66(2 Suppl 1):S74-8
Huntington disease research Authors: Glabe CG, Kayed R
Recent findings indicate that soluble amyloid oligomers may represent the primary pathologic species in degenerative diseases. These amyloid oligomers share common structural features and the ability to permeabilize membranes, suggesting that they also share a common primary mechanism of pathogenesis. Membrane permeabilization by amyloid oligomers may initiate a common group of downstream pathologic processes, including intracellular calcium dyshomeostasis, production of reactive oxygen species, altered signaling pathways, and mitochondrial dysfunction that represent key effectors of cellular dysfunction and cell death in amyloid-associated degenerative disease, such as sporadic inclusion-body myositis.
Huntington disease research PMID: 16432151 [PubMed - indexed for MEDLINE]Controlling autoimmunity in sporadic inclusion-body myositis. Related Articles
Controlling autoimmunity in sporadic inclusion-body myositis.
Neurology. 2006 Jan 24;66(2 Suppl 1):S56-8
Huntington disease research Authors: Steinman L
Huntington disease research PMID: 16432146 [PubMed - indexed for MEDLINE]Developing therapeutics for the diseases of protein misfolding. Related Articles
Developing therapeutics for the diseases of protein misfolding.
Neurology. 2006 Jan 24;66(2 Suppl 1):S118-22
Huntington disease research Authors: May BC, Govaerts C, Cohen FE
Our current structural and biologic understanding of the misfolding diseases has restricted the development of therapies that target these diseases at a molecular level. The prion diseases are illustrative of this group of misfolding disorders and provide a model system for therapeutic intervention. Strategies to inhibit the replication and accumulation of the prion protein are being developed and have entered animal and clinical studies. Due to the underlying molecular basis of this disease class, many of the therapeutic approaches used to target prion misfolding have parallels in other misfolding diseases.
Huntington disease research PMID: 16432139 [PubMed - indexed for MEDLINE]Atomic force microscopy analysis of the Huntington protein nanofibril formation. Related Articles
Atomic force microscopy analysis of the Huntington protein nanofibril formation.
Dis Mon. 2005 Jun;51(6):374-85
Huntington disease research Authors: Dahlgren PR, Karymov MA, Bankston J, Holden T, Thumfort P, Ingram VM, Lyubchenko YL
Huntington disease research PMID: 16242522 [PubMed - indexed for MEDLINE]Association between BDNF Val66Met polymorphism and age at onset in Huntington disease. Related Articles
Association between BDNF Val66Met polymorphism and age at onset in Huntington disease.
Neurology. 2005 Sep 27;65(6):964-5
Huntington disease research Authors: Alberch J, López M, Badenas C, Carrasco JL, Milà M, Muñoz E, Canals JM
Huntington disease research PMID: 16186551 [PubMed - indexed for MEDLINE]Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Related Articles
Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease.
Neurology. 2005 Sep 27;65(6):941-3
Huntington disease research Authors: van Oostrom JC, Maguire RP, Verschuuren-Bemelmans CC, Veenma-van der Duin L, Pruim J, Roos RA, Leenders KL
Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.
Huntington disease research PMID: 16186542 [PubMed - indexed for MEDLINE]Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Related Articles
Regional cortical thinning in preclinical Huntington disease and its relationship to cognition.
Neurology. 2005 Sep 13;65(5):745-7
Huntington disease research Authors: Rosas HD, Hevelone ND, Zaleta AK, Greve DN, Salat DH, Fischl B
The authors studied presymptomatic individuals with the Huntington disease (HD) mutation to determine whether cortical thinning was present. They found thinning that was regionally selective, semi-independent of striatal volume loss, and correlated with cognitive performance. Early, extensive cortical involvement occurs during the preclinical stages of HD.
Huntington disease research PMID: 16157910 [PubMed - indexed for MEDLINE]Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo- controlled trial. Related Articles
Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo- controlled trial.
Neurology. 2005 Jul 26;65(2):286-92
Huntington disease research Authors: Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, Manku M, Murck H
BACKGROUND: Preliminary evidence suggests beneficial effects of pure ethyl- eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). METHODS: A total of 135 patients with HD were randomized to enter a multicenter, double- blind, placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntington's Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS-4). Analysis of covariance (ANCOVA) and a chi2 test on response, defined as absence of increase in the TMS-4, were performed. RESULTS: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the chi2 test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. CONCLUSIONS: Ethyl-eicosapentaenoate (ethyl -EPA) (purity > 95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.
Huntington disease research PMID: 16043801 [PubMed - indexed for MEDLINE]Monozygotic twins discordant for Huntington disease after 7 years. Related Articles
Monozygotic twins discordant for Huntington disease after 7 years.
Arch Neurol. 2005 Jun;62(6):995-7
Huntington disease research Authors: Friedman JH, Trieschmann ME, Myers RH, Fernandez HH
BACKGROUND: Huntington disease (HD) has only rarely been identified in identical twins. All described twins have had disease onset within 1 year of each other, suggesting that disease onset is determined solely by genetic influences. OBJECTIVE: To describe a unique set of monozygotic twins in whom clinical HD onset is at least 7 years apart. DESIGN: A 71-year-old woman was diagnosed as having HD based on medical history, physical examination results consistent with HD, and a CAG trinucleotide repeat number of 39 in the HD gene on chromosome 4. Her onset was 6 years earlier. Her genetically confirmed identical twin, carrying the same number of CAG repeats, was neurologically healthy when examined the next year. Only the HD-manifest twin had chronic bronchitis, rheumatoid arthritis, type 2 diabetes mellitus, and chronic anemia. Both had hypertension. CONCLUSIONS: To our knowledge, this is the first report of monozygotic twins discordant for HD by more than 2 years. The onset of HD symptoms in a patient with 39 triplet repeats at least 7 years earlier than her identical twin suggests the possibility that the disease may be initiated (or delayed) by environmental factors. We have identified increased cigarette use and longer exposure to various industrial toxins as potential explanations for the earlier onset in one twin.
Huntington disease research PMID: 15956172 [PubMed - indexed for MEDLINE]Energy balance in early-stage Huntington disease. Related Articles
Energy balance in early-stage Huntington disease.
Am J Clin Nutr. 2005 Jun;81(6):1335-41
Huntington disease research Authors: Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN
BACKGROUND: Huntington disease (HD) is a genetic neurologic disorder. Weight loss is common in HD and is related to progression of the disease, but the cause of weight loss remains unclear. OBJECTIVE: The study objective was to compare 24-h energy expenditure (EE) and energy intake in persons with early midstage HD with those of matched control subjects to determine how HD affects energy balance. DESIGN: EE was assessed in 13 subjects with early- stage HD and in 9 control subjects via indirect calorimetry in a human respiratory chamber. Energy intake was determined by weighing all food provided and all leftovers from an ad libitum diet. Body composition was measured via air-displacement plethysmography. Stage of disease was estimated on the basis of the Unified Huntington's Disease Rating Scale and modified Mini-Mental Status examinations. Regression analysis included all 13 HD subjects; t tests were used for the comparisons between matched HD and control subjects. RESULTS: 24-h EE was 11% higher in the HD subjects than in the control subjects (NS). This difference was due to a higher (P = 0.043) waking metabolic rate, which was related to a significantly greater displacement of the center of mass by HD subjects than by control subjects (P = 0.028). On average, both groups were in positive energy balance and exceeded their energy expenditure by 2510-2929 kJ. CONCLUSIONS: Higher 24-h EE in persons with early midstage HD is due to increased physical activity, both voluntary and involuntary. However, HD subjects are able to maintain positive energy balance when offered adequate amounts of food in a controlled setting.
Huntington disease research PMID: 15941884 [PubMed - indexed for MEDLINE]The genetic epidemiology of neurodegenerative disease. Related Articles
The genetic epidemiology of neurodegenerative disease.
J Clin Invest. 2005 Jun;115(6):1449-57
Huntington disease research Authors: Bertram L, Tanzi RE
Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.
Huntington disease research PMID: 15931380 [PubMed - indexed for MEDLINE]Apraxia in movement disorders. Related Articles
Apraxia in movement disorders.
Brain. 2005 Jul;128(Pt 7):1480-97
Huntington disease research Authors: Zadikoff C, Lang AE
The definition of apraxia specifies that the disturbance of performed skilled movements cannot be explained by the more elemental motor disorders typical of patients with movement disorders. Generally this does not present a significant diagnostic problem when dealing with 'higher-level' praxic disturbances (e.g. ideational apraxia), but it can be a major confound in establishing the presence of limb-kinetic apraxia. Most motor disturbances characteristic of extrapyramidal disorders, particularly bradykinesia and dystonia, will compromise the ability to establish the presence of loss of dexterity and deftness that constitutes this subtype. The term 'apraxia' has also been applied to other motor disturbances, such as 'gait apraxia' and 'apraxia of eyelid opening', that perhaps are misnomers, demonstrating the lack of a coherent nomenclature in this field. Apraxia is a hallmark of corticobasal degeneration (CBD) and historically this has received the most attention among the movement disorders. Corticobasal degeneration is characterized by various forms of apraxia affecting limb function, particularly ideomotor apraxia and limb-kinetic apraxia, although buccofacial and oculomotor apraxia can be present as well. The syndrome of parkinsonism and prominent apraxia, designated the 'corticobasal syndrome' (CBS), may be caused by a variety of other central nervous system pathologies including progressive supranuclear palsy (PSP), Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementias. Distinct from the CBS, PSP and Parkinson's disease can demonstrate varying degrees of apraxia on selected tests, especially in those patients with more severe cognitive dysfunction. Diseases that cause the combination of apraxia and a primary movement disorder most often involve a variety of cerebral cortical sites as well as basal ganglia structures. Clinical-pathological correlates and functional imaging studies are compromised by both this diffuse involvement and the confusion experienced in the clinical evaluation of apraxia in the face of the additional elemental movement disorders. Finally, although apraxia results in clear disability in patients with the CBS, it is not clear how milder ideomotor apraxia found on specific testing contributes to patients' overall day-to-day motor disability.
Huntington disease research PMID: 15930045 [PubMed - indexed for MEDLINE]High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study. Related Articles
High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study.
Neurology. 2005 May 10;64(9):1655-6
Huntington disease research Authors: Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT
Huntington disease research PMID: 15883340 [PubMed - indexed for MEDLINE]Critical periods of suicide risk in Huntington's disease. Related Articles
Critical periods of suicide risk in Huntington's disease.
Am J Psychiatry. 2005 Apr;162(4):725-31
Huntington disease research Authors: Paulsen JS, Hoth KF, Nehl C, Stierman L
Contrary to popular belief, receiving a diagnosis of a devastating fatal disease does not exacerbate, and may even alleviate, the risk of suicide. Suicidal ideation was examined in 4,171 individuals in the Huntington Study Group database. Participants were grouped according to a standardized neurological examination from 0 (i.e., normal examination) to 3 (definite Huntington's disease). Patients with an unequivocal diagnosis of Huntington's disease were further divided by stage of disease, from stage 1 (early) to stage 5 (end stage). Findings showed that the frequency of suicidal ideation doubled from 9.1% in at-risk persons with a normal neurological examination to 19.8% in at-risk persons with soft neurological signs and increased to 23.5% in persons with "possible Huntington's disease." In persons with a diagnosis of Huntington's disease, 16.7% had suicidal ideation in stage 1, and 21.6% had suicidal ideation in stage 2, whereas the proportion of Huntington's disease patients with suicidal ideation diminished thereafter. Findings suggest two critical periods for increased risk of suicide in Huntington's disease. The first critical period is immediately before receiving a formal diagnosis of Huntington's disease, and the second is in stage 2 of the disease, when independence diminishes. Although the underlying mechanisms of suicidal ideation in Huntington's disease are poorly understood, it is critical for health care providers to be aware of periods during which patients may be at an increased risk.
Huntington disease research PMID: 15800145 [PubMed - indexed for MEDLINE]The role of the striatum in rule application: the model of Huntington's disease at early stage. Related Articles
The role of the striatum in rule application: the model of Huntington's disease at early stage.
Brain. 2005 May;128(Pt 5):1155-67
Huntington disease research Authors: Teichmann M, Dupoux E, Kouider S, Brugières P, Boissé MF, Baudic S, Cesaro P, Peschanski M, Bachoud-Lévi AC
The role of the basal ganglia, and more specifically of the striatum, in language is still debated. Recent studies have proposed that linguistic abilities involve two distinct types of processes: the retrieving of stored information, implicating temporal lobe areas, and the application of combinatorial rules, implicating fronto-striatal circuits. Studies of patients with focal lesions and neurodegenerative diseases have suggested a role for the striatum in morphological rule application, but functional imaging studies found that the left caudate was involved in syntactic processing and not morphological processing. In the present study, we tested the view that the basal ganglia are involved in rule application and not in lexical retrieving in a model of striatal dysfunction, namely Huntington's disease at early stages. We assessed the rule-lexicon dichotomy in the linguistic domain with morphology (conjugation of non-verbs and verbs) and syntax (sentence comprehension) and in a non-linguistic domain with arithmetic operations (subtraction and multiplication). Thirty Huntington's disease patients (15 at stage I and 15 at stage II) and 20 controls matched for their age and cultural level were included in this study. Huntington's disease patients were also assessed using the Unified Huntington's Disease Rating Scale (UHDRS) and MRI. We found that early Huntington's disease patients were impaired in rule application in the linguistic and non- linguistic domains (morphology, syntax and subtraction), whereas they were broadly spared with lexical processing. The pattern of performance was similar in patients at stage I and stage II, except that stage II patients were more impaired in all tasks assessing rules and had in addition a very slight impairment in the lexical condition of conjugation. Finally, syntactic rule abilities correlated with all markers of the disease evolution including bicaudate ratio and performance in executive function, whereas there was no correlation with arithmetic and morphological abilities. Together, this suggests that the striatum is involved in rule processing more than in lexical processing and that it extends to linguistic and non-linguistic domains. These results are discussed in terms of domain- specific versus domain-general processes of rule application.
Huntington disease research PMID: 15788544 [PubMed - indexed for MEDLINE]Genetic testing: practical, ethical, and counseling considerations. Related Articles
Genetic testing: practical, ethical, and counseling considerations.
Mayo Clin Proc. 2005 Jan;80(1):63-73
Huntington disease research Authors: Ensenauer RE, Michels VV, Reinke SS
Genetic testing is becoming a much more common practice in medicine today. This presents a unique set of challenges for medical professionals in virtually all specialties. The practical aspects of determining which test to order, and in interpreting the result accurately in the context of the family history, can be difficult. Additionally, the ethical conundrums that frequently present themselves when genetic risk assessment and/or genetic testing is being considered can be daunting. These challenges present real concerns for medical professionals and patients alike. Included in this article is a review of some of the practical and ethical complexities associated with genetic testing. Pretest and posttest genetic counseling is also emphasized as an important and essential process in today's medical practice.
Huntington disease research PMID: 15667031 [PubMed - indexed for MEDLINE]The basal ganglia and rule-governed language use: evidence from vascular and degenerative conditions. Related Articles
The basal ganglia and rule-governed language use: evidence from vascular and degenerative conditions.
Brain. 2005 Mar;128(Pt 3):584-96
Huntington disease research Authors: Longworth CE, Keenan SE, Barker RA, Marslen-Wilson WD, Tyler LK
The Declarative/Procedural Model of Pinker, Ullman and colleagues claims that the basal ganglia are part of a fronto-striatal procedural memory system which applies grammatical rules to combine morphemes (the smallest meaningful units in language) into complex words (e.g. talk-ed, talk-ing). We tested this claim by investigating whether striatal damage or loss of its dopaminergic innervation is reliably associated with selective regular past tense deficits in patients with subcortical cerebrovascular damage, Parkinson's disease or Huntington's disease. We focused on past tense morphology since this allows us to contrast the regular past tense (jump- jumped), which is rule-based, with the irregular past tense (sleep-slept), which is not. We used elicitation and priming tasks to test patients' ability to comprehend and produce inflected forms. We found no evidence of a consistent association between striatal dysfunction and selective impairment of regular past tense morphology, suggesting that the basal ganglia are not essential for processing the regular past tense as a sequence of morphemes, either in comprehension or production, in contrast to the claims of the Declarative/Procedural Model. All patient groups showed normal activation of semantic and morphological representations in comprehension, despite difficulties suppressing semantically appropriate alternatives when trying to inflect novel verbs. This is consistent with previous reports that striatal dysfunction spares automatic activation of linguistic information, but disrupts later language processes that require inhibition of competing alternatives.
Huntington disease research PMID: 15659423 [PubMed - indexed for MEDLINE]Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. Related Articles
Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways.
Arch Neurol. 2005 Jan;62(1):46-51
Huntington disease research Authors: Gunawardena S, Goldstein LS
The expansion of CAG repeats encoding glutamine (polyQ) causes, to date, 9 late-onset progressive neurodegenerative disorders, including Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. Although many studies using both knockout and transgenic mouse models suggest that a toxic gain of function is central to neuronal dysfunction, the exact mechanisms of neurotoxic effects remain elusive. Protein aggregations within neurons seem to be a common manifestation in almost all polyQ diseases, and such accumulations are perhaps major triggers of cellular stress and neuronal death. Recent data lead to the tantalizing proposal that disruption of axonal transport pathways within long, narrow-caliber axons could lead to protein accumulations that can elicit neuronal death, ultimately causing a neuronal dysfunction pathway observed in polyQ expanded diseases. Perhaps perturbations in transport pathways are an early event involved in instigating polyQ disease pathology.
Huntington disease research PMID: 15642849 [PubMed - indexed for MEDLINE]Scientists scope out Huntington disease. Related Articles
Scientists scope out Huntington disease.
JAMA. 2005 Jan 5;293(1):29
Huntington disease research Authors: Hampton T
Huntington disease research PMID: 15632323 [PubMed - indexed for MEDLINE]Leber hereditary optic neuropathy with chorea and dementia resembling Huntington disease. Related Articles
Leber hereditary optic neuropathy with chorea and dementia resembling Huntington disease.
Neurology. 2004 Dec 28;63(12):2451-2
Huntington disease research Authors: Morimoto N, Nagano I, Deguchi K, Murakami T, Fushimi S, Shoji M, Abe K
Huntington disease research PMID: 15623735 [PubMed - indexed for MEDLINE]In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease. Related Articles
In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease.
Neurology. 2004 Sep 28;63(6):989-95
Huntington disease research Authors: Fennema-Notestine C, Archibald SL, Jacobson MW, Corey-Bloom J, Paulsen JS, Peavy GM, Gamst AC, Hamilton JM, Salmon DP, Jernigan TL
OBJECTIVE: To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI. METHODS: Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter. RESULTS: As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD. CONCLUSIONS: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.
Huntington disease research PMID: 15452288 [PubMed - indexed for MEDLINE]Huntington's disease-like 2 can present as chorea-acanthocytosis. Related Articles
Huntington's disease-like 2 can present as chorea-acanthocytosis.
Neurology. 2004 Sep 14;63(5):939-40; author reply 939-40
Huntington disease research Authors: Saiki S, Sakai K, Saiki M, Hirose G
Huntington disease research PMID: 15365163 [PubMed - indexed for MEDLINE]Trinucleotide repeats and neurodegenerative disease. Related Articles
Trinucleotide repeats and neurodegenerative disease.
Brain. 2004 Nov;127(Pt 11):2385-405
Huntington disease research Authors: Everett CM, Wood NW
Major insights have been attained into the molecular pathology of the trinucleotide repeat neurodegenerative diseases over the past decade. Genetic definition has allowed subclassification into translated polyglutamine diseases, which are due to CAG repeat expansions, and a more heterogeneous group in which the trinucleotide repeat remains untranslated. The polyglutamine disorders are due to a toxic gain of function of mutant expanded proteins. Neuronal intranuclear inclusions (NIIs) characteristically occur. Protein misfolding, interference with DNA transcription and RNA processing, activation of apoptosis and dysfunction of cytoplasmic elements have all been invoked in the toxic process. The end result is apoptotic cell death with many aspects of neuronal function being perturbed. Promising progress has been made into arresting and reversing neurodegeneration in both cellular and animal models. The molecular mechanisms underlying the untranslated group remain less clear. Impedance of gene transcription secondary to abnormal DNA structures formed by repeats, modification of chromatin gene packaging and dysfunction at the RNA level have all been suggested as possible pathological mechanisms. These diseases remain irreversible. It is hoped that clarification of the molecular pathogenic mechanisms will provide the tools for future therapeutic intervention.
Huntington disease research PMID: 15329351 [PubMed - indexed for MEDLINE]Antigliadin antibodies in Huntington's disease. Related Articles
Antigliadin antibodies in Huntington's disease.
Neurology. 2004 Aug 24;63(4):762; author reply 762
Huntington disease research Authors: Barta Z, Mekkel G, Zeher M
Huntington disease research PMID: 15326272 [PubMed - indexed for MEDLINE]Left by the lakeside. Related Articles
Left by the lakeside.
Lancet. 2004 Aug 14-20;364(9434):569-70
Huntington disease research Authors: Ceaser M
Huntington disease research PMID: 15314834 [PubMed - indexed for MEDLINE]IV amantadine improves chorea in Huntington's disease: an acute randomized, controlled study. Related Articles
IV amantadine improves chorea in Huntington's disease: an acute randomized, controlled study.
Neurology. 2004 Aug 10;63(3):597-8; author reply 597-8
Huntington disease research Authors: Heckmann JM, Legg P, Sklar D, Fine J, Bryer A, Kies B
Huntington disease research PMID: 15304616 [PubMed - indexed for MEDLINE]Minocycline safety and tolerability in Huntington disease. Related Articles
Minocycline safety and tolerability in Huntington disease.
Neurology. 2004 Aug 10;63(3):547-9
Huntington disease research Authors:
Minocycline is an antibiotic with anti-inflammatory and antiapoptotic properties that prolongs survival in a transgenic Huntington disease (HD) mouse model. In a double-blind, randomized, placebo-controlled study of minocycline in 60 HD patients, the authors determined that over 8 weeks, minocycline at 100 and 200 mg/day was well tolerated and safe in HD patients. Tolerability and adverse event frequency were similar between treatment and placebo groups.
Huntington disease research PMID: 15304592 [PubMed - indexed for MEDLINE]Clinical laboratory monitoring of coenzyme Q10 use in neurologic and muscular diseases. Related Articles
Clinical laboratory monitoring of coenzyme Q10 use in neurologic and muscular diseases.
Am J Clin Pathol. 2004 Jun;121 Suppl:S113-20
Huntington disease research Authors: Steele PE, Tang PH, DeGrauw AJ, Miles MV
Coenzyme Q10 (Q10) is available as an over-the-counter dietary supplement in the United States. While its use could be considered a form of alternative therapy, the medical profession has embraced the use of Q10 in specific disease states, including a series of neurologic and muscular diseases. Clinical laboratory monitoring is available for measurement of total Q10 in plasma and tissue and for measurement of redox status, ie, the ratio of reduced and oxidized forms of Q10. Many published studies have been anecdotal, in part owing to the rarity of some diseases involved. Unfortunately, many studies do not report Q10 levels, and, thus, the relationship of clinical response to Q10 concentration in plasma frequently is not discernible. Consistent laboratory monitoring of patients treated with this compound would help ease interpretation of the results of the treatment, especially because so many formulations of Q10 exist in the marketplace, each with its own bioavailability characteristics. Q10 has an enviable safety profile and, thus, is ideal to study as an adjunct to more conventional therapy. Defining patient subpopulations and characteristics that predict benefit from exogenous Q10 and defining therapeutic ranges for those particular applications are major challenges in this field.
Huntington disease research PMID: 15298157 [PubMed - indexed for MEDLINE]Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela. Related Articles
Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela.
Neurology. 2004 Jul 27;63(2):340-3
Huntington disease research Authors: Okun MS, Thommi N
OBJECTIVE: To elucidate the role of Dr. Americo Negrette in diagnosing and reclassifying the dancing mania in Maracaibo, Venezuela as Huntington disease (HD). METHODS: All of the medical and nonmedical books and articles by Negrette were collected and reviewed. Personal interviews with Negrette were performed to confirm the details of his life and original work. His childhood, medical education, and contribution to HD, as well as contributions to medicine, art, and poetry, were covered in interview sessions. Excerpts from his autobiography, Ciudad de Fuego, were translated into English for publication. A complete bibliography of 70 books and research articles authored by Negrette was assembled. Negrette himself reviewed the compilation of this manuscript just days before his sudden death on September 14, 2003. RESULTS: Americo Negrette, a Venezuelan physician, biochemist, artist, and poet, observed a dancing epidemic in 1952. He acquired, through interviews with locals, the knowledge that there were two other small towns along Lake Maracaibo devastated by a syndrome called el mal (the bad). Negrette changed the diagnosis of these patients from a dancing mania to what he believed was Huntington chorea, later termed HD. He presented his findings at the Venezuelan Sixth Congress of Medical Science in 1955. He was met with reluctance in the local scientific community and a passive ear from government authorities. His description, written in Spanish, was not widely distributed beyond Venezuela, and its importance would have to wait until one of his students shared his observations (more than a decade later) with the HD research community and the rest of the world. CONCLUSION: The "dancing mania" of Maracaibo, because of the work of Americo Negrette, has been reclassified as Huntington disease.
Huntington disease research PMID: 15277631 [PubMed - indexed for MEDLINE]Targeting energy metabolism in Huntington's disease. Related Articles
Targeting energy metabolism in Huntington's disease.
Lancet. 2004 Jul 24-30;364(9431):312-3
Huntington disease research Authors: Walker FO, Raymond LA
Huntington disease research PMID: 15276373 [PubMed - indexed for MEDLINE]Onset and rate of striatal atrophy in preclinical Huntington disease. Related Articles
Onset and rate of striatal atrophy in preclinical Huntington disease.
Neurology. 2004 Jul 13;63(1):66-72
Huntington disease research Authors: Aylward EH, Sparks BF, Field KM, Yallapragada V, Shpritz BD, Rosenblatt A, Brandt J, Gourley LM, Liang K, Zhou H, Margolis RL, Ross CA
BACKGROUND: Huntington disease (HD) is characterized by striatal atrophy that begins long before the onset of motor symptoms. OBJECTIVE: To determine when striatal atrophy begins, the extent and rate of atrophy before diagnosis of motor symptoms, and whether striatal atrophy can predict when symptom onset will occur. METHODS: Caudate and putamen volumes were measured on MRI scans of 19 preclinical subjects with the HD gene expansion who were very far (9 to 20 years) from estimated onset, and on serial scans from 17 preclinical subjects, six of whom were diagnosed with HD within 5 years after the initial scan. RESULTS: Striatal volumes were significantly smaller for the subjects who were very far from estimated onset than for age-matched control subjects. Statistical models fit to the longitudinal data suggest that rate of caudate atrophy becomes significant when subjects are approximately 11 years from estimated onset and rate of putamen atrophy becomes significant approximately 9 years prior to onset. In the six incident cases, caudate and putamen were approximately one-third to one-half of normal volume at diagnosis, and caudate volume alone was able to predict with 100% accuracy those subjects who would be diagnosed within 2 years of imaging. CONCLUSIONS: Striatal atrophy begins many years prior to diagnosable HD, and assessment of atrophy on MRI may be very useful in both predicting HD onset and in tracking progression in future therapeutic trials in preclinical subjects.
Huntington disease research PMID: 15249612 [PubMed - indexed for MEDLINE]Huntington disease: volumetric, diffusion-weighted, and magnetization transfer MR imaging of brain. Related Articles
Huntington disease: volumetric, diffusion-weighted, and magnetization transfer MR imaging of brain.
Radiology. 2004 Sep;232(3):867-73
Huntington disease research Authors: Mascalchi M, Lolli F, Della Nave R, Tessa C, Petralli R, Gavazzi C, Politi LS, Macucci M, Filippi M, Piacentini S
PURPOSE: To investigate whether diffusion-weighted and magnetization transfer (MT) magnetic resonance (MR) imaging depict regional and/or global brain abnormalities in patients with Huntington disease (HD). MATERIALS AND METHODS: Twenty-one carriers of the HD mutation (mean age, 58 years +/- 11 [SD]) and 21 healthy control subjects (mean age, 54 years +/- 13) underwent conventional, diffusion-weighted, and MT MR imaging. Volumes, mean apparent diffusion coefficients (ADCs), and MT ratios (MTRs) for left and right caudate nucleus, putamen, and cerebral periventricular white matter-as well as an index of normalized brain volume and whole-brain ADC and MT histograms-were computed. Asymmetry in volume, ADC, and MTR measurements in caudate nucleus, putamen, and periventricular white matter in control subjects and HD carriers were evaluated with Wilcoxon testing for paired samples. Differences in MR imaging variables between HD carriers and control subjects were evaluated with Mann-Whitney U testing; correlations between stages of clinical severity and MR imaging data were investigated with Spearman rank correlation testing. RESULTS: No significant asymmetry was observed for any of the MR imaging variables. Caudate nucleus, putamen, and whole-brain volumes were smaller (P <.001 for all) in HD carriers than in control subjects. HD carriers also had increased ADC in the caudate nucleus (P =.002), putamen (P <. 001), cerebral periventricular white matter (P <.001), and whole brain (P <.001). MTR was not significantly different between HD carriers and control subjects. Correlation was observed between stages of increasing clinical disease severity and both decrease in volume of caudate nucleus (Spearman rho = -0.63), putamen (rho = -0.64), and whole brain (rho = -0.46) and increase in ADC in caudate nucleus (rho = 0.52), periventricular white matter (rho = 0.45), and whole brain (rho = 0.44). CONCLUSION: Regional and global volume loss in HD is accompanied by an increase in ADC; this correlates with disease severity.
Huntington disease research PMID: 15215553 [PubMed - indexed for MEDLINE]On-line motor control in patients with Parkinson's disease. Related Articles
On-line motor control in patients with Parkinson's disease.
Brain. 2004 Aug;127(Pt 8):1755-73
Huntington disease research Authors: Desmurget M, Gaveau V, Vindras P, Turner RS, Broussolle E, Thobois S
Recent models based, in part on a study of Huntington's disease, suggest that the basal ganglia are involved in on-line movement guidance. Two experiments were conducted to investigate this idea. First, we studied advanced Parkinson's disease patients performing a reaching task known to depend on on-line guidance. The task was to 'look and point' in the dark at visual targets displayed in the peripheral visual field. In some trials, the target location was slightly modified during saccadic gaze displacement (when vision is suppressed). In both patient and control groups, the target jump induced a gradual modification of the movement which diverged smoothly from its original path to reach the new target location. No deficit was found in the patients, except for an increased latency to respond to the target jump (Parkinson's disease: 243 ms; controls: 166 ms). A computational simulation indicated that this response slowing was likely to be a by- product of bradykinesia. The unexpected inconsistency between this result and previous reports was investigated in a second experiment. We hypothesized that the relevant factor was the characteristics of the corrections to be performed. To test this prediction, we investigated a task requiring corrections of the same type as investigated in Huntington's disease, namely large, consciously detected errors induced by large target jumps at hand movement onset. In contrast with the smooth adjustments observed in the first experiment, the subjects responded to the target jump by generating a discrete corrective sub-movement. While this iterative response was relatively rapid in the control subjects (220 ms), Parkinson's disease patients exhibited either dramatically late (>730 ms) or totally absent on-line corrections. When on-line corrections were absent, the initial motor response was completed before a second corrective response was initiated (the latency of the corrective response was the same as the latency of the initial response). Considered together, these results suggest that basal ganglia dependent circuits are not critical for feedback loops involving a smooth modulation of the ongoing command. These circuits may rather contribute to the generation of discrete corrective sub-movements. This deficit is in line with the general impairment of sequential and simultaneous actions in patients with basal ganglia disorders.
Huntington disease research PMID: 15215215 [PubMed - indexed for MEDLINE]Impact of presymptomatic genetic testing for hereditary ataxia and neuromuscular disorders. Related Articles
Impact of presymptomatic genetic testing for hereditary ataxia and neuromuscular disorders.
Arch Neurol. 2004 Jun;61(6):875-80
Huntington disease research Authors: Smith CO, Lipe HP, Bird TD
BACKGROUND: With the exception of Huntington disease, the psychological and psychosocial impact of DNA testing for neurogenetic disorders has not been well studied. OBJECTIVE: To evaluate the psychosocial impact of genetic testing for autosomal dominant forms of hereditary ataxia and neuromuscular disorders.Patients Fifty subjects at risk for autosomal dominant forms of spinocerebellar ataxia (n = 11), muscular dystrophy (n = 28), and hereditary neuropathy (n = 12). DESIGN AND SETTING: A prospective, descriptive, observational study in a university setting of individuals who underwent genetic counseling and DNA testing. Participants completed 3 questionnaires before testing and at regular intervals after testing. The questionnaire set included the Revised Impact of Event Scale, the Hospital Anxiety and Depression Scale, demographic information, and an assessment of attitudes and feelings about genetic testing. RESULTS: Thirty-nine subjects (78%) completed 6 months to 5 years of posttest follow-up. Common reasons for pursuing genetic testing were to provide an explanation for symptoms, emotional relief, and information for future planning. Thirty-four (68%) had positive and 16 (32%) had negative genetic results. In those with a positive result, 26 (76%) had nonspecific signs or symptoms of the relevant disorder. Forty-two participants (84%) felt genetic testing was beneficial. Groups with positive and negative test results coped well with results. However, 13 subjects (10 with positive and 3 with negative results) reported elevated anxiety levels, and 3 (1 with positive and 2 with negative results) expressed feelings of depression during the follow-up period. The test result was not predictive of anxiety or depression. CONCLUSIONS: Most individuals find neurogenetic testing to be beneficial, regardless of the result. Anxiety or depression may persist in some persons with positive or negative test results. Testing can have a demonstrable impact on family planning and interpersonal relationships. Further studies are needed to assess the long-term impact of such testing.
Huntington disease research PMID: 15210524 [PubMed - indexed for MEDLINE]Neural correlates associated with impaired disgust processing in pre- symptomatic Huntington's disease. Related Articles
Neural correlates associated with impaired disgust processing in pre- symptomatic Huntington's disease.
Brain. 2004 Jun;127(Pt 6):1446-53
Huntington disease research Authors: Hennenlotter A, Schroeder U, Erhard P, Haslinger B, Stahl R, Weindl A, von Einsiedel HG, Lange KW, Ceballos-Baumann AO
Disturbances in recognizing facial expressions of disgust have been reported previously in pre-symptomatic and manifest Huntington's disease. Given the substantial role of the insula and basal ganglia in the perception of disgust as revealed by functional imaging, lesion studies and intracerebral recordings, we propose dysfunction within the insula and/or basal ganglia as the underlying neural substrate. Using functional MRI (fMRI), we studied a group of nine pre-symptomatic Huntington's disease gene carriers and nine healthy controls, matched for age, gender, intelligence and years of education, while they were viewing disgusted facial expressions. As control conditions, surprised and neutral expressions were presented. Compared with healthy controls, Huntington's disease gene carriers showed reduced responses within the left dorsal anterior insula during processing of disgusted facial expressions. Moreover, processing of disgust was associated with significant activation of the left dorsal anterior insula and putamen in healthy controls, but not in Huntington's disease gene carriers. Furthermore, behavioural assessment revealed a selective impairment in recognizing facial expressions displaying disgust in Huntington's disease gene carriers. Our finding of dysfunctional decreased insula activation in pre-symptomatic Huntington's disease provides an explanation for the clinical deficit in recognizing facial expression of disgust. Furthermore, it underscores the role of the insula in the emotion of disgust.
Huntington disease research PMID: 15090475 [PubMed - indexed for MEDLINE]Integrating fetal neural transplants into a therapeutic strategy: the example of Huntington's disease. Related Articles
Integrating fetal neural transplants into a therapeutic strategy: the example of Huntington's disease.
Brain. 2004 Jun;127(Pt 6):1219-28
Huntington disease research Authors: Peschanski M, Bachoud-Lévi AC, Hantraye P
Fetal neural transplants have become clinically relevant over the past 15 years for two major neurodegenerative diseases, namely Parkinson's disease and Huntington's disease. It is therefore timely to consider how this neurosurgical procedure can integrate the therapeutic armamentarium, what can be expected of it, and what cannot. We use here the example of Huntington's disease to show what fetal neural transplants may uniquely offer for that disease. Up to very recent times, Huntington's disease has been one special example of those neurodegenerative diseases against which neurologists feel totally helpless. This has all changed today and, although results are essentially still to come, one can foresee the mobilization of very large scientific and medical forces against this disease, with definite steps forward in terms of physiopathology and a better view of the therapeutic challenges. While defining the role that fetal neural transplantation may play in meeting these challenges, we also try to show rationales and developments for all types of treatments attempted or suggested so far, as well as their limits and, when relevant, informative failures. The date of writing this review needs to be noted, because the rapid accumulation of data on molecular mechanisms of Huntington's disease pathogenesis and the increasing numbers of clinical trials do not allow much time for the ink of a review to dry.
Huntington disease research PMID: 15047588 [PubMed - indexed for MEDLINE]DHEA treatment of Alzheimer's disease: A randomized, double-blind, placebo- controlled trial. Related Articles
DHEA treatment of Alzheimer's disease: A randomized, double-blind, placebo- controlled trial.
Neurology. 2004 Mar 23;62(6):1030
Huntington disease research Authors: Leblhuber F, Haller H, Steiner K, Fuchs D
Huntington disease research PMID: 15037728 [PubMed - indexed for MEDLINE]Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Related Articles
Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis.
Neurology. 2004 Feb 10;62(3):523-4; author reply 524
Huntington disease research Authors: Kassubek J, Gaus W, Landwehrmeyer GB
Huntington disease research PMID: 14872054 [PubMed - indexed for MEDLINE]Cognitive and psychiatric aspects of Huntington disease contribute to functional capacity. Related Articles
Cognitive and psychiatric aspects of Huntington disease contribute to functional capacity.
J Nerv Ment Dis. 2004 Jan;192(1):72-4
Huntington disease research Authors: Nehl C, Paulsen JS,
Huntington disease research PMID: 14718780 [PubMed - indexed for MEDLINE]Antigliadin antibodies in Huntington's disease.
Antigliadin antibodies in Huntington's disease.
Neurology. 2004 Jan 13;62(1):132-3
Huntington disease research Authors: Bushara KO, Nance M, Gomez CM
The relevance of gluten sensitivity in sporadic and hereditary ataxia pathogenesis is unclear. The authors found high antigliadin antibody titers in 23 of 52 (44%) patients with Huntington's disease (HD), suggesting a previously unrecognized association between HD and gluten sensitivity. The results further question "gluten ataxia" as a distinct disease entity and raise the possibility that antigliadin antibodies in ataxia and other neurodegenerative diseases may be an epiphenomenon, the mechanisms of which remain to be investigated.
Huntington disease research PMID: 14718716 [PubMed - indexed for MEDLINE]Huntington's disease: phenomenological diversity of a neuropsychiatric condition that challenges traditional concepts in neurology and psychiatry. Related Articles
Huntington's disease: phenomenological diversity of a neuropsychiatric condition that challenges traditional concepts in neurology and psychiatry.
Am J Psychiatry. 2004 Jan;161(1):28-34
Huntington disease research Authors: Tost H, Wendt CS, Schmitt A, Heinz A, Braus DF
Huntington disease research PMID: 14702246 [PubMed - indexed for MEDLINE]Profile of cognitive progression in early Huntington's disease. Related Articles
Profile of cognitive progression in early Huntington's disease.
Neurology. 2003 Dec 23;61(12):1702-6
Huntington disease research Authors: Ho AK, Sahakian BJ, Brown RG, Barker RA, Hodges JR, Ané MN, Snowden J, Thompson J, Esmonde T, Gentry R, Moore JW, Bodner T,
OBJECTIVE: To examine the pattern of cognitive decline in early Huntington's disease (HD). METHODS: The authors studied 61 patients with mild to moderate HD who had at least three annual neuropsychological assessments using the Core Assessment Program for Intracerebral Transplantation in Huntington's Disease short battery. A subset of 34 patients had additional neuropsychological tests, and another subset of 21 patients was assessed annually on the Cambridge Neuropsychological Test Automated Battery. Neuropsychological measures that changed significantly over time were submitted to a multiple analysis of covariance to explore associations with demographic and neurologic indices. RESULTS: Patients showed a progressive impairment in attention, executive function, and immediate memory, with timed tests of psychomotor skill being particularly sensitive to decline. In contrast, general cognition, semantic memory, and delayed recall memory were relatively unaffected. CONCLUSION: The profile of cognitive performance shows selective and progressive dysfunction of attention and executive function in patients with mild to moderate HD, consistent with frontostriatal pathology at this stage of disease.
Huntington disease research PMID: 14694033 [PubMed - indexed for MEDLINE]Dosage effects of riluzole in Huntington's disease: a multicenter placebo- controlled study. Related Articles
Dosage effects of riluzole in Huntington's disease: a multicenter placebo- controlled study.
Neurology. 2003 Dec 9;61(11):1551-6
Huntington disease research Authors:
BACKGROUND: Riluzole retards striatal glutamate release and pathologic consequences in neurotoxic animal models of Huntington's disease (HD). OBJECTIVE: To determine the dosage-related impact of riluzole on chorea in HD. METHODS: An 8-week double-blind dose-ranging multicenter study of riluzole was conducted in 63 subjects (32 women, 31 men) with HD who were randomized to receive placebo, riluzole 100 mg/day, or riluzole 200 mg/day. The prespecified outcome measure was change in the total maximal chorea score of the Unified Huntington's Disease Rating Scale (UHDRS). RESULTS: Fifty-six (89%) subjects completed the study. A reduction (p < 0.01) in chorea at 8 weeks was found using a linear trend test with dose. Comparing the groups individually, the reduction in chorea for the riluzole 200-mg/day group (-2.2 +/- 3.3) was different (p = 0.01) from placebo (+0.7 +/- 3.4), but the riluzole 100-mg/day group (-0.2 +/- 2.9) was not. Riluzole did not improve other motor, cognitive, behavioral, or functional components of the UHDRS. Alanine aminotransferase was elevated in a dosage-dependent fashion (p = 0.01). CONCLUSIONS: Over 8 weeks of treatment, riluzole 200 mg/day ameliorated chorea intensity in HD without improving functional capacity or other clinical features of illness. Riluzole 200 mg/day was attended by reversible liver transaminase abnormalities that would require monitoring in long-term studies.
Huntington disease research PMID: 14663041 [PubMed - indexed for MEDLINE]Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model. Related Articles
Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model.
Brain. 2004 Mar;127(Pt 3):505-16
Huntington disease research Authors: Jarabek BR, Yasuda RP, Wolfe BB
Symptoms of Huntington's disease may be caused by a toxic insult triggered by the mutant human huntingtin (Htt) protein itself, by a maladaptive protective mechanism initiated in response to an insult, or by a combination of these. We observed a protection from N-methyl-d-aspartate (NMDA) receptor-induced excitotoxicity in striata of symptomatic N171-82Q mice, a new transgenic model of Huntington's disease. The goal of this study was to determine if NMDA receptor-mediated signalling pathways are altered in these mice. Multiple proteins of NMDA receptor and dopamine D1 receptor pathways are being regulated in ways predictive of the protection we observe. Although examining NMDA receptor subunit proteins showed no change in NR1, NR2A, or NR2B in the striata of the symptomatic mice, we observed a decrease in phosphorylation of NR1 at Ser897, previously reported to decrease NMDA receptor current. The dopamine D1 receptor, responsible for protein kinase A activation and subsequent phosphorylation of Ser897 of NR1, also showed an age-related decrease. Other proteins regulated in this disease were associated with PSD-95-like scaffolding proteins of the NMDA receptor. Specifically, we observed a decrease in membrane-associated neuronal nitric oxide synthase (nNOS), a decrease in PSD-95-like proteins, which link nNOS to the NMDA receptor complex, and a decrease in citron, a protein associated with dendritic spine formation. From these data, we conclude that the N171- 82Q mice seem to be regulating, in a protective direction, many of the known effector pathways of NMDA receptor-induced excitotoxicity. These regulations, although seemingly effective in decreasing neuronal death, may in fact be causing some of the symptoms associated with the disease.
Huntington disease research PMID: 14662521 [PubMed - indexed for MEDLINE]Striatal neural grafting improves cortical metabolism in Huntington's disease patients. Related Articles
Striatal neural grafting improves cortical metabolism in Huntington's disease patients.
Brain. 2004 Jan;127(Pt 1):65-72
Huntington disease research Authors: Gaura V, Bachoud-Lévi AC, Ribeiro MJ, Nguyen JP, Frouin V, Baudic S, Brugières P, Mangin JF, Boissé MF, Palfi S, Cesaro P, Samson Y, Hantraye P, Peschanski M, Remy P
Huntington's disease is a hereditary disease in which degeneration of neurons in the striatum leads to motor and cognitive deficits. Foetal striatal allografts reverse these deficits in phenotypic models of Huntington's disease developed in primates. A recent open-label pilot study has shown some clinical improvement or stabilization in three out of five Huntington's disease patients who received bilateral striatal grafts of foetal neurons. We show here that the clinical changes in these three patients were associated with a reduction of the striatal and cortical hypometabolism, demonstrating that grafts were able to restore the function of striato-cortical loops. Conversely, in the two patients not improved by the grafts, striatal and cortical hypometabolism progressed over the 2-year follow-up. Finally, detailed anatomical-functional analysis of the grafted striata, enabled by the 3D fusion of MRI and metabolic images, revealed considerable heterogeneity in the anatomic and metabolic profiles of grafted tissue, both within and between Huntington's disease patients. Our results demonstrate the usefulness of PET measurements of brain glucose metabolism in understanding the effects of foetal grafts in patients with Huntington's disease.
Huntington disease research PMID: 14607797 [PubMed - indexed for MEDLINE]Huntington's disease: clinical correlates of disability and progression. Related Articles
Huntington's disease: clinical correlates of disability and progression.
Neurology. 2003 Oct 28;61(8):1085-92
Huntington disease research Authors: Mahant N, McCusker EA, Byth K, Graham S,
OBJECTIVE: To define the phenotypic variation in a large population of patients with Huntington disease (HD) and to identity clinical features that predict disability and the rate of disease progression. METHODS: The authors analyzed data on 1,026 patients, followed for a median of 2.7 years, using a mixed effects model. The factors studied included the age at onset, the major clinical feature at onset, the severity of motor and cognitive impairment, and the level of disability. RESULTS: The mean age at onset was 41.5 (range 8 to 83) years, and patients were enrolled at all stages of disease. Younger onset was associated with more dystonia, less chorea, and a faster rate of motor, cognitive, and functional progression. The rate of progression was not related to the major clinical feature at onset or the sex of the affected parent. Disability correlated with the motor score (excluding chorea and dystonia) and the symbol-digit modalities test. Weight loss correlated with severe chorea. CONCLUSIONS: The rate of progression of HD was significantly more rapid with a younger age at onset. Therefore, CAG repeat length may be an important determinant of not only the age at onset, but also the rate of disease progression. Chorea was associated with weight loss, but chorea and dystonia were not major determinants of disability.
Huntington disease research PMID: 14581669 [PubMed - indexed for MEDLINE]Huntington's disease--like 2 can present as chorea-acanthocytosis.
Huntington's disease--like 2 can present as chorea-acanthocytosis.
Neurology. 2003 Oct 14;61(7):1002-4
Huntington disease research Authors: Walker RH, Rasmussen A, Rudnicki D, Holmes SE, Alonso E, Matsuura T, Ashizawa T, Davidoff-Feldman B, Margolis RL
Three patients from a previously described family with autosomal dominant chorea-acanthocytosis were found to have the CTG trinucleotide repeat expansion mutation of the junctophilin-3 gene associated with Huntington's disease-like 2 (HDL2). One of six previously identified patients with HDL2 had acanthocytosis on peripheral blood smear, suggesting that HDL2 should be considered in the differential of chorea-acanthocytosis.
Huntington disease research PMID: 14557581 [PubMed - indexed for MEDLINE]Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Related Articles
Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial.
Neurology. 2003 Oct 14;61(7):925-30
Huntington disease research Authors: Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R
OBJECTIVE: To evaluate the effect of creatine (Cr) supplementation (5 g/day) in Huntington's disease (HD). METHODS: A 1-year double-blind placebo- controlled study was performed in 41 patients with HD (stage I through III). At baseline and after 6 and 12 months, the functional, neuromuscular, and cognitive status of the patients was assessed by a test battery that consisted of 1) the Unified Huntington's Disease Rating Scale (UHDRS), 2) an exercise test on an isokinetic dynamometer to assess strength of the elbow flexor muscles, 3) a maximal exercise test on a bicycle ergometer to evaluate cardiorespiratory fitness, and 4) a test to assess bimanual coordination ability. Following the baseline measurements, the subjects were assigned to either a creatine (n = 26) or a placebo group (n = 15). RESULTS: Scores on the functional checklist of the UHDRS (p < 0.05), maximal static torque (p < 0.05), and peak oxygen uptake (p < 0.05) decreased from the start to the end of the study, independent of the treatment received. Cognitive functioning, bimanual coordination ability, and general motor function (total motor scale, UHDRS) did not change from baseline to 1 year in either group. CONCLUSION: One year of Cr intake, at a rate that can improve muscle functional capacity in healthy subjects and patients with neuromuscular disease (5 g/day), did not improve functional, neuromuscular, and cognitive status in patients with stage I to III HD.
Huntington disease research PMID: 14557561 [PubMed - indexed for MEDLINE]Teacher was refused job because relatives have Huntington's disease. Related Articles
Teacher was refused job because relatives have Huntington's disease.
BMJ. 2003 Oct 11;327(7419):827
Huntington disease research Authors: Burgermeister J
Huntington disease research PMID: 14551070 [PubMed - indexed for MEDLINE]MSJAMA. The dilemma of confidentiality in Huntington disease. Related Articles
MSJAMA. The dilemma of confidentiality in Huntington disease.
JAMA. 2003 Sep 3;290(9):1219-20
Huntington disease research Authors: Wusthoff C
Huntington disease research PMID: 12953009 [PubMed - indexed for MEDLINE]MSJAMA. Between a rock and a hard place. Related Articles
MSJAMA. Between a rock and a hard place.
JAMA. 2003 Sep 3;290(9):1217-8
Huntington disease research Authors: Garrison A
Huntington disease research PMID: 12953008 [PubMed - indexed for MEDLINE]MSJAMA. Genetic information and competing interests. Related Articles
MSJAMA. Genetic information and competing interests.
JAMA. 2003 Sep 3;290(9):1216
Huntington disease research Authors: Ihler E
Huntington disease research PMID: 12953007 [PubMed - indexed for MEDLINE]A randomized trial of amantadine in Huntington disease. Related Articles
A randomized trial of amantadine in Huntington disease.
Arch Neurol. 2003 Jul;60(7):996-8
Huntington disease research Authors: O'Suilleabhain P, Dewey RB
CONTEXT: Huntington chorea, like levodopa-induced dyskinesias, may be responsive to amantadine hydrochloride treatment. OBJECTIVES: To measure the effect of amantadine treatment on Huntington chorea and to test a hypothesis that the adventitious movements are associated with reduced central proprioception that can be corrected by amantadine treatment. DESIGN: A randomized placebo-controlled cross-over trial with 2 weeks of treatment. SETTING: A tertiary referral center. PARTICIPANTS: Twenty-four subjects with Huntington disease took amantadine hydrochloride, 100 mg 3 times daily for 2 weeks, and placebo for 2 weeks. METHODS: Chorea of the face, trunk, and limbs while seated was videotaped at baseline and after each study phase. Segments were viewed in random order by blinded reviewers and scored. Proprioception was determined using arm restraints in which the right and left elbows were set at slightly different angles, and the errors in selecting the more extended elbow over 40 trials were recorded. RESULTS: The chorea score was not correlated with a proprioception deficit. Neither chorea nor proprioception were significantly affected by amantadine therapy. The chorea score was 9.6 (3.1) points at baseline and 9.7 (3.7) points when the patient was receiving amantadine therapy. The 95% confidence interval for the difference between placebo effect and amantadine effect was -1.43 to 1.0 points. Despite this, 19 subjects felt improved during the amantadine phase compared with 6 subjects improved in the placebo phase (P =.006) and the quality of life was better (P<.001). CONCLUSIONS: Elbow proprioception was not shown to be related to Huntington chorea. Amantadine hydrochloride treatment at doses of 300 mg/d had no effect, on average, for Huntington chorea, although most patients felt subjectively better during the short course of amantadine treatment. "Recent Huntington disease publications are scanned daily from major neurology journals and updated here"
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