A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington's disease

Grafton, Scott T.; Mazziotta, John C.; Pahl, Jörg J.; George-Hyslop, Peter St; Haines, Jonathan L.; Gusella, James F.; Hoffman, John M.; Baxter, Lewis R.; Phelps, Michael E.

doi:10.1002/ana.410280503

Cited by 109 publications

(29 citation statements)

References 33 publications

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“…In addition, we demonstrated that there was no difference between baseline 2-DG labeling in WT and HD mice. Nevertheless, this issue could warrant additional investigation, especially in light of conflicting clinical studies concerning metabolic impairment in HD patients and presymptomatic HD gene carriers (Kuhl et al, 1982;Grafton et al, 1990;Feigin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

et al. 2005

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Huntington's disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.

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Section: Discussionmentioning

confidence: 99%

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

et al. 2005

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“…Terminal loss of markers may represent a response to perikaryal injury or dysfunction, or less likely, may indicate the primary site of neuronal damage in Huntington's disease. Richfield [4,7,8). Although the gene for HD was recently cloned, the pathogenesis of these progressive changes remains unknown [9}.…”

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confidence: 99%

Selective vulnerability in Huntington's disease: Preferential loss of cannabinoid receptors in lateral globus pallidus

Richfield

Herkenham

1994

Annals of Neurology

163

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Selective neuronal vulnerability is a key feature of the neuropathology of Huntington's disease. We used [3H]CP-55,940, a synthetic cannabinoid, to label cannabinoid receptors in tissue sections from individuals dying with Huntington's disease and from normal control subjects. The density of cannabinoid receptors in striatum and pallidum was measured using quantitative autoradiography. There was a greater loss of cannabinoid receptors on striatal nerve terminals in the lateral pallidum compared to the medial pallidum, in Huntington's disease of all neuropathological grades. The disparity in binding density between the lateral and medial pallidum increased with higher grades of disease. There was also a greater loss of receptors in the lateral pallidum than in the putamen. The disproportionate loss of receptors in the lateral pallidum compared to the putamen increased in magnitude with severity of neuropathological grade. These data support the relative preferential loss or dysfunction of striatal neurons projecting to the lateral pallidum compared to neurons projecting to the medial pallidum. Terminals in the lateral pallidum containing cannabinoid receptors may be affected earlier or more severely than terminals in the medial pallidum, and both pallidal segments may be affected before or more severely than cell bodies or dendrites in the striatum. Terminal loss of markers may represent a response to perikaryal injury or dysfunction, or less likely, may indicate the primary site of neuronal damage in Huntington's disease.

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“…These that huntingtin's normal function persists despite the presinclude apoptotic cascades, excitotoxicity, the possibility ence of a pathogenic glutamine repeat (11). Expression of huntingtin aggregate toxicity, and pernicious effects of levels for huntingtin are also critical, and mice expressing huntingtin protein-protein interactions, putatively via transglutaminase-catalyzed polyglutamine interactions that striatal hypometabolism precedes the bulk of tissue with glutamines, lysines, and polyamines in other proteins loss and occurs in asymptomatic at-risk subjects (44)(45)(46). (32)(33)(34).…”

Section: Introduction Discussionmentioning

confidence: 99%

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

Browne¹

2004

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Public reporting burden for this collection of InformaUion is estimated to average 1 hour per response, including the time for reviewing instructions, searching exsting data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information, Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and The initial three years of this project determined the contributions of bioenergetic defects and oxidative sress to neurodegenertion in Huntington's disease (HD) and amyotrophic lateral sclerouis (ALS), as previously reporto•. The current report period covms the second year of work on the Consortium project "Mitochondrial Free Radical Generation in Parkinson's Disease", which was appended to the original grant number. This project is to assess in vivo whether mitochondria are the source of free radical generation in animal models of Parkinson's disease (PD). In this period of the study we have continued studies examining the relationship between mitochondrial complex I inhibition and free radical-mediated oxidative damage. Using in vivo approaches we are optimizing the doses and time-courses for detection of complex I inhibition and reactive oxygen species (ROS) generation after intracerebral administration of rotenone and pyridaben. We have found increased production of the DNA oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) shortly (1 hour) after rotenone injection into rat striatum. Lipid peroxidation and induction of the stress-response marker heme oxygenase-I follow DNA oxidation, concomitant with complex I inhibition. Due to an unforeseen change in personnel, a no-cost extension of one year was requested, and granted, to complete these studies in the forthcoming year. INTRODUCTIONThe goal of the original three-year grant proposal was to gain insight into the roles of mitochondrial energy metabolism and oxidative stress in the etiology of neuronal degeneration in degenerative diseases, specifically Huntington's disease (HD) and amyotrophic lateral sclerosis Findings may give insight into potential drug targets for PD. These questions are somewhat easier to address by in vitro approaches (covered in other projects within the Consortium), given the extreme technical difficulties of discretely measuring purely mitochondrial events in vivo. Therefore we are taking an indirect approach, by measuring the time-course and nature of oxidative events caused by toxic insults directed against discrete mitochondrial components. Results for the second year of this consortium project are presented here. NB: In the course of this second year the post-doctoral fellow conducting the bulk of these studies left the department. Since it took some time to recruit a replacement, a no-cost extension of one year was requested, and grant...

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A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington's disease

Cited by 109 publications

References 33 publications

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

Selective vulnerability in Huntington's disease: Preferential loss of cannabinoid receptors in lateral globus pallidus

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

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