Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study.

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

[1]  S. Stone-Elander,et al.  Stereoselective binding of 11C-raclopride in living human brain — a search for extrastriatal central D2-dopamine receptors by PET , 2004, Psychopharmacology.

[2]  J. Fawcett,et al.  Brain Damage, Brain Repair , 2002 .

[3]  P. Bartolomeo,et al.  Retest effects and cognitive decline in longitudinal follow-up of patients with early HD , 2001, Neurology.

[4]  Michael Davis,et al.  The amygdala: vigilance and emotion , 2001, Molecular Psychiatry.

[5]  Anne-Catherine Bachoud-Lévi,et al.  Motor and cognitive improvements in patients with Huntington's disease after neural transplantation , 2000, The Lancet.

[6]  S B Dunnett,et al.  Aspects of PET imaging relevant to the assessment of striatal transplantation in Huntington's disease , 2000, Journal of anatomy.

[7]  K. Leenders,et al.  Bradykinesia in early Huntington’s disease , 2000, Neurology.

[8]  A. Rasia-Filho,et al.  Functional activities of the amygdala: an overview. , 2000, Journal of psychiatry & neuroscience : JPN.

[9]  R N Gunn,et al.  Huntington's disease progression. PET and clinical observations. , 1999, Brain : a journal of neurology.

[10]  J. Kordower,et al.  Cellular Delivery of Trophic Factors for the Treatment of Huntington's Disease: Is Neuroprotection Possible? , 1999, Experimental Neurology.

[11]  C Crouzel,et al.  Carbon-11 epidepride: a suitable radioligand for PET investigation of striatal and extrastriatal dopamine D2 receptors. , 1999, Nuclear medicine and biology.

[12]  Ralph Myers,et al.  Assessment of Spatial Normalization of PET Ligand Images Using Ligand-Specific Templates , 1999, NeuroImage.

[13]  R. Roos,et al.  Unified Huntington's disease rating scale: A follow up , 1998, Movement disorders : official journal of the Movement Disorder Society.

[14]  T. Robbins,et al.  The relationship between striatal dopamine receptor binding and cognitive performance in Huntington's disease. , 1998, Brain : a journal of neurology.

[15]  A E Rosser,et al.  Evidence for specific cognitive deficits in preclinical Huntington's disease. , 1998, Brain : a journal of neurology.

[16]  R. Ridley,et al.  Functional integration of striatal allografts in a primate model of Huntington's disease , 1998, Nature Medicine.

[17]  A. Myers,et al.  Dopamine D2 receptor bands in normal human temporal cortex are absent in Alzheimer's disease , 1998, Brain Research.

[18]  D. Eidelberg,et al.  [11C]Raclopride‐PET studies of the Huntington's disease rate of progression: Relevance of the trinucleotide repeat length , 1998, Annals of neurology.

[19]  L. Bäckman,et al.  Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes. , 1997, Brain : a journal of neurology.

[20]  Vincent J. Cunningham,et al.  Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model , 1997, NeuroImage.

[21]  M. Peschanski,et al.  Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease , 1997, Nature.

[22]  D L Hill,et al.  Automated three-dimensional registration of magnetic resonance and positron emission tomography brain images by multiresolution optimization of voxel similarity measures. , 1997, Medical physics.

[23]  P Boesiger,et al.  Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease. , 1996, Brain : a journal of neurology.

[24]  S. Wiegand,et al.  Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Christer Halldin,et al.  Autoradiographic localization of extrastriatal D2‐dopamine receptors in the human brain using [125I]epidepride , 1996, Synapse.

[26]  Jane S. Paulsen,et al.  Unified Huntington's disease rating scale: Reliability and consistency , 1996, Movement disorders : official journal of the Movement Disorder Society.

[27]  O. Lindvall,et al.  Core assessment program for intracerebral transplantation in Huntington's disease (CAPIT‐HD) , 1996, Movement disorders : official journal of the Movement Disorder Society.

[28]  Jane S. Paulsen,et al.  Unified Huntington's disease rating scale: Reliability and consistency , 1996, Movement disorders : official journal of the Movement Disorder Society.

[29]  S B Dunnett,et al.  Assessment of striatal graft viability in the rat in vivo using a small diameter PET scanner. , 1995, Neuroreport.

[30]  D. Brooks,et al.  Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study. , 1995, Brain : a journal of neurology.

[31]  S. Dunnett.  Functional repair of striatal systems by neural transplants: evidence for circuit reconstruction , 1995, Behavioural Brain Research.

[32]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[33]  J. Joyce,et al.  Dopamine D2 receptors in the hippocampus and amygdala in Alzheimer's disease , 1993, Neuroscience Letters.

[34]  Robert M. Kessler,et al.  Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride , 1993, Brain Research.

[35]  T J Spinks,et al.  Physical performance of a positron tomograph for brain imaging with retractable septa. , 1992, Physics in medicine and biology.

[36]  K. Neve,et al.  Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain. , 1991, The Journal of pharmacology and experimental therapeutics.

[37]  M. Torrens.  Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[38]  J. Penney,et al.  The functional anatomy of basal ganglia disorders , 1989, Trends in Neurosciences.

[39]  M. Gilardi,et al.  Physical performance of the latest generation of commercial positron scanner , 1988 .