Search

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.

To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement.Subjects were participants in the Huntington Study Group's Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using chi2 and Student's t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used.Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents' average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement.Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

Positron emission tomography (PET) has been promoted as a means of improving the diagnosis of Alzheimer's disease (AD), but the evidence to support its incremental value is unclear. To assess the evidence regarding the use of PET in the clinical evaluation of AD, a systematic review of the English-language literature indexed in MEDLINE (1975-January 2001), the Cochrane Library (issue 4, 2000), and health technology assessment (HTA) reports was conducted. Articles identified by this review process were graded for methodological and reporting quality using a standardized grading scheme. Sixteen original articles and seven HTA reports were identified. In general, the articles addressed: using PET to differentiate AD from normal aging or non-Alzheimer's dementias, PET imaging compared with single positron emission computed tomography imaging, using PET to predict the progression of dementia, and agreement and reliability in the interpretation of PET images. Serious problems with study design and methodology in all articles were identified. Previous HTA reports have generally recommended that PET not be used in the clinical evaluation of dementia. In conclusion, there is little evidence to support the addition of PET to the routine clinical evaluation of patients with suspected or established dementia. Suggestions for future research in this area are offered.

Background:Patients with Parkinsonism have a progressive disorder requiring substantial expertise to manage effectively.Methods:Over a six-year period we evaluated physician utilization and related costs for a large, unselected cohort of 15,304 Parkinsonian patients from the general population, comparing them to 30,608 age- and sex-matched controls within a universal health care system in Ontario, Canada.Results:On average, 45% of Parkinsonian patients saw neurologists annually. The cumulative rate of at least one neurological consultation was only 59.5% over the six years. Patients aged Conclusions:Parkinsonian patients had increased likelihood of utilizing neurologists, primary care physicians and internists compared to controls; related costs of physicians’ services were higher. Further research is necessary to evaluate differences in outcomes and costs between neurologists and other physician service providers.

The novel finding of decreased activity of aconitase, a key Krebs cycle enzyme highly sensitive to oxidative damage, in cybrid cell lines using mitochondrial DNA from patients with progressive supranuclear palsy (PSP) implies an enzyme abnormality in brain. However, the authors found that postmortem brain aconitase activity is normal in PSP. This suggests that patients with PSP do not have systemic aconitase deficiency and that data derived from cybrid cell models of neurodegenerative disorders might not always predict similar changes in human brain.

Background: PD was associated with increased mortality before levodopa therapy became available. There have been conflicting reports of PD mortality in the modern era. Objective: To assess current mortality rates in a large unselected population receiving treatment for parkinsonism (PKM) followed for up to 6 years. Methods: Cases were identified using linked administrative databases, including physician service and prescription drug claims, generated in Ontario’s universal health insurance system. Control subjects were identified from the provincial registry of citizens and age and sex matched to cases. Comparative mortality was evaluated over the 6-year period of the study (1993/94 to 1998/99). The sensitivity of the findings was tested with differing case definitions. Results: In 1993, 15,304 patients with PKM were identified and were age and sex matched to 30,608 control subjects (1:2 ratio). Over the study period, 50.8% (7,779) of the cases with PKM died compared with 29.1% (8,899) of the control subjects. The cases with PKM had an overall mortality odds ratio of 2.5 (95% CI: 2.4, 2.6) compared with the control group. Results were consistent whether cases were defined by physician diagnosis, use of anti-PD drugs, or both criteria. Conclusion: Despite modern drug therapy, PKM continues to confer a sharply increased mortality on unselected patients followed for several years.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Pramipexole is a non-ergot dopamine agonist recently approved for the treatment of early and advanced Parkinson's disease (PD). It has preferential affinity for the D 3 dopamine receptor, compared to previous dopamine agonists that have higher affinity for D 2 dopamine receptors. The ultimate question is whether its efficacy is linked to its action at the D 3 dopamine site or due to its binding to D 2 dopamine receptors. There is no direct experimental evidence available to answer this question. Based on a review of the pharmacological literature, it is likely that the motor benefits of pramipexole in PD patients are due to D 2 stimulation, whereas its putative effects on mood and apathy may be related to its D 3 agonist properties.

To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) concentration. These changes could reflect either a compensatory downregulation of dopamine biosynthesis in response to prolonged dopaminergic stimulation caused by heroin, or reduced axoplasmic transport of tyrosine hydroxylase. Striatal levels of serotonin were either normal or elevated whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were decreased by 27-38%. Our data suggest that chronic heroin exposure might produce a modest reduction in dopaminergic and serotonergic activity that could affect motivational state and impulse control, respectively.

Objective To characterize longitudinal changes in metabolic network activity during phenoconversion in preclinical Huntington's disease (pHD) patients. Background Metabolic changes accompanying phenoconversion in HD are not well understood. The ordinal trends (OrT) model is a novel multivariate voxel-based approach developed to identify and quantify progression-related networks in individual subjects (Habeck et al., 2005). We used serial PET imaging to examine activity of an OrT network during the transition from preclinical to symptomatic HD. Design/Methods Twelve pHD gene carriers (CAG repeat length, 41.6 ± 1.7; age, 46.8 ± 11.0 years; estimated years-to-onset, 10.3 ± 8.6 years) underwent FDG PET at baseline, 18, and 44 months. Of these 12, four became symptomatic by 44 months. Four patients (2 phenoconverted and 2 non-phenoconverted) were additionally scanned at 68 months. Results Using OrT, we identified a highly significant spatial covariance pattern associated with progression in preclinical HD ( p p Conclusion We found that OrT network activity increased in pHD subjects followed up to 68 months. This increasing trend was found in subjects who either did or did not phenoconvert during the follow-up period. However, the phenoconverters exhibited a higher level of network activity than the non-phenoconverters both before and after clinical onset. Thus, the OrT network is likely to be a useful biomarker of progression in preclinical HD, which may improve the prediction of symptom onset in mutation carriers.

Over the past decade, management of Parkinson's disease has changed significantly due to the expansion of medical and surgical treatment modalities. Neurologists now have the ability (and the challenge) of choosing from multiple medications to devise an individual management strategy for each patient depending on his/her clinical symptoms and needs. Several different surgical therapies are also available. The topics covered in this supplement have highlighted the new options that are now available, as well as the treatments that have been in clinical usage. This review attempts to synthesize the information that is currently available in an attempt to help clinical neurologists make the appropriate choice for their patients.

Background Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. Objective To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. Patients and Methods Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3–Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. Results Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, −12%) and Alzheimer disease (temporal cortex, −19%). Conclusion The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.

We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.

To estimate the threshold of nigrostriatal dysfunction required for symptomatic Parkinson's disease (PD), we employed [11C]RTI-32 and PET to study the dopamine transporter in striatal subdivisions of 11 L-dopa-naive patients with very early parkinsonism. As compared with the controls (N = 10), the PD group had on the side contralat-eral to the maximal clinical symptoms, significantly reduced binding in the posterior putamen (−56%) and anterior putamen (−28%), with the reduction in caudate (−12%) not significantly different. To the extent that dopamine transporter binding accurately reflects the number of nigrostriatal dopamine nerve terminals, these findings suggest that the clinical threshold for PD in the middle-age human is approximately 50% loss of dopaminergic innervation to the posterior putamen. Our data also suggest that damage to the putamen component of the striatum is sufficient for the clinical expression of PD.

Amyotrophic lateral sclerosis is a fatal paralytic disorder of unknown cause. Recent evidence implicated the role of free radicals in the death of motor neurons in this disease. To investigate this hypothesis further, we measured the activity of the main free radical scavenging enzymes copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase in postmortem brain samples from 9 patients with sporadic amyotrophic lateral sclerosis and from 9 control subjects. We examined samples from the precentral gyrus of the cerebral cortex, a region affected in amyotrophic lateral sclerosis, and from the cerebellar cortex, a region not affected. The two groups did not differ in age or postmortem delay. In the precentral gyrus from amyotrophic lateral sclerosis samples, glutathione peroxidase activity as measured by spectrophotometric assay (13.8 +/- 2.6 nmol/min/mg protein [mean +/- standard error of mean]) was reduced significantly compared to the activity in the precentral gyrus from control samples (22.7 +/- 0.5 nmol/min/mg protein). In contrast, glutathione peroxidase activity was not significantly altered in the cerebellar cortex from amyotrophic lateral sclerosis patients compared to controls. Copper/zinc superoxide dismutase, manganese superoxide dismutase (corrected or not corrected for citrate synthase), and catalase were not significantly altered in the precentral gyrus or cerebellar cortex in the patient samples. This study indicated that glutathione peroxidase activity is reduced in a brain region affected in amyotrophic lateral sclerosis, thus suggesting that free radicals may be implicated in the pathogenesis of the disease.

To test the hypothesis that brain-blood export of DOPA impairs dopamine synthesis and hence provides a rationale for upregulation of the activity of DOPA decarboxylase, we first used HPLC to confirm that [14C]DOPA, generated endogenously from [14C]tyrosine, is subject to removal from rat brain tissue in which DOPA decarboxylation is blocked by NSD-1015. Second, we measured the relative rates of decarboxylation and blood-brain transfer of [18F]fluoro-DOPA (FDOPA), a radiolabeled analog of DOPA. In Parkinson’s disease, the rate of brain-blood removal of FDOPA from the striatum was normal, compared to the 50% reduction of the rate of decarboxylation, causing additional loss of DOPA and consequent reduction of the rate of dopamine synthesis.

Autosomal dominant dopa-responsive dystonia (DRD) is mainly caused by mutations in GCH1 , which encodes GTP cyclohydrolase I (GTPCH), the enzyme in the biosynthesis of tetrahydrobiopterin (BH4; the cofactor for tyrosine hydroxylase [TH]).1 However, because of incomplete penetrance of GCH1 mutations in GTPCH-deficient DRD, it cannot be predicted whether an individual with a GCH1 mutation will develop DRD symptoms. Because dopamine is a prolactin-inhibiting factor and hyperprolactinemia was reported in patients with autosomal recessive BH4 deficiency,2-4⇓⇓ we compared serum prolactin levels between untreated patients with a heterozygous GCH1 mutation and asymptomatic carriers of the mutation in a three-generation DRD family to evaluate whether the prolactin level relates to the symptomatic state of DRD. We also determined prolactin concentration in a dopa-naive compound heterozygote for GCH1 mutations in the DRD family who developed relatively severe symptoms (dystonia with motor delay). The study was approved by the review board of the Centre for Addiction and Mental Health. After obtaining written informed consent, we conducted direct sequencing of GCH1 using genomic DNA from peripheral leukocytes,5 and measured serum prolactin levels by standard enzyme-immunoassay. Blood samples were …

Background There is a need for clinical scales specifically designed to measure the earliest clinical manifestations of Huntington disease (HD) and to track early changes in clinical symptoms in HD gene expansion carriers. Such a measurement tool could be used to evaluate the effect of novel therapies early in the course of disease. Aims The Functional Rating Scale Taskforce for pre-HD (FuRST-pHD) is a multinational, multidisciplinary collaboration to develop a valid functional rating scale to assess changes in symptom severity in prodromal (prHD) or early manifest HD gene expansion carriers. Methods FuRST-pHD has established a process for scale development using input from numerous sources, including HD individuals and companions, experts from a variety of fields, as well as from data mining of ongoing observational studies in HD. FuRST-pHD utilised an iterative process in which changes to items are made based on empirical evidence obtained during field testing in prHD and early HD individuals, utilising various types of analyses, including Item Response and Rasch analyses, factor analysis, correlations and descriptive analyses, as well as clinical judgement. The criteria for item reduction and modification include assessment of item discrimination, relevance and response range, item redundancy, and convergent validity. Results A total of 115 structured interview questions were developed to assess the presence and severity of motor, cognitive and psychiatric symptoms, as well as day-to-day functioning. Following multiple testing iterations in 784 prHD/early HD participants, a 40-item FuRST V1.0 was subsequently tested in prHD/early HD gene carriers (n=97), of which 21 items have been retained for inclusion in the primary scale (FuRST-21). Conclusions FuRST-21 is a structured interview that shows promise as a tool to measure symptoms in prHD and early HD. Validation of FuRST-21 is currently in the planning stages.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess cognitive symptoms in prHD and early HD individuals.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess functional impact in day-to-day activities in prHD and early HD individuals.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess Depression, Anxiety and Apathy in prHD and early HD individuals.

In 11 normal volunteers and six patients with Parkinson's disease, we compared six different analyses of dopaminergic function with l-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) and positron emission tomography (PET). The caudate nucleus, putamen, and several reference regions were identified in PET images, using magnetic resonance imaging (MRI). The six analyses included two direct determinations of DOPA decarboxylase activity ( kD3, k*3), the slope–intercept plot based on plasma concentration ( K), two slope–intercept plots based on tissue content ( kr3, ks3), and the striato–occipital ratio [ R( T)]. For all analyses, the difference between two groups of subjects (normal volunteers and patients with Parkinson's disease) was larger in the putamen than in the caudate. For the caudate nucleus, the DOPA decarboxylase activity ( kD3, k*3), tissue slope–intercept plots ( kr3, ks3), and striato–occipital ratio [ R( T)] analyses significantly discriminated between the normal volunteers and the patients with Parkinson's disease ( p < 0.005) [with least significance for k*3( p < 0.05)], while the plasma slope–intercept plot ( K) failed to do so. For the putamen, the values for kD3, k*3, K, kr3, ks3and R( T) of normal volunteers were significantly higher than those of patients ( p < 0.005) [with least significance for K ( p < 0.025)]. Linear correlations were significant between kD3and ks3; kD3and kr3; kD3and R( T); and kD3and k*3, in this order of significance. We found no correlation between kD3and K values in the caudate nucleus.

Udgivelsesdato: 1993-Oct L-DOPA is a large neutral amino acid subject to transport out of, as well as into, brain tissue. Competition between dopamine synthesis and L-DOPA egress from striatum must favor L-DOPA egress if decarboxylation declines relatively more than transport in Parkinson's disease. To test this hypothesis, we injected patients with Parkinson's disease with a radiolabeled analogue of L-DOPA and recorded regional brain radioactivity as a function of time by means of positron emission tomography. We simultaneously estimated the activity of the decarboxylating enzyme and the amino acid transport. In the striatum of patients, we found the L-DOPA decarboxylase activity to be reduced in the head of the caudate nucleus and the putamen. However, the rate of egress of the DOPA analogue was unaffected by the disease and thus inhibited dopamine synthesis more than predicted in the absence of L-DOPA egress.

γ-Hydroxybutyrate (GHB) is an endogenous CNS depressant employed in clinical trials for the treatment of narcolepsy and alcohol withdrawal.1 GHB has also become an increasingly popular recreational drug of abuse, presumably because of its sedative/disinhibitory and possible euphoric properties.1,2⇓ GHB inhibits firing of midbrain dopamine neurons, possibly via an action on a unique GHB receptor or on GABAB receptors.1,3⇓ Impaired dopaminergic activity is reflected in experimental biochemical studies by a striking accumulation of striatal dopamine and reduced dopamine metabolite level.1,4⇓ The increased (primarily intraneuronal) dopamine is considered to be consequent to reduced neurotransmitter release and to a short-term acceleration in presynaptic dopamine synthesis compensatory to decreased synaptic levels of the neurotransmitter.1 The ability of GHB to impair acutely dopaminergic neurotransmission has been hypothesized to explain part of the short-lasting sedative action of the drug.1,4⇓ This is supported by animal findings showing that the dopaminergic stimulant amphetamine can reverse part of the immobility caused by GHB.5,6⇓ Conversely, some …

Background Despite large gaps in evidence-based knowledge, clinical experience supports the use of pharmacologic treatments for many symptoms of Huntington9s disease (HD). Aims The project goal is to develop consensus guidelines based on expert clinical experience to improve quality of HD care. Methods The survey was developed by 9 international experts, and designed as a highly iterative and systematic method of soliciting expert opinions on the pharmacologic treatment of irritability, perseverative behaviors, and chorea in HD. Fifty-five experts from Australia, Europe and North America responded to at least one of the surveys. Results For irritability, SSRI was first choice of 58%, an antipsychotic was first choice for 22%, a mood stabilizing anticonvulsant 14%, and benzodiazepine 2%. For perseverative behaviors, SSRI was first choice of 75%, an antipsychotic choice of 4%, a mood stabilizing anticonvulsant choice of 6%, and clomipramine 2%. The remaining 13% chose to qualify the response to include 2 first choices. For chorea, an antipsychotic was first choice for 56%, tetrabenazine 15%, amantadine 6%, and benzodiazepines 4%. The remaining 13% chose to qualify the response to include 2 first choices. Drug choice for use as adjunctive therapy was widely variable. Conclusions Many areas of variability in treatment for irritability, perseverative behaviors, and chorea in HD, have been identified. Results will guide future rounds of the Delphi process to elicit rational causes for differences identified. When complete, this process will clarify useful treatment paradigms that will improve patient care and identify areas in which clinical trials would be most useful.

Background The earliest clinical manifestations of Huntington9s (HD) disease are poorly characterized, and there is a need for clinical scales designed specifically to measure early signs and symptoms in individuals with the huntingtin gene mutation. Aims The Functional Rating Scale Taskforce for pre-Huntington9s Disease (FuRST-pHD) is comprised of a multidisciplinary team of clinical experts, drug developers, and psychometricians that work in close association with advocacy groups and HD gene carriers to develop a valid functional rating scale to assess changes in symptom severity in pre- and early-HD. Such a measurement tool is essential in order to assess the efficacy of early intervention treatments. Methods FuRST-pHD has established a data-driven, iterative, and collaborative process to develop a clinical scale to assess symptoms and their functional impact in pre- and early-HD. The process involves input from numerous sources to identify relevant symptom domains, including gene expansion carriers, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing observational studies in HD (PREDICT-HD and REGISTRY) using existing clinical scales. Clinical scale interview questions were developed by expert teams of clinicians and psychometricians in order to gather data about the identified symptom domains through field testing in pre-HD individuals. We report here the progress of the FuRST-pHD initiative. Results At present, more than 60 structured interview questions aimed at determining the presence and extent of severity in a number of symptom domains have been developed, including motor, cognitive and psychiatric symptoms. The interview questions have undergone, or are undergoing, testing at various clinical centres involved with FuRST-pHD and PREDICT-HD. We present data supporting the development of items to assess a number of symptoms in pre-HD, including Anger and Irritability, Obsessions and Compulsions, and Depression and Anxiety. Conclusions Many CAG expanded individuals clearly exhibit a range of motor, cognitive and psychiatric signs years prior to clinical diagnosis. The present data suggest a number of behavioural/psychiatric symptom clusters that should be assessed in order to capture fully the scope of dysfunction in pre-HD individuals.

Background Identifying sensitive, specific, and reliable indicators of disease progression in Huntington9s disease (HD) is key to selecting the appropriate population for clinical trials that assess novel treatments that may slow or delay the onset of HD9s debilitating symptoms. The PREDICT-HD study is an NIH and CHDI-funded study that began in 2001, with the goal of documenting the neurobiological and neurobehavioral changes that occur in HD-gene carriers in the period leading up to the diagnosis of HD. The PREDICT-HD study provides a rich source of data that can be mined to identify HD-gene carriers who show rapid progression in the early stages of the disease, prior to diagnosis based on their motor symptoms. Aims To identify a population of PREDICT-HD participants who show rapid progression in motor symptoms over the course of the first four years of the PREDICT-HD study, and to determine if there are specific measures that classify participants a priori. Methods The change in the Unified Huntington9s Disease Rating Scale (UHDRS) Total Motor score between Baseline and Year 4 was calculated for all PREDICT-HD participants who had completed four annual visits. A model was generated to distinguish rapid progressors from gene-carriers not showing progression utilizing the baseline motor, cognitive, and imaging data from PREDICT-HD participants. Results Examination of the inter-quartile ranges of change-from-baseline total motor scores showed that PREDICT-HD participants in the top (fourth) quartile had a change in score of approximately 14 points; the average change in the third quartile was only 5 points. The classification model that was developed included disease burden score, striatal volume, motor and cognitive variables. The model was 82.4% accurate in identifying HD-gene carriers in PREDICT-HD who showed rapid progression in their UHDRS motor scores; the model was 91.9% accurate in identifying HD-gene carriers in PREDICT-HD who did not show a substantial increase in their motor scores. Conclusions There is a population of HD-gene carriers in the PREDICT-HD study that show a rapid progression in their motor symptoms as assessed by the UHDRS Motor Subscale. We have developed a model that is highly accurate in identifying these patients. This model needs to be further refined and validated. This model may be useful in identifying HD-gene carriers for recruitment in therapeutic clinical trials.

Background Despite large gaps in evidence-based knowledge, clinical experience supports the use of pharmacologic treatments for many symptoms of Huntington's disease (HD). The project goal is to develop consensus guidelines based on expert clinical experience that will improve the quality of HD care. Methods/Techniques The Delphi process, which provides an iterative formal strategy to gather expert opinion and form a consensus, was utilized. First steps of this process explored expert prescribing patterns. Step 1: Nine experts from Huntington's Study Group and European HD Network created initial statements for irritability, obsessive/compulsive behaviors (O/Cs), and chorea. Step 2: Statements were submitted via a web survey to a panel of 40 additional experts. Results Thirty expert neurologists and psychiatrists from Europe and North America responded. For irritability there was lack of consensus in first choice and in sequence of drugs used in combination therapy. For O/Cs there was high agreement (>80%) on SSRI as first choice; however, there was lack of consensus on adjuvant drug therapy. For chorea there was agreement that it should be treated when quality of life or ADL is affected, but there was lack of consensus on drug of first choice. The next round of the Delphi consensus process will begin in November of 2009. Conclusions Many areas of variability in the treatment for irritability, O/Cs, and chorea in HD, even among expert clinicians, have been identified. Results will guide future rounds of the Delphi process to elicit rational causes for the differences identified. Collection of further data on consensus will begin in November of 2009. When complete, this process will clarify useful treatment paradigms that will improve patient care and identify areas in which clinical trials would be most useful.

Although cognitive impairment is commonly associated with Parkinson's disease, the relative importance of cortical and subcortical pathologic changes to the development of dementia is controversial. Characteristic abnormalities in cortical glucose metabolism have been reported previously in Alzheimer's disease, a disease in which cortical changes predominate. We measured cerebral glucose metabolism with positron emission tomography in 20 control subjects and in 14 patients with PD with mental status ranging from normal to severely demented to determine whether changes in cortical glucose metabolism occur in early PD and whether the degree and pattern of metabolic change relate to the severity of dementia. The patients were divided into demented and nondemented groups according to the results of neuropsychological assessment. Age-adjusted covariance analyses were performed, since the age distribution varied between groups. The nondemented patients with PD showed widespread cortical glucose hypometabolism without any selective temporoparietal defects. The pattern of glucose hypometabolism seen in the demented patients with PD resembled that described in patients with Alzheimer's disease; ie, there was a global decrease in glucose metabolism, with more severe abnormalities observed in the temporoparietal regions.

Objective To describe a brain metabolic network selectively expressed in symptomatic Huntington's disease (HD) gene carriers. Background A metabolic network specifically associated with HD motor symptoms may be useful in assessing new therapies. We used PET imaging and network analysis to identify a spatial covariance pattern expressed in newly symptomatic HD patients. Design/Methods We utilized serial FDG PET to study 12 presymptomatic HD gene carriers at baseline, 18, and 44 months. Four subjects became symptomatic by 44 months. Additionally, two phenoconverters and two non-phenoconverters were scanned at 68 months. To identify a symptom-related pattern, we conducted network analysis to compare the phenoconverted and non-phenoconverted scans at 44 months. Scans from 12 age-matched healthy controls were included for comparison. Results We identified an HD symptom-related metabolic covariance pattern (HDSP), which separated symptomatic and preclinical gene carriers ( p p p Conclusion The HDSP network emerged as preclinical HD subjects neared clinical onset; its expression also increased as symptoms progressed. A unique feature of the HDSP is its high sensitivity for the motor symptoms of HD. The correlation of pattern activity with clinical ratings indicates that this network may be particularly useful in assessing the emergence of HD symptoms and their response to therapy.

Historically, the diagnosis of HD has been based on the presence of motor-related symptoms. There is emerging evidence, however, that prior to the manifestation of motor symptoms sufficient to warrant clinical diagnosis, many patients exhibit subtle motor, cognitive, and psychiatric signs, suggesting that people with HD may experience detectable changes before clinical diagnosis (i.e., pre-HD). There is currently a need for a rating scale that is sensitive enough to detect early symptomatic changes and disease progression in pre-HD. The Functional Rating Scale Taskforce for pre-HD (FuRST-pHD) has been established to develop such a measure. In the initial phase of this program, FuRST-pHD will identify which symptoms should be addressed in a clinical scale, and how best to measure those symptoms. Depression is thought to be a component of HD that may be present prior to clinical diagnosis. In the present study, FuRST-pHD examined the expression of signs and symptoms associated with depression using data obtained from PREDICT-HD, utilizing a non-parametric item response analysis of depression ratings (UHDRS-III, BDI-II). Item response modeling can be used to evaluate the performance of individual items (or symptoms) on rating scales, assessing the relationship between a score assigned to a particular item and overall severity of the disease. The results show that pre-HD CAG-expanded subjects (≥37 repeats, n = 752) reported greater depressive symptomatology compared to the comparison group (

Objective To examine and validate changes in striatal dopaminergic function and regional brain metabolism during phenocoversion of preclinical Huntington's disease (pHD). Background Our recent PET study (Feigin et al., 2007) found progressive declines in striatal D2-receptor binding in pHD subjects over 44 months, correlating with decreased metabolism in the striatum. During this period, thalamic metabolism was initially elevated above normal and then fell to subnormal levels in the subjects who developed symptoms. To validate these findings, we extended the previous study two years, to 68 months, and now report the preliminary results. Design/Methods Twelve presymptomatic HD gene carriers (CAG repeat length: 41.6 ± 1.7; estimated years-to-onset: 10.3 ± 8.6 years) underwent PET scanning with both 11C-raclopride and [18F]fluorodeoxyglucose at baseline, 18, and 44 months. Of these, four subjects were diagnosed with HD during the first 44 months of the study. At 68 months, two symptomatic and two asymptomatic subjects were additionally scanned. Results In the four subjects at 68 months, both the caudate and putamen D2 binding were further decreased relative to values at the first three time points. The decrease in striatal D2 binding was more pronounced in the two symptomatic subjects than the two pHD subjects, with greater progressive declines in striatal metabolism in the symptomatic subjects. However, thalamic metabolism at 68 months was similar to 44 months, i.e., thalamic metabolism was close to the lower limit of normal in the two symptomatic subjects, but remained above normal in the two pHD subjects. Conclusion At the extended 68-month time point, concurrent decreases in striatal D2 binding and metabolism indicate steady focal loss of striatal projection neurons in pHD. Further, the findings at 68 months support our prior hypothesis that persistently elevated thalamic metabolism is an essential compensatory feature of the preclinical state, with normalization of thalamic metabolism as subjects approach phenoconversion.

There is an unmet need for the development of treatments for Huntington's disease (HD). The ideal goal would be to develop drugs that can be administered sufficiently early (i.e., pre-HD), such that the full manifestations never develop or are at least delayed. Unfortunately, there is currently no sensitive validated tool capable of measuring symptomatic changes in pre-HD that can be used in clinical trials. The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal to develop a data-driven, comprehensive, psychometrically sound, sensitive, functional rating scale to be utilized in clinical trials to measure symptoms in patients at the pre-HD stage of the disease. The Taskforce will first identify signs and symptom clusters that should be assessed in pre-HD patients, based on input from a variety of sources, including clinical experts, patients, caregivers, and regulatory agencies. The Taskforce will then develop clinical measures of these signs and symptoms using an iterative processes involving field testing and psychometric analyses. The Taskforce will also rely on the analyses of existing datasets to identify items that may have utility in measuring pre-HD symptomatology. The Taskforce is currently analyzing data from PREDICT-HD, using item response theory (IRT), an approach that has been shown to be a powerful method for evaluating the performance of individual items of rating scales by assessing the relationship between item scores and severity. The development of a new data-driven, reliable, valid, and easily administered instrument would be valuable in the assessment of pre-HD symptoms in clinical trials. This collaborative effort welcomes input from HD researchers. FuRST-pHD is sponsored by CHDI Foundation.

We studied the effectiveness of OR-611 and OR-462, two novel inhibitors of the enzyme catechol-O-methyltransferase (COMT), on 3-O-methyldopa (OMD) formation in cynomolgus monkeys following intravenous levodopa administration. OR-611 dose-dependently reduced the area under the OMD concentration-vs-time curve, reduced maximum plasma OMD concentrations, delayed the time to peak OMD levels, reduced systemic levodopa clearance, and prolonged the elimination half-life of levodopa. Similar effects on peripheral levodopa metabolism were seen with doses of 15 mg/kg of OR-611 and OR-462, its sister compound, which lacks the ability to penetrate the central nervous system (CNS).

We performed positron emission tomography using 18F-6-fluorodopa on four Guamanians with an amyotrophic lateral sclerosis syndrome, eight Guamanians with parkinsonism, and seven clinically normal Guamanians; the results were compared with those of nine Vancouver control subjects. The Guamanian subjects had all been exposed to similar Chamorro lifestyles. The scans were analyzed using a graphic method that calculates a constant for whole striatal 18F-6-fluorodopa uptake. The parkinsonian subjects all had significantly reduced striatal 18F-6-fluorodopa uptake. The group with amyotrophic lateral sclerosis had significantly reduced uptake that was intermediate between that of the control group and the parkinsonian group. Two Guamanian normal subjects had reduced striatal 18F-6-fluorodopa uptake. The nigrostriatal dopaminergic lesion in Guamanian parkinsonism is similar to that found in idiopathic parkinsonism. The nigrostriatal lesions in the subjects with amyotrophic lateral sclerosis and the Guamanian normal subjects are examples of subclinical neuronal damage demonstrable in living subjects with positron emission tomography.

We measured concentrations of cocaine and its major metabolites (benzoylecgonine, ecgonine methylester, norcocaine, and cocaethylene) in 15 autopsied brain regions of 14 human chronic cocaine users. Only slight differences were observed in concentrations of cocaine and its metabolites amongst the examined brain areas. Although it is likely that some postmortem redistribution of the drug must have occurred, our data are consistent with the possibility that behaviorally relevant doses of cocaine are widely distributed throughout the brain of humans who use the drug on a chronic basis. Consideration should therefore be given to the possible pharmacological and toxicological actions of cocaine in both striatal and extra-striatal brain areas in human users of the drug.

D2 dopamine receptor densities were measured in postmortem samples of the caudate nucleus and putamen from 36 parkinsonian patients. The relationship between the age of the patient, duration of the disease, and duration of L-dopa therapy versus density of brain D2 dopamine receptors was examined using [3H]spiperone. Receptor density in parkinsonian tissues was constant over the age range of 56 to 90 years, as was the case for control tissues. Density did not change with duration of disease up to 24 years. Treatment with L-dopa did not cause progressive reduction in receptor density. The diminished clinical response in the final stages of Parkinson's disease is not due to receptor dropout, and must depend on other factors.

Transplantation of autologous adrenal medulla tissue into the striatum has recently been proposed as a treatment for Parkinson's disease. We report the use of positron emission tomography (PET) to evaluate patients who had adrenal implants placed into the right caudate. 6-[18F] fluoro-L-dopa (6-FD) scans were performed to study the integrity and activity of the implant, and the nigrostriatal dopamine system before and six weeks after transplantation surgery. [68Ga] Gallium-ethylenediaminetetraacetate (Ga) scans were also performed to assess the blood brain barrier. The Ga scans performed on two patients showed increased permeability of the blood brain barrier at the surgical site. 6-FD PET scans in five patients did not show a consistent change in striatal uptake following adrenal medullary implantation after six weeks. Further assessment of implant viability with 6-FD PET scans after longer follow up may provide useful information if the blood-brain barrier becomes re-established with the passage of time.

The study of neurotransmitter receptors aids in the understanding of the normal anatomy, pharmacology, therapeutics and pathophysiology of disease processes involving the basal ganglia. Receptors may be studied in vitro by homogenate binding experiments, enzyme analysis or quantitative autoradiography and in vivo with positron emission tomography. In the substantia nigra (SN), receptors have been identified for somatostatin, neurotensin, substance P, glycine, benzodiazepine and GABA, opiates, dopamine, angiotensin converting enzyme (ACE) and serotonin. The striatum has receptors for dopamine, GABA and benzodiazepines, acetylcholine, opiates, substance P, glutamate and cholecystokinin. GABA and benzodiazepine receptors are also located in the globus pallidus. In Parkinson's disease, striatal dopamine D-2 receptors are elevated in patients that have not received L-DOPA therapy. This supersensitivity is reversed with agonist therapy. Muscarinic binding to cholinergic receptors seems to correlate with dopamine receptors. Delta opiate receptors are increased in the caudate and mu binding is reduced in the striatum. In the SN of patients with Parkinson's disease, there is reduced binding of somatostatin, neurotensin, mu and kappa opiates, benzodiazepine and GABA and glycine. In Huntington's disease, there is reduced binding of GABA and benzodiazepines, dopamine, acetylcholine, glutamate and CCK. There is increased binding of GABA in both the SN and globus pallidus. Glycine binding is increased in the substantia nigra and ACE is reduced.

The pathophysiology of chorea in systemic lupus erythematosus (SLE) is uncertain. Pathologic examination has not identified a specific location for the causative lesion(s) and immunologic mechanisms have been suggested in its etiology. In other choreic disorders, such as Huntington's disease and benign hereditary chorea, glucose hypometabolism in the striatum has been demonstrated by positron computed tomography (PCT) using [18F]deoxyglucose. With this technique we have studied four patients with chorea secondary to SLE. In these patients the regional distribution of cerebral glucose metabolism was normal. In particular, striatal glucose metabolism was within the normal range, even though the ratio of striatal to cortical glucose metabolism was increased. Our results show that striatal hypometabolism, as seen in other disorders manifesting chorea, is not the PCT correlate of the dyskinesia.

Cultured human fetal sympathetic ganglion explants or adrenal chromaffin cell aggregates were implanted into the left striatum of monkeys whose left nigrostriatal pathway had been lesioned with the neurotoxin MPTP. There was no clinical reversal of parkinsonian symptoms and PET scans did not show increased striatal fluorodopa uptake from pre-implant levels. At sacrifice, left striatal contents of dopamine were not statistically different from MPTP-treated but non-implanted controls. Histological examinations revealed pockets of extrinsic cells which were found at the end of needle tracks. There was no evidence of immune rejection. The extrinsic cells did not stain for tyrosine hydroxylase or neurofilament, suggesting that they were not dopaminergic neurons. The failure to reverse clinical parkinsonian symptoms highlights the stage of infancy of neural implantation in Parkinson's disease.

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [ 18 F]fluorodopa PET, (+)-[ 11 C]dihydrotetrabenazine PET, [ 123 I]β-CIT SPECT, and [ 18 F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Cognitive impairment has been reported in some chronic users of psychostimulants, raising the possibility that long-term drug exposure might damage brain neuronal systems, including the cholinergic system, which are responsible for normal cognition. We measured the activity of choline acetyltransferase (ChAT), the marker enzyme for cholinergic neurones, in autopsied brain of chronic users of cocaine, methamphetamine, and, for comparison, heroin. As compared with the controls, mean ChAT levels were normal in all cortical and subcortical brain areas examined. However, the two of 12 methamphetamine users, who had the highest brain/blood drug levels at autopsy, had a severe (up to 94%) depletion of ChAT activity in cerebral cortex, striatum, and thalamus. Based on the subjects examined in the present study, our neurochemical data suggest that brain cholinergic neurone damage is unlikely to be a typical feature of chronic use of cocaine, methamphetamine, or heroin, but that exposure to very high doses of methamphetamine could impair, at least acutely, cognitive function requiring a normal nucleus basalis cholinergic neuronal system. Reduced brain ChAT might be explained in part by a hyperthermia-related mechanism as low ChAT levels have also been observed in brain of some patients with neuroleptic drug-associated hyperthermia. Studies of cognitive and brain cholinergic status in high dose users of MA are warranted.

This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of