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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 Huntington9s 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.

Background: Polymorphisms in the glutathione S-transferase pi gene ( GSTP1 ), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the Gene PD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. Methods: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. Results: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. Conclusions: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Objective: To identify a haplotype influencing onset age for Parkinson’s disease (PD) in the PARK3 region on chromosome 2p13. Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset ( p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) ( SPR ) gene, rs1876487 ( p = 0.02) and rs1150500 ( p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394 . The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP—rs2421095, rs1876487, rs1561244—revealed an association with onset age ( p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD ( p = 0.005). Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Objective: There is increasing evidence that neuron loss precedes the phenotypic expression of Huntington’s disease (HD). As genes for late-onset neurodegenerative diseases are identified, the need for accurate assessment of phenoconversion (i.e., the transition from health to the disease phenotype) will be important. Methods: Prospective longitudinal evaluation using the Unified Huntington’s Disease Rating Scale (UHDRS) was conducted by Huntington Study Group members from 36 sites. There were 260 persons considered “at risk” for HD who initially did not have manifest disease and had at least one subsequent evaluation. Repeat UHDRS data, obtained an average of 2 years later, showed that 70 persons were given a diagnosis of definite HD based on the quantified neurologic examination. Results: Baseline cognitive performances were consistently worse for the at-risk group who demonstrated conversion to a definitive diagnosis compared with those who did not. Longitudinal change scores showed that the at-risk group who did not demonstrate manifest disease during the follow-up study period demonstrated improvements in all cognitive tests, whereas performances in the at-risk group demonstrating conversion to disease during the study declined across cognitive domains. Conclusions: Neuropsychological measures show impairment 2 years before the development of more manifest motor disease. Findings suggest that these brief cognitive measures administered over time may capture early striatal neural loss in HD.

Background: Animal data indicate that chronic exposure to dopaminergic drugs can alter levels of the dopamine transporter (DAT), which is critically involved in regulation of synaptic dopamine levels. DAT changes could influence the response to therapy in PD. Methods: A randomized, assessor-blinded, placebo-controlled clinical trial was performed in subjects with early PD to determine whether l-dopa or pramipexole might regulate striatal DAT binding as measured by PET with [ 11 C]RTI-32. Thirty clinically asymmetrical patients were randomly assigned to receive 6 weeks of l-dopa (300/75 mg/d), pramipexole (1.5 mg/d), or placebo; PET studies were performed before and after treatment. Results: Mean interval change in DAT binding was significantly reduced by 16% to 22% in all striatal regions (caudate, anterior and posterior putamen) of the l-dopa–treated patients, whereas significant changes in the pramipexole-treated patients were limited to the contralateral caudate (−15%), ipsilateral anterior putamen (−14%), and posterior putamen (−20%). In the placebo group there were significant changes in contralateral caudate (−11%) and ipsilateral anterior putamen (−12%). l-dopa and pramipexole produced similar clinical benefit. Conclusions: Short-term therapy with l-dopa and, to a lesser extent, pramipexole can modestly down-regulate striatal DAT in patients with early PD. Decreased striatal DAT could increase dopaminergic neurotransmission with potential benefit, but might also play a role in the development of dopamine-related response fluctuations in patients with advanced disease. Our data also suggest caution in interpretation of longitudinal imaging studies employing DAT to assess disease progression and the efficacy of neuroprotective agents.

Pramipexole is a new, selective, nonergoline dopamine agonist that acts on D2 and preferentially on D3 dopamine receptors. Phase II and III clinical trials have shown this drug to be useful in treating both early and advanced Parkinson's disease (PD) patients. A double-blind, randomized, multicenter study was performed to compare the safety, tolerance, and efficacy of pramipexole versus placebo in patients with advanced PD with motor fluctuations. A bromocriptine treatment group was included to enable comparisons between bromocriptine and placebo groups, but the study was not powered to show statistical differences between the active treatment groups. The study included 247 patients with "wearing off." Patients were Hoehn and Yahr stages II to IV during "on" times. The trial included three phases: dose escalation, 6 months' maintenance, and dose reduction. The primary end points were the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. Up to 4.5 mg per day of pramipexole and 30 mg per day of bromocriptine were used. The results of the study showed that the UPDRS part II improved by 26.7% for pramipexole (p = 0.0002) and 14% for bromocriptine(p = 0.02) versus 4.8% for placebo. The UPDRS part III showed improvements of 34% for pramipexole (p = 0.0006) and 23.8% for bromocriptine (p = 0.01) versus 5.7% for placebo. There were no major differences in safety data. In the active treatment groups there were more reports of dyskinesia and nausea compared with placebo. In regard to comparison of the Global Clinical Assessment of Efficacy between active treatment groups, there was a trend to significance (p = 0.056) in favor of pramipexole. We conclude that pramipexole-treated patients with advanced PD improved significantly more than placebo for both primary end points.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers.These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([sup 3 H]GBR 12,935 and [sup 3 H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [sup 3 H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [sup 3 H]WIN 35,428 > [sup 3 H]DTBZ > [sup 3 H]GBR 12,935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.NEUROLOGY 1996;47: 718-726

3-O-Methyldopa (OMD) is the principal circulating metabolite formed from exogenously administered levodopa. We studied the effect of nitecapone (OR-462), a novel inhibitor of catechol-O-methyltransferase (COMT), on OMD formation in cynomolgus monkeys following intravenous levodopa administration. The drug does not cross the blood-brain barrier, and therefore inhibits only peripheral OMD formation. At a dose of 5 mg/kg, nitecapone reduced the area under the OMD concentration-time curve by 50%. Inhibition of OMD production was maximal at 65% following a dose of 10 mg/kg. A dose of 15 mg/kg produced no further inhibition. The plasma pharmacokinetics of carbidopa, levodopa, and OMD in the monkeys were similar to those in humans. No adverse physiological effects of nitecapone were observed. In single-dose studies, OR-462 is an effective peripheral COMT inhibitor.

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 …

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 …