Loss of nigrostriatal neurons leads to striatal dopamine deficiency and subsequent development of parkinsonism. The effects of this denervation on D2-like receptors in striatum remain unclear. Most ...studies have demonstrated increases in striatal dopamine D2-like receptors in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated denervation, but others have found either decreases or no change in binding. To clarify the response to denervation, we have investigated the time-dependent changes in dopamine D2, D3, and D4 receptor protein and mRNA levels in unilaterally MPTP-lesioned baboons. MPTP (0.4 mg/kg) was infused into one internal carotid artery, producing a contralateral hemi-parkinsonian syndrome. After MPTP treatment, the animals were maintained for 17-480 d and then euthanized. MPTP decreased ipsilateral dopamine content by >90%, which did not change with time. Ipsilateral D2-like receptor binding in caudate and putamen initially decreased then increased two- to sevenfold over the first 100 d and returned to near baseline levels by 480 d. Relative levels of D2 mRNA were essentially unchanged over this period. D4 mRNA was not detected. In contrast, D3 mRNA increased sixfold by 2 weeks and then decreased. At the peak period of increase in binding sites, all D2-like receptors were in a micromolar affinity agonist-binding state, implying an increase in uncoupled D2 but not D3 receptor protein. Taken together, these data suggest that MPTP-induced changes in D2-like dopamine receptors are complex and include translational or post-translational mechanisms.
Generator produced positron-emitting radionuclides could potentially expand the application of positron emission tomography (PET) to centers that do not have access to a local cyclotron. The ...zinc-62/copper-62 radionuclide generator system could serve as a source of positron-emitting copper-62 (62Cu) (t1/2 = 9.74 min) for physiologic imaging. Accordingly, we have prepared zinc-62/copper-62 generators capable of high output (greater than 300 mCi) and used the no-carrier-added eluate in a rapid high yield synthesis of 62Cu Cu(PTSM) that provides the radiopharmaceutical in a form suitable for intravenous injection (where Cu(PTSM) = pyruvaldehyde bis(N4-methylthiosemicarbazonato) copper(II. We then demonstrated in pilot studies that 62CuCu(PTSM) provides high quality brain and heart images with PET, accurately delineating cerebral and myocardial perfusion in both experimental animals and in humans (corroborating results of previous experimental studies utilizing longer-lived copper isotopes). The results of this work demonstrate that 62Cu can be conveniently obtained from high-level generators and, when used to label Cu(PTSM), provides a generator-produced radiopharmaceutical capable of providing estimates of cerebral and myocardial perfusion independent of cyclotron-produced radionuclides.
The aim of this study is to establish the safety and efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients with disabling motor ...fluctuations performed with an expedient procedure with limited intraoperative mapping.
Bilateral STN DBS systems were implanted in 110 PD patients. Targeting of STN was achieved with T2-weighted magnetic resonance imaging guidance and a stereotactic navigation system confirmed by limited electrophysiological mapping. The safety of the procedure was analyzed in all 110 patients. The efficacy of the procedure was assessed in the practically-defined off medication state in the 72 patients who underwent evaluations 3 to 12 months after electrode implantation.
Adverse effects were infrequent and transient with no incidence of death, hemiparesis, or seizure. In the 72 patients, STN DBS reduced total Unified Parkinson's Disease Rating Scale motor scores at the time of the follow-up evaluation by 47% from 43.4 +/- 16.1 with stimulators off to 22.8 +/- 11.6 with stimulators on (P < 0.001). The changes in Unified Parkinson's Disease Rating Scale motor subscores improved as follows: rest tremor, 74% (P < 0.001); rigidity, 58% (P < 0.001); bradykinesia, 37% (P < 0.001); pull test, 35% (P < 0.001); gait, 44% (P < 0.001); axial signs, 42% (P < 0.001); and speech, 13% (P = 0.002). The prescribed total daily levodopa-equivalent dose decreased 45 +/- 32%. We averaged 1.3 +/- 0.9 electrodes passes per lead implantation. The mean operating time from the mounting of the stereotactic frame to its removal was 5 hours 42 minutes (median, 5 h 25 min; standard deviation, 1 h 12 min).
This STN DBS surgical technique for PD is expedient with effective outcomes and low complication rates.
The σ
receptor is an important target for CNS disorders. We previously identified a σ
ligand TZ3108 having highly potent (
= 0.48 nM) and selective affinity for σ
versus σ
receptors. TZ3108 was
...F-labeled with F-18 for
evaluation. Biodistribution and blocking studies of
FTZ3108 in male Sprague-Dawley rats demonstrated high brain uptake, which was σ
-specific with no
defluorination. MicroPET studies in cynomolgus macaques showed high brain penetration of
FTZ3108; the regional brain distribution was consistent with that of the σ
receptor. Pseudo-equilibrium in the brain was reached ~ 45 min post-injection. Metabolite analysis of
FTZ3108 in NHP blood and rodent blood and brain revealed that ~ 70% parent remained in the plasma of NHPs 60 min post-injection and the major radiometabolite did not cross the blood-brain barrier in rats. In summary, the potent, selective and metabolically stable σ
specific radioligand
FTZ3108 represents a potentially useful PET radioligand for quantifying the σ
receptor in the brain.
The dystonias are a group of serious movement disorders characterized by involuntary muscle spasms of different parts of the body. We recently proposed that hypofunction of dopamine D2 ...receptor-mediated inhibition of the indirect output pathway of the basal ganglia can result in dystonia. In this review, we discuss the results of a variety of genetic and biochemical studies in light of this hypothesis. Several forms of early-onset dystonia show distinct autosomal dominant, recessive, or X-linked genetic transmission patterns. Late onset forms of dystonia, though not showing clear Mendelian transmission patterns, also appear to be highly familial. Recently, several genetic-linkage locations have been identified for early-onset dystonia and for two of these loci, mutations decreasing dopamine synthesis have been demonstrated. Biochemical studies of monkeys and man also demonstrate that several types of dystonia occur in a dopamine-deficiency state. Similarly, mice strains developed to be deficient in several dopamine-pathway components have motor abnormalities consistent with dystonia. Hypofunction of the dopamine D2 receptor-mediated inhibition of the indirect output pathway of the putamen may be a common feature of many of these heritable and secondary dystonic syndromes.
Electrical stimulation of the thalamus dramatically reduces essential tremor (ET). It has been hypothesized that the cerebellum and inferior olive are involved in the generation of ET, and thalamic ...stimulation is presumed to dampen ET through interactions with cerebellar output to the thalamus. Evidence suggests that abnormal timing of agonist and antagonist muscle responses contribute to cerebellar tremor (CbT); however, this relationship has not been investigated for ET. The mechanisms of the tremor and improvement are unknown.
To measure the effect of ventral intermediate thalamic stimulation in controlling the ET response to sudden stretch of an agonist muscle and to determine whether, in ET, the timing relationships between the initial agonist and antagonist electromyography (EMG) responses show abnormalities similar to those seen in CbT.
The authors studied ET subjects (with implanted thalamic stimulators turned off and on) and normal controls as they responded to mechanical torque pulses given at the wrist joint. The wrist joint angle, wrist agonist, and antagonist EMG were recorded.
Like CbT, patients with ET showed delayed onsets of antagonist EMG and excessive rebound. Thalamic stimulation reduced the tremor but did not alter the antagonist delay or the rebound.
In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist-antagonist timing.
We present optical photometry and spectroscopy of five Type Ia supernovae discovered by the Nearby Supernova Factory selected to be spectroscopic analogs of the candidate super-Chandrasekhar-mass ...events SN 2003fg and SN 2007if. Their spectra are characterized by hot, highly ionized photospheres near maximum light, for which SN 1991T supplies the best phase coverage among available close spectral templates. Like SN 2007if, these supernovae are overluminous (-19.5 < MV < -20) and the velocity of the Si II lambda6355 absorption minimum is consistent with being constant in time from phases as early as a week before, and up to two weeks after, B-band maximum light. We interpret the velocity plateaus as evidence for a reverse-shock shell in the ejecta formed by interaction at early times with a compact envelope of surrounding material, as might be expected for SNe resulting from the mergers of two white dwarfs. We use the bolometric light curves and line velocity evolution of these SNe to estimate important parameters of the progenitor systems, including super(56)Ni mass, total progenitor mass, and masses of shells and surrounding carbon/oxygen envelopes. We find that the reconstructed total progenitor mass distribution of the events (including SN 2007if) is bounded from below by the Chandrasekhar mass, with SN 2007if being the most massive. We discuss the relationship of these events to the emerging class of super-Chandrasekhar-mass SNe Ia, estimate the relative rates, compare the mass distribution to that expected for double-degenerate SN Ia progenitors from population synthesis, and consider implications for future cosmological Hubble diagrams.
We present a sample of 485 photometrically identified Type Ia supernova candidates mined from the first three years of data of the CFHT SuperNova Legacy Survey (SNLS). The images were submitted to a ...deferred processing independent of the SNLS real-time detection pipeline. Light curves of all transient events were reconstructed in the gM, rM, iM and zM filters and submitted to automated sequential cuts in order to identify possible supernovae. Pure noise and long-term variable events were rejected by light curve shape criteria. Type Ia supernova identification relied on event characteristics fitted to their light curves assuming the events to be normal SNe Ia. The light curve fitter SALT2 was used for this purpose, assigning host galaxy photometric redshifts to the tested events. The selected sample of 485 candidates is one magnitude deeper than that allowed by the SNLS spectroscopic identification. The contamination by supernovae of other types is estimated to be 4%. Testing Hubble diagram residuals with this enlarged sample allows us to measure the Malmquist bias due to spectroscopic selections directly. The result is fully consistent with the precise Monte Carlo based estimate used to correct SN Ia distance moduli in the SNLS 3-year cosmological analyses. This paper demonstrates the feasibility of a photometric selection of high redshift supernovae with known host galaxy redshifts, opening interesting prospects for cosmological analyses from future large photometric SN Ia surveys.
PD is largely a sporadic condition of unknown etiology, but specific inherited mutations are a cause of PD.
To describe a large, multi-incident Amish pedigree with PD.
Case ascertainment, calculation ...of population prevalence, and calculation of kinship coefficients (a measure of relatedness between two individuals) for affecteds and subjects in a large kindred with PD were conducted. Sequencing of genes with known mutations sufficient to cause PD and marker-by-marker haplotype analysis in chromosomal regions flanking previously described genes with known mutations were performed.
The authors have examined 113 members of this pedigree and classified 67 as normal (no evidence of PD), 17 as clinically definite PD, 6 as clinically probable PD, and 23 as clinically possible PD. The mean age at onset of the clinically definite subjects was 56.7 years. The phenotype in this family is typical of idiopathic PD, including rest tremor, rigidity, bradykinesia, postural instability, and response to levodopa. In addition, dementia occurred in six of the clinically definite subjects, and many subjects experienced levodopa-related motor complications including wearing off and dopa-induced dyskinesias. In the index Amish community, a minimum prevalence of PD in the population 40 years and older of 552/100,000 was calculated. The mean kinship coefficient in the subjects with PD and those with PD by history (0.036) was higher (p = 0.007) than in a group of age-matched normal Amish control subjects (0.016), providing evidence that PD is inherited in this family. Sequence analysis did not detect any mutations in known PD genes. No single haplotype cosegregates with the disease in any of the chromosomal regions previously found to be linked to PD, and no marker in these regions exhibits increased homozygosity among definite PD cases.
PD in this community is more common than in the general population, and this increased prevalence may be due in part to a novel gene(s).
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