Differential Components of Bradykinesia in Parkinson Disease Revealed by Deep Brain Stimulation.

Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.

Resting-State Functional Connectivity Predicts STN DBS Clinical Response.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. METHODS: We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. RESULTS: Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. DISCUSSION: Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates.

OBJECTIVE: We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. METHODS: Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C3 (n = 8) or placebo (n = 7) for 2 months starting 1 week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated nonhuman primate rating scale, kinematic analyses of peak upper extremity velocity, positron emission tomography imaging of 6-[(18) F]fluorodopa (FD; reflects dopa decarboxylase) and [(11) C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), ex vivo quantification of striatal dopamine, and stereologic counts of tyrosine hydroxylase-immunostained neurons in substantia nigra. RESULTS: After 2 months, C3 -treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 -treated animals developed any toxicity. INTERPRETATION: Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for Parkinson disease.

Functional anatomy of subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS. METHODS: Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site. RESULTS: Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive, and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory). INTERPRETATION: Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, because movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive, and limbic information in STN.

Validation of nigrostriatal positron emission tomography measures: critical limits.

OBJECTIVE: Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells. RESULTS: Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001). INTERPRETATION: Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques.

OBJECTIVE: Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. METHODS: Presynaptic PET tracers 6-[(18)F]-fluorodopa (FD), [(11)C]-2ß-methoxy-3ß-4-fluorophenyltropane (CFT), and [(11)C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration. RESULTS: We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R(2) = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = -0.77, -0.71, respectively, p < 0.001), but FD uptake did not. INTERPRETATION: Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function.

PET Quantification of [18F]VAT in Human Brain and Its Test-Retest Reproducibility and Age Dependence.

Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[18F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([18F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [18F]VAT. [3H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BPND). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [18F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [3H]VAT autoradiography-specific binding and PET [18F]VAT uptake were low in white matter. [18F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BPND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BPND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BPND calculations and demonstrate the viability, reproducibility, and utility of using the [18F]VAT tracer in humans to quantify cholinergic pathways.

Striatal dopamine D1-like receptor binding is unchanged in primary focal dystonia.

BACKGROUND: Multiple studies have demonstrated decreases in striatal D2-like (D2, D3) radioligand binding in primary focal dystonias. Although most investigations have focused on D2-specific receptors (D2R), a recent study suggests that the decreased D2-like binding may be due to a D3-specific (D3R) abnormality. However, only limited data exist on the role of D1-specific receptors (D1R) and the D1R-mediated pathways within basal ganglia in dystonia. Metabolic positron emission tomography (PET) data in primary generalized dystonia suggest resting state over activity in the D1R-mediated direct pathway, leading to excessive disinhibition of motor cortical areas. This work investigated whether striatal D1-like receptors are affected in primary focal dystonias. METHODS: Striatal-specific (caudate and putamen) binding of the D1-like radioligand [(11)C]NNC 112 was measured using PET in 19 patients with primary focal dystonia (cranial, cervical, or arm) and 18 controls. RESULTS: No statistically significant difference was detected in striatal D1-like binding between the two groups. The study had 91% power to detect a 20% difference, indicating that false-negative results were unlikely. CONCLUSIONS: Because [(11)C]NNC 112 has high affinity for D1-like receptors, very low affinity for D2-like receptors, and minimal sensitivity to endogenous dopamine levels, we conclude that D1-like receptor binding is not impaired in these primary focal dystonias.

Characterization of extrastriatal D2 in vivo specific binding of [¹8F](N-methyl)benperidol using PET.

PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near-equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [¹8F]N-methylbenperidol ([¹8F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [¹8F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR-PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [¹8F]NMB injection. Regional peak radioactivity was identified using a peak-finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [¹8F]NMB binding potentials (BP(ND) s) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP(ND) estimates were compared between Logan graphical methods and a three-compartment kinetic tracer model. Radioactivity and BP(ND) levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP(ND) s. BP(ND) estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [¹8F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states.

Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson's disease (PD) improves motor functioning but has variable effects on mood. Little is known about the relationship between electrode contact location and mood response. The authors identified the anatomical location of electrode contacts and measured mood response to stimulation with the Visual Analog Scale in 24 STN DBS PD patients. Participants reported greater positive mood and decreased anxiety and apathy with bilateral and unilateral stimulation. Left DBS improved mood more than right DBS. Right DBS-induced increase in positive mood was related to more medial and dorsal contact locations. These results highlight the functional heterogeneity of the STN.

Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect?

Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing twisting or abnormal postures. Several lines of evidence suggest that abnormalities of dopaminergic pathways contribute to the pathophysiology of dystonia. In particular, dysfunction of D2-like receptors that mediate function of the indirect pathway in the basal ganglia may play a key role. We have demonstrated with positron emission tomography that patients with primary focal cranial or hand dystonia have reduced putamenal specific binding of [(18)F]spiperone, a nonselective D2-like radioligand with nearly equal affinity for serotonergic 5-HT(2A) sites. We then repeated the study with [(18)F]N-methyl-benperidol (NMB), a more selective D2-like receptor radioligand with minimal affinity for 5-HT(2A). Surprisingly, there was no decrease in NMB binding in the putamen of subjects with dystonia. Our findings excluded reductions of putamenal uptake greater than 20% with 95% confidence intervals. The analysis of the in vitro selectivity of NMB and spiperone demonstrated that NMB was highly selective for D2 receptors relative to D3 receptors (200-fold difference in affinity), whereas spiperone has similar affinity for all three of the D2-like receptor subtypes. These findings when coupled with other literature suggest that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia.

The c.-237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia.

BACKGROUND: Sequence variants in coding and noncoding regions of THAP1 have been associated with primary dystonia. METHODS: In this study, 1,446 Caucasian subjects with mainly adult-onset primary dystonia and 1,520 controls were genotyped for a variant located in the 5'-untranslated region of THAP1 (c.-237_236GA>TT). RESULTS: Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P=0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein. DISCUSSION: Our findings indicate that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians.

Mapping Go-No-Go performance within the subthalamic nucleus region.

The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson's disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson's disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson's disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go-No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go-No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson's disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions.

Regional, not global, functional connectivity contributes to isolated focal dystonia.

OBJECTIVE: To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort of patients with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study, we obtained resting-state MRI scans (three or four 7.3-minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], or limb [10]) and age- and sex-matched controls. METHODS: Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia n = 58, control n = 47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia, and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences. RESULTS: Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups. CONCLUSION: Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiologic mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between patients with focal dystonia and control participants.

High-throughput mutational analysis of TOR1A in primary dystonia.

BACKGROUND: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some DeltaGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia. METHODS: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known DeltaGAG DYT1 dystonia and 88 subjects with DeltaGAG-negative dystonia. RESULTS: HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A DeltaGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic DeltaGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia. CONCLUSION: First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.

Validation of a fiducial-based atlas localization method for deep brain stimulation contacts in the area of the subthalamic nucleus.

Differences in the location of active contacts with respect to the subthalamic nucleus (STN) may account for much variability in motor, psychiatric and cognitive responses to deep brain stimulation (DBS) in Parkinson disease (PD) patients. Because localization of STN based on hypointensity in T2-weighted MR images is unreliable and further limited by artifacts from the metal electrodes, we developed and validated a method to transform brain images into stereotactic space [Mai JK, Assheuer J, Paxinos G. Atlas of the Human Brain, 2nd ed. San Diego: Elsevier Academic; 2004] using reliably-identified anatomic fiducials identified in high-resolution T2-weighted pre-operative MR images. Average intraclass correlation between two raters for 29 PD patients was 0.93 for those fiducials used to define the atlas. Accuracy of the registration was tested by comparing the rater-identified centers of the red nuclei with their predicted locations from the fiducial-based atlas transformation. Mean discrepancies were 0.1, 0.9, and 0.0mm (x, y, z) with standard deviations of 0.9, 0.7 and 1.1mm, respectively. Because post-operative determination of contact location with respect to the STN is necessary due to possible shifting of electrodes during surgical placement, we identified active contacts on post-operative CT images and transformed their locations into stereotactic space. This method provides an accurate and reliable means for STN DBS contact localization.

Validation of diffusion tensor imaging measures of nigrostriatal neurons in macaques.

OBJECTIVE: Interpretation of diffusion MRI in the living brain requires validation against gold standard histological measures. We compared diffusion values of the nigrostriatal tract to PET and histological results in non-human primates (NHPs) with varying degrees of unilateral nigrostriatal injury induced by MPTP, a toxin selective for dopaminergic neurons. METHODS: Sixteen NHPs had MRI and PET scans of three different presynaptic radioligands and blinded video-based motor ratings before and after unilateral carotid artery infusion of variable doses of MPTP. Diffusion measures of connections between midbrain and striatum were calculated. Then animals were euthanized to quantify striatal dopamine concentration, stereologic measures of striatal tyrosine hydroxylase (TH) immunostained fiber density and unbiased stereologic counts of TH stained nigral cells. RESULTS: Diffusion measures correlated with MPTP dose, nigral TH-positive cell bodies and striatal TH-positive fiber density but did not correlate with in vitro nigrostriatal terminal field measures or in vivo PET measures of striatal uptake of presynaptic markers. Once nigral TH cell count loss exceeded 50% the stereologic terminal field measures reached a near zero floor effect but the diffusion measures continued to correlate with nigral cell counts. CONCLUSION: Diffusion measures in the nigrostriatal tract correlate with nigral dopamine neurons and striatal fiber density, but have the same relationship to terminal field measures as a previous report of striatal PET measures of presynaptic neurons. These diffusion measures have the potential to act as non-invasive index of the severity of nigrostriatal injury. Diffusion imaging of the nigrostriatal tract could potentially have diagnostic value in humans with Parkinson disease or related disorders.

Modified high-performance liquid chromatography with electrochemical detection method for plasma measurement of levodopa, 3-O-methyldopa, dopamine, carbidopa and 3,4-dihydroxyphenyl acetic acid.

Plasma measurements of levodopa and its major metabolites including dopamine and 3-O-methyldopa have been limited by cumbersome methods and poor sensitivity within relatively narrow ranges of plasma levels. We now report a modification of an HPLC method that permits concomitant measurements of a wide range of concentrations of levodopa, dopamine (DA), carbidopa, 3-O-methyldopa (3-OMD) and 3,4-dihydroxyphenyl acetic acid (DOPAC) from one HPLC injection. The recoveries ranged from 77 to 107% with an intra-day precision around 5% (CV) and inter-day CV's about 10-20%. This validated method will simplify pharmacokinetic studies of levodopa and its metabolites for mechanistic studies or therapeutic clinical monitoring which play a crucial role in development of strategies to prolong motor benefits from individual doses and reduce involuntary movements called dykinesias.

Absorbed radiation dosimetry of the D3-specific PET radioligand [18F]FluorTriopride estimated using rodent and nonhuman primate.

[18F]FluorTriopride ([18F]FTP) is a dopamine D3-receptor preferring radioligand with potential for investigation of neuropsychiatric disorders including Parkinson disease, dystonia and schizophrenia. Here we estimate human radiation dosimetry for [18F]FTP based on the ex-vivo biodistribution in rodents and in vivo distribution in nonhuman primates. Biodistribution data were generated using male and female Sprague-Dawley rats injected with ~370 KBq of [18F]FTP and euthanized at 5, 30, 60, 120, and 240 min. Organs of interest were dissected, weighed and assayed for radioactivity content. PET imaging studies were performed in two male and one female macaque fascicularis administered 143-190 MBq of [18F]FTP and scanned whole-body in sequential sections. Organ residence times were calculated based on organ time activity curves (TAC) created from regions of Interest. OLINDA/EXM 1.1 was used to estimate human radiation dosimetry based on scaled organ residence times. In the rodent, the highest absorbed radiation dose was the upper large intestines (0.32-0.49 mGy/MBq), with an effective dose of 0.07 mSv/MBq in males and 0.1 mSv/MBq in females. For the nonhuman primate, however, the gallbladder wall was the critical organ (1.81 mGy/MBq), and the effective dose was 0.02 mSv/MBq. The species discrepancy in dosimetry estimates for [18F]FTP based on rat and primate data can be attributed to the slower transit of tracer through the hepatobiliary track of the primate compared to the rat, which lacks a gallbladder. Out findings demonstrate that the nonhuman primate model is more appropriate model for estimating human absorbed radiation dosimetry when hepatobiliary excretion plays a major role in radiotracer elimination.