Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism.

Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.

Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain.

PURPOSE: Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [18F]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls. METHODS: Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 ± 12.2 MBq [18F]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (Vt) and binding potentials (BPnd). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications. RESULTS: [18F]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated Vts in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BPnd values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BPnd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BPnd estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification. CONCLUSIONS: [18F]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable Vts or BPnds, and good test-retest reliability for precise quantification of DAT in human subjects.

Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients.

Secondary paroxysmal dyskinesias (SPDs) are short, episodic, and recurrent movement disorders, classically related to multiple sclerosis (MS). Carbamazepine is effective, but with risk of adverse reactions. We identified 7 patients with SPD among 457 MS patients (1.53%). SPD occurred in face ( n = 1), leg ( n = 2), or arm +leg ( n = 4) several times during the day. Magnetic resonance imaging (MRI) showed new or enhancing lesions in thalamus ( n = 1), mesencephalic tegmentum ( n = 1), and cerebellar peduncles ( n = 5). Patients were treated with clonazepam and then acetazolamide ( n = 1), acetazolamide ( n = 5), or levetiracetam ( n = 1) with response within hours (acetazolamide) to days (levetiracetam). No recurrences or adverse events were reported after a median follow-up of 33 months.

Monoaminergic PET imaging and histopathological correlation in unilateral and bilateral 6-hydroxydopamine lesioned rat models of Parkinson's disease: a longitudinal in-vivo study.

Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate that (11)C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat.

Plasma urate in REM sleep behavior disorder.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with a high risk of developing Parkinson's disease (PD). Higher urate levels are associated with a lower risk of PD. We conducted a study to evaluate plasma urate levels in patients with RBD and their role in the development of PD. METHODS: We evaluated plasma urate levels in a cohort of 24 patients with idiopathic RBD. Patients were divided into 2 groups according to the presence or absence of PD. Other known markers of the risk of developing PD, such as olfaction testing, and substantia nigra (SN) hyperechogenicity, were evaluated in the 2 groups. RESULTS: No differences were observed regarding age, years of evolution of the RBD, SN hyperechogenicity, or plasma urate levels between the 2 groups. In patients without PD, there was a positive correlation between years of evolution of RBD and the levels of uric acid (R(2) =0.88). Patients without PD and those who had more than 5 years of RBD exhibited higher levels of uric acid than patients with PD (P=0.02). CONCLUSIONS: Higher levels of plasma urate were associated with a longer duration of RBD without converting to PD. Future prospective studies would be needed to confirm this finding. Disorder Society

[Parkinson disease mortality rates in Chile]. / Mortalidad por enfermedad de Parkinson en Chile.

BACKGROUND: Parkinson disease (PD) is the second more common neurodegenerative disorder and determines a loss in quality of life, caregiver burden and increased mortality in those affected. AIM: To determine the rates of mortality due to Parkinson disease in Chile. MATERIAL AND METHODS: Data were collected from death certificates between 1997 and 2008. Mortality rates were calculated and the mortality trend was established along the study period, and analyzed by age, sex and geographic región of Chile. RESULTS: There was a steady increase in mortality over the years, particularly since 2001 (r²= 0.85, p < 0.01). The increase in mortality rates was 0.25 per 100.000 habitants/year (r²: 0.89, p < 0.01). Mortality was always higher in men and in those older than 80 years. The highest rate (per 100,000 habitants) in Chile was observed in the región of Valparaíso (2.4) while the lowest was in Antofagasta (0.8) (t = 3.72, p < 0.05). CONCLUSIONS: Mortality associated with PD has increased progressively, consistent with the expected increase in prevalence of the disease in the population.

Statistical parametric maps of ¹8F-FDG PET and 3-D autoradiography in the rat brain: a cross-validation study.

PURPOSE: Although specific positron emission tomography (PET) scanners have been developed for small animals, spatial resolution remains one of the most critical technical limitations, particularly in the evaluation of the rodent brain. The purpose of the present study was to examine the reliability of voxel-based statistical analysis (Statistical Parametric Mapping, SPM) applied to (18)F-fluorodeoxyglucose (FDG) PET images of the rat brain, acquired on a small animal PET not specifically designed for rodents. The gold standard for the validation of the PET results was the autoradiography of the same animals acquired under the same physiological conditions, reconstructed as a 3-D volume and analysed using SPM. METHODS: Eleven rats were studied under two different conditions: conscious or under inhalatory anaesthesia during (18)F-FDG uptake. All animals were studied in vivo under both conditions in a dedicated small animal Philips MOSAIC PET scanner and magnetic resonance images were obtained for subsequent spatial processing. Then, rats were randomly assigned to a conscious or anaesthetized group for postmortem autoradiography, and slices from each animal were aligned and stacked to create a 3-D autoradiographic volume. Finally, differences in (18)F-FDG uptake between conscious and anaesthetized states were assessed from PET and autoradiography data by SPM analysis and results were compared. RESULTS: SPM results of PET and 3-D autoradiography are in good agreement and led to the detection of consistent cortical differences between the conscious and anaesthetized groups, particularly in the bilateral somatosensory cortices. However, SPM analysis of 3-D autoradiography also highlighted differences in the thalamus that were not detected with PET. CONCLUSION: This study demonstrates that any difference detected with SPM analysis of MOSAIC PET images of rat brain is detected also by the gold standard autoradiographic technique, confirming that this methodology provides reliable results, although partial volume effects might make it difficult to detect slight differences in small regions.

[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease.

INTRODUCTION: Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer. METHODS: Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I-II), and 13 moderate-advanced PD patients (Hoehn-Yahr III-IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings. RESULTS: [18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations. CONCLUSIONS: [18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.

Progression of dopaminergic depletion in a model of MPTP-induced Parkinsonism in non-human primates. An (18)F-DOPA and (11)C-DTBZ PET study.

UNLABELLED: Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's disease (PD). Although numerous efforts have been made to determine the evolution of dopaminergic depletion in PD, "in vivo" data concerning the stages of this process are still scarce. We evaluated 6-[18F]-fluoro-l-DOPA ((18)F-DOPA) and 11C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) using PET in a model of chronically MPTP-induced parkinsonism in non-human primates. METHODS: Sixty-seven cynomolgus monkeys (Macacafascicularis) were included in the study. Progressive parkinsonism was induced by repeated administration of small doses of MPTP (iv) over several months. Animals were classified as controls, asymptomatic, recovered (having exhibited parkinsonian features transiently) and stable parkinsonian, according to their motor status. Analysis of striatal dopaminergic activity was conducted by regions of interest (ROI) and statistical parametric mapping (SPM) over normalized parametric images. RESULTS: A progressive loss of striatal uptake was evident among groups for both radiotracers, which correlated significantly with the clinical motor status. Changes occurred earlier, i.e. in the less affected stages, with (11)C-DTBZ. Similar results were achieved by ROI and SPM analysis. Uptake was similar with both radiotracers for the asymptomatic and recovered groups. CONCLUSIONS: Serial assessment with (18)F-DOPA and (11)C-DTBZ PETs provides an effective approach to evaluate evolution of dopaminergic depletion in monkeys with MPTP-induced parkinsonism. This approach could be useful to perform studies aiming to test the effect of early therapeutic intervention and putative neuroprotective treatments.

Intranigral transplantation of epigenetically induced BDNF-secreting human mesenchymal stem cells: implications for cell-based therapies in Parkinson's disease.

It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 ± 12 pg/day/106 cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestin-positive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH)(+) cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.

Features associated with the development of non-motor manifestations in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the presence of motor symptoms. However, the non motor manifestations (NMM) are a frequent complaint in the PD patients. There is a lack of information about the risk factors associated with the NMM in these patients. The aim of this study is to evaluate the prevalence of the more common NMM in a population of PD patients and to determine the features associated with its development. We studied 124 ambulatory PD patients. NMM were defined by the presence of neuropsychiatric manifestations, cognitive disorder, autonomic dysfunction or sleep related problems. In a multivariate analysis we found that the years of evolution of the PD and the presence of cognitive dysfunction are the risk factors for the neuropsychiatric and autonomic manifestations, whereas axial impairment is a risk factor for cognitive disorders and dyskinesias is for sleep related problems. In conclusion, this study shows that the features related to the PD progression appear as the main risk factors associated with NMM.

Is treatment with stem cells effective in Parkinson's disease? / ¿Es efectivo el tratamiento con células madre en la enfermedad de Parkinson?

INTRODUCTION: There are many patients with Parkinson's disease who have a limited response to conventional pharmacological treatment. The use of stem cells has been postulated as an alternative, although its effectiveness remains a matter of controversy. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews including 21 studies overall, of which three were randomized trials. We concluded it is not clear whether stem cells have any effect on the symptoms of Parkinson's disease because the certainty of the available evidence is very low.

INTRODUCCIÓN: Muchos pacientes con enfermedad de Parkinson tienen una respuesta limitada con el tratamiento farmacológico convencional. Se ha postulado el uso de células madre como una alternativa, aunque su efectividad sigue siendo un tema de controversia. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos dos revisiones sistemáticas que en conjunto incluyeron 21 estudios primarios, de los cuales tres corresponden a ensayos aleatorizados. Concluimos que no está claro si las células madre podrían tener algún efecto sobre la sintomatología de la enfermedad de Parkinson porque la certeza de la evidencia disponible es muy baja.

Is acupuncture an alternative for the treatment of Parkinson’s Disease? / ¿Tiene la acupuntura un rol en el tratamiento de la enfermedad de Parkinson?

INTRODUCTION: It has been proposed that acupuncture has several benefits for patients with Parkinson’s disease. However, its real clinical effect is still under discussion. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified nine systematic reviews including 53 studies overall, of which 45 were randomized trials. We concluded acupuncture might have a small effect in improving motor symptoms and disability in Parkinson’s disease, but the certainty of the evidence is low.

INTRODUCCIÓN: Se postula que la acupuntura podría tener diversos beneficios para pacientes con enfermedad de Parkinson. No obstante, su real efectividad clínica aún es discutida. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos nueve revisiones sistemáticas que en conjunto incluyen 53 estudios primarios, de los cuales 45 corresponden a ensayos aleatorizados. Concluimos que la acupuntura podría tener un efecto mínimo en mejorar los síntomas motores y la discapacidad en la enfermedad de Parkinson, pero la certeza de la evidencia es baja.

Are cannabinoids effective for Parkinson’s disease? / ¿Son efectivos los cannabinoides en la enfermedad de Parkinson?

It is postulated cannabinoids may have benefits in Parkinson's disease. However, its actual clinical effectiveness is still discussed. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified six systematic reviews including eight studies overall, of which four were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies included in these reviews, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded cannabinoids probably do not decrease symptoms in Parkinson’s disease or dyskinesia, and probably are associated to frequent adverse effects in patients with Parkinson’s disease.

Se postula que los cannabinoides pudieran tener beneficios en la enfermedad de Parkinson. No obstante, su real efectividad clínica aún es discutida. Para responder a esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos seis revisiones sistemáticas que en conjunto incluyen ocho estudios, de los cuales cuatro corresponden a ensayos aleatorizados. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que los cannabinoides probablemente no disminuyen los síntomas ni las discinesias, y se asocian a efectos adversos frecuentes en pacientes con enfermedad de Parkinson.

Quetiapine for insomnia in Parkinson disease: results from an open-label trial.

Quetiapine is an atypical antipsychotic with sedative properties frequently used to treat hallucinations and psychosis in Parkinson disease (PD). The objective of this trial is to evaluate quetiapine for insomnia in nonpsychotic PD patients. Fourteen consecutive PD patients with frequent insomnia and without psychotic symptoms were treated openly for 12 weeks with a single evening dose of quetiapine. The dose was adjusted according to clinical improvement and tolerance. The severity of insomnia was assessed using the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness was evaluated with the Epworth Sleep Scale (ESS), and motor performance was evaluated using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). All evaluations were done before and 1, 2, and 3 months after initiation of treatment. Total PSQI basal scores were 13.6 +/- 3.7 points. The PSQI score improved in 11 patients and was reduced by 3.8 +/- 3.9 points by the end of the study (P < 0.01). The ESS score was reduced by 4.3 +/- 3.7 points (P < 0.01). The mean quetiapine dose was 31.9 mg/day. No significant change was observed in the motor scale. Two patients were discontinued due to nonserious adverse effects. These results suggest that quetiapine may be a safe and effective treatment of insomnia in PD patients. Double-blind studies will probably confirm these findings.

Imaging Nigrostriatal Dopaminergic Deficit in Holmes Tremor with 18F-PR04.MZ-PET/CT.

Holmes tremor is an infrequent clinical syndrome characterized by unilateral rest, postural, and action tremor often secondary to a brain lesion. We herein report an interesting case of Holmes tremor studied with PET and F-PR04.MZ, a new high-affinity radioligand for dopamine transporters, currently under investigation at our center. F-PR04.MZ-PET can be useful to study the integrity of the nigrostriatal dopaminergic system to improve diagnosis and therapeutic outcome in patients with Holmes tremor and Parkinson disease.

Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion: a possible compensatory mechanism in Parkinson's disease.

The onset of Parkinson's disease (PD) is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA) hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory inter-dependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 6-[(18)F]fluoro-L-dopa ((18) F-DOPA) positron emission tomography (PET) was associated with a higher threshold (i.e., greater dopaminergic loss) for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity. Control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with (18)F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods. Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric inter-dependence in the compensation of striatal DA deficit in PD.

The pathophysiological basis of sensory disturbances in Parkinson's disease.

The diagnosis of Parkinson's disease (PD) is still based on the recognition of the cardinal motor features. However, it is now recognized that non-motor manifestations (NMM) may actually precede the emergence of motor manifestations. NMM are very frequently present in the overall population of PD patients and are a major determinant of their quality of life. In this article we discuss the origin of sensory manifestations in PD, particularly focus on pain mechanisms, which is the most frequent and better studied NMM. Analysis of experimental and clinical data reveals that the basal ganglia (BG) indeed have an anatomo-functional organization which sustains sensory functions. In addition, the dopaminergic system is also engaged in the modulation and integration of sensory information and the response to pain. In patients with PD, pain is often related with motor fluctuations and dyskinesias induced by dopaminergic treatments, which suggest some common mechanisms with the origin of motor complications in PD. Clinically, sensory manifestations are often disturbing and poorly treated and may occasionally become a major cause of disability for PD patients. Thus, more clinical and basic studies are warranted to clarify pain mechanisms in PD, with the aim of achieving better treatments.