Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Early L-dopa, but not pramipexole, restores basal ganglia activity in partially 6-OHDA-lesioned rats.

The most appropriate time for the initiation of dopaminergic symptomatic therapy in Parkinson's disease remains debatable. It has been suggested that early correction of basal ganglia pathophysiological abnormalities may have long-term beneficial effects. To test this hypothesis, we investigated the early and delayed actions of L-dopa and pramipexole, using a delayed-start protocol of treatment. The effects of early and delayed administration of these drugs on motor response, development of dyskinesias, neurogenesis and molecular markers in basal ganglia were studied in rats with a unilateral and partial 6-hydroxydopamine-induced nigrostriatal lesion. Ten days after lesioning, rats received treatment with: a) L-dopa methyl ester (25mg/kg with 6.25mg/kg of benserazide, i.p., twice a day); b) pramipexole (0.5mg/kg, sc, twice a day) or c) saline for 4weeks. Four weeks after treatment initiation, rats from the saline group were distributed in three groups that then received the following treatments: d) L-dopa, e) pramipexole or f) saline, for 4weeks more. Three animals in each treatment arm received 5-bromo-2-deoxyuridine injections (200mg/kg) 3days before starting treatment. When compared with delayed-start L-dopa, early-start L-dopa treatment induced a lower rotational response (p<0.01), an improvement in limb akinesia (p<0.05), a lower level of dyskinesia (p<0.01) and a normalization of lesion-induced molecular changes in basal ganglia. When compared with delayed-start pramipexole, early-start pramipexole induced a higher rotational response (p<0.01), but did not improve limb akinesia, induce dyskinesia nor normalize lesion-induced molecular changes. Neither significant modifications of striatal dopamine D1-D3 receptor heteromerization nor subventricular zone neurogenesis was found after any L-dopa or pramipexole treatments. Our data support a possible restoration of basal ganglia physiological mechanisms by early-start L-dopa therapy.

What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity.

One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state.

Dopaminergic denervation and associated MRI microstructural changes in the nigrostriatal projection in early Parkinson's disease patients.

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD). However, it's unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[18F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (Ki), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen's d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (-67%) and posterolateral SNc (-11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA Ki (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA Ki loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.

The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study.

Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET ((18)F-DOPA K(i) and (11)C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features.

Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population.

BACKGROUND AND PURPOSE: Linkage analysis in familial Parkinson's disease (PD) identified a locus in 2q36-37 (PARK11). Sequencing of GIGYF2 identified several variants only present amongst PD individuals. METHODS: We analyzed the presence of disease-associated GIGYF2 variants in familial and sporadic PD from Spanish origin by sequencing of 147 PD individuals. The entire GIGYF2 coding sequence was analyzed in 122 familial PD individuals and exons 2, 4, 8-11, 14 and 25-26 were sequenced in 25 sporadic PD to identify disease-associated variants. RESULTS: We found no variants associated with PD and failed to identify any of previously PD-associated GIGYF2 variants in our sample. We identified four novel missense changes in GIGYF2. p.Met48Ile was found in a PD individual who also was a carrier of two PARKIN mutations. p.Q1244_Q1247del variant was present only in one PD individual but not found in 70 controls. However, its location in the highly polymorphic GIGYF2 glutamine/proline-rich region does not support a role in PD. Two variants (p.P1238insAGC and p.Q1249del) were present both in PD subjects and in controls. Additionally, the p.L1230_Q1237del variant, which was previously considered as a PD-associated change, was found in one control. CONCLUSION: Our findings suggest that GIGYF2 mutations are not a frequent cause of PD in the Spanish population, since we found no clearly segregating variants. We propose further analyses in PD subjects from different populations to define the role of GIGYF2. A clear pathogenic mutation in other gene at 2q36-37 in the PARK11-linked PD families would definitively disprove GIGYF2 as the responsible gene.

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates.

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification.

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of (18)F-DOPA and (11)C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, (18)F-DOPA and (11)C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of (11)C-DTBZ PET. A symmetric reduction in striatal (11)C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Effects of early vs. late initiation of levodopa treatment in hemiparkinsonian rats.

We investigated the effect of early vs. late initiation of levodopa treatment on dyskinetic movements, rotational behavior and molecular markers in hemiparkinsonian rats. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Rats were divided into three groups treated with: (i) levodopa (6 mg/kg) twice daily for 22 days starting at 4 weeks after 6-OHDA (Early group); (ii) levodopa at the same dose, regimen and duration but starting at 12 weeks after 6-OHDA (Late group), and (iii) saline starting at 4 weeks after 6-OHDA and continuing until the Late group finished treatment. Dyskinesias were quantified on days 1 and 22 of levodopa treatment. Striatal expression of preproenkephalin and preprodynorphin mRNAs, subthalamic cytochrome oxidase mRNA, and glutamate decarboxylase 67 mRNA in the pars reticulata of the substantia nigra was measured by in-situ hybridization. After 22 days of levodopa treatment, the percentage of rats showing dyskinesia was lower in the Early group than in the Late group (60% vs. 100%, respectively). No significant differences in total dyskinesia score were observed between both groups with the exception of the orolingual dyskinesias that were significantly less frequent in the Late group (P < 0.01). No significant differences were observed in the molecular markers between the Early and Late groups. Prompt initiation of levodopa treatment might be able to delay some of the basal ganglia molecular and circuitry changes underlying the development of dyskinesia but, once developed, they are behaviorally and molecularly similar to those appearing after late initiation of levodopa.

Therapeutic efficacy of unilateral subthalamotomy in Parkinson's disease: results in 89 patients followed for up to 36 months.

BACKGROUND: Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson's disease (PD). PATIENTS AND METHODS: 89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months. RESULTS: The Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved significantly contralaterally to the lesion in the "off" and "on" states throughout the follow-up, except for the "on" state at the last evaluation. Axial features and signs ipsilateral to the lesion progressed steadily throughout the study. Levodopa daily doses were significantly reduced by 45%, 36% and 28% at 12, 24 and 36 months post-surgery. 14 patients (15%) developed postoperative hemichorea-ballism which required pallidotomy in eight. These 14 patients had significantly higher dyskinesia scores (levodopa induced) preoperatively than the entire cohort. CONCLUSION: Unilateral subthalamotomy was associated with significant and sustained motor benefit contralateral to the lesion. Further work is needed to ascertain what factors led to severe, persistent chorea-ballism in a subset of patients. Subthalamotomy may be considered an option in circumstances when deep brain stimulation is not viable.

Entacapone potentiates the long-duration response but does not normalize levodopa-induced molecular changes.

Coadministration of entacapone with levodopa attenuates motor complications in experimental models of Parkinson's disease. The mechanisms underlying entacapone effects are unknown. We investigated the effect of entacapone, on: long-duration response (LDR) to levodopa, levodopa-induced postsynaptic pharmacodynamic mechanisms and molecular changes in hemiparkinsonian rats. 6-Hydroxydopamine-unilaterally lesioned rats were treated with levodopa (25 mg/kg)+vehicle; levodopa+entacapone (30 mg/kg) or saline, twice daily for 22 days. The LDR and the apomorphine-induced rotations were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin and dopamine D-3 receptor mRNAs, subthalamic cytochrome oxidase mRNA and nigral glutamic acid decarboxylase mRNA. Entacapone potentiated the LDR but did not modify either the apomorphine-induced rotational behavior or the molecular changes. Our results suggest that the effects of entacapone on levodopa-induced motor response are not mediated by postsynaptic mechanisms and that administration of entacapone is not able to normalize the molecular alterations induced by levodopa in the basal ganglia.

[Quick and simple synthesis of (11)C-(+)-alpha-dihydrotetrabenazine to be used as a PET radioligand of vesicular monoamine transporters]. / Síntesis rápida y simplificada de C-(+)-alpha-dihidrotetrabenazina para su utilización como radioligando PET de los transportadores vesiculares de monoaminas.

UNLABELLED: Dihydrotetrabenazine (2-hydroxy-3-isobutyl-9,10-dimethoxy-1,3,4,6,7-hexahydro-11bH-benzo[a]-quinolizine, DTBZ) has become the ideal radioligand for the presynaptic vesicular monoamine transporter VMAT2 based on its high binding affinity and optimal lipophilicity. OBJECTIVE: To develop an automatic procedure for labelling DTBZ with carbon-11, which has been shown to be a highly effective marker for in vivo studies of neuronal losses in animal models with Parkinson's disease using positron emission tomography (PET). MATERIALS AND METHODS: We have developed a new fully automated synthesis procedure to obtain 11C-(+)DTBZ quickly and simply through labelling the precursor -(+)desmethyldihy-drotetrabenazine- at room temperature in the presence of dimethyl sulfoxide (DMSO) and potassium hydroxide (KOH), using 11CH3I as primary precursor. The final purification was carried out by solid phase extraction using commercially available cartridges and the residual solvents (DMSO and ethyl ether) were eliminated by evaporation. RESULTS: The whole procedure was automated, and after 54 syntheses, an average production of 1.94 GBq of sterile, pyrogen-free 11C-(+)DTBZ with a radiochemical purity > 99 % was obtained with 5 minutes irradiation and 6 minutes of synthesis after 11CH3I production. 11C-(+)DTBZ binding to presynaptic dopamine nerve terminals has been demonstrated by MicroPET studies in Wistar rats and M. Fascicularis monkeys. CONCLUSIONS: This new synthesis procedure is quick and simple, due to optimised techniques, which have allowed elimination of residual solvents based on their polarity for the final purification. It is also applicable to other automatic syntheses for obtaining compounds labelled by methylation reactions.

Author Correction: Computer keyboard interaction as an indicator of early Parkinson's disease.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson's disease.

The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinson's disease is not well understood. We have recorded local field potentials (LFP) from macroelectrodes implanted in the subthalamic nucleus (STN) of 14 patients with Parkinson's disease following surgical treatment with deep brain stimulation. Patients were studied in the 'Off' medication state and in the 'On' motor state after administration of levodopa-carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power spectrum of the LFP in selected frequency bands (4-10, 11-30 and 60-80 Hz) was compared between the 'Off' and 'On' medication states. A peak in the 11-30 Hz band was recorded in the 'Off' medication state and reduced by 45.2% (P < 0.001) in the 'On' state. The 'On' was also associated with an increment of 77. 6% (P < 0.001) in the 4-10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60-80 Hz band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4-10 Hz peak was only recorded in the contralateral STN. These findings suggest that the 4-10 Hz oscillation is associated with the expression of LID in Parkinson's disease.

Short- and long-term effects induced by repeated 6-OHDA intraventricular administration: A new progressive and bilateral rodent model of Parkinson's disease.

The pathological hallmark of Parkinson's disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and the resulting striatal dopamine deficiency, which are responsible for the classic motor features. Although a diagnosis of PD relies on the clinical effects of dopamine deficiency, this disease is also associated with other neurotransmitter deficits that are recognized as causing various motor and non-motor symptoms. However, the cause of dopaminergic nigral neurodegeneration in PD and the underlying mechanisms remain unknown. While animal models are considered valuable tools with which to investigate dopaminergic cell vulnerability, rodent models usually fail to mimic the neurodegeneration progression that occurs in human PD. To find a convenient rat model for studying the progression of dopaminergic cell degeneration and motor signs, we have developed a progressive rodent model using a repeated daily, intraventricular administration of the neurotoxin 6-hydroxydopamine (6-OHDA) (100µg/day) in awakened rats for 1 to 10 consecutive days. The short- (6-day) and long-term (32-day) progression of motor alterations was studied. This model leads to a bilateral and progressive increase in catalepsy (evident from the 3rd infusion in the short-term groups (p<0.01) and from the 7th infusion in the long-term groups (p<0.01), which was associated with a progressive nigrostriatal dopaminergic deficit. All together this makes the new model an interesting experimental tool to investigate the mechanisms involved in the progression of dopaminergic neurodegeneration.

Dopamine-dependent changes of cortical excitability induced by transcranial static magnetic field stimulation in Parkinson's disease.

Transcranial static magnetic field stimulation (tSMS) is a recent low-cost non-invasive brain stimulation technique that decreases cortical excitability in healthy subjects. The objective of the present study was to test the ability of tSMS to modulate cortical excitability in patients with Parkinson's disease. We performed a randomized double-blind sham-controlled cross-over study to assess cortical excitability before and immediately after tSMS (or sham) applied for 10 min to the more affected motor cortex of patients with Parkinson's disease. Cortical excitability was quantified by the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS). tSMS significantly decreased MEP amplitudes in patients OFF medication (after overnight withdrawal of dopaminergic drugs), but not ON medication (after an acute dose of levodopa). The between-patients variability of tSMS-induced changes was significantly greater ON medication. The variability ON medication could be partly explained by disease progression, i.e. the more advanced the patient, the more likely it was to observe a switch from inhibitory tSMS plasticity OFF medication to paradoxical facilitatory plasticity ON medication. These results suggest that tSMS induces dopamine-dependent changes of cortical excitability in patients with Parkinson's disease.

Levodopa motor complications in Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disorder with an average onset age of 60 years. In the United States, approximately one million persons suffer from PD, and there are 60,000 newly diagnosed cases every year. The estimated cost of PD to society is $27 billion per year. Based on United States Census Bureau projections, it is estimated that the frequency of PD will increase fourfold by the year 2040, making it an even larger burden on patients, their families and society.

Continuous dopamine-receptor stimulation in advanced Parkinson's disease.

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of the motor fluctuations and dyskinesia that complicate long-term L-dopa therapy of Parkinson's disease. As a corollary to this hypothesis, continuous dopamine-receptor stimulation can avoid or reverse these complications. Such continuous stimulation is unlikely to mimic completely the normal function of the dopaminergic system, but should avoid the supra-physiological swings in extracellular dopamine that accompany intermittent L-dopa dosing. The concern is that this continuous stimulation might induce tolerance rather than sensitization to some effects of L-dopa. Open clinical trials support the value of continuous dopaminergic stimulation in Parkinson's disease with established motor complications, but rigorous studies, although experimentally difficult, are needed.

Pathophysiology of the basal ganglia in Parkinson's disease.

Insight into the organization of the basal ganglia in the normal, parkinsonian and L-dopa-induced dyskinesia states is critical for the development of newer and more effective therapies for Parkinson's disease. We believe that the basal ganglia can no longer be thought of as a unidirectional linear system that transfers information based solely on a firing-rate code. Rather, we propose that the basal ganglia is a highly organized network, with operational characteristics that simulate a non-linear dynamic system.

Metabolic effects of nigrostriatal denervation in basal ganglia.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.