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Objective The objective of this study was to assess the efficacy and safety of nabilone, a synthetic tetrahydrocannabinol analogue, as a treatment for non-motor symptoms (NMS) in Parkinson's disease (PD). Methods This was a phase II placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal trial conducted at the Medical University Innsbruck. A random sample of 47 patients with PD with stable motor disease and disturbing NMS defined by a score of ≥4 points on the Movement Disorder Society - Unified PD Rating Scale-I (MDS-UPDRS-I) underwent open-label nabilone titration (0.25 mg once daily to 1 mg twice daily, phase I). Responders were randomized 1:1 to continue with nabilone or switch to placebo for 4 weeks (phase II). The primary efficacy criterion was the change of the MDS-UPDRS-I between randomization and week 4. Safety was analyzed in all patients who received at least one nabilone dose. Results Between October 2017 and July 2019, 19 patients received either nabilone (median dose = 0.75 mg) or placebo. At week 4, mean change of the MDS-UPDRS-I was 2.63 (95% confidence interval [CI] 1.53 to 3.74, p = 0.002, effect size = 1.15) in the placebo versus 1.00 (95% CI -0.16 to 2.16, p = 0.280, effect size = 0.42) in the nabilone-group (difference: 1.63, 95% CI 0.09 to 3.18, p = 0.030, effect size = 0.66). Seventy-seven percent of patients had adverse events (AEs) during open-label titration, most of them were transient. In the double-blind phase, similar proportions of patients in each group had AEs (42% in the placebo group and 32% in the nabilone group). There were no serious AEs. Interpretation Our results highlight the potential efficacy of nabilone for patients with PD with disturbing NMS, which appears to be driven by positive effects on anxious mood and night-time sleep problems. Trial registry ClinicalTrials.gov (NCT03769896) and EudraCT (2017-000192-86). ANN NEUROL 2020;88:712-722.

Objective: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic REM sleep behavior disorder (IRBD) patients at risk for short-term development of clinically-defined synucleinopathy. Methods: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123I-FP-CIT DAT-SPECT. Results were compared with 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed-up during 5.7 ± 2.2 (range, 2.6-9.9) years. Results: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up 25 (28.7%) subjects developed clinically-defined synucleinopathy (Parkinson disease in 11, dementia with Lewy bodies in 13, multiple system atrophy in one) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs. 6% at three years, 33% vs. 18% at five years; log rank test, p=0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease-free after three years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and like-hood ratio 1.54 to predict synucleinopathy. Interpretation: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after three years follow-up. These observations may be useful to select candidates for disease-modification trials in IRBD. This article is protected by copyright. All rights reserved.

We assessed loss of dorsolateral nigral hyperintensity (DNH) on high-field susceptibility-weighted imaging (SWI), a novel magnetic resonance imaging marker for Parkinson's disease (PD), in 15 subjects with idiopathic rapid eye movement sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HCs) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate observed in PD and is in contrast to findings in HCs. We propose that absence of DNH on high-field SWI could identify prodromal degenerative parkinsonism in iRBD. Ann Neurol 2016;79:1026-1030.

To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short-term development of clinically defined synucleinopathy.Eighty-seven patients with polysomnography-confirmed IRBD underwentBaseline DAT deficit was found in 51 (58.6%) patients. During follow-up, 25 (28.7%) subjects developed clinically defined synucleinopathy (Parkinson's disease in 11, dementia with Lewy bodies in 13, and multiple system atrophy in 1) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs 6% at 3 years, 33% vs 18% at 5 years; log rank test, p = 0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease free after 3 years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and likelihood ratio 1.54 to predict synucleinopathy.DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after 3 years' follow-up. These observations may be useful to select candidates for disease modification trials in IRBD. Ann Neurol 2017;82:419-428.

We assessed loss of dorsolateral nigral hyperintensity (DNH) on high-field susceptibility-weighted imaging (SWI), a novel magnetic resonance imaging marker for Parkinson's disease (PD), in 15 subjects with idiopathic rapid eye movement sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HCs) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate observed in PD and is in contrast to findings in HCs. We propose that absence of DNH on high-field SWI could identify prodromal degenerative parkinsonism in iRBD. Ann Neurol 2016;79:1026-1030.

Objective We applied diffusion-tensor imaging (DTI) including measurements of mean diffusivity (MD), a parameter of brain tissue integrity, fractional anisotropy (FA), a parameter of neuronal fiber integrity, as well as voxel-based morphometry (VBM), a measure of gray and white matter volume, to detect brain tissue changes in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Methods Magnetic resonance imaging (MRI) was performed in 26 patients with iRBD (mean disease duration, 9.2 ± 6.4 years) and 14 age-matched healthy control subjects. Statistical parametric mapping (SPM) was applied to objectively identify focal changes of MRI parameters throughout the entire brain volume. Results SPM localized significant decreases of FA in the tegmentum of the midbrain and rostral pons and increases of MD within the pontine reticular formation overlapping with a cluster of decreased FA in the midbrain (p < 0.001). VBM revealed increases of gray matter densities in both hippocampi of iRBD patients (p < 0.001). Interpretation The observed changes in the pontomesencephalic brainstem localized 2 areas harboring key neuronal circuits believed to be involved in the regulation of REM sleep and overlap with areas of structural brainstem damage causing symptomatic RBD in humans. Bilateral increases in gray matter density of the hippocampus suggest functional neuronal reorganization in this brain area in iRBD. This study indicates that DTI detects distinct structural brainstem tissue abnormalities in iRBD in the regions where REM is modulated. Further studies should explore the relationship between MRI pathology and the risk of patients with iRBD of developing alpha-synuclein–related neurodegenerative diseases like Parkinson disease. Ann Neurol 2011.

To this day, the cause of multiple system atrophy (MSA) remains stubbornly enigmatic. A growing body of observations regarding the clinical, morphological, and biochemical phenotypes of MSA has been published, but the interested student is still left without a clue as to its underlying cause. MSA has long been considered a rare cousin of Parkinson's disease and cerebellar degeneration; it is rich in acronyms but poor in genetic and environmental leads. Because of the worldwide research efforts conducted over the last two decades and the discovery of the α-synuclein–encoding SNCA gene as a cause of rare familial Parkinson's disease, the MSA field has seen advances on three fronts: the identification of its principal cellular target, that is, oligodendrocytes; the characterization of α-synuclein–rich glial cytoplasmic inclusions as a suitable marker at autopsy; and improved diagnostic accuracy in living patients resulting from detailed clinicopathological studies. The working model of MSA as a primary glial disorder was recently strengthened by the finding of dysregulation in the metabolism of myelin basic protein and p25α, a central nervous system–specific phosphoprotein (also called tubulin polymerization promoting protein, TPPP). Intriguingly, in early cases of MSA, the oligodendrocytic changes in myelin basic protein and p25α processing were recorded even before formation of glial cytoplasmic inclusions became detectable. Here, we review the evolving concept that MSA may not just be related to Parkinson's disease but also share traits with the family of demyelinating disorders. Although these syndromes vary in their respective cause of oligodendrogliopathy, they have in common myelin disruption that is often followed by axonal dysfunction. Ann Neurol 2008;64:239–246

In patients with Parkinson's disease, hyperechogenicity of the substantia nigra using transcranial ultrasound has been related to increased tissue concentrations of iron. Recently, deficient iron transport mechanisms in substantia nigra neurons have been described in postmortem tissue of patients with restless legs syndrome (RLS). This study was performed to study substantia nigra echogenicity in RLS patients compared with normal control subjects and Parkinson's disease patients. RLS patients had significantly reduced midbrain areas of hyperechogenicity compared with control subjects, and even more markedly reduced hyperechogenicity compared with Parkinson's disease patients. These findings lend further support to nigral iron deficiency as a pathogenetic factor in RLS.

Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.

There are still insufficient data on the natural course of Parkinson's disease (PD) owing to lack of standardized longitudinal follow-up studies. Reported progression rates in early PD vary considerably by a factor of 2 to 3. Similarly, data from sequential [18F]dopa PET studies in PD patients have produced variable decline rates of PET indices ranging between 7 and 70% per decade. Risk factors for rapid progression include old age at onset, concomitant major depression, dementia, and akinetic-rigid symptom presentation. The introduction of levodopa into the routine treatment of PD patients had a dramatic impact on symptomatic control without affecting the underlying rate of disease progression. By contrast, monoamine oxidase (MAO) B inhibition by deprenyl monotherapy in early PD was shown to delay the need for levodopa by around 9 months. However, the neuroprotective action disappeared after 2 years of follow-up. Furthermore, deprenyl also failed to influence the subsequent development of levodopa-induced motor complications. Available studies on mortality in PD provide heterogeneous mortality rates, probably because of discrepancies between patient populations with respect to co-morbidity, disease stage at study entry, and diagnostic accuracy. However, the most recent follow-up from the DATATOP cohort suggests normal life expectancy in carefully selected patients without significant co-morbidity and with adequate treatment and expert follow-up.

Objective L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life. Methods We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4× daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia. Results In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001). Interpretation Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group. ANN NEUROL 2010;68:18–27

High-speed memory scanning as assessed by the Sternberg paradigm was studied in 12 nondemented patients with fluctuating Parkinson's disease and 13 age-matched healthy controls. Patients were first assessed before taking their morning dose of levodopa ("off") and again after that dose had produced full clinical effect ("on") after that dose had produced full clinical effect ("on"). Although motor components of the measured choice reaction time were slower in patients when off than in control subjects, memory scanning speed was not different. After levodopa (on), patients' motor time normalized, but cognitive processing speed became significantly slower when compared with previous performance in the off condition and with controls. Contrary to previous concepts of bradyphrenia in patients with Parkinson's disease, these results indicate that dopaminergic stimulation can reduce cognitive processing speed.

To this day, the cause of multiple system atrophy (MSA) remains stubbornly enigmatic. A growing body of observations regarding the clinical, morphological, and biochemical phenotypes of MSA has been published, but the interested student is still left without a clue as to its underlying cause. MSA has long been considered a rare cousin of Parkinson's disease and cerebellar degeneration; it is rich in acronyms but poor in genetic and environmental leads. Because of the worldwide research efforts conducted over the last two decades and the discovery of the alpha-synuclein-encoding SNCA gene as a cause of rare familial Parkinson's disease, the MSA field has seen advances on three fronts: the identification of its principal cellular target, that is, oligodendrocytes; the characterization of alpha-synuclein-rich glial cytoplasmic inclusions as a suitable marker at autopsy; and improved diagnostic accuracy in living patients resulting from detailed clinicopathological studies. The working model of MSA as a primary glial disorder was recently strengthened by the finding of dysregulation in the metabolism of myelin basic protein and p25alpha, a central nervous system-specific phosphoprotein (also called tubulin polymerization promoting protein, TPPP). Intriguingly, in early cases of MSA, the oligodendrocytic changes in myelin basic protein and p25alpha processing were recorded even before formation of glial cytoplasmic inclusions became detectable. Here, we review the evolving concept that MSA may not just be related to Parkinson's disease but also share traits with the family of demyelinating disorders. Although these syndromes vary in their respective cause of oligodendrogliopathy, they have in common myelin disruption that is often followed by axonal dysfunction.

To determine the role of recombinant human erythropoietin as a possible treatment option in Friedreich's ataxia, we performed an open-label clinical pilot study. Primary outcome measure was the change of frataxin levels at week 8 versus baseline. Twelve Friedreich's ataxia patients received 5,000 units recombinant human erythropoietin three times weekly subcutaneously. Frataxin levels were measured in isolated lymphocytes by enzyme-linked immunosorbent assay. In addition, urinary 8-hydroxydeoxyguanosine and serum peroxides, were measured. Treatment with recombinant human erythropoietin showed a persistent and significant increase in frataxin levels after 8 weeks (p < 0.01). All patients showed a reduction of oxidative stress markers.

We studied the features of dystonia in 9 patients with untreated idiopathic Parkinson's disease and in 56 patients on sustained treatment with L-dopa. Dystonia was seen as an initial symptom in patients with both early- and late-onset Parkinson's disease and included action dystonia of the limbs and cranial dystonia. Although the coexistence of parkinsonism and dystonia suggests a common pathophysiology, antiparkinsonian drugs did not consistently influence dystonic spasms. L-dopa-induced dystonia was seen as an off-period, biphasic, or peak-dose phenomenon. Each type showed a distinctive pattern of localization of dystonic spasms, possibly reflecting neurochemical aspects of basal ganglia somatotopy. Neuropharmacological studies performed in 12 patients suggest that off-period dystonia is genuinely induced by L-dopa and best relieved by antiparkinsonian agents.