Evaluation of an optimized [18 F]fluoro-deoxy-glucose positron emission tomography voxel-wise method to early support differential diagnosis in atypical Parkinsonian disorders.

BACKGROUND AND PURPOSE: Atypical Parkinsonian disorders (APD) frequently overlap in clinical presentations, making the differential diagnosis challenging in the early stages. The present study aimed to evaluate the accuracy of the [18 F]fluoro-deoxy-glucose positron emission tomography Statistical Parametric Mapping (SPM) optimized procedure in supporting the early and differential diagnosis of APD. METHODS: Seventy patients with possible APD were retrospectively included from a large clinical cohort. The included patients underwent [18 F]fluoro-deoxy-glucose positron emission tomography within 3 months of the first clinical assessment and a diagnostic follow-up. An optimized SPM voxel-wise procedure was used to produce t-maps of brain hypometabolism in single subjects, which were classified by experts blinded to any clinical information. We compared the accuracy of both the first clinical diagnosis and the SPM t-map classifications with the diagnosis at follow-up as the reference standard. RESULTS: At first diagnosis, 60% of patients were classified as possible APD (progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy) and about 40% as APD with uncertain diagnosis, providing 52% sensitivity, 97% specificity and 86% accuracy with respect to the reference standard. SPM t-map classification showed 98% sensitivity, 99% specificity and 99% accuracy, and a significant agreement with the diagnosis at follow-up (P < 0.001). CONCLUSIONS: The SPM t-map classification at entry predicted the second diagnosis at follow-up. This indicates its significantly superior role for an early identification of APD subtypes, particularly in cases of uncertain diagnosis. The use of a metabolic biomarker at entry in the instrumental work-up of APD may shorten the diagnostic time, producing benefits for treatment options and support to the patients.

Gender differences in microRNA expression in levodopa-naive PD patients.

Gender is an important factor influencing epidemiological and clinical features of Parkinson's disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman's correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment.

Neurodegeneration in the course of Langerhans cell histiocytosis.

Cerebral involvement in the course of Langerhans cell histiocytosis has been described especially in children. It is mainly characterized by hypothalamic-pituitary functional deficit, due to granuloma growth. Here we describe a rare case of adult-onset histiocytosis developing a neurodegenerative disease resembling multiple system atrophy. The patient we describe here started suffering from subtle personality changes which progressed to a severe neurological syndrome 2 years after the diagnosis of histiocytosis. Twenty years before she developed a diabetes insipidus, without any apparent cause. Brain MRI scans at the time of neurodegeneration revealed slight signal alterations at the cerebellum, especially involving the dentate nuclei and the white matter. Despite being rare, histiocytosis should be considered in adult patients with cerebellar abnormalities and/or with unexplained diabetes insipidus to rapidly discern and treat histiocytosis before the onset of its neurodegenerative, untreatable phase.

Pain in multiple system atrophy.

Pain is a recognized feature of idiopathic Parkinson's disease (IPD) but has never been studied in multiple system atrophy (MSA), the commonest cause of atypical parkinsonism. We retrospectively analysed histories of pain in 100 consecutive cases of clinically probable MSA. Details were obtained from the medical records of 100 patients with MSA, comprising 82 with the striatonigral degeneration (SND) type and 18 with the olivopontocerebellar atrophy (OPCA) type of MSA. Pain was reported in 47% of the MSA patients. It was classified as rheumatic in 64% of MSA patients reporting pain, sensory in 28%, dystonic in 21%, and levodopa-related in 16%, mostly related to off-period or diphasic dystonias. There was a mixed pain syndrome in 19% of these patients. Pain was significantly more commonly reported by females (P = 0.02), and by patients with levodopa-induced dyskinesias (P = 0.02). No other clinical feature differentiated MSA patients who reported pain from those who did not. The mean delay between disease onset and onset of pain was 2.9 years, but pain was reported at the time of, or before, disease onset in about 30% of patients. The overall prevalence of pain in MSA was similar to that reported in IPD, but the distribution of pain categories was different.

Striatal hand in Parkinson's disease: the re-evaluation of an old clinical sign.

Among postural abnormalities in Parkinson's disease (PD), striatal hand (SH) is a particularly underexplored phenomenon. It leads to extreme abnormalities of hand posture, causing altered dexterity, pain and disfigurement. In our study, three blinded investigators examined several pictures of the hands of individuals with PD (N = 40) and controls (N = 15). The investigators quantified postural alterations using the Striatal Hand Score. Demographic and clinical data were also collected. As no differences were detected among investigators agreement, a final Hand Score (HS, range 0-4) was obtained for each hand. The Striatal Hand Score in both the left and right hand was significantly different in PD compared to controls (p < 0.001 for both left and right hand). Striatal hand was significantly worse on the side of PD onset, and on the side with greater PD symptomatology. The finding of a striatal hand was 100 % specific for a diagnosis of PD. Nine PD subjects were evaluated both on and off medication, and dopaminergic treatment did not significantly change the Striatal Hand Score. Our findings suggest that in patients without any explanation for hand deformities other than PD, striatal hand occurs very often, and is highly specific for the side of worst PD involvement. We recommend including an evaluation for SH as part of routine practice. This study emphasizes the importance of a careful observation of the patient in order to improve diagnostic accuracy.

Excitatory deep repetitive transcranial magnetic stimulation with H-coil as add-on treatment of motor symptoms in Parkinson's disease: an open label, pilot study.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a potential treatment for Parkinson's disease (PD). H-coils, inducing deeper and wider magnetic fields compared to traditional coils, may be potentially useful in PD, characterized by widespread, bilateral involvement of cortico-subcortical circuits. OBJECTIVE: To evaluate the safety of repetitive deep TMS (rDTMS) with H-coil as add-on treatment of motor symptoms in PD. METHODS: Twenty-seven PD patients (aged 60.1 ± 6.8 y; PD-duration: 6.3 ± 2.8 y; motor-UPDRS: 39.6 ± 10.1) underwent 12 rDTMS sessions over 4 weeks at excitatory (10 Hz) frequency over primary motor (M1) and bilateral prefrontal (PF) regions. Motor UPDRS off therapy was assessed before and after the last rDTMS session, together with safety records at each treatment session. RESULTS: No drop-outs or adverse events were recorded. Motor UPDRS significantly improved after rDTMS (10.8 points average reduction; P < 0.0001). CONCLUSIONS: High-frequency rDTMS might be a safe treatment for PD motor symptoms. Further placebo-controlled, randomized studies are warranted.

Painful cervical dystonia triggered by the extension wire of a deep brain stimulator.

Deep brain stimulation (DBS) can be complicated by adverse events, which are generally classified as surgical-hardware or stimulation-related. Here we report the onset of a painful cervical dystonia probably triggered by the extension wire of a subthalamic nucleus (STN)-DBS device in a woman suffering from advanced Parkinson's disease (PD). Two months after implantation of the STN-DBS device, our patient developed a painful cervical dystonia, which was not responsive to neurostimulation or to medication. No sign of infections or fibrosis was detected. A patch test with the components of the device was performed, revealing no hypersensibility. The patient was referred back to surgery to reposition the pulse generator in the contralateral subclavian region. A deeper channeling of the wire extensions produced a complete remission of the painful dystonia.

Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced Parkinson's disease.

BACKGROUND: Despite its large clinical application, our understanding about the mechanisms of action of deep brain stimulation of the subthalamic nucleus is still limited. Aim of the present study was to explore cortical and subcortical metabolic modulations measured by Positron Emission Tomography associated with improved motor manifestations after deep brain stimulation in Parkinson disease, comparing the ON and OFF conditions. PATIENTS AND METHODS: Investigations were performed in the stimulator off- and on-conditions in 14 parkinsonian patients and results were compared with a group of matched healthy controls. The results were also used to correlate metabolic changes with the clinical effectiveness of the procedure. RESULTS: The comparisons using Statistical parametric mapping revealed a brain metabolic pattern typical of advanced Parkinson disease. The direct comparison in ON vs OFF condition showed mainly an increased metabolism in subthalamic regions, corresponding to the deep brain stimulation site. A positive correlation exists between neurostimulation clinical effectiveness and metabolic differences in ON and OFF state, including the primary sensorimotor, premotor and parietal cortices, anterior cingulate cortex. CONCLUSION: Deep brain stimulation seems to operate modulating the neuronal network rather than merely exciting or inhibiting basal ganglia nuclei. Correlations with Parkinson Disease cardinal features suggest that the improvement of specific motor signs associated with deep brain stimulation might be explained by the functional modulation, not only in the target region, but also in surrounding and remote connecting areas, resulting in clinically beneficial effects.

Clinical assessment of dysphagia in early phases of Parkinson's disease.

Dysphagia is a frequent symptom in parkinsonism, but it is less commonly reported by patients with idiopathic Parkinson's disease (IPD), especially in the early phases. Sixty-five patients with IPD were questioned about symptoms of dysphagia and an objective swallowing test was administered. Reduced swallowing speed for food and complaints of food sticking in the throat, wet voice and cough after liquid intake and nocturnal sialorrhea were reported, respectively, by 35%, 20% and 15% of patients. On objective examination, oral-phase (facial, tongue and palatal musculature) abnormalities were found in 70% of patients. Lingual transfer movements, mainly propulsion, and palatal elevation were severely hypokinetic. Wet voice after liquid intake and cough reflex after solid/liquid intake were detected in 40% of patients. On the other hand, severe dysphagia with frequent food aspiration and chest infections requiring antibiotics in the last 12 months was not found; cough reflex was retained in all patients. On the basis of these results, a regular assessment on swallowing abilities in patients with IPD is warranted in the clinical setting because with simple dietary advice and a short rehabilitative training, the quality of life in these patients can be improved.

Acute effects of L-dopa on event-related desynchronization in Parkinson's disease.

We tested whether dispersible L-dopa has acute effects on event-related desynchronization (ERD) of the mu rhythm in patients with idiopathic Parkinson's disease (IPD). ERD to voluntary movement is delayed in akinetic IPD patients and improves after chronic L-dopa treatment. We evaluated ERD to self-paced finger movement in 14 IPD patients (before and 30-40 min after oral administration of dispersible L-dopa) and in 10 normal subjects. Sensorimotor ERD onset contralateral to movement was significantly delayed in IPD patients compared to normal subjects. This abnormality was no longer significant after L-dopa treatment. We conclude that a single dose of dispersible L-dopa can improve not only motor performance in IPD patients but also the timing of cortical activation of sensorimotor areas during motor programming.

Focal task-specific tremors.

Focal task-specific tremors besides primary writing tremor have rarely been reported in the literature. We describe nine cases of focal tremors induced by different specific tasks, involving a repetitive and frequently performed movement. Only one of these patients had a family history of any similar disorders. There was no overt dystonia in any of the cases, but these tremors may be forms of focal dystonia, rather than a manifestation of essential tremor.

A PET study with [11-C]raclopride in Parkinson's disease: preliminary results on the effect of amantadine on the dopaminergic system.

Amantadine has been proved to be beneficial in Parkinson's disease. Although it is still uncertain which neurochemical events are modified at therapeutic doses, an increase in dopaminergic tone secondary to NMDA receptor blockade and a direct inhibition of the glutamatergic overactivity have been suggested to be involved in its clinical effects. The aim of this study was to evaluate the effects of amantadine on the dopaminergic system by measuring the in vivo binding of [11-C]raclopride to D2 dopamine receptors in the basal ganglia of 6 patients with idiopathic Parkinson's disease. Each patient underwent a PET study, before and after 14 days of treatment with amantadine (200 mg/day). Repeated treatment with therapeutic doses of amantadine induced a moderate increase in the in vivo binding of [11C]raclopride in the putamen of PD patients. This observation indicates that in PD patients, 200 mg/day amantadine does not produce an increase in extracellular levels of dopamine sufficiently to inhibit raclopride binding or that, if present, is it masked by a concurrent increase in receptor availability, as recently reported in rat striatum.

Regression of ventral striatum hypometabolism after calcium/calcitriol therapy in paroxysmal kinesigenic choreoathetosis due to idiopathic primary hypoparathyroidism.

A [(18)F]-FDG PET study was performed in a 44 year old man with proximal kinesigenic choreoathetosis (PKC) secondary to idiopathic primary hypoparathyroidism (IPH) before and 1 year after calcium/calcitriol therapy. The [(18)F]-FDG PET performed before the start of the therapy disclosed a significant bilateral hypometabolism in the ventral striatum. One year later, with the patient still under calcium/calcitriol therapy and free of any occurrence of PKC episodes, the [(18)F]-FDG PET did not show the previously detected hypometabolism. The hypometabolism of the ventral striatum secondary to hypocalcaemia seems to play a crucial part in the pathogenesis of paroxysmal kinesigenic choreoathetosis associated with IPH.

Event-related desynchronization to contingent negative variation and self-paced movement paradigms in Parkinson's disease.

The event-related desynchronization (ERD) to voluntary movement is an indicator of cortical activation with a high time resolution and a specific spatial representation. We have evaluated 10 patients affected by Parkinson's disease (PD), free from L-dopa treatment for at least 12 hours, and 10 control subjects. Each subject underwent ERD examination during self-paced movement (SPM) and during contingent negative variation (CNV) paradigms. ERD was measured as the percentage decrease of alpha band power and calculated for frequency bands of 1 Hz, ranging between 8 and 12 Hz. For group comparisons, the frequency showing the highest ERD was selected for each subject and for each side. In the control group, ERD in the CNV paradigm began over the contralateral centroparietal electrodes 1475 ms before movement onset of the right hand and 1375 ms for the left. In the SPM paradigm, ERD started over the contralateral central electrodes 2150 ms and 1775 ms before movement onset of the right and left hand, respectively. In the PD group, ERD started over the contralateral central areas 800 ms and 475 ms before movement onset of the right and left hand, respectively, for CNV paradigm and 1200 ms and 750 ms for the right and left hand, respectively, for SPM paradigm. Therefore, contralateral ERD began closer to movement onset in PD compared with the control group in both paradigms. ERD over the sensorimotor areas ipsilateral to the movement was not significantly different in PD compared with the control group. The finding of delayed contralateral ERD in PD is according to the view that functional cortical activation related to movement preparation is impaired in PD. The lack of group differences in the onset of ipsilateral ERD, which appears close to movement execution than contralateral ERD both in normal subjects and in PD, suggests that different mechanisms may be involved in generating ERD over the hemispheres ipsilateral and contralateral to the movement, and that only the latter are impaired in PD.

New perspectives on neurochemical effects of amantadine in the brain of parkinsonian patients: a PET - [(11)C]raclopride study.

Amantadine, is a non competitive NMDA receptors antagonist that has been proved beneficial in Parkinson's disease. However its mechanism of action at therapeutic doses is still under discussion. Aim of this study was to evaluate the effect of repeated administration of amantadine on striatal dopaminergic system by measuring [(11)C]raclopride binding to striatal D(2) dopamine receptors, in patients with moderate idiopathic Parkinson's disease. Eight patients completed the study undergoing a PET scan, before and after 10-14 days treatment with Amantadine (200 mg/day). Patients were on treatment with L-DOPA, which was suspended 1 night before each PET scans, and free from dopaminergic agonists, anticholinergic and antidepressants. Amantadine treatment significantly increased [(11)C-]Raclopride binding (caudate: 10% p = 0.04; putamen 11% p = 0.01). A slight reduction (-7.3%, p = 0.062) of UPDRS total scores was also observed. The increased availability of striatal D(2) receptors, is likely to be caused by drug induced modification of receptors expression. This hypothesis is consistent with previous experiments, indicating an increase in striatal D(2) receptors in rats treated with amantadine or other non competitive NMDA antagonists and suggests that the neo-synthesis of D(2) receptors may represent a reinforcing mechanism of drug efficacy.

Transcranial magnetic stimulation and silent period in spasmodic torticollis.

OBJECTIVE: Our objective was to study the corticobulbar projections to neck muscles in cervical dystonia. DESIGN: We compared both the motor evoked potentials and the electromyographic silent period after transcranial magnetic stimulation from sternocleidomastoid and trapezius muscles in a group of 13 patients with spasmodic torticollis with those of 20 healthy volunteers. RESULTS: With the target muscle at rest, no changes of motor threshold, motor evoked potentials latency, and amplitude were observed in dystonic patients. With facilitation, the mean amplitude of the motor evoked potentials was increased in patients compared with controls, the significant difference being for the trapezius muscle, whereas the latency did not differ between groups. The cortical silent period was significantly shorter in dystonic patients than in healthy subjects in both muscles. The duration of the cortical silent period recorded from the sternocleidomastoid muscle showed a positive correlation with the degree of neurologic disability assessed by Tsui's scale. No abnormalities of both nerve conduction velocity and peripheral silent period by stimulation of accessory nerve were found. CONCLUSIONS: These results indicate an impairment of the mechanisms of inhibitory motor control in patients with spasmodic torticollis, which could be the result of a decrease of the basal ganglia inhibitory output over the motor cortex.