Faculty Bibliography

We used positron emission tomography (PET) and the dopamine transporter (DAT) ligand [(11)C]FECIT to measure loss of nigrostriatal dopaminergic neurons in early phase of early onset (EOPD) and late onset Parkinson's disease (LOPD). The analysis was carried out with both regions of interest and voxelwise method (SPM2), at group and single subject levels. Genetic analysis tested for the mutations occurring most frequently in Caucasian population. A significant, bilateral, asymmetric DAT reduction was observed in both EOPD and LOPD. Noteworthy, the side and severity of DAT binding reduction significantly correlated with the severity and asymmetry of motor clinical scores. The two EOPD patients carrying mutations in the PARK2 and PARK6 genes, respectively, displayed the lowest values, bilaterally. This work demonstrates that severity of nigrostriatal damage in early disease phase of sporadic PD is not dependent on age at onset. Genetically determined PD is associated with more severe and widespread dopaminergic impairment.

We analysed the parkin gene in a large consecutive series (146) of unrelated early onset Parkinson's disease (onset ?40 years of age) patients. Twelve cases (8.2%) had homozygous or compound heterozygous point mutations and/or exon rearrangements, while a single mutation was found in four subjects (2.7%). We identified eight exon rearrangements and nine point mutations, two of which were novel: c.735delT (p.C212/X224) and c.815C>G (p.C238W). Genotype-phenotype correlation revealed that parkin carriers had features similar to those of non-carrier early onset Parkinson disease patients.

We assessed the status of dopamine nerve terminals in patients treated with dopamine receptor blocking agents (DRBAs) who had developed drug-induced parkinsonism (DIP). We performed [(123)I]FP-CIT SPET in 32 consecutive patients who were on DRBAs for at least 6 months and developed extrapyramidal signs. The UPDRS-III was used to assess clinical severity. Twenty-six age- and sex-matched healthy subjects served as control group. Putamen [(123)I]FP-CIT SPET binding was reduced in 14 and normal in the remaining 18 patients. There was no difference between the two groups for age, duration of DRBAs treatment, UPDRS III, tremor, rigidity, and bradykinesia subscores for upper and lower limbs. Conversely, symmetry of parkinsonian signs and presence bucco-linguo-masticatory dyskinesias were more frequent in individuals with normal tracer binding. Imaging of the dopamine transporter may help to identify subjects with DIP secondary to a loss of dopamine nerve terminals.

BACKGROUND AND METHODS: We used (123)I-Ioflupane SPECT to study 32 unrelated patients with essential tremor (16 with positive familial history), 47 sporadic tremor dominant patients with Parkinson's disease and 31 healthy control subjects. Discriminant analysis was used to categorize healthy subjects and patients with Parkinson's disease or essential tremor. RESULTS: Patients with essential tremor had higher uptake values (50% putamen and 21% caudate, P<0.001) compared to those with Parkinson's disease but lower than healthy subjects (15% putamen and 21% caudate, P<0.05). Discriminant analysis classified seven essential tremor patients in the healthy subjects cohort (22%) and two as Parkinson's disease (6%). CONCLUSIONS: Our results show that some essential tremor patients may present mild abnormalities of striatal dopamine transporters and a typical Parkinson's disease-like pattern of uptake loss. These findings suggest a link between the two disorders.

Pallidal deep brain stimulation (DBS) is currently the most effective treatment for advanced, medically refractory dystonia. However, factors predicting clinical outcome are not well defined. We reviewed the clinical records of 39 consecutive patients with medically refractory primary dystonia who underwent pallidal DBS implants. Thirty-five patients were implanted bilaterally and four unilaterally. Seven patients had fixed skeletal deformities (FSD). The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores at baseline, 3 and 12 months after DBS were used to evaluate clinical outcome. We investigated the outcome predictive role of several demographic and clinical factors. FSD patients had a significantly inferior outcome at 12 months, mostly affected by axial scores. All other patients (n = 32) showed a remarkable improvement (median BFMDRS percentage improvement = 87.8). Only disease duration showed a significant correlation with DBS outcome at 3 and 12 months. No other demographic and baseline clinical features predicted DBS outcome. This study confirms that patients with primary, medically refractory dystonia are generally outstanding candidates for pallidal DBS, with the possible exception of axial FSD. Patients with shorter duration of disease may expect a better general outcome. No particular predictive value should be assigned to age at onset, age at surgery, severity of disease, DYT1 status and the presence of phasic or tonic involuntary movements.

We describe clinical and imaging features of a patient with sporadic progressive ataxia and palatal tremor (PAPT) of unknown etiology. There was hypertrophy of bilateral inferior olivary nuclei with hyperintense T2-weighted signal and mild cerebellar atrophy at brain magnetic resonance imaging. 18F-fluoro-2-desoxy-d-glucose positron emission tomography scanning (FDG-PET) showed hypometabolism in the red nucleus, external globus pallidus and precuneus while FP-CIT-SPECT imaging revealed mild and progressive loss of striatal dopaminergic terminals. Our findings suggest that in idiopathic PAPT involvement of the dentato-rubro-olivary pathway occurs along with some dopaminergic dysfunction.

We performed [123I]FP-CIT/SPECT in 20 drug-naive Parkinson's disease (PD) patients, 10 with unilateral akinesia/rigidity at onset (arPD) and 10 with additional tremor-at-rest (tPD), to evaluate whether resting tremor at onset is associated with differences in striatal dopamine transporter binding. Patients of the two cohorts were matched for age, disease duration (<3 years) and severity of non-tremor motor symptoms; 31 healthy participants served as controls. Mean striatal dopamine transporter binding reduction in PD patients vs. controls was 42% for arPD and 50% for tPD; mean ipsilateral striatum and caudate nucleus uptake values were lower by 12 and 24%, respectively, in tPD than arPD. We conclude that widespread degeneration of the nigrostriatal dopaminergic pathway might be necessary for the development of parkinsonian tremor-at-rest.

We assessed prospectively clinical and quality of life changes in 9 patients with Parkinson's disease (PD; H&Y > or = 3) with severe motor fluctuations and dyskinesia who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy. Seven patients completed the follow-up period. Duration of "off" periods and time with disabling dyskinesia shortened significantly in all patients (P < 0.01). Total daily dose of levodopa infused did not differ from baseline equivalents. There were significant improvements in UPDRS-II (activities of daily living) and -IV (motor complications) in the "on" condition (P < 0.02), and in four PDQ-39 domains (mobility, activities of daily living, stigma, bodily discomfort; P < 0.05). Two patients withdrew for adverse events. Our results demonstrate that a satisfactory therapeutic window can be achieved and maintained for several months in advanced PD patients.

We prospectively evaluated 20 patients with Parkinson's disease (PD) preoperatively and 12 months after subthalamic nucleus-deep brain stimulation (STN-DBS). All patients had clinical (UPDRS III) and neuropsychological evaluations as well as brain perfusion SPECT-ECD. Clinical and cognitive data were compared with 12 matched PD patients who had not undergone surgery. STN-DBS patients improved in motor symptoms and reduced medications but selectively declined in category fluency (p<0.01). No clinical and cognitive changes were found in the control group at follow-up. Worsening fluency was associated with perfusion decrements in left dorsolateral prefrontal cortex, anterior cingulate cortex and ventral caudate nucleus (p<.001).