Faculty Bibliography

The diagnosis of Parkinson's disease is clinical and relies on the presence of characteristic motor symptoms such as bradykinesia, rigidity and resting tremor with non-motor features increasingly recognized among the very early manifestations of the disorder. Functional imaging with tracers targeting specifically the dopamine system and regional brain function may show discrete abnormalities helping the clinician shorten considerably the diagnostic process. In this review, we will discuss the contribution of single-photon emission computed tomography imaging in supporting the clinical diagnosis (motor and pre-motor) of Parkinson's disease and its differential diagnosis with essential tremor and other parkinsonian syndromes.

OBJECTIVE: To survey the safety of MRI in PD patients implanted with DBS devices. BACKGROUND: MRI in patients with DBS implants is useful to confirm electrode placement, optimize programming and investigating complications. However, several medical centers do not perform MRI studies in DBS patients because of safety concerns. The safety profile of MRI in DBS patients has not been documented in large clinical series. METHODS: 42 NPF Centers of Excellence (COEs) were asked to complete a questionnaire on MRI use and DBS. RESULTS: Investigators from 40 of 42 (95%) NPF COEs completed the survey and 23 (58%) reported that they were currently performing brain MRI in DBS patients, while 3 (7.5%) had done it in the past. The 17 COEs currently not performing post-operative MRI for DBS listed the following reasons: 1) industry guidelines and/or warnings (53%); 2) decision deferred to outside department (29%); 3) liability/risk/safety (18%); 4) no active DBS program (18%); 5) no available MRI (12%); and 6) insurance and reimbursement concerns (6%). A total of 3304 PD patients with one or more DBS leads had a brain MRI scan, and 177 DBS patients had MRI of other body regions. In one case MRI was associated with an IPG failure without neurological sequelae after IPG replacement. No other complications were reported. CONCLUSIONS: these data provide evidence for a favorable risk/benefit ratio for brain MRI in patients with DBS implants. Further studies will need to address whether a re-assessment of more restrictive recommendations (i.e. very low SAR values) may be warranted.

BACKGROUND: Pallidal deep brain stimulation (DBS) is the best therapeutic option for patients with disabling primary generalized dystonia (PGD) that is refractory to medications. However, little is known about its long-term effects. OBJECTIVE: To describe long-term clinical outcomes in patients with PGD who underwent pallidal DBS. DESIGN: Case series. SETTING: University hospital. PATIENTS: Thirty consecutive patients with at least 2 years' follow-up after pallidal DBS for intractable PGD. INTERVENTIONS: Pallidal DBS and annual follow-up examinations up to 8 years after DBS implantation. MAIN OUTCOME MEASURES: Clinical outcome as measured by changes in the Burke-Fahn-Marsden dystonia scale, incidence and prevalence of adverse events, total electrical energy delivered, and implantable pulse generator longevity. RESULTS: Twenty-three patients were followed for 3 years, 13 for 4 years, 9 for 5 years, 5 for 6 years, 5 for 7 years, and 1 for 8 years after DBS. Overall improvement at 1 year was maintained in all at successive yearly examinations. There were no intraoperative complications; hardware-related adverse events were infrequent. Rare stimulation-related adverse events primarily affected speech. Implantable pulse generators were replaced every 24 months on average in patients who received initial stimulation at 130-Hz frequency. No battery was replaced, for up to 48 months, in 20 patients initially stimulated using 60 Hz. Clinical outcome did not depend on high energies of stimulation. CONCLUSIONS: Pallidal DBS is a safe and effective treatment for PGD, with improvement sustained for up to 8 years in 1 patient. Low energies of stimulation, although they did not affect clinical outcome, were associated with longer battery life.

PURPOSE: Depression is a common symptom in patients suffering from Parkinson's disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD-D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [(123)I]FP-CIT. METHODS: A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [(123)I]FP-CIT binding coefficient V(3)'' in the striatum, thalamus and midbrain/brainstem regions. RESULTS: PD+D patients had significantly lower V(3)'' compared with PD-D patients in the striatum (p<0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V(3)'' than controls (p<0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V(3)'' nor midbrain/brainstem V(3)'' differed from those in PD-D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318). CONCLUSION: Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN-DBS) improves motor symptoms in advanced Parkinson's disease (PD), but the mechanisms are still unclear. Functional imaging evidenced pathological overactivity in motor cortical areas in advanced PD that can be normalized by effective therapies. PATIENTS AND METHODS: We studied resting state cerebral blood flow pre-operatively and 12 months after surgery in 40 patients with advanced PD using ECD-SPECT. SPECT scans were also acquired 1 year apart in 21 matched PD controls who did not undergo surgery. Statistical analysis was performed using statistical parametric mapping (SPM2) software. In addition, we correlated brain perfusion changes after surgery with clinical improvement, assessed using the unified PD rating scale motor score (UPDRS-III). RESULTS: Patients showed marked motor improvement and medication reduction after surgery. Stimulated PD patients revealed bilateral rCBF decrements in motor cortical areas and prefrontal cortex bilaterally compared to pre-surgical condition as well as versus PD controls (p<.01 FDR corrected). Perfusion increases were found in cerebellum, temporal and occipital lobes. Clinical improvement was associated with perfusion decrements in primary motor and premotor cortices. CONCLUSIONS: Effective STN-DBS is associated with neuronal activity changes in brain regions implicated in movement programming and performance. We hypothesize that clinical benefit might be associated with stimulation-induced normalization of the abnormal overactivity within the cortico-basal ganglia-thalamo-cortical motor loop in advanced PD.

BACKGROUND: Pathological gambling (PG) may develop in patients with Parkinson disease (PD) during dopamine replacement therapy, but the underlying neural correlates are still unclear. OBJECTIVE: To investigate resting state brain perfusion in PD patients with active PG compared with matched PD controls and healthy controls. DESIGN: Case-control study. SETTING: Outpatient tertiary clinic. PARTICIPANTS: Eleven right-handed PD patients with active PG according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria, 40 matched PD controls, and 29 age-matched healthy controls. INTERVENTION: All the participants underwent resting state brain perfusion single-photon emission computed tomography using technetium TC 99m ethylcysteinate dimer bicisate. All PD subjects were taking dopaminergic medication. MAIN OUTCOME MEASURE: Statistical Parametric Mapping was used for data analysis (P<.005, false discovery rate corrected). RESULTS: PD patients with PG showed resting state overactivity in a right hemisphere network that included the orbitofrontal cortex, the hippocampus, the amygdala, the insula, and the ventral pallidum. No areas of perfusion reduction were detected. CONCLUSIONS: We found that PD patients with PG have abnormal resting state dysfunction of the mesocorticolimbic network possibly associated with a drug-induced overstimulation of relatively preserved reward-related neuronal systems. These findings support the concept that PG is a "behavioral" addictive disorder.

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.

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.

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.