Giorgio Marotta

Reduced dopamine transporter density in the ventral striatum of patients with Parkinson's disease and pathological gambling

Pathological gambling (PG) represents a behavioral side effect of dopamine replacement therapy in a minority of patients with Parkinsons disease (PD). Using striatal dopamine transporter (DAT) with single photon emission tomography we assessed presynaptic dopaminergic function in 8 PD patients with PG, 21 matched PD control subjects, and 14 healthy subjects. Statistical Parametric Mapping was applied for image analysis. The analysis of variance (ANOVA) revealed that the three groups differed in dorsal and ventral striata bilaterally. The post-hoc analysis displayed a reduced tracer binding in the ventral striatum of PD patients with PG compared to PD controls, possibly reflecting either a reduction of mesolimbic projections or, alternatively, a lower membrane DAT expression on presynaptic terminals. The latter hypothesis is most likely given that the functional reduction of presynaptic reuptake would be more consistent with the increased dopamine levels in the ventral striatum recently reported in PD gamblers.

Pathological gambling in patients with Parkinson's disease is associated with fronto‐striatal disconnection: A path modeling analysis

Pathological gambling may occur in Parkinsons disease (PD) as a complication of dopaminergic therapy. Neuroimaging studies have suggested an abnormal dopamine transmission within the reward system, but the changes in the neural network characterizing PD patients with pathological gambling have never been investigated.

Parkinson's disease in GTP cyclohydrolase 1 mutation carriers

Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinsons disease in both DRD pedigrees and in patients with Parkinsons disease but without a family history of DRD.

Imaging essential tremor.

To investigate over time changes in striatal dopamine transporter (DAT), we performed two sequential N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl) tropane single photon computed tomography (SPECT) scans in 20 subjects with essential tremor (ET), in 13 with Parkinson disease (PD) and in 23 healthy controls (HC, one scan only). We also performed an [99mTc]ethyl cysteinate dimer bicisate SPECT exam for regional brain network analysis in 9 ET, in a second group of 18 PD (9 with tremor, tPD and 9 akinetic‐rigid dominant, arPD) and in 8 HC. PD subjects had a reduced DAT binding in comparison to ET and HC with an annual decline rate of 7.3% in the contralateral putamen. There were no mean uptake differences between ET and HC at baseline and no uptake loss over time in ET. A discriminant analysis grouped 30% (first scan) and 5% (second scan) of ET as PD and a partition analysis showed overlap between ET and PD for caudate nucleus uptake. Spatial covariance analysis revealed that the expression of the PD‐related regional pattern separated both tPD and arPD from ET and HC. In conclusion, PD and ET do not share a common pattern of dopaminergic loss over time. However, mild impairment of dopamine transporter in the caudate nucleus may contribute to tremor onset in ET.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinsons disease (PD) with and without mutations on the glucocerebrosidase gene (GBA).

[123I]FP-CIT striatal binding in early Parkinson's disease patients with tremor vs. akinetic-rigid onset.

We performed [123I]FP-CIT/SPECT in 20 drug-naive Parkinsons 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 nontremor 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.

Clinical and cerebral activity changes induced by subthalamic nucleus stimulation in advanced Parkinson's disease: A prospective case-control study

BACKGROUND High-frequency stimulation of the subthalamic nucleus (STN-DBS) improves motor symptoms in advanced Parkinsons 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.

Role of Tc-99m sestamibi scintigraphy in the diagnosis and surgical decision-making process in primary hyperparathyroid disease

Purpose Ultrasound (US) and scintigraphy are used most frequently of all the available imaging techniques for the preoperative evaluation of patients with possible primary hyperparathyroid disease. The aim of this study was to assess the value of dual-phase Tc-99m MIBI scintigraphy compared with US in the detection of adenomatous or hyperplastic glands and in the surgical decision-making process for patients with a biochemical diagnosis of primary hyperparathyroid disease. Methods Ninety-seven patients with increased levels of parathyroid hormone and calcium, and at least 6 months’ follow-up after US and scintigraphy, were examined retrospectively to assess the influence of the diagnostic work-up on the therapeutic decision of the referring clinicians and to evaluate the sensitivity of these diagnostic tools in the surgically treated patients. Forty-eight patients underwent surgery. Results Parathyroid adenomas were found in 43 patients and hyperplasia in 1, whereas 4 patients had no evidence at surgery. The sensitivity and specificity rates were 84.4% and 95.9% for scintigraphy, and 66.6% and 98.6% for US, respectively. Of the 49 nonsurgically treated patients, 35 had negative results with both MIBI and US; only 3 had positive findings with both imaging methods. Patients treated conservatively had significantly lower parathyroid hormone and serum calcium levels than did the patients who had surgery. Conclusions The data suggest that the high sensitivity of dual-phase MIBI scintigraphy can improve the detection of hyperfunctioning parathyroid glands. Furthermore, despite the controversy surrounding the use of imaging methods in the preoperative assessment of primary hyperparathyroid disease, these data suggest that the decision of the clinician to order surgery for a patient with a moderate increase of serum PTH level may be influenced by the results of the imaging methods.

A role for locus coeruleus in Parkinson tremor

We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease (PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [123I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor.

Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease

Parkinsons disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [123I] N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease.