Commissioning and clinical implementation of an independent dose calculation system for scanned proton beams.

PURPOSE: Experimental patient-specific QA (PSQA) is a time and resource-intensive process, with a poor sensitivity in detecting errors. Radiation therapy facilities aim to substitute it by means of independent dose calculation (IDC) in combination with a comprehensive beam delivery QA program. This paper reports on the commissioning of the IDC software tool myQA iON (IBA Dosimetry) for proton therapy and its clinical implementation at the MedAustron Ion Therapy Center. METHODS: The IDC commissioning work included the validation of the beam model, the implementation and validation of clinical CT protocols, and the evaluation of patient treatment data. Dose difference maps, gamma index distributions, and pass rates (GPR) have been reviewed. The performance of the IDC tool has been assessed and clinical workflows, simulation settings, and GPR tolerances have been defined. RESULTS: Beam model validation showed agreement of ranges within ± 0.2 mm, Bragg-Peak widths within ± 0.1 mm, and spot sizes at various air gaps within ± 5% compared to physical measurements. Simulated dose in 2D reference fields deviated by -0.3% ± 0.5%, while 3D dose distributions differed by 1.8% on average to measurements. Validation of the CT calibration resulted in systematic differences of 2.0% between IDC and experimental data for tissue like samples. GPRs of 99.4 ± 0.6% were found for head, head and neck, and pediatric CT protocols on a 2%/2 mm gamma criterion. GPRs for the adult abdomen protocol were at 98.9% on average with 3%/3 mm. Root causes of GPR outliers, for example, implants were identified and evaluated. CONCLUSION: IDC has been successfully commissioned and integrated into the MedAustron clinical workflow for protons in 2021. IDC has been stepwise and safely substituting experimental PSQA since February 2021. The initial reduction of proton experimental PSQA was about 25% and reached up to 90% after 1 year.

Implementation of Sphinx/Lynx as daily QA equipment for scanned proton and carbon ion beams.

PURPOSE: Reporting on the first implementation of a proton dedicated commercial device (IBA Sphinx/Lynx) for daily Quality Assurance (QA) of scanned proton and carbon ion beams. METHODS: Daily QA trendlines over more than 3 years for protons and more than 2 years for carbon ions have been acquired. Key daily QA parameters were reviewed, namely the spot size and position, beam range, Bragg peak width, coincidence (between beam and imaging system isocenters), homogeneity and dose. RESULTS: The performance of the QA equipment for protons and carbon ions was evaluated. Daily QA trendlines allowed us to detect machine performance drifts and changes. The definition of tolerances and action levels is provided and compared with levels used in the literature. CONCLUSION: The device has been successfully implemented for routine daily QA activities in a dual particle therapy facility for more than 2 years. It improved the efficiency of daily QA and provides a comprehensive QA process.

Technical note: Impact of beamline-specific particle energy spectra on clinical plans in carbon ion beam therapy.

PURPOSE: The Local Effect Model version one (LEM I) is applied clinically across Europe to quantify the relative biological effectiveness (RBE) of carbon ion beams. It requires the full particle fluence spectrum differential in energy in each voxel as input parameter. Treatment planning systems (TPSs) use beamline-specific look-up tables generated with Monte Carlo (MC) codes. In this study, the changes in RBE weighted dose were quantified using different levels of details in the simulation or different MC codes. METHODS: The particle fluence differential in energy was simulated with FLUKA and Geant4 at 500 depths in water in 1-mm steps for 58 initial carbon ion energies (between 120.0 and 402.8 MeV/u). A dedicated beam model was applied, including the full description of the Nozzle using GATE-RTionV1.0 (Geant4.10.03p03). In addition, two tables generated with FLUKA were compared. The starting points of the FLUKA simulations were phase space (PhS) files from, firstly, the Geant4 nozzle simulations, and secondly, a clinical beam model where an analytic approach was used to mimic the beamline. Treatment plans (TPs) were generated with RayStation 8B (RaySearch Laboratories AB, Sweden) for cubic targets in water and 10 clinical patient cases using the clinical beam model. Subsequently, the RBE weighted dose was re-computed using the two other fluence tables (FLUKA PhS or Geant4). RESULTS: The fluence spectra of the primary and secondary particles simulated with Geant4 and FLUKA generally agreed well for the primary particles. Differences were mainly observed for the secondary particles. Interchanging the two energy spectra (FLUKA vs. GEANT4) to calculate the RBE weighted dose distributions resulted in average deviations of less than 1% in the entrance up to the end of the target region, with a maximum local deviation at the distal edge of the target. In the fragment tail, larger discrepancies of up to 5% on average were found for deep-seated targets. The patient and water phantom cases demonstrated similar results. CONCLUSION: RBE weighted doses agreed well within all tested setups, confirming the clinical beam model provided by the TPS vendor. Furthermore, the results showed that the open source and generally available MC code Geant4 (in particular using GATE or GATE-RTion) can also be used to generate basic beam data required for RBE calculation in carbon ion therapy.

Beam monitor calibration of a synchrotron-based scanned light-ion beam delivery system.

PURPOSE: This paper presents the implementation and comparison of two independent methods of beam monitor calibration in terms of number of particles for scanned proton and carbon ion beams. METHODS: In the first method, called the single-layer method, dose-area-product to water (DAPw) is derived from the absorbed dose to water determined using a Roos-type plane-parallel ionization chamber in single-energy scanned beams. This is considered the reference method for the beam monitor calibration in the clinically relevant proton and carbon energy ranges. In the second method, called the single-spot method, DAPw of a single central spot is determined using a Bragg-peak (BP) type large-area plane-parallel ionization chamber. Emphasis is given to the detailed characterization of the ionization chambers used for the beam monitor calibration. For both methods a detailed uncertainty budget on the DAPw determination is provided as well as on the derivation of the number of particles. RESULTS: Both calibration methods agreed on average within 1.1% for protons and within 2.6% for carbon ions. The uncertainty on DAPw using single-layer beams is 2.1% for protons and 3.1% for carbon ions with major contributions from the available values of kQ and the average spot spacing in both lateral directions. The uncertainty using the single-spot method is 2.2% for protons and 3.2% for carbon ions with major contributions from the available values of kQ and the non-uniformity of the BP chamber response, which can lead to a correction of up-to 3.2%. For the number of particles, an additional dominant uncertainty component for the mean stopping power per incident proton (or the CEMA) needs to be added. CONCLUSION: The agreement between both methods enhances confidence in the beam monitor calibration and the estimated uncertainty. The single-layer method can be used as a reference and the single-spot method is an alternative that, when more accumulated knowledge and data on the method becomes available, can be used as a redundant dose monitor calibration method. This work, together with the overview of information from the literature provided here, is a first step towards comprehensive information on the single-spot method.

Computer-assisted beam modeling for particle therapy.

PURPOSE: To develop a computer-driven and thus less user-dependent method, allowing for a simple and straightforward generation of a Monte Carlo (MC) beam model of a scanned proton and carbon ion beam delivery system. METHODS: In a first step, experimental measurements were performed for proton and carbon ion energies in the available energy ranges. Data included depth dose profiles measured in water and spot sizes in air at various isocenter distances. Using an automated regularization-based optimization process (AUTO-BEAM), GATE/Geant4 beam models of the respective beam lines were generated. These were obtained sequentially by using least square weighting functions with and without regularization, to iteratively tune the beam parameters energy, energy spread, beam sigma, divergence, and emittance until a user-defined agreement was reached. Based on the parameter tuning for a set of energies, a beam model was semi-automatically generated. The resulting beam models were validated for all centers comparing to independent measurements of laterally integrated depth dose curves and spot sizes in air. For one representative center, three-dimensional dose cubes were measured and compared to simulations. The method was applied on one research as well as four different clinical beam lines for proton and carbon ions of three different particle therapy centers using synchrotron or cyclotron accelerator systems: (a) MedAustron ion therapy center, (b) University Proton Therapy Dresden, and (c) Center Antoine Lacassagne Nice. RESULTS: Particle beam ranges in the MC beam models agreed on average within 0.2 mm compared to measurements for all energies and beam lines. Spot sizes in air (full-width at half maximum) at all positions differed by less than 0.4% from the measurements. Dose calculation with the beam model for the clinical beam line at MedAustron agreed better than 1.7% in absolute dose for a representative clinical case treated with protons. For protons, beam model generation, including geometry creation, data conversion, and validation, was possible within three working days. The number of iterations required for the optimization process to converge, was found to be similar for all beam line geometries and particle types. CONCLUSION: The presented method was demonstrated to work independently of the beam optics behavior of the different beam lines, particle types, and geometries. Furthermore, it is suitable for non-expert users and requires only limited user interaction. Beam model validation for different beam lines based on different beam delivery systems, showed good agreement.

Evaluation of GATE-RTion (GATE/Geant4) Monte Carlo simulation settings for proton pencil beam scanning quality assurance.

PURPOSE: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. METHODS: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. RESULTS: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). CONCLUSIONS: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.

A GATE/Geant4 beam model for the MedAustron non-isocentric proton treatment plans quality assurance.

PURPOSE: To present a reference Monte Carlo (MC) beam model developed in GATE/Geant4 for the MedAustron fixed beam line. The proposed model includes an absolute dose calibration in Dose-Area-Product (DAP) and it has been validated within clinical tolerances for non-isocentric treatments as routinely performed at MedAustron. MATERIAL AND METHODS: The proton beam model was parametrized at the nozzle entrance considering optic and energy properties of the pencil beam. The calibration in terms of absorbed dose to water was performed exploiting the relationship between number of particles and DAP by mean of a recent formalism. Typical longitudinal dose distribution parameters (range, distal penumbra and modulation) and transverse dose distribution parameters (spot sizes, field sizes and lateral penumbra) were evaluated. The model was validated in water, considering regular-shaped dose distribution as well as clinical plans delivered in non-isocentric conditions. RESULTS: Simulated parameters agree with measurements within the clinical requirements at different air gaps. The agreement of distal and longitudinal dose distribution parameters is mostly better than 1 mm. The dose difference in reference conditions and for 3D dose delivery in water is within 0.5% and 1.2%, respectively. Clinical plans were reproduced within 3%. CONCLUSION: A full nozzle beam model for active scanning proton pencil beam is described using GATE/Geant4. Absolute dose calibration based on DAP formalism was implemented. The beam model is fully validated in water over a wide range of clinical scenarios and will be inserted as a reference tool for research and for independent dose calculation in the clinical routine.

Clinical implementation and commissioning of the MedAustron Particle Therapy Accelerator for non-isocentric scanned proton beam treatments.

PURPOSE: This paper describes the clinical implementation and medical commissioning of the MedAustron Particle Therapy Accelerator (MAPTA) for non-isocentric scanned proton beam treatments. METHODS: Medical physics involvement during technical commissioning work is presented. Acceptance testing procedures, including advanced measurement methods of intra-spill beam variations, are defined. Beam monitor calibration using two independent methods based on a dose-area product formalism is described. Emphasis is given to the medical commissioning work and the specificities related to non-isocentric irradiation, since a key feature of MedAustron is the routine delivery of non-isocentric scanned proton beam treatments. RESULTS: Key commissioning results and beam stability trend lines for more than 2 yr of clinical operation have been provided. Intra-spill beam range, size, and position variations were within specifications of 0.3 mm, 15%, and 0.5 mm, respectively. The agreement between two independent beam monitor calibration methods was better than 1.0%. Non-isocentric treatment delivery allowed lateral penumbra reduction of up to about 30%. Daily QA measurements of the beam range, size, position, and dose were always within 1 mm, 10%, 1 mm, and 2% from the baseline data, respectively. CONCLUSIONS: Non-isocentric treatments have been successfully implemented at MedAustron for routine scanned proton beam therapy using horizontal and vertical fixed beamlines. Up to now every patient was treated in non-isocentric conditions. The presented methodology to implement a new Scanned Ion Beam Delivery (SIBD) system into clinical routine for proton therapy may serve as a guidance for other centers.

Reply to Comment on 'Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry'.

Shen (2019) commented on our paper 'Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry' regarding the impact of the low dose tail of the collimated x-ray beam we used to acquire individual response maps of large area ionization chambers. The behavior of this low dose tail was measured and compared to the simulations performed by Shen (2019). It was shown that the model of the tail by Shen (2019) is too simplistic and overestimates its effect.

Evaluation of electromagnetic and nuclear scattering models in GATE/Geant4 for proton therapy.

PURPOSE: The dose core of a proton pencil beam (PB) is enveloped by a low dose area reaching several centimeters off the central axis and containing a considerable amount of the dose. Adequate modeling of the different components of the PB profile is, therefore, required for accurate dose calculation. In this study, we experimentally validated one electromagnetic and two nuclear scattering models in GATE/Geant4 for dose calculation of proton beams in the therapeutic energy window (62-252 MeV) with and without range shifter (RaShi). METHODS: The multiple Coulomb scattering (MCS) model was validated by lateral dose core profiles measured for five energies at up to four depths from beam plateau to Bragg peak region. Nuclear halo profiles of single PBs were evaluated for three (62.4, 148.2, and 252.7 MeV) and two (97.4 and 124.7 MeV) energies, without and with RaShi, respectively. The influence of the dose core and nuclear halo on field sizes varying from 2-20 cm was evaluated by means of output factors (OFs), namely frame factors (FFs) and field size factors (FSFs), to quantify the relative increase of dose when increasing the field size. RESULTS: The relative increase in the dose core width in the simulations deviated negligibly from measurements for depths until 80% of the beam range, but was overestimated by up to 0.2 mm in σ toward the end of range for all energies. The dose halo region of the lateral dose profile agreed well with measurements in the open beam configuration, but was notably overestimated in the deepest measurement plane of the highest energy or when the beam passed through the RaShi. The root-mean-square deviations (RMSDs) between the simulated and the measured FSFs were less than 1% at all depths, but were higher in the second half of the beam range as compared to the first half or when traversing the RaShi. The deviations in one of the two tested hadron physics lists originated mostly in elastic scattering. The RMSDs could be reduced by approximately a factor of two by exchanging the default elastic scattering cross sections for protons. CONCLUSIONS: GATE/Geant4 agreed satisfyingly with most measured quantities. MCS was systematically overestimated toward the end of the beam range. Contributions from nuclear scattering were overestimated when the beam traversed the RaShi or at the depths close to the end of the beam range without RaShi. Both, field size effects and calculation uncertainties, increased when the beam traversed the RaShi. Measured field size effects were almost negligible for beams up to medium energy and were highest for the highest energy beam without RaShi, but vice versa when traversing the RaShi.

Efficacy and tolerability of perampanel and levetiracetam as first add-on therapy in patients with epilepsy: A retrospective single center study.

Perampanel (PER) is a third generation antiepileptic drug (AED), recently approved as add-on therapy in both focal and generalized seizures. Levetiracetam (LEV) is a second generation AED, widely used in patients with epilepsy because of its favorable safety and efficacy profiles. Perampanel and LEV treatments have been associated with the occurrence of similar adverse events (AEs) (sleepiness, irritability, depression, anxiety, aggressiveness). The aim of the present retrospective single center study was to verify the efficacy and tolerability of PER and LEV used as first add-on therapy in patients with epilepsy affected by secondarily generalized seizures. We collected data from 15 patients treated with PER and 26 patients treated with LEV and followed at our site with follow-up visits at 3, 6, and 12months. This retrospective study documented the comparable efficacy of PER and LEV as first add-on treatments in patients affected by uncontrolled secondarily generalized seizures. However, more patients withdrawn LEV because of AEs compared with PER at the 3- and 12-month follow-up visits. The better tolerability of PER observed in this study could be related to the low therapeutic dose of PER prescribed when it is used as first adjunctive treatment for better controlling secondarily generalized seizures.

Cerebrospinal fluid biomarkers profile of idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a disabling neurological disorder whose potential treatability is significantly limited by diagnostic uncertainty. In fact, typical clinical presentation occurs at late phases of disease, when CSF shunting could be ineffective. In recent years, measurement of different CSF proteins, whose concentration directly reflects neuropathological changes of CNS, has significantly improved both diagnostic timing and accuracy of neurodegenerative disease. Unfortunately iNPH lacks neuropathological hallmarks allowing the identification of specific disease biomarkers. However, neuropathology of iNPH is so rich and heterogeneous that many processes can be tracked in CSF, including Alzheimer's disease core pathology, subcortical degeneration, neuroinflammation and vascular dysfunction. Indeed, a huge number of CSF biomarkers have been analyzed in iNPH patients, but a unifying profile has not been provided yet. In this brief survey, we thus attempted to summarize the main findings in the field of iNPH CSF biomarkers, aimed at outlining a synthetic model. Although defined cut-off values for biomarkers are not available, a better knowledge of CSF characteristics may definitely assist in diagnosing the disease.

Implementation of dosimetry equipment and phantoms at the MedAustron light ion beam therapy facility.

PURPOSE: To describe the implementation of dosimetry equipment and phantoms into clinical practice of light ion beam therapy facilities. This work covers not only standard dosimetry equipment such as computerized water scanners, films, 2D-array, thimble, and plane parallel ionization chambers, but also dosimetry equipment specifically devoted to the pencil beam scanning delivery technique such as water columns, scintillating screens or multilayer ionization chambers. METHOD: Advanced acceptance testing procedures developed at MedAustron and complementary to the standard acceptance procedures proposed by the manufacturer are presented. Detailed commissioning plans have been implemented for each piece of dosimetry equipment and include an estimate of the overall uncertainty budget for the range of clinical use of each device. Some standard dosimetry equipment used in many facilities was evaluated in detail: for instance, the recombination of a 2D-array or the potential use of a microdiamond detector to measure reference transverse dose profiles in water in the core of the primary pencil beams and in the low-dose nuclear halo (over four orders of magnitude in dose). RESULTS: The implementation of dosimetry equipment as described in this work allowed determining absolute spot sizes and spot positions with an uncertainty better than 0.3 mm. Absolute ranges are determined with an uncertainty comprised of 0.2-0.6 mm, depending on the measured range and were reproduced with a maximum difference of 0.3 mm over a period of 12 months using three different devices. CONCLUSION: The detailed evaluation procedures of dosimetry equipment and phantoms proposed in this work could serve as a guidance for other medical physicists in ion beam therapy facilities and also in conventional radiation therapy.

Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry.

Large area ionization chambers (LAICs) can be used to measure output factors of narrow beams. Dose area product measurements are proposed as an alternative to central-axis point dose measurements. Using such detectors requires detailed information on the uniformity of the response along the sensitive area. Eight LAICs were investigated in this study: four of type PTW-34070 (LAICThick) and four of type PTW-34080 (LAICThin). Measurements were performed in an x-ray unit using peak voltages of 100-200 kVp and a collimated beam of 3.1 mm (FWHM). The LAICs were moved with a step size of 5 mm to measure the chamber response at lateral positions. To account for beam positions where only a fraction of the beam impinged within the sensitive area of the LAICs, a corrected response was calculated which was the basis to calculate the relative response. The impact of a heterogeneous LAIC response, based on the obtained response maps was henceforth investigated for proton pencil beams and small field photon beams. A pronounced heterogeneity of the responses was observed in the investigated LAICs. The response of LAICThick generally decreased with increasing radius, resulting in a response correction of up to 5%. This correction was more pronounced and more diverse (up to 10%) for LAICThin. Considering a proton pencil beam the systematic offset for reference dosimetry was 2.4-4.1% for LAICThick and -9.5 to 9.4% for LAICThin. For relative dosimetry (e.g. integral depth-dose curves) systematic response variation by 0.8-1.9% were found. For a decreasing photon field size the systematic offset for absolute dose measurements showed a 2.5-4.5% overestimation of the response for 6 × 6 mm2 field sizes for LAICThick. For LAICThin the response varied even over a range of 20%. This study highlights the need for chamber-dependent response maps when using LAICs for absolute and relative dosimetry with proton pencil beams or small photon beams.

Continuous dopaminergic stimulation in a patient treated with daytime Levodopa-carbidopa intestinal gel and overnight Rotigotine: a case report.

Patients with Parkinson's disease (PD) receiving long-term L-Dopa therapy eventually develop motor complications with unpredictable "on-off" response fluctuations and involuntary movements, leading to progressive disability. Hence, the search for alternative therapeutic choices based on continuous dopaminergic stimulation (CDS) becomes crucial for the treatment of advanced PD. Here, we describe the case of a 70-year-old man with a 9-year history of PD, treated with daytime levodopa-carbidopa intestinal gel (LCIG) and overnight Rotigotine transdermal patch. LCIG monotherapy significantly reduced motor fluctuations and prevented the appearance of unpredictable off periods; concurrently, overnight Rotigotine improved his sleep quality and morning akinesia. Both LCIG and Rotigotine induce CDS, which conceptually mimics physiologic striatal dopamine receptor function. Hence, they both represent a good therapeutic option for the treatment of advanced PD.

Rotigotine may control drooling in patients with Parkinson's Disease: Preliminary findings.

OBJECTIVE: To evaluate the efficacy of rotigotine in controlling the drooling of Parkinson's Disease (PD) patients. PATIENTS AND METHODS: We assessed 7 PD patients (Hoehn and Yahr scale >2.5) with three different clinical scores (Drooling Severity and Frequency Scale - DSFS, Drooling Rating Scale - DRS and Sialorrhea Clinical Scale for PD - SCS) before and after 4 weeks of therapy. Statistical differences were analyzed with Wilcoxon signed-rank test. RESULTS: We observed that rotigotine significantly improves drooling as measured by the lowering of the three scores (p<0.05). CONCLUSIONS: Among non-motor symptoms of PD, drooling is one of the most embarrassing and disabling for patients. Current treatments are unsatisfactory and novel approaches are thus desirable. In this open-label pilot study we demonstrated on a small sample of patients that up to 4mg/24h of rotigotine, a non-ergolinic dopamine agonist with continuous transdermal delivery, may be helpful in the management of drooling in advanced PD.

Outlining a Population "at Risk" of Parkinson's Disease: Evidence from a Case-Control Study.

The multifactorial pathogenesis of Parkinson's Disease (PD) requires a careful identification of populations "at risk" of developing the disease. In this case-control study we analyzed a large Italian population, in an attempt to outline general criteria to define a population "at risk" of PD. We enrolled 300 PD patients and 300 controls, gender and age matched, from the same urban geographical area. All subjects were interviewed on demographics, family history of PD, occupational and environmental toxicants exposure, smoking status, and alcohol consumption. A sample of 65 patients and 65 controls also underwent serum dosing of iron, copper, mercury, and manganese by means of Inductively Coupled-Plasma-Mass-Spectrometry (ICP-MS). Positive family history, toxicants exposure, non-current-smoker, and alcohol nonconsumer status occurred as significant risk factors in our population. The number of concurring risk factors overlapping in the same subject impressively increased the overall risk. No significant differences were measured in the metal serum levels. Our findings indicate that combination of three to four concurrent PD-risk factors defines a condition "at risk" of PD. A simple stratification, based on these questionnaires, might be of help in identifying subjects suitable for neuroprotective strategies.

Occurrence of Writing Tremor in Patients With Scans Without Evidence of Dopaminergic Deficit.

Asymmetric rest tremor is one of the main features of patients diagnosed with scans without evidence of dopaminergic deficit (SWEDD). Clinical and neurophysiological evidence suggests a dystonic origin of this tremor, although the underlying pathophysiology is still unclear. Dystonic tremor has a great tendency to vary with different postures or voluntary motor tasks. Here, we performed a phenomenological analysis of tremor in 14 patients with normal scans and in 14 tremor-dominant Parkinson's disease (PD) patients by assessing the presence of writing tremor. The Wilcoxon-Mann-Whitney's test revealed that patients with normal scans exhibit writing tremor more frequently, regardless of the side mostly affected by motor disturbances in handwriting (P < 0.01) and drawing (right hand: P = 0.01; left hand: P < 0.05). Our findings show that patients with asymmetric rest tremor and normal scans, contrarily to PD patients, present more commonly action tremor during writing tasks. This feature may thus be helpful to distinguish the two conditions.