Successful MRI-Guided Focused Ultrasound Thalamotomy after Ipsilateral Gamma Knife Radiosurgery for Essential Tremor: A Case Report with Video.

We report the case of a 67-year-old left-handed female patient with disabling medically refractory essential tremor who underwent successful right-sided magnetic resonance-guided focused ultrasound (MRgFUS) of the ventral intermediate nucleus after ipsilateral gamma knife radiosurgery (GKRS) thalamotomy performed 3 years earlier. The GKRS had a partial effect on her postural tremor without side effects, but there was no reduction of her kinetic tremor or improvement in her quality of life (QoL). The patient subsequently underwent a MRgFUS thalamotomy, which induced an immediate and marked reduction in both the postural and kinetic tremor components, with minor complications (left upper lip hypesthesia, dysmetria in her left hand, and slight gait ataxia). The MRgFUS-induced lesion was centered more medially than the GKRS-induced lesion and extended more posteriorly and inferiorly. The MRgFUS-induced lesion interrupted remaining fibers of the dentatorubrothalamic tract (DRTT). The functional improvement 1-year post-MRgFUS was significant due to a marked reduction of the patient's kinetic tremor. The QoL score (Quality of Life in Essential Tremor) improved by 88% and her Clinical Rating Scale for Tremor left hand score by 62%. The side effects persisted but were minor, with no impact on her QoL. The explanation for the superior efficacy of MRgFUS compared to GKRS in our patient could be due to either a poor response to the GKRS or to a better localization of the MRgFUS lesion with a more extensive interruption of DRTT fibers. In conclusion, MRgFUS can be a valuable therapeutic option after unsatisfactory GKRS, especially because MRgFUS has immediate clinical effectiveness, allowing intra-procedural test lesions and possible readjustment of the target if necessary.

Validation of Lead-DBS ß-Oscillation Localization with Directional Electrodes.

In deep brain stimulation (DBS) studies in patients with Parkinson's disease, the Lead-DBS toolbox allows the reconstruction of the location of ß-oscillations in the subthalamic nucleus (STN) using Vercise Cartesia directional electrodes (Boston Scientific). The objective was to compare these probabilistic locations with those of intraoperative monopolar ß-oscillations computed from local field potentials (0.5-3 kHz) recorded by using shielded single wires and an extracranial shielded reference electrode. For each electrode contact, power spectral densities of the ß-band (13-31 Hz) were compared with those of all eight electrode contacts on the directional electrodes. The DBS Intrinsic Template AtLas (DISTAL), electrophysiological, and DBS target atlases of the Lead-DBS toolbox were applied to the reconstructed electrodes from preoperative MRI and postoperative CT. Thirty-six electrodes (20 patients: 7 females, 13 males; both STN electrodes for 16 of 20 patients; one single STN electrode for 4 of 20 patients) were analyzed. Stimulation sites both dorsal and/or lateral to the sensorimotor STN were the most efficient. In 33 out of 36 electrodes, at least one contact was measured with stronger ß-oscillations, including 23 electrodes running through or touching the ventral subpart of the ß-oscillations' probabilistic volume, while 10 did not touch it but were adjacent to this volume; in 3 out of 36 electrodes, no contact was found with ß-oscillations and all 3 were distant from this volume. Monopolar local field potentials confirmed the ventral subpart of the probabilistic ß-oscillations.

Dopaminergic imaging in degenerative parkinsonisms, an established clinical diagnostic tool.

Parkinson's disease (PD) and other neurodegenerative parkinsonisms are characterised by loss of striatal dopaminergic neurons. Dopamine functional deficits can be measured in vivo using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) ligands assessing either presynaptic (e.g. dopamine synthesis and storage, transporter density) or postsynaptic terminals (i.e. D2 receptors availability). Nuclear medicine imaging thus helps the clinician to separate degenerative forms of parkinsonism with other neurological conditions, e.g. essential tremor or drug-induced parkinsonism. With the present study, we aimed at summarizing the current evidence about dopaminergic molecular imaging in the diagnostic evaluation of PD, atypical parkinsonian syndromes and dementia with Lewy bodies (DLB), as well as its potential to distinguish these conditions and to estimate disease progression. In fact, PET/SPECT methods are clinically validated and have been increasingly integrated into diagnostic guidelines (e.g. for PD and DLB). In addition, there is novel evidence on the classification properties of extrastriatal signal. Finally, dopamine imaging has an outstanding potential to detect neurodegeneration at the premotor stage, including REM-sleep behavior disorder and olfactory loss. Therefore, inclusion of subjects at an early stage for clinical trials can largely benefit from a validated in vivo biomarker such as presynaptic dopamine pathways PET/SPECT assessment.

Longitudinal study of speech and dual-task performance in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation.

INTRODUCTION: Impairments in speech and executive functions are both observed in Parkinson's disease (PD) and might be influenced by subthalamic nucleus deep brain stimulation (STN-DBS). We investigated the effects of STN-DBS on speech and executive functions and their mutual interference in PD. METHODS: 14 PD patients eligible for bilateral STN-DBS (PD-DBS), and 16 PD patients with best medical treatment (PD-BMT) were included. Global cognition, executive functions (inhibition and verbal fluency), speech tasks with acoustic measures, and a dual-task (DT) combining a speech task with a Go or Go/NoGo task were performed at baseline and 12 months follow-up. A normative group of matched healthy participants was included at baseline for the evaluation of speech and DT performance. RESULTS: In both patient groups, global cognition mildly decreased after 12 months (p < .001). PD-DBS showed decreased inhibition (p = .016) whereas PD-BMT deteriorated in vowel articulation (p = .011). Using the DT paradigm, PD-DBS showed a slowing of speech rate after 12 months (p = .009) in contrast to PD-BMT (p = .203). CONCLUSION: STN-DBS does not seem to impair speech and global cognition but might affect certain executive functions (notably inhibition). Speech-cognition interference is relatively preserved in PD patients, even though PD-DBS present larger DT cost on speech rate at 12 months post-DBS compared to PD-BMT. An evaluation with a longer follow-up using a larger sample is needed to confirm long-term effects.

Assessing preoperative hope and expectations related to functional neurosurgery: a new questionnaire.

BACKGROUND: Despite successful functional neurosurgery, patients suffering from epilepsy or Parkinson's disease may experience postoperative psychological distress and social maladjustments. Difficulties in coping with postoperative changes, even positive ones, have shown to be related to patients' presurgery cognitive representations (i.e., expectations, hope). The aim of this study was to develop an instrument assessing various key features of surgery outcomes' representations, namely the Preoperative Hope and Expectations Questionnaire (PHEQ). METHODS: Participants were patients (n = 50) diagnosed with Parkinson's disease (n = 25) or epilepsy (n = 25), candidates for functional neurosurgery (i.e., Deep brain stimulation, anterior temporal lobectomy). Two to three weeks before the planned surgery, they were administrated items assessing their actual state, preoperative expectations, and hope regarding surgery outcomes. They also completed measures assessing optimism, quality of life and mood. RESULTS: Exploratory analysis resulted in a 14-item version of the PHEQ composed of two factors (abstract representations, including psychological well-being and concrete representations, such as direct surgery outcomes). The PHEQ demonstrated high internal consistency and good convergent validity. Patients were more prone to express postoperative improvements in terms of hope rather than expectations. They generally focused on concrete rather than abstract features, although patients with Parkinson's disease had higher abstract future-oriented representations. CONCLUSIONS: The PHEQ presents satisfactory psychometric properties and may be considered as a reliable instrument for research and clinical practice.

Electrophysiological confrontation of Lead-DBS-based electrode localizations in patients with Parkinson's disease undergoing deep brain stimulation.

Microelectrode recordings (MERs) are often used during deep brain stimulation (DBS) surgeries to confirm the position of electrodes in patients with advanced Parkinson's disease. The present study focused on 32 patients who had undergone DBS surgery for advanced Parkinson's disease. The first objective was to confront the anatomical locations of intraoperative individual MERs as determined electrophysiologically with those determined postoperatively by image reconstructions. The second aim was to search for differences in cell characteristics among the three subthalamic nucleus (STN) subdivisions and between the STN and other identified subcortical structures. Using the DISTAL atlas implemented in the Lead-DBS image reconstruction toolbox, each MER location was determined postoperatively and attributed to specific anatomical structures (sensorimotor, associative or limbic STN; substantia nigra [SN], thalamus, nucleus reticularis polaris, zona incerta [ZI]). The STN dorsal borders determined intraoperatively from electrophysiology were then compared with the STN dorsal borders determined by the reconstructed images. Parameters of spike clusters (firing rates, amplitudes - with minimum amplitude of 60 µV -, spike durations, amplitude spectral density of ß-oscillations) were compared between structures (ANOVAs on ranks). Two hundred and thirty one MERs were analyzed (144 in 34 STNs, 7 in 4 thalami, 5 in 4 ZIs, 34 in 10 SNs, 41 others). The average difference in depth of the electrophysiological dorsal STN entry in comparison with the STN entry obtained with Lead-DBS was found to be of 0.1 mm (standard deviation: 0.8 mm). All 12 analyzed MERs recorded above the electrophysiologically-determined STN entry were confirmed to be in the thalamus or zona incerta. All MERs electrophysiologically attributed to the SN were confirmed to belong to this nucleus. However, 6/34 MERs that were electrophysiologically attributed to the ventral STN were postoperatively reattributed to the SN. Furthermore, 44 MERs of 3 trajectories, which were intraoperatively attributed to the STN, were postoperatively reattributed to the pallidum or thalamus. MER parameters seemed to differ across the STN, with higher spike amplitudes (H = 10.64, p < 0.01) and less prevalent ß-oscillations (H = 9.81, p < 0.01) in the limbic STN than in the sensorimotor and associative subdivisions. Some cells, especially in the SN, showed longer spikes with lower firing rates, in agreement with described characteristics of dopamine cells. However, these probabilistic electrophysiological signatures might become clinically less relevant with the development of image reconstruction tools, which deserve to be applied intraoperatively.

Childhood-Onset Movement Disorders Can Mask a Primary Immunodeficiency: 6 Cases of Classical Ataxia-Telangiectasia and Variant Forms.

Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classical ataxia-telangiectasia (classical A-T) phenotype, a variant phenotype (variant A-T) exists with partly overlapping but some distinctive disease characteristics. Here we present a case series of 6 patients with classical A-T and variant A-T, which illustrates the phenotypic variability of A-T that can present in childhood with prominent extrapyramidal features, with or without cerebellar ataxia. We report the clinical data, together with a detailed genotype description, immunological analyses, and related expression of the ATM protein. We show that the presence of some residual ATM kinase activity leads to the clinical phenotype variant A-T that differs from the classical A-T. Our data illustrate that the diagnosis of the variant form of A-T can be delayed and difficult, while early recognition of the variant form as well as the classical A-T is a prerequisite for providing a correct prognosis and appropriate rehabilitation and support, including the avoidance of diagnostic X-ray procedures, given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment.

Multiomic Analyses of Dopaminergic Neurons Isolated from Human Substantia Nigra in Parkinson's Disease: A Descriptive and Exploratory Study.

Dopaminergic neurons (DA) of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson's disease (PD). Until now, molecular analyses of DA in PD have been limited to genomic or transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined multiomic study examining the protein profile of these neurons is currently available. In this exploratory study, we used laser capture microdissection to extract regions from DA in 10 human SNpc obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nanoliquid chromatography-mass spectrometry, respectively, and the differential expression between PD and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This multiomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of laser-dissected neuronal parts from SNpc in PD. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.

Robot-induced hallucinations in Parkinson's disease depend on altered sensorimotor processing in fronto-temporal network.

Hallucinations in Parkinson's disease (PD) are disturbing and frequent non-motor symptoms and constitute a major risk factor for psychosis and dementia. We report a robotics-based approach applying conflicting sensorimotor stimulation, enabling the induction of presence hallucinations (PHs) and the characterization of a subgroup of patients with PD with enhanced sensitivity for conflicting sensorimotor stimulation and robot-induced PH. We next identify the fronto-temporal network of PH by combining MR-compatible robotics (and sensorimotor stimulation in healthy participants) and lesion network mapping (neurological patients without PD). This PH-network was selectively disrupted in an additional and independent cohort of patients with PD, predicted the presence of symptomatic PH, and associated with cognitive decline. These robotics-neuroimaging findings extend existing sensorimotor hallucination models to PD and reveal the pathological cortical sensorimotor processes of PH in PD, potentially indicating a more severe form of PD that has been associated with psychosis and cognitive decline.

Characterisation of advanced Parkinson's disease: OBSERVE-PD observational study - results of the Swiss subgroup.

AIMS OF THE STUDY: Currently, the characterisation of advanced Parkinson’s disease (APD) does not follow standardised diagnostic criteria, which complicates the evaluation of ongoing care and treatment strategies, such as eligibility for device-aided treatment (DAT). Therefore, this study aimed to determine the proportion of APD and non-advanced Parkinson’s disease (non-APD) patients treated at specialised movement disorder centres in Switzerland, to compare clinical characteristics of APD versus non-APD patients and to assess eligibility for and use of DAT. Furthermore, potential differences between the Swiss and international situation should be uncovered. METHODS: OBSERVE-PD was a cross-sectional, international, observational study including 2615 patients from 128 movement disorder centres in 18 countries. For the Swiss subgroup of the study analysed here, which included 134 patients from 5 movement disorder centres, motor and non-motor symptoms, activities of daily living and quality of life were assessed as endpoints. The correlation between physician’s judgement of APD and the Delphi criteria for APD, which were developed by an international expert group, as well as the clinical burden in APD and non-APD patients and eligibility for and use of DAT were evaluated. The results for the Swiss subgroup were subsequently compared with the international full analysis set of the OBSERVE-PD study. RESULTS: Based on physician’s judgement, 69.4% of patients included in the Swiss study suffered from APD. A moderate correlation between physician’s judgement and the Delphi criteria for APD was observed (Κ = 0.480, 95% confidence interval 0.317–0.642). Clinical burden was higher for APD patients, as shown by worse scores for activities of daily living, motor symptom severity, dyskinesia duration/disability, duration of “off” time, non-motor symptoms and quality of life as compared with non-APD patients (p <0.0001 for all). The Swiss data for disease burden were comparable to the international findings, except that the Swiss patients showed less “off” time. Amongst APD patients eligible for DAT, the main reason for no DAT in Switzerland was patient refusal, whereas patients needing more time to decide about it was the most frequent reason in the international analysis. CONCLUSIONS: The study shows that the burden of APD in tertiary care centres in Switzerland is comparable to the international situation. Patient refusal is the main reason for no DAT amongst eligible APD patients in such centres. The identification of standard APD classification parameters and evaluation of the reasons for no DAT are relevant for optimising treatment strategies and the transition to DAT.

Oral Dysbiosis and Inflammation in Parkinson's Disease.

BACKGROUND: Oral microbiota has largely escaped attention in Parkinson's disease (PD), despite its pivotal role in maintaining oral and systemic health. OBJECTIVE: The aim of our study was to examine the composition of the oral microbiota and the degree of oral inflammation in PD. METHODS: Twenty PD patients were compared to 20 healthy controls. Neurological, periodontal and dental examinations were performed as well as dental scaling and gingival crevicular fluid sampling for cytokines measurement (interleukine (IL)-1ß, IL-6, IL-1 receptor antagonist (RA), interferon-γ and tumor necrosis factor (TNF)-α). Two months later, oral microbiota was sampled from saliva and subgingival dental plaque. A 16S rRNA gene amplicon sequencing was used to assess bacterial communities. RESULTS: PD patients were in the early and mid-stage phases of their disease (Hoehn & Yahr 2-2.5). Dental and periodontal parameters did not differ between groups. The levels of IL-1ß and IL-1RA were significantly increased in patients compared to controls with a trend for an increased level of TNF-α in patients. Both saliva and subgingival dental plaque microbiota differed between patients and controls. Streptococcus mutans, Kingella oralis, Actinomyces AFQC_s, Veillonella AFUJ_s, Scardovia, Lactobacillaceae, Negativicutes and Firmicutes were more abundant in patients, whereas Treponema KE332528_s, Lachnospiraceae AM420052_s, and phylum SR1 were less abundant. CONCLUSION: Our findings show that the oral microbiome is altered in early and mid-stage PD. Although PD patients had good dental and periodontal status, local inflammation was already present in the oral cavity. The relationship between oral dysbiosis, inflammation and the pathogenesis of PD requires further study.

Sensitivity and specificity of an acoustic- and perceptual-based tool for assessing motor speech disorders in French: the MonPaGe-screening protocol.

To respond to the need of objective screening tools for motor speech disorders (MSD), we present the screening version of a speech assessment protocol (MonPaGe-2.0.s), which is based on semi-automated acoustic and perceptual measures on several speech dimensions in French. We validate the screening tool by testing its sensitivity and specificity and comparing its outcome with external standard assessment tools. The data from 80 patients diagnosed with different types of mild to moderate MSD and 62 healthy test controls were assessed against the normative data obtained on 404 neurotypical speakers, with Deviance Scores computed on seven speech dimensions (voice, speech rate, articulation, prosody, pneumophonatory control, diadochokinetic rate, intelligibility) based on acoustic and perceptual measures. A cut-off of the MonPaGe total deviance score (TotDevS) >2 allowed MSD to be diagnosed with specificity of 95% and an overall sensitivity of 83.8% on all patients pulled, reaching 91% when very mildly impaired patients were excluded. A strong correlation was found between the MonPaGe TotDevS and an external composite perceptual score of MSD provided by six experts. The MonPaGe screening protocol has proven its sensitivity and specificity for diagnosing presence and severity of MSD. Further implementations are needed to complement the characterization of impaired dimensions in order to distinguish subtypes of MSD.

Geospatial analysis of individual-based Parkinson's disease data supports a link with air pollution: A case-control study.

BACKGROUND: The etiology of Parkinson's disease (PD) remains unknown. To approach the issue of PD's risk factors from a new perspective, we hypothesized that coupling the geographic distribution of PD with spatial statistics may provide new insights into environmental epidemiology research. The aim of this case-control study was to examine the spatial dependence of PD prevalence in the Canton of Geneva, Switzerland (population = 474,211). METHODS: PD cases were identified through Geneva University Hospitals, private neurologists and nursing homes medical records (n = 1115). Controls derived from a population-based study (n = 12,614) and a comprehensive population census dataset (n = 237,771). All individuals were geographically localized based on their place of residence. Spatial Getis-Ord Gi* statistics were used to identify clusters of high versus low disease prevalence. Confounder-adjustment was performed for age, sex, nationality and income. Tukey's honestly significant difference was used to determine whether nitrogen dioxide and particulate matters PM10 concentrations were different within PD hotspots, coldspots or neutral areas. RESULTS: Confounder-adjustment greatly reduced greatly the spatial association. Characteristics of the geographic space influenced PD prevalence in 6% of patients. PD hotspots were concentrated in the urban centre. There was a significant difference in mean annual nitrogen dioxide and PM10 levels (+3.6 µg/m3 [p < 0.001] and +0.63 µg/m3 [p < 0.001] respectively) between PD hotspots and coldspots. CONCLUSION: PD prevalence exhibited a spatial dependence for a small but significant proportion of patients. A positive association was detected between PD clusters and air pollution. Our data emphasize the multifactorial nature of PD and support a link between PD and air pollution.

Embarrassment and Shame in People With Parkinson's Disease: A New Tool for Self-Assessment.

Shame and embarrassment related to Parkinson's disease (PD) are rarely addressed in clinical practice nor studied in neuroscience research, partly because no specific tool exists to detect them in PD. Objective: To develop a self-applied assessment tool of shame and embarrassment specifically related to PD or its treatment, to promptly identify the presence and severity of these two emotions in PD. Methods: Identification and selection of relevant items were obtained from the collection of PD patients' opinions during support groups and interviews. Several further items were added following a literature review. Subsequently, a two-phase pilot study was performed for identification of ambiguous items and omissions, and to obtain preliminary data on acceptability, reliability, validity and relevance of the new scale (SPARK). Results: A total of 105 PD patients were enrolled in the study. Embarrassment was reported in 85% of patients, while shame was present in 26%. Fifteen percent of patients did not describe any shame or embarrassment. On average, the intensity of these two emotions was low with a marked floor effect in SPARK items and subscales. However, SPARK total score inter-individual variability was important (range 1-84 out of 99). Acceptability and quality of data were satisfactory with no floor or ceiling effects (2.9% each) or missing data. Internal consistency (Cronbach's alpha) was 0.94 for total score and 0.73-0.87 for subscales. The scale correlated ≥0.60 with instruments measuring related constructs. Content validity was satisfactory. SPARK total score strongly correlated with impaired health-related quality of life (rS = 0.81), the propensity to feel embarrassed or ashamed (rS = 0.68 and 0.66, respectively), and anxiety (rS = 0.72) and depression (rS = 0.63) levels. Moderate to high correlations were observed between SPARK total score and apathy (rS = 0.46) and a more pronounced personality trait directed toward harm avoidance (rS = 0.46). No significant differences in SPARK scores were found by sex, education level, PD duration, Hoehn and Yahr stages or PD phenotype. Conclusion: Preliminary analysis of psychometric properties suggests that SPARK could be an acceptable and reliable instrument for assessing shame and embarrassment in PD. SPARK could help healthcare professionals to identify and characterize PD-induced shame and embarrassment.

Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome).

YY1 mutations cause Gabriele-de Vries syndrome, a recently described condition involving cognitive impairment, facial dysmorphism and intrauterine growth restriction. Movement disorders were reported in 5/10 cases of the original series, but no detailed description was provided. Here we present a 21-year-old woman with a mild intellectual deficit, facial dysmorphism and a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia as the presenting and most striking feature. Whole-exome sequencing revealed a novel heterozygous de novo mutation in YY1 [NM: 003403.4 (YY1): c.907 T > C; p.(Cys303Arg)], classified as pathogenic according to the ACMG guidelines.

Modeling of Electric Fields in Individual Imaging Atlas for Capsular Threshold Prediction of Deep Brain Stimulation in Parkinson's Disease: A Pilot Study.

Background: Modeling of deep brain stimulation electric fields and anatomy-based software might improve post-operative management of patients with Parkinson's disease (PD) who have benefitted from subthalamic nucleus deep brain stimulation (STN-DBS). Objective: We compared clinical and software-guided determination of the thresholds for current diffusion to the pyramidal tract, the most frequent limiting side effect in post-operative management of STN-DBS PD patients. Methods: We assessed monopolar reviews in 16 consecutive STN-DBS PD patients and retrospectively compared clinical capsular thresholds, which had been assessed according to standard clinical practice, to those predicted by volume of tissue activated (VTA) model software. All the modeling steps were performed blinded from patients' clinical evaluations. Results: At the group level, we found a significant correlation (p = 0.0001) when performing statistical analysis on the z-scored capsular thresholds, but with a low regression coefficient (r = 0.2445). When considering intra-patient analysis, we found significant correlations (p < 0.05) between capsular threshold as modeled with the software and capsular threshold as determined clinically in five patients (31.2%). Conclusions: In this pilot study, the VTA model software was of limited assistance in identifying capsular thresholds for the whole cohort due to a large inter-patient variability. Clinical testing remains the gold standard in selecting stimulation parameters for STN-DBS in PD.

Extrastriatal 123I-FP-CIT SPECT impairment in degenerative parkinsonisms.

INTRODUCTION: Neuropathological data and nuclear medicine imaging show extensive serotonergic impairment in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS). The study aims at performing a case-controlled region-of-interest (ROI)-based analysis of 123I-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT) images to measure extrastriatal regional deficits in PD and APS, and assess their added diagnostic value in discriminating degenerative parkinsonisms from other conditions. METHODS: We included 157 patients with early degenerative parkinsonism (mean age 72.6 years, 44% female, mean disease duration at scan 1.6 years), i.e. PD (n = 59), multiple system atrophy parkinsonian variant (MSA-P, n = 17), progressive supranuclear palsy (PSP, n = 28), corticobasal syndrome (CBS, n = 19), dementia with Lewy bodies (DLB, n = 34) as well as 58 similarly-aged control participants. 123I-FP-CIT SPECT images were processed with statistical parametric mapping 12 (SPM12)-based PETPVE12 software and subjected to partial volume effect correction for ROI-based group comparisons. RESULTS: Relative to controls, all forms of degenerative parkinsonism showed decreased 123I-FP-CIT uptake in caudate nucleus, putamen but also pallidum and insula. In addition, a significant uptake reduction was observed in thalamus for MSA-P and PSP, in midbrain for PD and PSP, and in the amygdala for PSP (ANCOVA controlling for age, sex and antidepressant medication, all Bonferroni-corrected p < 0.007). Receiver-operating characteristics area-under-the-curve showed that adding extrastriatal evaluation led to higher accuracies in separating degenerative conditions from control participants (96.1% vs 94.9% with striatal ROIs only, p = 0.045). CONCLUSION: This study provides evidence of a major extrastriatal 123I-FP-CIT impairment, and therefore of an altered serotonergic transmission in PD and APS, confirming previous neuropathological and SERT imaging findings.

Preserved Extrastriatal 123I-FP-CIT Binding in Scans Without Evidence of Dopaminergic Deficit (SWEDD).

PURPOSE: Scans without evidence of dopaminergic deficit (SWEDD) have been initially described in a minority of subjects with suspected Parkinson's disease (PD). Although a highly controversial entity, longitudinal studies showed that SWEDD cases mostly involve non-degenerative conditions mimicking PD or misattribution of scan images to normal status. Using the Parkinson's Progression Markers Initiative (PPMI) cohort, we undertook a case-controlled analysis of [123I]N-ω-fluoropropyl-2ß-carbomethoxy-iodophenyl nortropane ([123I]FP-CIT) single photon emission computed tomography (SPECT) images to measure extrastriatal serotonergic transporter (SERT) density in SWEDD and PD. PROCEDURES: We included 37 SWEDD cases (mean age 60 years, 33 % female) with available [123I]FP-CIT SPECT imaging and high-resolution T1-weighted magnetic resonance imaging (MRI) for coregistration. Sixty-one controls and 62 similarly aged PD subjects were included for group comparisons. Regional [123I]FP-CIT was extracted with PETPVE12 using geometric transfer matrix and partial volume effect correction. RESULTS: PD subjects showed significantly lower [123I]FP-CIT binding in both striatal (caudate nucleus and putamen) and extrastriatal regions (pallidum and insula) compared with controls and SWEDD (all between-group p < 0.0001). PD group also showed lower binding in the thalamus relative to controls (p = 0.007). Receiver operating characteristics (ROC) area under the curve (AUC) did not show a significant difference when using extrastriatal region in addition to striatal ROIs for the separation of SWEDD and PD (95 % ROC-AUC for both methods, p = 0.52). In addition, striatal [123I]FP-CIT binding contralateral to the clinically more affected side was usually lower for PD (> 75 %) but not for SWEDD (< 49 %, p < 0.002). No significant difference regarding [123I]FP-CIT binding was observed between SWEDD and controls. CONCLUSION: These findings corroborate the view that SWEDD cases represent a heterogeneous group of conditions not involving dopaminergic and serotonergic terminals. Further studies are warranted to be assessed whether using extrastriatal [123I]FP-CIT evaluation can be of help in the assessment of degenerative parkinsonism.

Extrastriatal 123I-FP-CIT SPECT impairment in Parkinson's disease - the PPMI cohort.

BACKGROUND: Neuropathological data and nuclear medicine imaging show extensive serotonergic impairment in Parkinson's disease (PD). We undertook a case-controlled analysis of 123I-FP-CIT SPECT images to measure extrastriatal serotonergic transporters (SERT) in PD using the Parkinson's Progression Markers Initiative (PPMI) cohort. METHODS: We included all PD (n = 154) and Control subjects (n = 62) with available 123I-FP-CIT SPECT imaging and high-resolution T1-weighted MRI for coregistration (PD: mean age 61.6 years, 62% male, disease duration 26 months, MDS-UPDRS III score 22). 123I-FP-CIT SPECT images were processed with PETPVE12 using an exploratory voxel-wise analysis including partial-volume effect correction. Linear regressions were performed in the PD group to assess correlations between region of interest 123I-FP-CIT uptake and clinical motor and non-motor impairment. RESULTS: Compared to Controls, PD exhibited an uptake reduction in bilateral caudate nucleus, putamen, insula, amygdala and right pallidum (family-wise error (FWE)-corrected p <  0.05). While lower putaminal uptake on the contralateral side to clinically more affected side was associated with higher MDS-UPDRS III score (p = 0.022), we found a trend association between higher geriatric depression scale and lower pallidum uptake (p = 0.09). Higher SCOPA-AUT gastrointestinal subscore was associated with lower uptake in mean putamen and caudate nucleus (p = 0.01 to 0.03), whereas urological subscore was inversely correlated with mean caudate nucleus, putamen, and pallidum uptake (p = 0.002 to 0.03). REM sleep behaviour disorder screening questionnaire was associated with lower 123I-FP-CIT binding in caudate nucleus, putamen and pallidum (all p <  0.05). No significant association was found for Montreal Cognitive Assessment (all p > 0.45) or excessive daytime sleepiness (all p > 0.29). CONCLUSIONS: In addition to the well-established striatal deficit, this study provides evidence of a major extrastriatal 123I-FP-CIT impairment, and therefore of an altered serotonergic transmission in early PD.