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[Introduction] [18F]fluoroetoxybenzovesamicol ([18F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [18F]FEOBV PET to study the cholinergic topography of the healthy human brain., [Materials and methods] [18F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [18F]FEOBV PET uptake was compared with histological and gene expression data., [Results] Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene., [Discussion] Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [18F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo.

Comorbid Lewy body (LB) pathology is common in Alzheimer disease (AD). The effect of LB copathology on 18F-FDG PET patterns in AD is yet to be studied. We analyzed associations of neuropathologically assessed tau pathology, LB pathology, and substantia nigra neuronal loss (SNnl) with antemortem 18F-FDG PET hypometabolism in patients with a clinical AD presentation., [Methods] Twenty-one patients with autopsy-confirmed AD without LB neuropathologic changes (LBNC) (pure-AD), 24 with AD and LBNC copathology (AD-LB), and 7 with LBNC without fulfilling neuropathologic criteria for AD (pure-LB) were studied. Pathologic groups were compared regarding regional and voxelwise 18F-FDG PET patterns, the cingulate island sign ratio (CISr), and neuropathologic ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with 18F-FDG PET patterns., [Results] Pure-AD and AD-LB showed highly similar patterns of AD-typical temporoparietal hypometabolism and did not differ in CISr, regional 18F-FDG SUVR, or SNnl. By contrast, pure-LB showed the expected pattern of pronounced posterior-occipital hypometabolism typical for dementia with LB (DLB), and both CISr and SNnl were significantly higher compared with the AD groups. In continuous analyses, Braak tangle stage correlated significantly with more AD-like, and SNnl with more DLB-like, 18F-FDG PET patterns., [Conclusion] In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional 18F-FDG PET pattern. A more DLB-like 18F-FDG PET pattern was observed in relation to SNnl, but advanced SNnl was mostly limited to relatively pure LB cases. AD pathology may have a dominant effect over LB pathology in determining the regional neurodegeneration phenotype.

Conventional clustering techniques for neuroimaging applications usually focus on capturing differences between given subjects, while neglecting arising differences between features and the potential bias caused by degraded data quality. In practice, collected neuroimaging data are often inevitably contaminated by noise, which may lead to errors in clustering and clinical interpretation. Additionally, most methods ignore the importance of feature grouping towards optimal clustering. In this paper, we exploit the underlying heterogeneous clusters of features to serve as weak supervision for improved clustering of subjects, which is achieved by simultaneously clustering subjects and features via nonnegative matrix tri-factorization. In order to suppress noise, we further introduce adaptive regularization based on coefficient distribution modeling. Particularly, unlike conventional sparsity regularization techniques that assume zero mean of the coefficients, we form the distributions using the data of interest so that they could better fit the non-negative coefficients. In this manner, the proposed approach is expected to be more effective and robust against noise. We compared the proposed method with standard techniques and recently published methods demonstrating superior clustering performance on synthetic data with known ground truth labels. Furthermore, when applying our proposed technique to magnetic resonance imaging (MRI) data from a cohort of patients with Parkinson's disease, we identified two stable and highly reproducible patient clusters characterized by frontal and posterior cortical/medial temporal atrophy patterns, respectively, which also showed corresponding differences in cognitive characteristics.

[ES] Introducción: Las nuevas tecnologías (NT) están cada vez más presentes en el ámbito biomédico. Utilizando la definición de consenso de NT del Comité Ad-Hoc de Nuevas Tecnologías de la Sociedad Española de Neurología (SEN), se evalúa su impacto en la neurología española a través de las comunicaciones de las reuniones anuales de la SEN. Material y métodos: Se define el concepto de NT en neurología como una tecnología novedosa o aplicación de una tecnología anterior, caracterizada por un cierto grado de coherencia persistente en el tiempo, con potencial de tener impacto en el presente y futuro de la neurología. Se plantea un estudio descriptivo tomando como fuente las comunicaciones de las reuniones de la SEN desde 2012 hasta 2018 y analizando los tipos de NT empleadas, la subespecialidad, así como su distribución territorial. Resultados: De las 8.139 comunicaciones presentadas, 299 estaban relacionadas con NT (3,7%), incluyendo 120 pósteres y 179 comunicaciones orales, variando desde el 1,6% en 2012 hasta el 6,8% en 2018. Los tipos de tecnología mayormente representados fueron neuroimagen avanzada (24,7%), biosensores (17,1%), electrofisiología y neuroestimulación (14,7%) y telemedicina (13,7%). Las áreas neurológicas con mayor empleo de NT fueron trastornos del movimiento (18,4%), enfermedades cerebrovasculares (15,7%) y demencias (13,4%). Madrid fue la comunidad que presentó más comunicaciones (32,8%), seguida por Cataluña (26,8%) y Andalucía (9,0%). Conclusiones: Las comunicaciones sobre NT siguen una tendencia creciente. El número de NT empleadas ha ido aumentando de manera paralela a la disponibilidad tecnológica. Se encontraron comunicaciones en todas las subespecialidades neurológicas, con una distribución geográfica heterogénea., [EN] Introduction: New technologies (NT) are increasingly widespread in biomedicine. Using the consensus definition of NT established by the New Technologies Ad-Hoc Committee of the Spanish Society of Neurology (SEN), we evaluated the impact of these technologies on Spanish neurology, based on communications presented at Annual Meetings of the SEN. Material and methods: We defined the concept of NT in neurology as a novel technology or novel application of an existing technology, characterised by a certain degree of coherence persisting over time, with the potential to have an impact on the present and/or future of neurology. We conducted a descriptive study of scientific communications presented at the SEN's annual meetings from 2012 to 2018, analysing the type of NT, the field of neurology, and the geographical provenance of the studies. Results: We identified 299 communications related with NT from a total of 8,139 (3.7%), including 120 posters and 179 oral communications, ranging from 1.6% of all communications in 2012 to 6.8% in 2018. The technologies most commonly addressed were advanced neuroimaging (24.7%), biosensors (17.1%), electrophysiology and neurostimulation (14.7%), and telemedicine (13.7%). The neurological fields where NT were most widely employed were movement disorders (18.4%), cerebrovascular diseases (15.7%), and dementia (13.4%). Madrid was the region presenting the highest number of communications related to NT (32.8%), followed by Catalonia (26.8%) and Andalusia (9.0%). Conclusions: The number of communications addressing NT follows an upward trend. The number of NT used in neurology has increased in parallel with their availability. We found scientific communications in all neurological subspecialties, with a heterogeneous geographical distribution.

Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regio

[Background] Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive., [Objective] To characterize the cortical structural correlates of homocysteine levels in PD., [Methods] From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample., [Results] A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = −2.2, p = 0.03), correlating in turn with cognitive performance (r = −0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected)., [Conclusions] Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.

[Background and purpose] Impulse control disorders (ICDs) are frequent in Parkinson’s disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD., [Methods] We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease for ICDs screening. Motor, nonmotor, and treatment‐related features were evaluated according to the presence of ICDs. Twenty‐one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs., [Results] Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical–genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms., [Conclusions] Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient’s genetic background to identify individuals at risk for ICDs.

[Background] The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is a well-established inflammatory marker, but its role in Parkinson's disease (PD) remains unclear., [Objectives] To determine whether a different peripheral immune profile and NLR were present in PD patients., [Methods] We conducted a case–control study that included 377 PD patients and 355 healthy controls (HCs). Leukocytes, subpopulations, and the NLR were measured. Multivariate linear regression analyses were applied to determine the differences between groups and the association between NLR and clinical characteristics in PD. A meta-analysis was performed to clarify the association between NLR and PD., [Results] In our case–control study, the NLR was significantly higher in PD patients compared with HCs (2.47 ± 1.1 vs. 1.98 ± 0.91, P < 0.001). No association between NLR and age at onset, disease severity, or disease duration was found. The meta-analysis showed that the NLR was likely to be higher in PD patients., [Conclusions] PD patients had an altered peripheral immune profile and a higher NLR compared with HCs. © 2021 International Parkinson and Movement Disorder Society

[Introduction] We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia., [Methods] The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models., [Results] Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02)., [Conclusions] Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum., [Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis., [Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time., [Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Brain cholesterol metabolism has been described as altered in Parkinson’s disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson’s disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose.

[Introduction] Both recessive and dominant genetic forms of Parkinson’s disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson’s disease in a cohort from central Spain., [Methods/patients] We analyzed a cohort of 117 unrelated patients with early onset Parkinson’s disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson’s disease and other Parkinsonisms and CNV screening., [Results] Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes., [Conclusions] Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson’s disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson’s disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson’s disease.

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. Objectives: To perform the largest PD genome-wide association study restricted to a single country. Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.

[Introduction] Oxidative stress plays a key role in Parkinson's disease (PD) etiopathology. Heme oxygenase, an important enzyme which regulates oxidative balance, converts heme molecules into carbon monoxide, iron and biliverdin/bilirubin. The role of bilirubin has not been fully studied in PD, showing controversial results over the last few decades. Our aim was to investigate the relationship between bilirubin levels and PD. Secondly, we sought to evaluate the link between bilirubin concentration with PD progression, severity and dopaminergic treatment., [Methods] We included 420 PD patients (56% males, mean age: 64 ± 12 years) and 435 healthy controls (47% males, mean age: 58 ± 17 years). Bilirubin levels in both groups were compared using linear regression and multivariate analysis adjusted according to age and sex. Secondly, a case study with the PD cohort was carried out and bilirubin levels were correlated with current treatment, duration and severity of disease., [Results] Bilirubin levels were significantly higher in PD patients than in controls (PD: 0.56 ± 0.26 mg/dl, controls: 0.45 ± 0.22 mg/dl; p < 0.001). In PD patients, we demonstrated a negative correlation between bilirubin levels and disease duration (p < 0.05). Higher bilirubin concentrations were identified in PD patients with Hoehn & Yahr stage ≤3. No relationship between bilirubin and treatment was found in PD patients., [Conclusions] Increased bilirubin levels are particularly related to the first years of PD. Overexpression of oxidative enzymes could play an important role in PD etiology, leading to higher bilirubin levels in the early stages of PD.

The present study focuses on sexual recidivism displayed in a group of 43 incarcerated sexual aggressors in Madrid (Spain). Two groups were analyzed: the control group, comprising 21 inmates who received no treatment in the “control of sexual aggression” program (CAS, in Spanish), and the experimental group (comprising 22 inmates), who were receiving treatment in this program. Results showed that the experimental group had a lower recidivism rate than the control group (13% vs. 4.5%). Only 7 inmates had at least one occurrence of recidivism and only one was in treatment. Only three inmates carried out sexual recidivism. Lastly, practical considerations are discussed., El presente estudio se ha centrado en el estudio de la reincidencia sexual en una población de 43 agresores sexuales recluidos en un Centro Penitenciario de Madrid (España). Se analizaron dos grupos: el grupo control, compuesto por 21 internos que no estaban bajo tratamiento en el programa de “Control de la Agresión Sexual” (CAS), y el grupo experimental, compuesto por 22 internos, que sí estaban bajo este tratamiento. Los resultados mostraron que el grupo experimental tuvo una reincidencia menor que el grupo control (13% vs. 4,5%). De 43 sujetos, sólo 7 reincidieron y únicamente uno estaba en tratamiento. Es de destacar que sólo 3 sujetos tuvieron una reincidencia de tipo sexual. Finalmente, se discuten algunas implicaciones prácticas de estudio.