Brainstem neuromelanin and iron MRI reveals a precise signature for idiopathic and LRRK2 Parkinson's disease.

Neuromelanin (NM) loss in substantia nigra pars compacta (SNc) and locus coeruleus (LC) reflects neuronal death in Parkinson's disease (PD). Since genetically-determined PD shows varied clinical expressivity, we wanted to accurately quantify and locate brainstem NM and iron, to discover whether specific MRI patterns are linked to Leucine-rich repeat kinase 2 G2019S PD (LRRK2-PD) or idiopathic Parkinson's disease (iPD). A 3D automated MRI atlas-based segmentation pipeline (3D-ABSP) for NM/iron-sensitive MRI images topographically characterized the SNc, LC, and red nucleus (RN) neuronal loss and calculated NM/iron contrast ratio (CR) and normalized volume (nVol). Left-side NM nVol was larger in all groups. PD had lower NM CR and nVol in ventral-caudal SNc, whereas iron increased in lateral, medial-rostral, and caudal SNc. The SNc NM CR reduction was associated with psychiatric symptoms. LC CR and nVol discriminated better among subgroups: LRRK2-PD had similar LC NM CR and nVol as that of controls, and larger LC NM nVol and RN iron CR than iPD. PD showed higher iron SNc nVol than controls, especially among LRRK2-PD. ROC analyses showed an AUC > 0.92 for most pairwise subgroup comparisons, with SNc NM being the best discriminator between HC and PD. NM measures maintained their discriminator power considering the subgroup of PD patients with less than 5 years of disease duration. The SNc iron CR and nVol increase was associated with longer disease duration in PD patients. The 3D-ABSP sensitively identified NM and iron MRI patterns strongly correlated with phenotypic PD features.

Increased Phospho-AKT in Blood Cells from LRRK2 G2019S Mutation Carriers.

The purpose of this study was to investigate whether  differential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). We assessed phospho(P)-Ser-935-LRRK2 and P-Ser-473-AKT levels in peripheral blood cells from patients with G2019S LRRK2-associated PD (L2PD, n = 31), G2019S LRRK2 non-manifesting carriers (L2NMC, n = 26), idiopathic PD (iPD, n = 25), and controls (n = 40, total n = 122). We found no differences at P-Ser-935-LRRK2 between groups but detected a specific increase of P-Ser-473-AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD. Although insensitive to LRRK2 inhibition, our study identifies P-Ser-473-AKT as an endogenous candidate biomarker for peripheral inflammation in G2019S carriers using accessible blood cells. ANN NEUROL 2022;92:888-894.

Utility of Postoperative Imaging Software for Deep Brain Stimulation Targeting in Patients with Movement Disorders.

OBJECTIVE: The objective of this study was to evaluate the accuracy of the SureTune3 postoperative imaging software in determining the location of a deep brain stimulation (DBS) electrode based on clinical outcomes and the adverse effects (AEs) observed. METHODS: Twenty-six consecutive patients with Parkinson disease (n = 17), essential tremor (n = 8), and dystonia (n = 1) who underwent bilateral DBS surgery (52 electrodes) were included in this study. Presurgical assessments were performed in all patients prior to surgery and at 3 and 6 months after surgery, using quality-of-life and clinical scales in each case. The SureTune3 software was used to evaluate the anatomical positioning of the DBS electrodes. RESULTS: Following DBS surgery, motor and quality-of-life improvement was observed in all patients. Different AEs were detected in 12 patients, in 10 of whom (83.3%) SureTune3 related the symptoms to the positioning of an electrode. A clinical association was observed with SureTune3 for 48 of 52 (92.3%) electrodes, whereas no association was found between the AEs or clinical outcomes and the SureTune3 reconstructions for 4 of 52 electrodes (7.7%) from 4 different patients. In 2 patients, the contact chosen was modified based on the SureTune3 data, and in 2 cases, the software helped determine that second electrode replacement surgery was necessary. CONCLUSIONS: The anatomical position of electrodes analyzed with SureTune3 software was strongly correlated with both the AEs and clinical outcomes. Thus, SureTune3 may be useful in clinical practice, and it could help improve stimulation parameters and influence decisions to undertake electrode replacement surgery.

Peripheral insulin and amylin levels in Parkinson's disease.

BACKGROUND: Type-2-diabetes (T2D) has surfaced as a potential risk factor for Parkinson's disease (PD) in some epidemiological studies. Evidence of glucose metabolism alterations in PD from molecular studies remains conflicting. Amylin, the T2D amyloid protein, has been implicated in PD in pathological studies. We aimed to assess peripheral levels of amylin and insulin in PD patients and control subjects (Cs). METHODS: We conducted an observational cross-sectional study of 111 participants: 73 PD and 38 Cs, similar in age, sex and body mass index. All underwent motor (UPDRS-MDS-III), non-motor (NMSS) and cognitive (MDRS) scales as well as determination of four parameters: fasting glycaemia, glycated haemoglobin, fasting plasma insulin (FPI) and fasting plasma amylin (FPA). RESULTS: FPI was significantly lower in PD than Cs (p = 0.034). In participants with age above cohort-median-age, FPA was higher in PD than Cs (p = 0.046). The FPA/FPI ratio (FPAIR) was significantly higher in PD than Cs (p = 0.024). In PD, modest correlation was found between higher insulin-resistance and NMSS scores. CONCLUSIONS: PD patients had lower FPI and increased FPAIR. In older PD subgroup, FPA was increased. The more the insulin resistance, the higher the non-motor scores. These findings provide an additional link between pathophysiology of diabetes and PD. This might be related to a dissociated insulin and amylin secretion in PD, in line with recent evidence of endocrine pancreas role in PD pathogeny.

Single-Center Complication Analysis Associated with Surgical Replacement of Implantable Pulse Generators in Deep Brain Stimulation.

BACKGROUND/AIMS: Internal pulse generator (IPG) replacement is considered a relatively minor surgery but exposes the deep brain stimulation system to the risk of infectious and mechanical adverse events. We retrospectively reviewed complications associated with IPG replacement surgery in our center and reviewed the most relevant publications on the issue. METHODS: A retrospective analysis of all the IPG replacements performed in our center from January 2003 until March 2018 was performed. A logistic regression model was used to analyze the risk factors associated with IPG infections at our center. RESULTS: A total of 171 IPG replacements in 93 patients were analyzed. The overall rate of replacement complications was 8.8%, whereas the rate of infection was 5.8%. IPG removal was required in 8 out of 10 infected cases. An increased risk of infection was found in patients with subcutaneous thoracic placement of the IPG (OR 5.3, p = 0.016). The most commonly isolated germ was Staphylococcus coagulase negative (60%). We found a non-significant trend towards increased risk of infection in patients with more than 3 replacements (p = 0.07). CONCLUSIONS: Infection is the most frequent complication related to IPG replacement. Staphylococcus coagulase negative is the most commonly isolated bacteria causing the infection. According to our results, the subcutaneous thoracic placement represents a greater risk of infection compared to subcutaneous abdominal placement.

Malignant Glioma Developed on a Patient Under Deep Brain Stimulation: Pitfalls in Management.

BACKGROUND: Glioblastoma (GBM) is the most common aggressive malignant primary brain tumor, rarely concurrent in patients who require deep brain stimulation (DBS) implants. Despite the high incidence of these circumstances alone, the coexistence of both in a patient has been seldom reported. In this paper, we report a case of a patient suffering from a movement disorder treated with DBS who developed a GBM. CASE DESCRIPTION: A patient with bilateral DBS of the globus pallidus internus for refractory secondary dystonia developed a GBM close to the electrode leads, 2.5 years after implantation. The clinical findings, medical management and pitfalls, and possible relationship between the DBS device and the tumor development are discussed. We withdrew the system to perform brain magnetic resonance imaging safely. This revealed an extended lesion that was biopsied. The removal led to a clinical worsening that resulted in fatality, without the possibility of receiving adjuvant treatment. The available literature shows similar management, which depends mainly on the stimulation system used. CONCLUSIONS: We advise the use of magnetic resonance imaging-safe devices; otherwise, we recommend keeping the system and proceeding with computed tomography imaging for diagnostic and management if necessary. The true relationship between chronic DBS stimulation and GBM is to be clarified.

[High risk cytogenetic abnormalities in patients with multiple myeloma]. / Características citogenéticas y detección de anormalidades de alto riesgo en mieloma múltiple.

BACKGROUND: Cytogenetic abnormalities observed in the bone marrow of patients with multiple myeloma (MM) are an important prognostic factor for risk stratification. AIM: To investigate karyotype characteristics and frequency of the high-risk cytogenetic abnormalities t(4;14), t(14;16) and del(17p) in Chilean patients with MM. MATERIAL AND METHODS: We studied 30 patients with MM by conventional cytogenetics (CC) and fluorescent in situ hybridization of plasma cells selected using cytoplasmic immunoglobulin staining (cIg-FISH). RESULTS: Overall, the two techniques in combination allowed us to identify clonal genetic abnormalities in 47% of patients. The t(4;14) abnormality was observed in 19% of patients, del(17p) was observed in 10% of patients, and t(14;16) was not detected. CONCLUSIONS: Our results showed frequencies of high-risk abnormalities similar to those reported abroad. Cytogenetic studies should be performed routinely for all MM patients at the moment of diagnosis.

Unilateral pallidal stimulation for disabling dystonia due to Rasmussen's disease.

OBJECTIVE: To describe an adult patient with Rasmussen's disease with focal dystonia as the most disabling symptom and the good response to unilateral globus pallidus internus (GPi) deep brain stimulation (DBS). METHODS: Retrospective review of clinical records and diagnostic tests. RESULTS: The patient had displayedmild focal seizures with sensory and motor symptoms on the left arm and hemiface since the age of 22. Ten years later she experienced abrupt onset of focal left dystonia involving mainly the leg. Brain MRI showed progressive right hemisphere atrophy, and  18 fluorodeoxyglucose-positron emission tomography (18FDG-PET) showed right hypometabolism mainly over the frontal and insular regions. Brain biopsy confirmed chronic encephalitis. The dystonia became very severe and made walking extremely difficult. Different treatments including dopaminergic, anticholinergic, immunomodulatory drugs and botulinum toxin were ineffective. Finally the patient was treated with unilateral GPi DBS. Shortly after the onset of the stimulation, the dystonia started to improve. Parameters have been adjusted, and 18 months after surgery the patient is able to walk and run unaided, although a mild left leg dystonia persists. CONCLUSION: Rasmussen's disease may be difficult to diagnose in adult patients. Associated movement disorders may be more disabling than seizures. Focal dystonia may be treated successfully with DBS.

Características citogenéticas y detección de anormalidades de alto riesgo en mieloma múltiple / High risk cytogenetic abnormalities in patients with multiple myeloma

Background: Cytogenetic abnormalities observed in the bone marrow of patients with multiple myeloma (MM) are an important prognostic factor for risk stratification. Aim: To investigate karyotype characteristics and frequency of the high-risk cytogenetic abnormalities t(4;14), t(14;16) and del(17p) in Chilean patients with MM. Material and Methods: We studied 30 patients with MM by conventional cytogenetics (CC) and fluorescent in situ hybridization of plasma cells selected using cytoplasmic immunoglobulin staining (cIg-FISH). Results: Overall, the two techniques in combination allowed us to identify clonal genetic abnormalities in 47% of patients. The t(4;14) abnormality was observed in 19% of patients, del(17p) was observed in 10% of patients, and t(14;16) was not detected. Conclusions: Our results showed frequencies of high-risk abnormalities similar to those reported abroad. Cytogenetic studies should be performed routinely for all MM patients at the moment of diagnosis.

Hipercalcemia, peak monoclonal y leucemización como presentación de un linfoma de células B de alto grado, con reordenamiento de MYC, BCL-2 y BCL-6 (Triple Hit). Caso clínico / Hypercalcemia, monoclonal peak and leukemic presentation of a High-grade B-cell lymphoma with MYC, BCL-2 and BCL-6 translocations (triple hit). Report of one case

High-grade B-cell lymphomas with rearrangement of MYC, BCL-2 and/or BCL-6 were introduced by the update of the WHO classification of lymphoid neoplasms. They usually present unique morphological and molecular characteristics, with an aggressive clinical outcome and worse prognosis. We report a 48 year-old female patient presenting with B symptoms and enlarged lymph nodes. Blood count showed pancytopenia and peripheral blood smears showed large lymphoid cells, some with nuclei and vacuoles. LDH was 3524 g/L and serum calcium was 11.5 mg/dL. Flow cytometry immunophenotyping showed pathological mature B lymphocytes. Protein electrophoresis showed a slight monoclonal peak. The biopsy disclosed a triple expressor diffuse large B-cell lymphoma, arising from germinal center. FISH was positive for MYC, BCL-2 and BCL-6 (triple hit) with a clonal evolution. Conventional cytogenetics showed a complex karyotype. Chemotherapy was started with R-CHOP (Rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone). She developed impaired consciousness; the brain CT scan showed a large brain mass. The patient died within 3 weeks.

Environmental tobacco smoke exposure and EGFR and ALK alterations in never smokers' lung cancer. Results from the LCRINS study.

Environmental tobacco smoke (ETS) exposure is a main risk factor of lung cancer in never smokers. Epidermal Growth Factor Receptor (EGFR) mutations and ALK translocations are more frequent in never smokers' lung cancer than in ever-smokers. We performed a multicenter case-control study to assess if ETS exposure is associated with the presence of EGFR mutations and its types and if ALK translocations were related with ETS exposure. All patients were never smokers and had confirmed lung cancer diagnosis. ETS exposure during childhood showed a negative association on the probability of EGRF mutation though not significant. Exposure during adulthood, at home or at workplace, did not show any association with EGFR mutation. The mutation type L858R seemed the most associated with a lower probability of EGFR alterations for ETS exposure at home in adult life. There is no apparent association between ETS exposure and ALK translocation. These results might suggest that ETS exposure during childhood or at home in adult life could influence the EGFR mutations profile in lung cancer in never smokers, reducing the probability of presenting EFGR mutation.

Residential radon, EGFR mutations and ALK alterations in never-smoking lung cancer cases.

The aim of this study was to assess if residential radon exposure might cause EGFR mutations or ALK rearrangements in never-smokers.We designed a multicentre case-control study in a radon-prone area (Galicia, Spain); only lung cancer cases were included in the study. We obtained residential radon measurements and clinical information for all the participants. We compared the median values of residential radon between patients with EGFR mutations or ALK rearrangements versus those without them.323 patients were included. Median age was 70 years and 19.5% were males. 42 and 15% of patients were EGFR- and ALK-positive, respectively. The most frequent EGFR alterations were exon 19 deletions and exon 21 (L858R) single-point substitution mutations. ALK-positive patients were 10 years younger than ALK-negative patients. Residential radon levels were two-fold higher in patients with exon 19 deletions compared with patients with exon 21 (L858R) single-point substitution mutations (216 versus 118 Bq·m-3; p=0.057). There were no differences in residential radon levels by EGFR mutation status. ALK-positive patients (n=12) essentially had two-fold residential radon levels compared with ALK-negative patients (290 versus 164 Bq·m-3, respectively).Residential radon may have a role in the molecular signature of lung cancer in never-smokers, although more studies with larger sample sizes are needed to support this hypothesis.

Small cell lung cancer in never-smokers.

Our aim was to describe the characteristics of a case-series of never-smoker small cell lung cancer (SCLC) cases.Cases of SCLC were selected from a prospective, multicenter, hospital-based case-control study performed in Spain. Participants were never-smokers older than 30 years with an anatomo-pathological confirmation of primary lung cancer. We collected clinical and epidemiological variables according to the study's protocol.We included 19 SCLC cases, 18 females (94.7%), median age 75 years (interquartile range (IQR) 70-80 years). Median residential radon concentration was 195 Bq·m(-3) (IQR 130-229 Bq·m(-3)). 10 patients had limited disease and nine had extended disease. Median survival was 242 days (IQR 94-496 days); 1- and 2-year survival were 36.8% and 17.6%, respectively. Survival was much higher for individuals with limited disease than for those with extended disease (median 336 versus 235 days; 1-year survival 50% versus 22.2% and 2-year survival 27% versus 0%, respectively). Performance status at diagnosis was closely related to survival.SCLC is an infrequent, highly aggressive disease in never-smokers. Survival is poor, even for limited disease. Age at diagnosis in SCLC is higher than that observed for never-smokers with adenocarcinoma. Residential radon exposure is higher than the action levels recommended by the World Health Organization.

Alpha-1 Antitrypsin Deficiency and Lung Cancer Risk: A Case-Control Study in Never-Smokers.

BACKGROUND: Never-smokers comprise up to 25% of all lung cancer cases. They could have different molecular pathways for lung cancer induction compared with smokers. Alpha-1 antitrypsin (AAT) deficiency is a hereditary trait whose main characteristic is early onset of lung emphysema. Our aim is to know if AAT-deficient carriers have a higher risk of lung cancer in a study performed exclusively in never-smokers. METHODS: We designed a multicentre hospital-based case-control study, which included incident never-smoking lung cancer cases. Controls were never-smokers attending nonmajor surgery at the participating hospitals. Controls were frequency matched on age and gender with cases. We determined AAT variants (alleles S and Z) through polymerase chain reaction. RESULTS: Two hundred and twelve cases and 318 controls were included. PiSS individuals showed a lung cancer risk of 4.64 (95% confidence interval: 1.08-19.92) compared with those with normal genotype (PiMM). When the analysis was restricted to women, the risk for PiSS increased to 7.58 (95% confidence interval: 1.40-40.87). This risk for homozygous SS was even higher for individuals exposed to environmental tobacco smoke (greater than 20 years). The presence of other alleles did not show any effect on lung cancer risk. CONCLUSIONS: Never smoking SS homozygous individuals pose an increased risk of lung cancer. The risk is higher for individuals exposed to environmental tobacco smoke.

Residential radon and lung cancer characteristics in never smokers.

PURPOSE: The aim of this study is to assess if there is a relationship between residential radon and lung cancer histological types and patients' age at diagnosis. MATERIALS AND METHODS: We conducted a multicenter hospital-based case-control study with eight participating hospitals. We included 216 never-smoking cases with primary lung cancer and 329 never-smoking controls. Controls were frequency matched with cases on age and sex distribution. Of them, 198 cases (91.7%) and 275 controls (83.5%) had residential radon measurements. RESULTS: Lung cancer risk reached statistical significance only for adenocarcinoma (Odds ratio [OR] 2.19; 95% Confidence interval [CI] 1.44-3.33), for other histologies the results were marginally significant. Residential radon level was higher for patients diagnosed before 50 and 60 years old than for older lung cancer cases. CONCLUSIONS: Residential radon in never smokers seems to be a risk factor for all lung cancer histologies. Individuals diagnosed at a younger age have a higher residential radon concentration, suggesting an accumulative effect on lung cancer appearance.

The MC1R melanoma risk variant p.R160W is associated with Parkinson disease.

Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.