Speech impairment in Parkinson’s disease: acoustic analysis of unvoiced consonants in Italian native speakers

The study of the influence of Parkinson’s Disease (PD) on vocal signals has received much attention over the last decades. Increasing interest has been devoted to articulation and acoustic characterization of different phonemes. Method: In this study we propose the analysis of the Transition Regions (TR) of specific phonetic groups to model the loss of motor control and the difficulty to start/stop movements, typical of PD patients. For this purpose, we extracted 60 features from pre-processed vocal signals and used them as input to several machine learning models. We employed two data sets, containing samples from Italian native speakers, for training and testing. The first dataset - 28 PD patients and 22 Healthy Control (HC) - included recordings in optimal conditions, while in the second one - 26 PD patients and 18 HC- signals were collected at home, using non-professional microphones. Results: We optimized two support vector machine models for the application in controlled noise conditions and home environments, achieving 98% ± 1.1 and 88% ± 2.8 accuracy in 10-fold cross-validation, respectively. Conclusion: This study confirms the high capability of the TRs to discriminate between PD patients and healthy controls, and the feasibility of automatic PD assessment using voice recordings. Moreover, the promising performance of the implemented model discloses the option of voice processing using low-cost devices and domestic recordings, possibly self-managed by the patients themselves

Deep Brain Stimulation Selection Criteria for Parkinson’s Disease: Time to Go beyond CAPSIT-PD

Despite being introduced in clinical practice more than 20 years ago, selection criteria for deep brain stimulation (DBS) in Parkinson’s disease (PD) rely on a document published in 1999 called ‘Core Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease’. These criteria are useful in supporting the selection of candidates. However, they are both restrictive and out-of-date, because the knowledge on PD progression and phenotyping has massively evolved. Advances in understanding the heterogeneity of PD presentation, courses, phenotypes, and genotypes, render a better identification of good DBS outcome predictors a research priority. Additionally, DBS invasiveness, cost, and the possibility of serious adverse events make it mandatory to predict as accurately as possible the clinical outcome when informing the patients about their suitability for surgery. In this viewpoint, we analyzed the pre-surgical assessment according to the following topics: early versus delayed DBS; the evolution of the levodopa challenge test; and the relevance of axial symptoms; patient-centered outcome measures; non-motor symptoms; and genetics. Based on the literature, we encourage rethinking of the selection process for DBS in PD, which should move toward a broad clinical and instrumental assessment of non-motor symptoms, quantitative measurement of gait, posture, and balance, and in-depth genotypic and phenotypic characterization

Conserved presence of G-quadruplex forming sequences in the Long Terminal Repeat Promoter of Lentiviruses

G-quadruplexes (G4s) are secondary structures of nucleic acids that epigenetically regulate cellular processes. In the human immunodeficiency lentivirus 1 (HIV-1), dynamic G4s are located in the unique viral LTR promoter. Folding of HIV-1 LTR G4s inhibits viral transcription; stabilization by G4 ligands intensifies this effect. Cellular proteins modulate viral transcription by inducing/unfolding LTR G4s. We here expanded our investigation on the presence of LTR G4s to all lentiviruses. G4s in the 5'-LTR U3 region were completely conserved in primate lentiviruses. A G4 was also present in a cattle-infecting lentivirus. All other non-primate lentiviruses displayed hints of less stable G4s. In primate lentiviruses, the possibility to fold into G4s was highly conserved among strains. LTR G4 sequences were very similar among phylogenetically related primate viruses, while they increasingly differed in viruses that diverged early from a common ancestor. A strong correlation between primate lentivirus LTR G4s and Sp1/NF\u3baB binding sites was found. All LTR G4s folded: their complexity was assessed by polymerase stop assay. Our data support a role of the lentiviruses 5'-LTR G4 region as control centre of viral transcription, where folding/unfolding of G4s and multiple recruitment of factors based on both sequence and structure may take place

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease

Background and purpose: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. Methods: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. Results: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate. Conclusions: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia

Design of a study to investigate the mechanisms of obstructive sleep apnoea by means of drug-induced sleep endoscopy

Background Obstructive sleep apnoea (OSA) is an independent risk factor of hypertension and cardiovascular diseases. Recurrent episodes of upper airways collapse during sleep causing blood oxygen desaturation, hypercapnia, and micro-arousals, are known to activate the sympathetic nervous system (SNS). However, whether changes in the renin-angiotensin-aldosterone system and endothelial activation also occur remains contentious. Methods Based on routine use of drug-induced sleep endoscopy (DISE) for the work-up of OSA patients in our centre, we designed a prospective study to investigate the haemodynamic and humoral changes occurring during the apnoeic episodes reproduced in vivo in the course of DISE. Specifically, plasma aldosterone concentration and renin activity, C-terminal fragment of proendothelin-1, as a marker of endothelial damage, and free plasma catecholamines, will be measured at fixed times during DISE. The activity of catechol-O-methyltransferase (COMT), a key catecholamine-inactivating enzyme that has been scantly investigated thus far owing to the lack of commercially available kits, will be also determined by a newly developed high performance liquid chromatography method, which is herein described. Results and conclusions The aim of this study is to provide novel information on the haemodynamic, hormonal, and SNS changes, and also on COMT activity modification concomitantly occurring during apnoea, thus contributing substantively to the understanding of the pathophysiology of OSA

G-Quadruplex Visualization in Cells via Antibody and Fluorescence Probe

G-quadruplexes (G4s) are noncanonical nucleic acids structures involved in key regulatory and pathological roles in eukaryotes, prokaryotes, and viruses: the development of specific antibodies and fluorescent probes represent an invaluable tool to understand their biological relevance. We here present three protocols for the visualization of G4s in cells, both uninfected and HSV-1 infected, using a specific antibody and a fluorescent G4 ligand, and the effect of the fluorescent ligand on a G4 binding protein, nucleolin, upon binding of the molecule to the nucleic acids structure

Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms

With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2,000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in-vitro-expanded CD3+ T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG, and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest DIPSS-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing an NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score

Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort

Background: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. Objective: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. Methods: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. Results: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms. At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. Conclusions: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up