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.

Striatal Dopamine Deficit and Motor Impairment in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. OBJECTIVES: To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. METHODS: We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123 I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. RESULTS: A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. CONCLUSIONS: Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.

GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson's Disease.

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson's disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal-lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.

PSEN1 Compound Heterozygous Mutations Associated with Cerebral Amyloid Angiopathy and Cognitive Decline Phenotype.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aß) aggregates. Aß aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS. Both mutations altered the presenilin 1 protein, truncating its C-terminal portion. This is the first case of CAA and cognitive decline caused by two compound mutations in PSEN1. With this report, we suggest extending the genetic analysis to PSEN1 when cerebral microbleeds are observed by MRI investigation in a patient affected by presenile cognitive decline.

Different miRNA Profiles in Plasma Derived Small and Large Extracellular Vesicles from Patients with Neurodegenerative Diseases.

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.

Substantia Nigra Volumetry with 3-T MRI in De Novo and Advanced Parkinson Disease.

Background Magnetization transfer-prepared T1-weighted MRI can depict a hyperintense subregion of the substantia nigra involved in the degeneration process of Parkinson disease. Purpose To evaluate quantitative measurement of substantia nigra volume by using MRI to support clinical diagnosis and staging of Parkinson disease. Materials and Methods In this prospective study, a high-spatial-resolution magnetization transfer-prepared T1-weighted volumetric sequence was performed with a 3-T MRI machine between January 2014 and October 2015 for participants with de novo Parkinson disease, advanced Parkinson disease, and healthy control participants. A reproducible semiautomatic quantification analysis method that entailed mesencephalic intensity as an internal reference was used for hyperintense substantia nigra volumetry normalized to intracranial volume. A general linear model with age and sex as covariates was used to compare the three groups. Results Eighty participants were evaluated: 20 healthy control participants (mean age ± standard deviation, 56 years ± 11; 11 women), 29 participants with de novo Parkinson disease (64 years ± 10; 19 men), and 31 participants with advanced Parkinson disease (60 years ± 9; 16 women). Volumetric measurement of hyperintense substantia nigra from magnetization transfer-prepared T1-weighted MRI helped differentiate healthy control participants from participants with advanced Parkinson disease (mean difference for ipsilateral side, 64 mm3 ± 14, P < .001; mean difference for contralateral side, 109 mm3 ± 14, P < .001) and helped distinguish healthy control participants from participants with de novo Parkinson disease (mean difference for ipsilateral side, 45 mm3 ± 15, P < .01; mean difference for contralateral side, 66 mm3 ± 15, P < .001) and participants with de novo Parkinson disease from those with advanced Parkinson disease (mean difference for ipsilateral side, 20 mm3 ± 13, P = .40; mean difference for contralateral side, 43 mm3 ± 13, P = .004). Conclusion Magnetization transfer-prepared T1-weighted MRI volumetry of the substantia nigra helped differentiate the stages of Parkinson disease. © RSNA, 2020 Online supplemental material is available for this article.

GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort.

BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. OBJECTIVES: We determined the frequency of GBA-related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. METHODS: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. ß-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed. RESULTS: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest ß-glucocerebrosidase activity. CONCLUSIONS: GBA-PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. © 2020 International Parkinson and Movement Disorder Society.

Validation of the Italian version of the PSP Quality of Life questionnaire.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. The use of health-related quality of life (HR-QoL) measures allows assessing changes in health status induced by therapeutic interventions or disease progress in neurodegenerative diseases. The PSP-QoL is a 45-item, self-administered questionnaire designed to evaluate HR-QoL in PSP. METHODS AND RESULTS: Here, the PSP-QoL was translated into Italian and validated in 190 PSP (96 women and 94 men; mean age ± standard deviation, 72 ± 6.5; mean disease duration, 4.2 ± 2.3) patients diagnosed according to the Movement Disorder Society criteria and recruited in 16 third level movement disorders centers participating in the Neurecanet project. The mean PSP-QoL total score was 77.8 ± 37 (physical subscore, 46.5 ± 18.7; mental subscore, 33.6 ± 19.2). The internal consistency was high (Cronbach's alpha = 0.954); corrected item-total correlation was > 0.40 for the majority of items. The significant and moderate correlation of the PSP-QoL with other HR-QoL measures as well as with motor and disability assessments indicated adequate convergent validity of the scale. Gender and geographic location presented a significant impact on the PSP-QoL in our sample with women and patients from the South of Italy scoring higher than their counterparts. CONCLUSION: In conclusion, the Italian version of the PSP-QoL is an easy, reliable and valid tool for assessment of HR-QoL in PSP.

Validation of the Italian version of carers' quality-of-life questionnaire for parkinsonism (PQoL Carer) in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. Caring for a partner or relative who suffers from PSP entails a strenuous and demanding task, usually lasting for years that affects carers' everyday life routines and emotional and social well-being. The 26-item Parkinsonism Carers QoL (PQoL Carer) is a self-administered, concise instrument evaluating the quality of life of caregivers of patients with atypical parkinsonism (both PSP and multiple system atrophy). Here, the PQoL Carer was translated into Italian and validated in 162 carers of PSP patients (54.3% women; mean age (standard deviation), 62.4 (15.4)) diagnosed according to the Movement Disorder Society criteria and recruited in 16 third-level movement disorders centers participating in the Neurecanet project. The mean PQoL total score was 40.66 ± 19.46. The internal consistency was excellent (Cronbach's alpha = 0.941); corrected item-total correlation was > 0.40 for all the items. A correlation with other health-related quality of life measures as well as with behavioral assessments was shown suggesting adequate convergent validity of the scale. PQoL also correlated with patients' severity of disease. The discriminant validity of the scale was evidenced by its capacity to differentiate between carers with varying levels of self-reported health (p < 0.001). In conclusion, the Italian version of the PQoL Carer is an easy, consistent, and valid tool for the assessment of the quality of life in carers of PSP patients.

Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. METHODS: Primary fibroblast cultures were established from skin biopsies. Increased susceptibility to the PD-related toxin rotenone was determined with apoptosis- and necrosis-specific cell death assays. Protein quality control was evaluated assessing the efficiency of the Ubiquitin Proteasome System (UPS) and protein levels of autophagic markers. Changes in cellular bioenergetics were monitored by measuring oxygen consumption and glycolysis-dependent medium acidification. The oxido-reductive status was determined by detecting mitochondrial superoxide production and oxidation levels in proteins and lipids. RESULTS: PD fibroblasts showed higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced UPS function and decreased maximal and rotenone-sensitive mitochondrial respiration. No changes in autophagy and redox markers were detected. CONCLUSIONS: Our study shows that increased susceptibility to rotenone and the presence of proteolytic and bioenergetic deficits that typically sustain the neurodegenerative process of PD can be detected in fibroblasts from idiopathic PD patients. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease.

Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells.

Heterozygous mutations in GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are a major risk factor for sporadic Parkinson's disease (PD). Defective GCase has been reported in fibroblasts of GBA1-mutant PD patients and pharmacological chaperone ambroxol has been shown to correct such defect. To further explore this issue, we investigated GCase and elements supporting GCase function and trafficking in fibroblasts from sporadic PD patients--with or without heterozygous GBA1 mutations--and healthy subjects, in basal conditions and following in vitro exposure to ambroxol. We assessed protein levels of GCase, lysosomal integral membrane protein-2 (LIMP-2), which mediates GCase trafficking to lysosomes, GCase endogenous activator saposin (Sap) C and parkin, which is involved in degradation of defective GCase. We also measured activities of GCase and cathepsin D, which cleaves Sap C from precursor prosaposin. GCase activity was reduced in fibroblasts from GBA1-mutant patients and ambroxol corrected this defect. Ambroxol increased cathepsin D activity, GCase and Sap C protein levels in all groups, while LIMP-2 levels were increased only in GBA1-mutant PD fibroblasts. Parkin levels were slightly increased only in the PD group without GBA1 mutations and were not significantly modified by ambroxol. Our study confirms that GCase activity is deficient in fibroblasts of GBA1-mutant PD patients and that ambroxol corrects this defect. The drug increased Sap C and LIMP-2 protein levels, without interfering with parkin. These results confirm that chemical chaperone ambroxol modulates lysosomal markers, further highlighting targets that may be exploited for innovative PD therapeutic strategies.

Transcranial direct current stimulation (tDCS) of the cortical motor areas in three cases of cerebellar ataxia.

The excitability of the motor areas of the cerebral cortex is reduced in ataxia. Since transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique able to increase the cortical excitability, we assessed the effect of anodal tDCS over the motor cortex in three patients with ataxia. A clinical evaluation, a video-taped SARA rating scale and a gait analysis with cinematic parameters, were performed pre- and post-sham and anodal tDCS cycle. The full cycle was composed by five consecutive constant current sessions of stimulation. Anodal tDCS (2.0 mA, 20 min,max current density: 0.0278 mA/cm2, max total charge:0.033 C/cm2) was performed on the M1 area of the most affected side. The contralateral primary motor cortex underwent cathodal stimulation (2.0 mA, 20 min, max current density:0.0278 mA/cm2, max total charge: 0.033 C/cm2). After anodal tDCS, gait analysis revealed an improvement of the symmetry of step execution and reduction of base-width lasting 30 days associated to patients' perception of amelioration. No relevant changes were found after sham stimulation. Our results suggest tDCS can improve gait symmetry in patients with ataxia for a short-term period. Future researches are needed in order to standardize time, amplitude, and area of stimulation in order to reach a long lasting effect on cerebellar ataxia.

Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies.

Knowledge of sleep architecture and disorders of nocturnal sleep in dementia with Lewy bodies (DLB) is limited by a lack of systematic video-polysomnographic (video-PSG) investigations. We describe video-PSG findings in 29 consecutive subjects diagnosed with DLB. All the patients underwent a clinical interview and overnight video-PSG monitoring. Twenty-nine nondemented patients with Parkinson's disease (PD) matched for age and sex with the DLB cases were selected for comparison. The DLB subjects showed less 1NREM sleep (P = .000) and more 2NREM sleep (P = .000) than the PD subjects. Sleep apnea (30.7% vs. 34.8%) and periodic limb movements (60.9% versus 50.0%) were frequent in both groups. Disruptive motor behavioral manifestations were more frequent in subjects with DLB (69.6% vs. 26.9%, P = .008) and consisted of not only REM sleep behavior disorder (RBD) but also confusional events (30.3% vs. 3.8%, P = .020) and arousal-related episodes mimicking RBD. Subjects with DLB in whom a sleep disturbance had been the presenting symptom performed better than those with other onset symptoms on both the Mini-Mental State Examination (22.2 ± 4.1 vs. 18.1 ± 4.6, P = .019) and the Frontal Assessment Battery (15.8 vs. 10.3, P = .010). Polysomnographic findings in DLB show a complex mix of overlapping sleep alterations: impaired sleep structure, sleep comorbidities, and various motor-behavioral events (not restricted to RBD). Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities, and consider performing polysomnographic sleep investigations in selected cases. We found evidence that a sleep disturbance as the presenting symptom might indicate a different phenotype of the disease, characterized by milder cognitive impairment.

The effects of levodopa and deep brain stimulation on subthalamic local field low-frequency oscillations in Parkinson's disease.

New adaptive systems for deep brain stimulation (DBS) could in the near future optimize stimulation settings online so as to achieve better control over the clinical fluctuations in Parkinson's disease (PD). Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) in PD patients show that levodopa and DBS modulate STN oscillations. Because previous research has shown that levodopa and DBS variably influence beta LFP activity (8-20 Hz), we designed this study to find out how they affect low-frequency (LF) oscillations (2-7 Hz). STN LFPs were recorded in 19 patients with PD during DBS, after levodopa medication, and during DBS and levodopa intake combined. We investigated the relationship between LF modulations, DBS duration and levodopa intake. We also studied whether LF power depended on disease severity, the patient's clinical condition and whether LF modulations were related to electrode impedances. LF power increased during DBS, after levodopa intake and under both experimental conditions combined. The LF power increase correlated with the levodopa-induced clinical improvement and the higher the electrode impedance, the greater was the LF power change. These data suggest that the LF band could be useful as a control neurosignal for developing novel adaptive DBS systems for patients with PD.

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an 'Official MDS translation,' the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case-Control Study.

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches. Objectives: To estimate LED of safinamide 50 and 100 mg. Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg (N = 130), safinamide 50 mg (N = 144), or rasagiline 1 mg (N = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B (N = 129). Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED. Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings.

Pisa syndrome in Parkinson's disease: clinical, electromyographic, and radiological characterization.

Abnormal postures of the trunk are a typical feature of Parkinson's disease (PD). These include Pisa syndrome (PS), a tonic lateral flexion of the trunk associated with slight rotation along the sagittal plane. In this study we describe clinical, electromyographic (EMG), and radiological features of PS in a group of 20 PD patients. All patients with trunk deviation underwent EMG and radiological (RX and CT scan) investigation. Clinical characteristics of patients with PS were compared with a control group of PD patients without trunk deviation. PD patients with PS showed a significantly higher score of disease asymmetry compared with the control group. In the majority of patients with PS, trunk bending was contralateral to the side of symptom onset. EMG showed abnormal tonic hyperactivity on the side of the deviation in the paravertebral thoracic muscles and in the abdominal oblique muscles. CT of the lumbar paraspinal muscles showed muscular atrophy more marked on the side of the deviation, with a craniocaudal gradient. PS may represent a complication of advanced PD in a subgroup of patients who show more marked asymmetry of disease and who have detectable hyperactivity of the dorsal paravertebral muscles on the less affected side. This postural abnormality deserves attention and proper early treatment to prevent comorbidities and pain.

Diagnostic accuracy of quantitative susceptibility mapping in multiple system atrophy: The impact of echo time and the potential of histogram analysis.

The non-invasive quantification of iron stores via Quantitative Susceptibility Mapping (QSM) could play an important role in the diagnosis and the differential diagnosis of atypical Parkinsonisms. However, the susceptibility (χ) values measured via QSM depend on echo time (TE). This effect relates to the microstructural organization within the voxel, whose composition can be altered by the disease. Moreover, pathological iron deposition in a brain area may not be spatially uniform, and conventional Region of Interest (ROI)-based analysis may fail in detecting alterations. Therefore, in this work we evaluated the impact of echo time on the diagnostic accuracy of QSM on a population of patients with Multiple System Atrophy (MSA) of either Parkinsonian (MSAp) or cerebellar (MSAc) phenotypes. In addition, we tested the potential of histogram analysis to improve QSM classification accuracy. We enrolled 32 patients (19 MSAp and 13 MSAc) and 16 healthy controls, who underwent a 7T MRI session including a gradient-recalled multi-echo sequence for χ mapping. Nine histogram features were extracted from the χ maps computed for each TE in atlas-based ROIs covering deep brain nuclei, and compared among groups. Alterations of susceptibility distribution were found in the Putamen, Substantia Nigra, Globus Pallidus and Caudate Nucleus for MSAp and in the Substantia Nigra and Dentate Nucleus for MSAc. Increased iron deposition was observed in a larger number of ROIs for the two shortest TEs and the standard deviation, the 75th and the 90th percentile were the most informative features yielding excellent diagnostic accuracy with area under the ROC curve > 0.9. In conclusion, short TEs may enhance QSM diagnostic performances, as they can capture variations in rapidly-decaying contributions of high χ sources. The analysis of histogram features allowed to reveal fine heterogeneities in the spatial distribution of susceptibility alteration, otherwise undetected by a simple evaluation of ROI χ mean values.

Extracellular Vesicles Derived From Plasma of Patients With Neurodegenerative Disease Have Common Transcriptomic Profiling.

OBJECTIVES: There is a lack of effective biomarkers for neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia. Extracellular vesicle (EV) RNA cargo can have an interesting potential as a non-invasive biomarker for NDs. However, the knowledge about the abundance of EV-mRNAs and their contribution to neurodegeneration is not clear. METHODS: Large and small EVs (LEVs and SEVs) were isolated from plasma of patients and healthy volunteers (control, CTR) by differential centrifugation and filtration, and RNA was extracted. Whole transcriptome was carried out using next generation sequencing (NGS). RESULTS: Coding RNA (i.e., mRNA) but not long non-coding RNAs (lncRNAs) in SEVs and LEVs of patients with ALS could be distinguished from healthy CTRs and from other NDs using the principal component analysis (PCA). Some mRNAs were found in commonly deregulated between SEVs of patients with ALS and frontotemporal dementia (FTD), and they were classified in mRNA processing and splicing pathways. In LEVs, instead, one mRNA and one antisense RNA (i.e., MAP3K7CL and AP003068.3) were found to be in common among ALS, FTD, and PD. No deregulated mRNAs were found in EVs of patients with AD. CONCLUSION: Different RNA regulation occurs in LEVs and SEVs of NDs. mRNAs and lncRNAs are present in plasma-derived EVs of NDs, and there are common and specific transcripts that characterize LEVs and SEVs from the NDs considered in this study.

A multinational consensus on dysphagia in Parkinson's disease: screening, diagnosis and prognostic value.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. OBJECTIVE: To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: Eighty-five papers were used to inform the Panel's statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. CONCLUSIONS: The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.