Publications by authors named "Micol Avenali"

21 Publications

  • Page 1 of 1

From DYMUS to DYPARK: Validation of a Screening Questionnaire for Dysphagia in Parkinson's Disease.

Dysphagia 2021 Jul 15. Epub 2021 Jul 15.

Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia, Italy.

Dysphagia is a common debilitating symptom in people with Parkinson's Disease (PD), adequate screening of swallowing disorders is fundamental. The DYMUS questionnaire has shown very good characteristics for the screening of dysphagia in Multiple Sclerosis, and it might also prove useful for screening dysphagia in PD. The primary aim was to test and validate the DYMUS questionnaire in PD patients. This is an observational multicentric study involving 103 patients affected by PD. All subjects filled in the DYMUS and the Eating Assessment Tool (EAT-10) questionnaires. A subgroup of patients (n = 53) underwent a fiber-optic endoscopic evaluation of swallowing (FEES) and their dysphagia was scored by means of the Dysphagia Outcome Severity Scale (DOSS). DYMUS showed a relatively high level of internal consistency (Cronbach's alpha 0.79). A significant positive correlation was found between the DYMUS and the EAT-10 scores (p < 0.001), while a negative correlation was found between the DYMUS and the DOSS scores (p < 0.001). DYMUS showed a good sensitivity and specificity compared to FEES for detecting dysphagia (area under the curve: 0.82, p < 0.001). The ROC curve analysis showed that a DYMUS score ≥ 6 represents a reliable cut-off for the risk of dysphagia. The DYMUS questionnaire proved to be a reliable screening tool to detect dysphagia in patients suffering from PD. It is easy to understand, it can be self-administered and therefore adequate for adoption in the clinical practice with the more convenient name of DYPARK.
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http://dx.doi.org/10.1007/s00455-021-10332-1DOI Listing
July 2021

Evaluation of the efficacy of physical therapy on cognitive decline at 6-month follow-up in Parkinson disease patients with mild cognitive impairment: a randomized controlled trial.

Aging Clin Exp Res 2021 May 12. Epub 2021 May 12.

IRCCS Mondino Foundation, Via Mondino 2, 20100, Pavia, Italy.

Background: In Parkinson's disease (PD), physical activity may represent a possible non-pharmacological intervention not only for improving motor symptoms but also for modulating cognitive impairment.

Aims: To evaluate the efficacy of an intensive physical program on cognitive functions in mid-stage PD patients with mild cognitive impairment (PD-MCI) over a 6-month follow-up.

Methods: This is a 6-month randomized controlled follow-up study. 40 PD-MCI patients were randomized to receive physical therapy (PT) or no specific intervention beside drug treatment (CT). Cognitive and motor assessments were performed at baseline (T0), 4 weeks after baseline (T1) and 6 months after T0. In a previous study, we reported a significant improvement in global cognitive functioning and attention/working-memory at T1. Here, we evaluated the residual effect of the training intervention at 6 months on both cognitive and motor performances.

Results: Intra-group analysis showed that at T2 most of cognitive and motor performances remained stable in the PT when compared to T0, while a significant worsening was observed in the CT. Between-group comparison at T2 showed significantly better results in PT than CT as regards MoCA and motor scales. The percentage change of cognitive and motor performances between T1 and T2 confirmed the benefit of physical therapy on global cognitive functioning scores (MMSE and MoCA).

Conclusions: In this follow-up extension of a longitudinal randomized controlled study, we demonstrated that physical therapy has a positive effect on cognitive functions, which extends beyond the duration of the treatment itself to, at least temporarily, reducing cognitive decline.

Trial Registration: Trial registration number (ClinicalTrials.gov): NCT04012086 (9th July 2019).
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http://dx.doi.org/10.1007/s40520-021-01865-4DOI Listing
May 2021

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

Int J Mol Sci 2021 Mar 8;22(5). Epub 2021 Mar 8.

Genomic and post-Genomic Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy.

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.
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http://dx.doi.org/10.3390/ijms22052737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962970PMC
March 2021

Clinical and Electrophysiological Outcome Measures of Patients With Post-Infectious Neurological Syndromes Related to COVID-19 Treated With Intensive Neurorehabilitation.

Front Neurol 2021 12;12:643713. Epub 2021 Mar 12.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

The clinical spectrum of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be quite wide, including neurological symptoms. Among them, para-infectious or post-infectious neurological syndromes (PINS), caused by an inflammatory response against the central and/or peripheral nervous system, have been reported. The aim of this paper is to illustrate the functional and neurophysiological recovery in a series of subjects with COVID-19-related PINS who underwent intensive neurorehabilitation. Five patients with PINS associated with COVID-19 were evaluated at baseline and followed up for 6 months. Three of them had polyradiculoneuropathy and two patients had myelitis. The onset of the neurological syndromes was temporally associated with the SARS-CoV-2 infection. After completing the acute neurological treatments in the intensive care unit, patients underwent a personalized multidisciplinary rehabilitation program. An in-depth clinical, functional, and electrophysiological assessment was carried out at baseline and at 3- and 6-month follow-ups. Among patients with polyradiculoneuropathy, the electrophysiological evaluation at baseline disclosed an acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in two patients and an acute motor and sensory axonal neuropathy (AMSAN) in the third patient. At follow-up, the electrophysiological features improved in one subject with AIDP and were stable in the remaining two cases. The functional assessment after neurorehabilitation showed global recovery and full independence in walking and in activities of daily life in one patient and mild improvement in the other two cases. Of the two subjects with myelitis, the baseline electrophysiological examination showed a prolonged central motor conduction time, which returned to normal in one patient, whereas it improved but remained pathological in the other patient at follow-up. The neurorehabilitation led to a substantial functional improvement in both subjects. This is the first study to describe clinical and electrophysiological aspects along with medium-term outcome in patients with COVID-19-related neurological manifestations who underwent an intensive rehabilitation program. The functional outcome following neurorehabilitation in patients with PINS related to SARS-CoV-2 infection is variable. In our small case series, subjects with polyradiculoneuropathy had a poorer recovery compared to patients with myelitis. The clinical course largely paralleled the follow-up electrophysiological findings.
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http://dx.doi.org/10.3389/fneur.2021.643713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994589PMC
March 2021

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

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy.

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.
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http://dx.doi.org/10.3390/ijms22042215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927041PMC
February 2021

Profiling the Biochemical Signature of GBA-Related Parkinson's Disease in Peripheral Blood Mononuclear Cells.

Mov Disord 2021 05 22;36(5):1267-1272. Epub 2021 Feb 22.

Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Background: GBA mutations are the commonest genetic risk factor for Parkinson's disease (PD) and also impact disease progression.

Objective: The objective of this study was to define a biochemical profile that could distinguish GBA-PD from non-mutated PD.

Methods: 29 GBA-PD, 37 non-mutated PD, and 40 controls were recruited; α-synuclein levels in plasma, exosomes, and peripheral blood mononuclear cells were analyzed, GCase and main GCase-related lysosomal proteins in peripheral blood mononuclear cells were measured.

Results: Assessment of plasma and exosomal α-synuclein levels did not allow differentiation between GBA-PD and non-mutated PD; conversely, measurements in peripheral blood mononuclear cells clearly distinguished GBA-PD from non-mutated PD, with the former group showing significantly higher α-synuclein levels, lower GCase activity, higher LIMP-2, and lower Saposin C levels.

Conclusion: We propose peripheral blood mononuclear cells as an easily accessible and manageable model to provide a distinctive biochemical profile of GBA-PD, potentially useful for patient stratification or selection in clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247888PMC
May 2021

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism.

Brain 2020 10;143(10):3041-3051

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

There is increasing evidence for a role of inflammation in Parkinson's disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson's disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson's disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson's disease patients. These results highlight the potential of IL6 as progression marker in Parkinson's disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson's disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson's disease and Parkinson's disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson's disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson's disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson's disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson's disease, at least in this subset of patients.
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http://dx.doi.org/10.1093/brain/awaa246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586086PMC
October 2020

KCTD17-related myoclonus-dystonia syndrome: clinical and electrophysiological findings of a patient with atypical late onset.

Parkinsonism Relat Disord 2020 09 6;78:129-133. Epub 2020 Aug 6.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Myoclonus-dystonia is a rare syndrome typically occurring during childhood or adolescence, mainly due to SGCE pathogenic variants. Early-onset, atypical presentations of myoclonus-dystonia have recently been associated with KCTD17 variants. In these cases, laryngeal involvement was reported in the advanced stages.

Methods: We evaluated a 52-year-old man with myoclonus-dystonia and positive family history. He underwent an electromyographic investigation of vocal cord and forearm muscles. Whole-exome sequencing was also performed.

Results: Onset of symptoms was at 51 years with dysphonia and vocal tremor. Electromyography disclosed abductor spasmodic dysphonia and laryngeal myoclonus. The patient later developed writer's cramp, upper limb myoclonus, and blepharospasm. Botulinum toxin injection led to improvement of the writer's cramp and to a lesser extent of the spasmodic dysphonia. Genetic analysis identified a heterozygous missense variant in exon 2 of KCTD17: c.229 C > A (p.Leu77Ile), consistently predicted as damaging.

Conclusions: We suggest that the KCTD17-associated phenotypic spectrum may include late onset (even in late adulthood) as well as early and prominent laryngeal involvement.
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http://dx.doi.org/10.1016/j.parkreldis.2020.07.026DOI Listing
September 2020

Reproducibility and reaction time of swallowing as markers of dysphagia in parkinsonian syndromes.

Clin Neurophysiol 2020 09 9;131(9):2200-2208. Epub 2020 Jul 9.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Pavia, Italy.

Objective: To investigate reproducibility and reaction time of oropharyngeal swallowing in patients with Parkinson's disease (PD) and atypical parkinsonisms (APs).

Methods: We enrolled 19 patients with PD, 30 with APs, and 20 healthy subjects. Presence and severity of dysphagia were assessed with clinical and fiberoptic endoscopic evaluations of swallowing. Reproducibility of the oral and pharyngeal phases of swallowing were respectively assessed by calculating the 'similarity index' of the electromyography activity of the submental/suprahyoid muscles and of the laryngeal-pharyngeal mechanogram during consecutive swallows. These were performed both 'on command' and spontaneously. The swallowing reaction time was also recorded.

Results: Reproducibility of the oral phase of swallowing was reduced in patients with dysphagia, mainly when swallowing 'on command'. Swallowing reaction time was prolonged in dysphagic patients. These electrophysiological parameters did not vary among different parkinsonian syndromes and correlated with dysphagia severity.

Conclusions: Increased variability of oral swallowing automatisms and abnormal sensorimotor integration may be of relevance for the pathophysiology of dysphagia in parkinsonian syndromes.

Significance: The electrophysiological assessment represents a valuable tool to investigate swallowing alterations in parkinsonian syndromes. It may also provide useful insights into clinical severity and pathophysiology of dysphagia, giving clues for the choice of the best therapeutic approach.
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http://dx.doi.org/10.1016/j.clinph.2020.06.018DOI Listing
September 2020

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

Mov Disord 2020 11 13;35(11):2106-2111. Epub 2020 Jul 13.

Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy.

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. β-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 β-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.
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http://dx.doi.org/10.1002/mds.28195DOI Listing
November 2020

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson's Disease.

Front Aging Neurosci 2020 21;12:97. Epub 2020 Apr 21.

Laboratory of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation, Pavia, Italy.

Heterozygous mutations of the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), occur in a considerable percentage of all patients with sporadic Parkinson's disease (PD), varying between 8% and 12% across the world. Genome wide association studies have confirmed the strong correlation between PD and GBA1 mutations, pointing to this element as a major risk factor for PD, possibly the most important one after age. The pathobiological mechanisms underlying the link between a defective function of GCase and the development of PD are still unknown and are currently the focus of intense investigation in the community of pre-clinical and clinical researchers in the PD field. A major controversy regards the fact that, despite the unequivocal correlation between the presence of GBA1 mutations and the risk of developing PD, only a minority of asymptomatic carriers with GBA1 mutations convert to PD in their lifetime. GBA1 mutations reduce the enzymatic function of GCase, impairing lysosomal efficiency and the cellular ability to dispose of pathological alpha-synuclein. Changes in the cellular lipidic content resulting from the accumulation of glycosphingolipids, triggered by lysosomal dysfunction, may contribute to the pathological modification of alpha-synuclein, due to its ability to interact with cell membrane lipids. Mutant GCase can impair mitochondrial function and cause endoplasmic reticulum stress, thereby impacting on cellular energy production and proteostasis. Importantly, reduced GCase activity is associated with clear activation of microglia, a major mediator of neuroinflammatory response within the brain parenchyma, which points to neuroinflammation as a major consequence of GCase dysfunction. In this present review article, we summarize the current knowledge on the role of GBA1 mutations in PD development and their phenotypic correlations. We also discuss the potential role of the GCase pathway in the search for PD biomarkers that may enable the development of disease modifying therapies. Answering these questions will aid clinicians in offering more appropriate counseling to the patients and their caregivers and provide future directions for PD preclinical research.
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http://dx.doi.org/10.3389/fnagi.2020.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186450PMC
April 2020

Proprioceptive Focal Stimulation (Equistasi®) May Improve the Quality of Gait in Middle-Moderate Parkinson's Disease Patients. Double-Blind, Double-Dummy, Randomized, Crossover, Italian Multicentric Study.

Front Neurol 2019 18;10:998. Epub 2019 Sep 18.

Parkinson Excellence Center of the Fresco Institute for Italy, Villa Margherita Clinic of Vicenza, Vicenza, Italy.

The object of the study was to evaluate the efficacy of Proprioceptive Focal Stimulation on Gait in middle-advanced Parkinson (PD) patients by a crossover, randomized, double Blind double dummy study using Equistasi®, a nano-technological device of the dimension of a plaster which generates High Frequency Vibration (FV). The efficacy of Gait Analysis (GA) on evaluating gait modification on Parkinson's disease (PD) Patients is already well-known. Therefore, GA was recorded in a group of PD patients using Equistasi® device and its placebo. Forty PD patients on optimal therapy were enrolled in the study. Patients were randomly assigned to receive active or sham stimulation for 8 weeks and, following a wash-out period, switched to an additional 8-week period with the reverse intervention. GA was performed at baseline and at the end of both 8-weeks treatment periods Clinical state was monitored by MDUPDRS part III. Active stimulation induced a significant improvement in Mean Velocity (Velocity), Stride Length (SL), Stance (STA), and Double Support (DST) percentage, both in left and right stride. The ANOVA analysis using H&Y stage as a factor, showed that DST and MDUPDRS III scores improved significantly more in the more severely affected subjects. The findings obtained in this randomized controlled study show the efficacy of mechanical focal vibration, as stimulation of the proprioceptive system, in PD and encourage further investigation. The effect of the device on more severe patients may open a new possibility to identify the most appropriate candidate for the management of gait disturbances and postural instability with FV delivered with Equistasi®.
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http://dx.doi.org/10.3389/fneur.2019.00998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760030PMC
September 2019

Evolution of prodromal parkinsonian features in a cohort of mutation-positive individuals: a 6-year longitudinal study.

J Neurol Neurosurg Psychiatry 2019 10 20;90(10):1091-1097. Epub 2019 Jun 20.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK

Objectives: mutations are a frequent risk factor for Parkinson disease (PD). The aim of this study is to evaluate clinical features in a group of mutation-positive individuals over a 6-year follow-up.

Methods: This is a longitudinal study on a cohort of -positive carriers. We enrolled 31 patients with Gaucher disease type 1 (GD), 29 heterozygous carriers (Het group) and 30 controls (HC) at baseline and followed them for 6 years. We assessed baseline motor and non-motor signs of PD in all subjects using clinical questionnaires and scales (reduced Unified Multiple System Atrophy Rating Scale (UMSARS), Montreal Cognitive assessment (MoCA), University of Pennsylvania Smell Identification Test (UPSIT), REM Sleep Behavior Disorder screening questionnaire (RBDsq), Movement Disorders Society Unified Parkinson's Disease Rating Scale motor subscale (MDS-UPDRS III) and Beck Depression Inventory (BDI). We repeated these at the 6-year follow-up alongside venous blood sampling for measurement of glucocerebrosidase enzymatic activity (GCase). We explored whether the GCase activity level was altered in leucocytes of these subjects and how it was related to development of PD.

Results: We observed a significant worsening in UMSARS, RBDsq, MDS-UPDRS III and BDI scores at the 6-year follow-up compared with baseline in both the GD and Het groups. Intergroup comparisons showed that GD subjects had significantly worse scores in UPSIT, UMSARS, MoCA and MDS-UPDRS III than HC, while Het displayed worse outcomes in UPSIT and MDS-UPDRS III compared with HC. In mutation-positive individuals (Het and GD), an UPSIT score of 23 at baseline was correlated with worse outcome at 6 years in UPSIT, MoCA, MDS-UPDRS III and BDI.

Conclusion: In this 6-year-long longitudinal study, mutation-positive subjects showed a worsening in motor and non-motor prodromal PD features.
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http://dx.doi.org/10.1136/jnnp-2019-320394DOI Listing
October 2019

Body Weight Support Combined With Treadmill in the Rehabilitation of Parkinsonian Gait: A Review of Literature and New Data From a Controlled Study.

Front Neurol 2018 8;9:1066. Epub 2019 Feb 8.

Neurorehabilitation Unit and Parkinson Unit, IRCCS Mondino Foundation, Pavia, Italy.

Gait disorders represent disabling symptoms in Parkinson's Disease (PD). The effectiveness of rehabilitation treatment with Body Weight Support Treadmill Training (BWSTT) has been demonstrated in patients with stroke and spinal cord injuries, but limited data is available in PD. The aim of the study is to investigate the efficacy of BWSTT in the rehabilitation of gait in PD patients. Thirty-six PD inpatients were enrolled and performed rehabilitation treatment for 4-weeks, with daily sessions. Subjects were randomly divided into two groups: both groups underwent daily 40-min sessions of traditional physiokinesitherapy followed by 20-min sessions of overground gait training (Control group) or BWSTT (BWSTT group). The efficacy of BWSTT was evaluated with clinical scales and Computerized Gait Analysis (CGA). Patients were tested at baseline (T0) and at the end of the 4-weeks rehabilitation period (T1). Both BWSTT and Control groups experienced a significant improvement in clinical scales as FIM and UPDRS and in gait parameters for both interventions. Even if we failed to detect any statistically significant differences between groups in the different clinical and gait parameters, the intragroup analysis captured a specific pattern of qualitative improvement associated to cadence and stride duration for the BWSTT group and to the swing/stance ratio for the Control group. Four patients with chronic pain or anxious symptoms did not tolerate BWSTT. BWSTT and traditional rehabilitation treatment are both effective in improving clinical motor functions and kinematic gait parameters. BWSTT may represent an option in PD patients with specific symptoms that limit traditional overground gait training, e.g., severe postural instability, balance disorder, orthostatic hypotension. BWSTT is generally well-tolerated, though caution is needed in subjects with chronic pain or with anxious symptoms. www.ClinicalTrials.gov, identifier: NCT03815409.
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http://dx.doi.org/10.3389/fneur.2018.01066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375880PMC
February 2019

Psychological, clinical, and therapeutic predictors of the outcome of detoxification in a large clinical population of medication-overuse headache: A six-month follow-up of the COMOESTAS Project.

Cephalalgia 2019 01 27;39(1):135-147. Epub 2018 Jun 27.

1 Headache Science Centre, IRCCS Mondino Foundation, Pavia, Italy.

Aim: To identify factors that may be predictors of the outcome of a detoxification treatment in medication-overuse headache.

Methods: Consecutive patients entering a detoxification program in six centres in Europe and Latin America were evaluated and followed up for 6 months. We evaluated anxious and depressive symptomatology (though patients with severe psychiatric comorbidity were excluded), quality of life, headache-related disability, headache characteristics, and prophylaxis upon discharge.

Results: Of the 492 patients who completed the six-month follow up, 407 ceased overuse following the detoxification (non overusers), another 23 ceased overuse following detoxification but relapsed during the follow-up. In the 407 non-overusers, headache acquired an episodic pattern in 287 subjects (responders). At the multivariate analyses, lower depression scores (odds ratio = 0.891; p = 0.001) predicted ceasing overuse. The primary headache diagnosis - migraine with respect to tension-type headache (odds ratio = 0.224; p = 0.001) or migraine plus tension-type headache (odds ratio = 0.467; p = 0.002) - and the preventive treatment with flunarizine (compared to no such treatment) (odds ratio = 0.891; p = 0.001) predicted being a responder. A longer duration of chronic headache (odds ratio = 1.053; p = 0.032) predicted relapse into overuse. Quality of life and disability were not associated with any of the outcomes.

Conclusions: Though exploratory in nature, these findings point to specific factors that are associated with a positive outcome of medication-overuse headache management, while identifying others that may be associated with a negative outcome. Evaluation of the presence/absence of these factors may help to optimize the management of this challenging groups of chronic headache sufferers.
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http://dx.doi.org/10.1177/0333102418783317DOI Listing
January 2019

The Exosomal/Total α-Synuclein Ratio in Plasma Is Associated With Glucocerebrosidase Activity and Correlates With Measures of Disease Severity in PD Patients.

Front Cell Neurosci 2018 18;12:125. Epub 2018 May 18.

Laboratory of Functional Neurochemistry, IRCCS Mondino Foundation Pavia, Italy.

Intensive research efforts in the field of Parkinson's disease (PD) are focusing on identifying reliable biomarkers which possibly help physicians in predicting disease onset, diagnosis, and progression as well as evaluating the response to disease-modifying treatments. Given that abnormal alpha-synuclein (α-syn) accumulation is a primary component of PD pathology, this protein has attracted considerable interest as a potential biomarker for PD. Alpha-synuclein can be detected in several body fluids, including plasma, where it can be found as free form or in association with exosomes, small membranous vesicles secreted by virtually all cell types. Together with α-syn accumulation, lysosomal dysfunctions seem to play a central role in the pathogenesis of PD, given the crucial role of lysosomes in the α-syn degradation. In particular, heterozygous mutations in the GBA1 gene encoding lysosomal enzyme glucocerebrosidase (GCase) are currently considered as the most important risk factor for PD. Different studies have found that GCase deficiency leads to accumulation of α-syn; whereas at the same time, increased α-syn may inhibit GCase function, thus inducing a bidirectional pathogenic loop. In this study, we investigated whether changes in plasma total and exosome-associated α-syn could correlate with disease status and clinical parameters in PD and their relationship with GCase activity. We studied 39 PD patients (mean age: 65.2 ± 8.9; men: 25), without GBA1 mutations, and 33 age-matched controls (mean age: 61.9 ± 6.2; men: 15). Our results showed that exosomes from PD patients contain a greater amount of α-syn compared to healthy subjects (25.2 vs. 12.3 pg/mL, < 0.001) whereas no differences were found in plasma total α-syn levels (15.7 vs. 14.8 ng/mL, = 0.53). Moreover, we highlighted a significant increase of plasma exosomal α-syn/total α-syn ratio in PD patients (1.69 vs. 0.89, < 0.001), which negatively correlates with disease severity ( = 0.014). Intriguingly, a significant inverse correlation between GCase activity and this ratio in PD subjects was found ( = 0.006). Additional and large-scale studies comparing GCase activity and pathological protein levels will be clearly needed to corroborate these data and determine whether the association between key players in the lysosomal system and α-syn can be used as diagnostic or prognostic biomarkers for PD.
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http://dx.doi.org/10.3389/fncel.2018.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968118PMC
May 2018

Pain in focal dystonias - A focused review to address an important component of the disease.

Parkinsonism Relat Disord 2018 09 27;54:17-24. Epub 2018 Apr 27.

Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy; Department of Neurology and Neurorehabilitation, Mondino Foundation IRCCS, Pavia, Italy.

Focal dystonia is characterized by involuntary muscle contractions that cause abnormal postures and/or twisting movements in a segment of the body. Motor symptoms have a major impact on disability in this condition, but the presence of pain represents an additional source of impairment and poor quality of life. Notwithstanding that pain occurs in up to 70% of patients with cervical dystonia and in a relevant proportion of subjects with focal dystonia of the limbs, it has received very little attention from researchers and controlled trials are scant. The aim of this review is to summarize the current knowledge on the clinical assessment and management of pain in focal dystonias. The search results will inform on the types of pain reported in focal dystonias, on the tools that are used to quantify pain and on the efficacy of pharmacological and non-pharmacological approaches. The collated data will hopefully improve the clinical management of focal dystonia and also stimulate future research on dystonia-associated pain. Optimization of the outcome indeed requires the identification and the management of all the factors that determine disability and hence relies on a multidisciplinary approach.
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http://dx.doi.org/10.1016/j.parkreldis.2018.04.030DOI Listing
September 2018

Botulinum toxin for chronic migraine: Clinical trials and technical aspects.

Toxicon 2018 Jun 4;147:111-115. Epub 2017 Sep 4.

Headache Science Center and Headache Unit, National Neurological Institute C. Mondino Foundation, Pavia, Italy; Dept of Brain and Behavioral Sciences, University of Pavia, Italy.

OnabotulinumtoxinA has been approved for the prophylaxis of chronic migraine following the demonstration of efficacy in two large controlled trials. Data collected from pragmatic studies in the real-life setting have contributed important additional information useful for the management of this group of extremely disabled and challenging patients. The main findings from these studies are presented and discussed.
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http://dx.doi.org/10.1016/j.toxicon.2017.08.026DOI Listing
June 2018

Pain processing in atypical Parkinsonisms and Parkinson disease: A comparative neurophysiological study.

Clin Neurophysiol 2017 10 17;128(10):1978-1984. Epub 2017 Jul 17.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; Department of Neurology and Neurorehabilitation, C. Mondino National Neurological Institute, Pavia, Italy.

Objective: Pain is a frequent non-motor feature in Parkinsonism but mechanistic data on the alteration of pain processing are insufficient to understand the possible causes and to define specifically-targeted treatments.

Methods: we investigated spinal nociception through the neurophysiological measure of the threshold (TR) of nociceptive withdrawal reflex (NWR) and its temporal summation threshold (TST) comparatively in 12 Progressive Supranuclear Palsy (PSP) subjects, 11 Multiple System Atrophy (MSA) patients, 15 Parkinson's disease (PD) subjects and 24 healthy controls (HC). We also investigated the modulatory effect of L-Dopa in these three parkinsonian groups.

Results: We found a significant reduction in the TR of NWR and in the TST of NWR in PSP, MSA and PD patients compared with HC. L-Dopa induced an increase in the TR of NWR in the PSP group while TST of NWR increased in both PSP and PD.

Conclusions: Our neurophysiological findings identify a facilitation of nociceptive processing in PSP that is broadly similar to that observed in MSA and PD. Specific peculiarities have emerged for PSP.

Significance: Our data advance the knowledge of the neurophysiology of nociception in the advanced phases of parkinsonian syndromes and on the role of dopaminergic pathways in the control on pain processing.
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http://dx.doi.org/10.1016/j.clinph.2017.06.257DOI Listing
October 2017

Changes in anxiety and depression symptoms associated to the outcome of MOH: A post-hoc analysis of the Comoestas Project.

Cephalalgia 2018 04 11;38(4):646-654. Epub 2017 Apr 11.

1 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Aims To evaluate the impact of treatment success on depression and anxiety symptoms in medication-overuse headache (MOH) and whether depression and anxiety can be predictors of treatment outcome. Methods All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion over a six-month period. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. Results A total of 663 MOH patients were evaluated, and 492 completed the entire protocol. Of these, 287 ceased overuse and reverted to an episodic pattern (responders) and 23 relapsed into overuse. At the final evaluation, the number of patients with depressive symptoms was reduced by 63.2% among responders ( p < 0.001) and did not change in relapsers ( p = 0.13). Anxious symptomatology was reduced by 43.1% in responders ( ps < 0.001) and did not change in relapsers ( p = 0.69). At the multivariate analysis, intake of a prophylactic drug and absence of symptoms of depression at six months emerged as prognostic factors for being a responder (OR 2.406; p = 0.002 and OR 1.989; p = 0.019 respectively), while lack of antidepressant drugs and presence of symptoms of depression at six months were prognostic factors for relapse into overuse (OR 3.745; p = 0.004 and OR 3.439; p = 0.031 respectively). Conclusions Symptomatology referred to affective state and anxiety can be significantly reduced by the treatment of MOH. Baseline levels of depression and anxiety do not generally predict the outcome at six months. Their persistence may represent a trait of patients with a negative outcome, rather than the consequence of a treatment failure.
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http://dx.doi.org/10.1177/0333102417704415DOI Listing
April 2018

Assessing and treating pain in movement disorders, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness, dementia, oncology and neuroinfectivology. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

Eur J Phys Rehabil Med 2016 Dec 31;52(6):841-854. Epub 2016 Aug 31.

"Cardinal Ferrari" Rehabilitation Center, Parma, Italy -

Pain is an important non-motor symptom in several neurological diseases, such as Parkinson's disease, cervical dystonia, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness and dementia, as well as in oncology and neuroinfectivology. To overcome the lack of evidence-based data on pain management in these diseases, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) has defined criteria for good clinical practice among Italian neurorehabilitation professionals. Here a review of the literature (PubMed, EMBASE and gray literature) on pain characteristics, treatment and impact of pain in a neurorehabilitation setting is provided. Despite the heterogeneity of data, a consensus was reached on pain management for patients with these diseases: it is an approach originating from an analysis of the available data on pain characteristics in each disease, the evolution of pain in relation to the natural course of the disease and the impact of pain on the overall process of rehabilitation. There was unanimous consensus regarding the utility of a multidisciplinary approach to pain therapy, combining the benefits of pharmacological therapy with the techniques of physiotherapy and neurorehabilitation for all the conditions considered. While some treatments could be different depending on pathology, a progressive approach to the pharmacological treatment of pain is advisable, starting with non-opioid analgesics (paracetamol) and nonsteroidal anti-inflammatory drugs as a first-line treatment, and opioid analgesics as a second-line treatment. In cases of pain secondary to spasticity, botulinum neurotoxin, and, in some cases, intrathecal baclofen infusion should be considered. Randomized controlled trials and prospective multicenter studies aimed at documenting the efficacy of pain treatment and their risk-benefit profile are recommended for these conditions.
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December 2016
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