Publications by authors named "Sonia Mazzucchi"

29 Publications

  • Page 1 of 1

Prevalence and Clinical Correlates of Comorbid Anxiety and Panic Disorders in Patients with Parkinson's Disease.

J Clin Med 2021 May 25;10(11). Epub 2021 May 25.

2nd Psychiatric Unit, Department of Clinical and Experimental Medicine, Santa Chiara University Hospital, University of Pisa, 56100 Pisa, Italy.

Mood and anxiety disorders are the most common neuropsychiatric syndromes associated with Parkinson's disease (PD). The aim of our study was to estimate the prevalence of lifetime and current anxiety disorders in patients with Parkinson's Disease (PD), to explore possible distinctive neurological and psychiatric features associated with such comorbidity. One hundred patients were consecutively recruited at the Movement Disorders Section of the Neurological Outpatient Clinic of the University of Pisa. According to the MINI-Plus 5.0.0, 41 subjects were diagnosed with lifetime anxiety disorder (22 with panic disorder) and 26 were diagnosed with current anxiety disorders. Patients with anxiety disorders were more frequently characterized by psychiatric symptoms preceding PD, lifetime major depression and antidepressant treatments. They showed more anxious temperamental traits and scored higher at Parkinson Anxiety Scale (PAS) and persistent anxiety subscale. Current anxiety disorders were associated with more severe psychopathology, depressive symptomatology, and avoidant behavior. Among anxiety subtypes, patients with lifetime panic disorder showed higher rates of psychiatric symptoms before PD, lifetime unipolar depression, current psychiatric treatment, and a more severe psychopathology. Given the overall high impact of anxiety on patients' quality of life, clinicians should not underestimate the extent of different anxiety dimensions in PD.
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http://dx.doi.org/10.3390/jcm10112302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198165PMC
May 2021

Functional motor phenotypes: to lump or to split?

J Neurol 2021 May 7. Epub 2021 May 7.

IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms.

Objective: To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities.

Methods: Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted.

Results: A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors.

Conclusions: Our data support the evidence of a large overlap between FMD phenotypes.
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http://dx.doi.org/10.1007/s00415-021-10583-wDOI Listing
May 2021

Supersaturation of VEP in Migraine without Aura Patients Treated with Topiramate: An Anatomo-Functional Biomarker of the Disease.

J Clin Med 2021 Feb 15;10(4). Epub 2021 Feb 15.

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

Migraine is a primary headache with high prevalence among the general population, characterized by functional hypersensitivity to both exogenous and endogenous stimuli particularly affecting the nociceptive system. The hyperresponsivity of cortical neurons could be due to a disequilibrium in the excitatory/inhibitory signaling. This study aimed to investigate the anatomo-functional pathway from the retina to the primary visual cortex using visual evoked potentials (VEP). Contrast gain protocol was used in 15 patients diagnosed with migraine without aura (at baseline and after 3 months of topiramate therapy) and 13 controls. A saturation (S) index was assessed to monitor the response of VEP's amplitude to contrast gain. Non-linear nor monotone growth of VEP (S < 0.95) was defined as supersaturation. A greater percentage of migraine patients (53%) relative to controls (7%) showed this characteristic. A strong inverse correlation was found between the S index and the number of days separating the registration of VEP from the next migraine attack. Moreover, allodynia measured through the Allodynia Symptoms Check-list (ASC-12) correlates with the S index both at baseline and after 3 months of topiramate treatment. Other clinical characteristics were not related to supersaturation. Topiramate therapy, although effective, did not influence electrophysiological parameters suggesting a non-intracortical nor retinal origin of the supersaturation (with possible involvement of relay cells from the lateral geniculate nucleus). In conclusion, the elaboration of visual stimuli and visual cortex activity is different in migraine patients compared to controls. More data are necessary to confirm the potential use of the S index as a biomarker for the migraine cycle (association with the pain-phase) and cortical sensitization (allodynia).
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http://dx.doi.org/10.3390/jcm10040769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918918PMC
February 2021

Functional motor disorders associated with other neurological diseases: Beyond the boundaries of "organic" neurology.

Eur J Neurol 2021 May 2;28(5):1752-1758. Epub 2021 Jan 2.

Movement Disorder Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background And Purpose: The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases ("comorbid FMDs"), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases ("pure FMDs").

Methods: For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables).

Results: Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non-neurological comorbidities.

Conclusions: Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non-neurological diseases.
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http://dx.doi.org/10.1111/ene.14674DOI Listing
May 2021

Bipolar Spectrum disorders in Parkinson's disease: a systematic evaluation.

CNS Spectr 2020 Dec 7:1-7. Epub 2020 Dec 7.

Department of Clinical and Experimental Medicine-Psychiatry Unit, University of Pisa, Pisa, Italy.

Objective: Psychiatric disorders are very common in patients affected by Parkinson's disease (PD). However, comorbidity with Bipolar Spectrum disorders is understudied. The aim of this study is to explore the clinical correlates of PD associated with Bipolar Spectrum disorders.

Methods: One hundred PD patients were screened for psychiatric comorbidities, cognitive profile, motor, and non-motor symptoms. The sample was divided into three groups: PD-patients with Bipolar Spectrum disorders (bipolar disorder type I, type II, and spontaneous or induced hypomania; N = 32), PD-patients with others psychiatric comorbidities (N = 39), PD-patients without psychiatric comorbidities (N = 29). Clinical features were compared among the groups using analysis of variance and chi-square test. A logistic regression was performed to evaluate the association between Bipolar Spectrum disorders and early onset of PD (≤50 years) controlling for lifetime antipsychotic use.

Results: In comparison with PD patients with and without other psychiatric comorbidity, subjects affected by Bipolar Spectrum disorders were younger, showed more frequently an early onset PD, reported more involuntary movements and a higher rate of impulse control disorders and compulsive behaviors. No differences were observed in indexes of exposure to dopamine agonist treatments. The early onset of PD was predicted by Bipolar Spectrum comorbidity, independently from lifetime antipsychotic use.

Conclusion: Bipolar Spectrum disorders are common in early onset PD. The presence of bipolar comorbidity could identify a particular subtype of PD, showing higher rates of neurological and psychiatric complications and deserving further investigation.
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http://dx.doi.org/10.1017/S1092852920002126DOI Listing
December 2020

Clinical Correlates of Functional Motor Disorders: An Italian Multicenter Study.

Mov Disord Clin Pract 2020 Nov 22;7(8):920-929. Epub 2020 Sep 22.

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

Background: Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases.

Objective: The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables.

Methods: For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms.

Results: Of 410 FMDs (71% females; mean age, 47 ± 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs.

Conclusions: Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.
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http://dx.doi.org/10.1002/mdc3.13077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604660PMC
November 2020

A New MRI Measure to Early Differentiate Progressive Supranuclear Palsy From De Novo Parkinson's Disease in Clinical Practice: An International Study.

Mov Disord 2021 03 5;36(3):681-689. Epub 2020 Nov 5.

Neuroscience Research Center, University "Magna Graecia", Catanzaro, Italy.

Background: Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP).

Methods: We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test.

Results: In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results.

Conclusion: Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28364DOI Listing
March 2021

The role of synaptic biomarkers in the spectrum of neurodegenerative diseases.

Expert Rev Proteomics 2020 Jul - Aug;17(7-8):543-559. Epub 2020 Oct 18.

Department of Clinical and Experimental Medicine, University of Pisa , Pisa, Italy.

Introduction: The quest for reliable fluid biomarkers tracking synaptic disruption is supported by the evidence of a tight association between synaptic density and cognitive performance in neurodegenerative diseases (NDD), especially Alzheimer's disease (AD).

Areas Covered: Neurogranin (Ng) is a post-synaptic protein largely expressed in neurons involved in the memory networks. Currently, Ng measured in CSF is the most promising synaptic biomarker. Several studies show Ng elevated in AD dementia with a hippocampal phenotype as well as in MCI individuals who progress to AD. Ng concentrations are also increased in Creutzfeldt Jacob Disease where widespread and massive synaptic disintegration takes place. Ng does not discriminate Parkinson's disease from atypical parkinsonisms, nor is it altered in Huntington disease. CSF synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1) are emerging candidates.

Expert Opinion: CSF Ng revealed a role as a diagnostic and prognostic biomarker in NDD. Ng increase seems to be very specific for typical AD phenotype, probably for a prevalent hippocampal involvement. Synaptic biomarkers may serve different context-of-use in AD and other NDD including prognosis, diagnosis, and tracking synaptic damage - a critical pathophysiological mechanism in NDD - thus representing reliable tools for a precision medicine-oriented approach to NDD.
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http://dx.doi.org/10.1080/14789450.2020.1831388DOI Listing
October 2020

Prevalence and impact of COVID-19 in Parkinson's disease: evidence from a multi-center survey in Tuscany region.

J Neurol 2021 Apr 3;268(4):1179-1187. Epub 2020 Sep 3.

Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy.

Background: If Parkinson's Disease (PD) may represent a risk factor for Coronavirus disease 2019 (COVID-19) is debated and there are few data on the direct and indirect effects of this pandemic in PD patients.

Objective: In the current study we evaluated the prevalence, mortality and case-fatality of COVID-19 in a PD cohort, also exploring possible risk factors. We also aimed to investigate the effect of lockdown on motor/non-motor symptoms in PD patients as well as their acceptability/accessibility to telemedicine.

Method: A case-controlled survey about COVID-19 and other clinical features in PD patients living in Tuscany was conducted. In non-COVID-19 PD patients motor/non-motor symptoms subjective worsening during the lockdown as well as feasibility of telemedicine were explored.

Results: Out of 740 PD patients interviewed, 7 (0.9%) were affected by COVID-19, with 0.13% mortality and 14% case-fatality. COVID-19 PD patients presented a higher presence of hypertension (p < 0.001) and diabetes (p = 0.049) compared to non-COVID-19. In non-COVID-19 PD population (n = 733) about 70% did not experience a subjective worsening of motor symptoms or mood, anxiety or insomnia. In our population 75.2% of patients was favorable to use technology to perform scheduled visits, however facilities for telemedicine were available only for 51.2% of cases.

Conclusion: A higher prevalence of COVID-19 respect to prevalence in Tuscany and Italy was found in the PD population. Hypertension and diabetes, as for general population, were identified as risk factors for COVID-19 in PD. PD patients did not experience a subjective worsening of symptoms during lockdown period and they were also favorable to telemedicine, albeit we reported a reduced availability to perform it.
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http://dx.doi.org/10.1007/s00415-020-10002-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471534PMC
April 2021

Connected speech in progressive supranuclear palsy: a possible role in differential diagnosis.

Neurol Sci 2021 Apr 27;42(4):1483-1490. Epub 2020 Aug 27.

Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy.

Background: Progressive supranuclear palsy (PSP) is an atypical Parkinsonism characterized by motor and neuropsycological disorders. Language could be impaired in PSP patients, also in Richardson variant (PSP-RS). The analysis of connected speech is used in neurodegenerative disorder to investigate different levels of language organization, including phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic processing.

Objective: In our study, we aimed to investigate the language profile, especially connected speech, in early-stage PSP-RS and Parkinson's disease (PD) patients without predominant speech or language disorders.

Methods: Language was assessed using the Screening for Aphasia in NeuroDegeneration (SAND); connected speech analysis was conducted from the picture description subtest.

Results: We enrolled 48 patients, 22 PD and 26 PSP (18 PSP-RS and 8 non-RS). PSP-RS patients presented an impairment in language domain, particularly regarding connected speech. PSP-RS patients presented worse performances than PD in different scores. The output of PSP-RS patients was characterized by a reduction in number of sentences and subordinates with respect to PD; PSP presented also more repaired sequences and phonological and lexico-semantic errors than PD. Number of sentences and number of subordinates of the picture description task were identified as predictors of PSP diagnosis.

Conclusion: In summary, the SAND scale is able to identify language impairment in PSP patients. The analysis of connected speech could highlight some important aspects of language impairment in PSP-RS patients, and it could be helpful in the differential diagnosis with PD.
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http://dx.doi.org/10.1007/s10072-020-04635-8DOI Listing
April 2021

Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.

Mol Neurobiol 2020 Nov 9;57(11):4667-4691. Epub 2020 Aug 9.

Unit of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).
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http://dx.doi.org/10.1007/s12035-020-02035-9DOI Listing
November 2020

Does the Degree of Trunk Bending Predict Patient Disability, Motor Impairment, Falls, and Back Pain in Parkinson's Disease?

Front Neurol 2020 31;11:207. Epub 2020 Mar 31.

Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Postural abnormalities in Parkinson's disease (PD) form a spectrum of functional trunk misalignment, ranging from a "typical" parkinsonian stooped posture to progressively greater degrees of spine deviation. To analyze the association between degree of postural abnormalities and disability and to determine cut-off values of trunk bending associated with limitations in activities of daily living (ADLs), motor impairment, falls, and back pain. The study population was 283 PD patients with ≥5° of forward trunk bending (FTB), lateral trunk bending (LTB) or forward neck bending (FNB). The degrees were calculated using a wall goniometer (WG) and software-based measurements (SBM). Logistic regression models were used to identify the degree of bending associated with moderate/severe limitation in ADLs (Movement Disorders Society Unified PD Rating Scale [MDS-UPDRS] part II ≥17), moderate/severe motor impairment (MDS-UPDRS part III ≥33), history of falls (≥1), and moderate/severe back pain intensity (numeric rating scale ≥4). The optimal cut-off was identified using receiver operating characteristic (ROC) curves. We found significant associations between modified Hoehn & Yahr stage, disease duration, sex, and limitation in ADLs, motor impairment, back pain intensity, and history of falls. Degree of trunk bending was associated only with motor impairment in LTB (odds ratio [OR] 1.12; 95% confidence interval [CI], 1.03-1.22). ROC curves showed that patients with LTB of 10.5° (SBM, AUC 0.626) may have moderate/severe motor impairment. The severity of trunk misalignment does not fully explain limitation in ADLs, motor impairment, falls, and back pain. Multiple factors possibly related to an aggressive PD phenotype may account for disability in PD patients with FTB, LTB, and FNB.
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http://dx.doi.org/10.3389/fneur.2020.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136533PMC
March 2020

Automated MRI Classification in Progressive Supranuclear Palsy: A Large International Cohort Study.

Mov Disord 2020 06 24;35(6):976-983. Epub 2020 Feb 24.

Neuroscience Centre, Magna Graecia University, Catanzaro, Italy.

Background: The Magnetic Resonance Parkinsonism Index is listed as one of the most reliable imaging morphometric markers for diagnosis of progressive supranuclear palsy (PSP). However, the use of this index in diagnostic workup has been limited until now by the low generalizability of published results because of small monocentric patient cohorts, the lack of data validation in independent patient series, and manual measurements used for index calculation. The objectives of this study were to investigate the generalizability of Magnetic Resonance Parkinsonism Index performance validating previously established cutoff values in a large international cohort of PSP patients subclassified into PSP-Richardson's syndrome and PSP-parkinsonism and to standardize the use of the automated Magnetic Resonance Parkinsonism Index by providing a web-based platform to obtain homogenous measures around the world.

Methods: In a retrospective international multicenter study, a total of 173 PSP patients and 483 non-PSP participants were enrolled. A web-based platform (https://mrpi.unicz.it) was used to calculate automated Magnetic Resonance Parkinsonism Index values.

Results: Magnetic Resonance Parkinsonism Index values showed optimal performance in differentiating PSP-Richardson's syndrome and PSP-parkinsonism patients from non-PSP participants (93.6% and 86.5% of accuracy, respectively). The Magnetic Resonance Parkinsonism Index was also able to differentiate PSP-Richardson's syndrome and PSP-parkinsonism patients in an early stage of the disease from non-PSP participants (90.1% and 85.9%, respectively). The web-based platform provided the automated Magnetic Resonance Parkinsonism Index calculation in 94% of cases.

Conclusions: Our study provides the first evidence on the generalizability of automated Magnetic Resonance Parkinsonism Index measures in a large international cohort of PSP-Richardson's syndrome and PSP-parkinsonism patients. The web-based platform enables widespread applicability of the automated Magnetic Resonance Parkinsonism Index to different clinical and research settings. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28007DOI Listing
June 2020

The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.

Expert Rev Mol Diagn 2020 04 27;20(4):421-441. Epub 2020 Feb 27.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

: The examination still represents the reference standard for detecting the pathological nature of chronic neurodegenerative diseases (NDD). This approach displays intrinsic conceptual limitations since NDD represent a dynamic of partially overlapping phenotypes, shared pathomechanistic alterations that often give rise to mixed pathologies.: We scrutinized the international clinical diagnostic criteria of NDD and the literature to provide a roadmap toward a biomarker-based classification of the NDD . A few pathophysiological biomarkers have been established for NDD. These are time-consuming, invasive, and not suitable for preclinical detection. Candidate screening biomarkers are gaining momentum. Blood neurofilament light-chain represents a robust first-line tool to detect neurodegeneration and serum progranulin helps detect genetic frontotemporal dementia. Ultrasensitive assays and retinal scans may identify Aβ pathology early, in blood and the eye, respectively. Ultrasound also represents a minimally invasive option to investigate the . Protein misfolding amplification assays may accurately detect α-synuclein in biofluids.: Data-driven strategies using quantitative rather than categorical variables may be more reliable for quantification of contributions from pathophysiological mechanisms and their spatial-temporal evolution. A systems biology approach is suitable to untangle the dynamics triggering loss of proteostasis, driving neurodegeneration and clinical evolution.
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http://dx.doi.org/10.1080/14737159.2020.1731306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445079PMC
April 2020

Validity of the wall goniometer as a screening tool to detect postural abnormalities in Parkinson's disease.

Parkinsonism Relat Disord 2019 12 30;69:159-165. Epub 2019 Oct 30.

Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. Electronic address:

Introduction: Software-based measurements of postural abnormalities in Parkinson's disease (PD) are the gold standard but may be time-consuming and not always feasible in clinical practice. Wall goniometer (WG) is an easier, quicker, and inexpensive instrument for screening patients with postural abnormalities, but no studies have investigated its validity so far. The aim of this study was to investigate the validity of the WG to measure postural abnormalities.

Methods: A total of 283 consecutive PD outpatients with ≥5° forward trunk, lateral trunk or forward neck bending (FTB, LTB, FNB, respectively) were recruited from seven centers for movement disorders. Postural abnormalities were measured in lateral and posterior view using a freeware program (gold standard) and the WG. Both angles were expressed in degrees (°). Sensitivity and specificity for the diagnosis of camptocormia, Pisa syndrome, and anterocollis were assessed.

Results: WG showed good to excellent agreement (intraclass correlation coefficient from 0.80 to 0.98) compared to the gold standard. Bland-Altman plots showed a mean difference between the methods from -7.4° to 0.4° with limits of agreements from -17.7° to 9.5°. Sensitivity was 100% for the diagnosis of Pisa syndrome, 95.74% for anterocollis, 76.67% for upper camptocormia, and 63.64% for lower camptocormia. Specificity was 59.57% for Pisa syndrome, 71.43% for anterocollis, 89.80% for upper camptocormia, and 100% for lower camptocormia. Overall, the WG underestimated measurements, especially in lower camptocormia with an average of -8.7° (90% of cases).

Conclusion: WG is a valid tool for screening Pisa syndrome and anterocollis, but approximately 10° more should be added for camptocormia.
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http://dx.doi.org/10.1016/j.parkreldis.2019.10.024DOI Listing
December 2019

Plasma Levels of Oxidative Stress Markers, before and after Treatment, in Chronic Migraine.

Toxins (Basel) 2019 10 19;11(10). Epub 2019 Oct 19.

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

The pathophysiological mechanisms of migraine transformation are debated. Modifications of plasma oxidative stress biomarkers have been described in chronic migraine. OnabotulintoxinA (BoNT/A) treatment, approved for chronic migraine prophylaxis, possibly reduces pain neurotransmitters release and oxidative stress products. Aims of our study were to investigate differences in the levels of selected plasmatic oxidative stress biomarkers (Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), Thiolic Groups (SH)) comparing chronic migraineurs (CM) and healthy controls (HC). We also explored possible clinical and biochemical modifications in the CM group after six months of treatment with BoNT/A. At the baseline, we found higher values of AOPP ( < 0.001), and lower values of SH ( < 0.001) and FRAP ( = 0.005) in the CM group. At the six-month follow-up we found a reduction of AOPP ( < 0.001) and an increase of FRAP ( < 0.001) and SH ( = 0.023) within the CM group. BoNT/A treatment improved migraine symptoms in the CM group. We confirmed previous reports of imbalanced antioxidant mechanisms in chronic migraine showing lower antioxidant capacities in patients than controls. BoNT/A improved the levels of plasma oxidative stress biomarkers and confirmed its role as an effective prophylactic treatment for CM. Other studies should investigate the potential antioxidant properties of BoNT/A treatment.
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http://dx.doi.org/10.3390/toxins11100608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832499PMC
October 2019

Quantitative susceptibility mapping in atypical Parkinsonisms.

Neuroimage Clin 2019 31;24:101999. Epub 2019 Aug 31.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address:

Background And Purpose: Differential diagnosis between Parkinson's disease (PD) and Atypical Parkinsonisms, mainly Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA), remains challenging. The low sensitivity of macroscopic findings at imaging might limit early diagnosis. The availability of iron-sensitive MR techniques and high magnetic field MR scanners provides new insights in evaluating brain structures in degenerative parkinsonisms. Quantitative Susceptibility Mapping (QSM) allows quantifying tissue iron content and could be sensitive to microstructural abnormalities which precede the appearence of regional atrophy. We measured the magnetic susceptibility (χ) of nigral and extranigral regions in patients with PD, PSP and MSA to evaluate the potential utility of the QSM technique for differential diagnosis.

Materials And Methods: 65 patients (36 PD, 14 MSA, 15 PSP) underwent clinical and radiological evaluation with 3 T MRI. QSM maps were obtained from GRE sequences. ROI were drawn on substantia nigra (SN), red nucleus (RN), subthalamic nucleus (STN), putamen, globus pallidus and caudate. χ values were compared to detect inter-group differences.

Results: The highest diagnostic accuracy for PSP (area under the ROC curve, AUC, range 0.9-0.7) was observed for increased χ values in RN, STN and medial part of SN whereas in MSA (AUC range 0.8-0.7) iron deposition was significantly higher in the putamen, according to the patterns of pathological involvement that characterize the different diseases.

Conclusion: QSM could be used for iron quantification of nigral and extranigral structures in all degenerative parkinsonisms and should be tested longitudinally in order to identify early microscopical changes.
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http://dx.doi.org/10.1016/j.nicl.2019.101999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812245PMC
September 2020

Postural Abnormalities in Parkinson's Disease: An Epidemiological and Clinical Multicenter Study.

Mov Disord Clin Pract 2019 Sep 29;6(7):576-585. Epub 2019 Jun 29.

Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy.

Introduction: The overall frequency of postural abnormalities (PA) in Parkinson's disease (PD) is unknown. We evaluated the overall prevalence of PA and assessed the association with demographic and clinical variables.

Methods: For this multicenter, cross-sectional study, consecutive PD outpatients attending 7 tertiary Italian centers were enrolled. Patients were evaluated and compared for the presence of isolated PA such as camptocormia, Pisa syndrome, and anterocollis and for combined forms (ie, camptocormia + Pisa syndrome) together with demographic and clinical variables.

Results: Of the total 811 PD patients enrolled, 174 (21.5%; 95% confidence interval [CI], 18.6%-24.3%) presented PA, 144 of which had isolated PA and 30 had combined PA. The prevalence of camptocormia was 11.2% (95% CI, 9%-13.3%), Pisa syndrome 8% (95% CI, 6.2%-9.9%), and anterocollis 6.5% (95% CI, 4.9%-8.3%). Patients with PA were more often male and older with longer disease duration, more advanced disease stage, more severe PD symptoms, a bradykinetic/rigid phenotype, and poorer quality of life. They were initially treated with l, and more likely to be treated with a combination of l and dopamine agonist, took a higher daily l equivalent daily dose, and had more comorbidities. Falls and back pain were more frequent in PD patients with PA than in those without PA. Multiple logistic regression models confirmed an association between PA and male gender, older age, Hoehn and Yahr stage, and total Unified Parkinson's Disease Rating Scale score.

Conclusions: PA are frequent and disabling complications in PD, especially in the advanced disease stages.
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http://dx.doi.org/10.1002/mdc3.12810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749805PMC
September 2019

Botulinum toxin for the treatment of dystonia and pain in corticobasal syndrome.

Brain Behav 2019 06 9;9(6):e01182. Epub 2019 May 9.

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Dystonia is a key symptom in corticobasal syndrome (CBS), and upper limb dystonia is the most common phenotype. Dystonia-associated pain is frequently reported and can be disabling, with poor benefit from oral treatments.

Aims Of The Study: To investigate the role of botulinum toxin A (BoTNA) in the treatment of dystonia and associated pain in CBS.

Methods: Ten consecutive patients with a clinical diagnosis of probable CBS and dystonia with/without associated pain were treated with BoTNA every 3 months. Treatment efficacy was assessed during the first follow-up visit, three months after the first injection, by means of caregiver impression (CI), evaluation of muscle tone with the Ashworth scale (AS), severity of pain measured with the visual analog scale (VAS).

Results: Nine subjects underwent at least three treatments, four patients discontinued for progressive reduction in efficacy or disease progression, five patients are ongoing with good response, and one completed the 10th treatment. No local or systemic side effects were reported, and levodopa equivalent daily dose remained unchanged in most cases during the observational period. Significant improvement of AS was recorded (from 2.9 ± 0.7 to 2.0 ± 0.5, p = 0.003). CI ranged from mild to moderate benefit. All patients reported efficacy on pain, with a significant reduction of VAS score (from 7.7 ± 1.7 to 1.7 ± 0.7 in the Pain group, p = 0.016).

Conclusions: Our study confirms safety, efficacy, and tolerability of BoTNA in the treatment of dystonia associated with CBS. Local treatment should be considered as a valid alternative to oral treatment modulation mainly in the presence of associated pain.
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http://dx.doi.org/10.1002/brb3.1182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576166PMC
June 2019

Freezing of gait and dementia in parkinsonism: A retrospective case-control study.

Brain Behav 2019 06 9;9(6):e01247. Epub 2019 May 9.

Department of Clinical and Experimental Medicine, Unit of Neurology, University of Pisa, Pisa, Italy.

Objectives: To support the cognitive model of Freezing of Gait (FoG) we investigated FoG in a cohort of patients with Dementia with Lewy Bodies (DLB).

Materials And Methods: We assessed FoG frequency in 19 DLB patients compared to 19 control PD patients within 2 years from symptom onset and with at least 5 years follow-up. The two groups were matched by age and motor presentation at onset, severity of parkinsonism and disease duration. The presence and severity of FoG was identified as those with a score of 1 or greater on subitem 14 of the Unified Parkinson's Disease Rating Scale Part II  (UPDRS II).

Results: At T0, 68.4% DLB and 10.5% PD patients experienced FoG ≥1. The prevalence of FoG increased with disease progression (94.7% DLB and 47.3% PD subjects had FoG ≥1 at T5). DLB also showed a more severe FoG (FoG ≥2) than PD (21% vs. 0% at T0 and 52.6% vs. 10.5% at T5), consistently with previous studies reporting FoG prevalence in DLB.

Conclusion: This is the first study looking specifically at FoG in DLB, identifying it as a frequent and early feature of DLB and emphasizing the crucial role of cognitive impairment in the occurrence of this mysterious phenomenon.
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http://dx.doi.org/10.1002/brb3.1247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577616PMC
June 2019

Social Cognition and Oxytocin in Huntington's Disease: New Insights.

Brain Sci 2018 Aug 26;8(9). Epub 2018 Aug 26.

Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

This study is aimed at relating social cognition in Huntington's Disease (HD) to plasma levels of the social hormone oxytocin (OT). Indeed, HD patients commonly display reduced social skills and OT is involved in bonding behavior and improved recognition of facial emotions. Twelve mild-symptomatic HD patients (stage II Shoulson & Fahn) and 11 gender/age matched controls (healthy controls, HC), without concurrent psychiatric disorders, were investigated at baseline (T₀) for OT plasma levels and social cognition through an extensive battery of neuropsychological tests. Social cognition was also re-examined after two years (T1) in 8 of the 12 patients. Results showed a trend for reduced T₀-OT levels in HD vs. HC, mean ± stardard deviation: 6.5 ± 2.4 vs. 9.9 ± 7.2 pg/mL, without reaching statistical significance. At T₀, patients showed significantly lower performances than controls at the "Faux-Pas" and "Strange Stories" tests ( < 0.05; < 0.01); a reduced perception of visual emotions ( < 0.01) and verbal stimuli ( < 0.01) was also reported, involving anger, fear, and sadness ( < 0.05; < 0.01). Additionally, in the HD population, OT concentrations positively correlated with T1-performances at Neutral\Faux-Pas test ( < 0.05), whereas the cognitive Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) scores positively correlated with psychosocial perception at the "Strange Stories" and Karolinska Directed Emotional Faces (KDEF) tests ( < 0.05). This study, despite its limitations, supports correlations between OT and HD social cognition, suggesting a possible therapeutic use of this hormone. More subjects and additional body tissues/fluids, such as cerebrospinal fluid, should be investigated to confirm this hypothesis.
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http://dx.doi.org/10.3390/brainsci8090161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162368PMC
August 2018

Efficacy of a combined therapeutic approach in the management of Pisa Syndrome.

NeuroRehabilitation 2017 ;41(1):249-253

Department of Neuroscience, Unit of Neurorehabilitation, University Hospital of Pisa, Pisa, Italy.

Background: Pisa syndrome (PS) represents an important source of disability in Parkinson's disease (PD). Currently no consensus has been reached on its definition or diagnostic criteria, and therapeutic approaches are unspecific and often futile. Recently the role of abdominal muscles, and in particular of the external oblique (EO), in the pathogenesis of PS was hypothesized.

Objectives: To evaluate the role of EO and propose a combined therapeutic approach in the management of PS.

Methods: Ten PD patients with PS underwent a combined protocol based on repeated lidocaine injection in EO and rehabilitation program.

Results: Our data confirm the primary role of EO muscles in PS pathogenesis and showed an improvement in truncal flexion and balance with a positive impact on patients' quality of life after treatment.

Conclusions: These data highlight the need for accurate characterization of PS focusing on the role of abdominal muscles and the need for a specific rehabilitation protocol for PS management.
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http://dx.doi.org/10.3233/NRE-171478DOI Listing
March 2018

P058. Refractory chronic migraine, fatigue and OnabotulinumtoxinA: a clinic setting experience.

J Headache Pain 2015 Dec;16(Suppl 1):A113

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759129PMC
December 2015

Migraine features in migraineurs with and without anxiety-depression symptoms: a hospital-based study.

Clin Neurol Neurosurg 2015 May 10;132:74-8. Epub 2015 Mar 10.

Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy.

Background: Migraine, anxiety and depression often coexist. A "neurolimbic" model of migraine has been recently proposed accounting for a dynamic influence of pain, mood and anxiety on the migraine disease. However, very few data exist concerning clinical migraine features in patients reporting anxiety-depression symptoms.

Objective: Aim of our study was to test differences in clinical migraine features between migraineurs with anxiety-depression symptoms and migraineurs without ones.

Materials And Methods: We recruited 200 consecutive migraineurs. Other primary headaches comorbidity and migraine prophylaxis were exclusion criteria. Each patient was interviewed following a structured questionnaire including general features about migraine, triggers, allodynia. Anxiety and depression symptoms were evaluated in each patient by two brief self-reported scales: the generalized anxiety disorder 7-item scale (GAD-7) and the Patient Health Questionnaire 9-item scale (PHQ-9). A cut-off of 5 in both the GAD-7 and the PHQ-9 was considered positive for the presence of anxiety-depressive symptoms.

Results: One hundred and one patients (51.5%) had anxiety-depression symptoms (GAD-7 and PHQ-9 ≥ 5). They reported a more headaches/month (p = 0.004), higher number of triggers (p < 0.001), and were more allodynic (p = 0.005). In a binary logistic regression model triggers and allodynia made a unique statistical contribution on reporting anxiety-depression symptoms.

Conclusion: Our results showed that the presence of anxiety-depression symptoms affects migraine clinical presentation. They are associated with enhanced migraine triggers susceptibility, more ictal allodynic symptoms as well as more headaches/month. An altered sensation in migraineurs with anxiety-depression symptoms could be a result of a lower pain threshold and an increased cortical excitability in a broader context of a neurolimbic dysfunction.
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http://dx.doi.org/10.1016/j.clineuro.2015.02.017DOI Listing
May 2015

Symptomatic orthostatic tremor associated with Graves' disease.

Neurol Sci 2014 Jun 16;35(6):929-31. Epub 2014 Feb 16.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

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http://dx.doi.org/10.1007/s10072-014-1672-1DOI Listing
June 2014

Nigral involvement and nigrostriatal dysfunction in Huntington's disease: evidences from an MRI and SPECT study.

Parkinsonism Relat Disord 2013 Sep 12;19(9):800-5. Epub 2013 Jun 12.

Department of Clinical and Experimental Medicine, Section of Neurology, University of Pisa, Italy.

Background: Huntington disease (HD) is pathologically characterized by a selective neurodegeneration of vulnerable populations of neurons, with an early marked neuronal loss and atrophy in the neostriatum. Dopaminergic innervations of neostriatal neurons originate in the substantia nigra pars compacta. Few studies investigated the neuronal loss and the functional role of the substantia nigra in modulating clinical features in HD.

Methods: 12 patients and 12 age-matched controls underwent SPECT scans with (123)I-FP-CIT and a 1.5 T MRI scan with inversion recovery technique. The association between both clinical and neuropsychological features and striatal uptake and volume of substantia nigra was explored.

Results: Striatal (p < 0.05), caudate (p < 0.05), and putaminal (p < 0.01) uptake was significantly lower in patients with respect to controls. Further, the volume of substantia nigra was reduced in HD when compared to controls (p < 0.01). No relationship between the volume of SN and tracer striatal uptake was found as well as between clinical and neuropsychological features with the SPECT and MRI results.

Conclusions: Our results confirm that the degeneration of nigrostriatal pathway may occur in symptomatic HD patients. If confirmed by larger studies, the lack of any kind of correlation between clinical and neuropsychological features with striatal uptake and volume of substantia nigra suggests that motor and cognitive aspects in HD are not directly related to nigrostriatal degeneration.
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http://dx.doi.org/10.1016/j.parkreldis.2013.05.005DOI Listing
September 2013

The relationship between motor symptom lateralization and cognitive performance in newly diagnosed drug-naïve patients with Parkinson's disease.

J Clin Exp Neuropsychol 2013 10;35(2):124-31. Epub 2012 Dec 10.

Department of Neuroscience, University of Pisa, Pisa, Italy.

The side of motor symptom predominance may influence cognitive performance in patients with Parkinson's disease (PD): PD patients with right-side motor symptom predominance typically present difficulties in tasks of language and verbal memory, whereas PD patients with left-side motor symptom predominance typically present difficulties in visuospatial tasks. The current study aimed at investigating the relationship between motor symptom lateralization and cognitive performance in PD patients without the possible confounding effect of dopaminergic drugs, which may enhance or impair cognition on the basis of assessed function and disease stage. From the initial sample of 137 consecutive newly diagnosed drug-naïve (de novo) PD patients, clinical follow-ups and neurological examinations identified 108 right-handed patients with a unilateral motor presentation or a clear motor asymmetry (59 right-PD: 54.6%; 49 left-PD: 45.4%). Any cognitive difference emerged between right-PD patients and left-PD patients at this disease stage. Scores of lateralized motor impairment severity correlated with some cognitive performances: Right motor impairment correlated with a measure of set shifting (Trail Making Test B-A), and left motor impairment correlated with phonemic fluency and tasks with visuospatial material (Colored Progressive Matrices of Raven, Rey-Osterrieth Complex Figure Copy and Immediate Recall). Findings of the current study supported the conclusion that the side of clinical motor predominance scarcely influences cognition in the early untreated stages of PD, suggesting that cognitive differences between subgroups of lateralized PD patients probably may appear in more advanced disease stages.
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http://dx.doi.org/10.1080/13803395.2012.751966DOI Listing
August 2013