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Introduction: Movement Disorder Society (MDS) new diagnostic criteria for Progressive Supranuclear palsy (PSP) identifying different disease phenotypes were recently released. The aim of the present study is to report on the cognitive and behavioral features of the different phenotypes diagnosed according to the MDS criteria. Methods: Forty-nine PSP patients underwent an extensive battery of clinical assessments. Differences between PSP subtypes were computed with χ2 or ANOVA tests. Using the z scores, subjects were classified as having normal cognition, mild cognitive impairment, single or multiple domain, and dementia. A logistic regression model was implemented to investigate the major determinants of PSP non-Richardson’s syndrome phenotype. Results: Half of the cohort presented Richardson’s syndrome (46.9%), followed by PSP with parkinsonism and corticobasal syndrome (22.4% and 14.2%, respectively). Richardson’s syndrome and PSP with corticobasal syndrome presented a similar burden of disease. The only cognitive testing differentiating the phenotypes weresemantic fluency and ideomotor apraxia. The majority of our cohort was either affected by dementia or presented normal cognition. Richardson’s syndrome presented the highest rate of dementia. The only marker of PSP non-Richardson’s syndrome phenotype was better performance in visuo-spatial testing, implying worse visuo-spatial abilities in PSP Richardson’s syndrome. Conclusion: Available clinical assessments hardly capture differences between PSP phenotypes. The cognitive testing differentiating the PSP phenotypes were semantic fluency and ideomotor apraxia. In PSP, mild cognitive impairment likely represents an intermediate step from normal cognition to dementia. The only marker of PSP non-Richardson’s syndrome phenotype was better performance in visuo-spatial testing.

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.

OBJECTIVES: To explore the impact of sex and age on relationship between prodromal constipation and disease phenotype in Parkinson's disease at early stages. METHODS: A total of 385 Parkinson's disease patients from the PRIAMO study were classified according to the presence of prodromal constipation and followed for 24 months. Multivariable mixed-effect models were applied. All analyses were performed separately for sex (64.1% men) and median age (different by sex: 67 years-old in men and 68 years-old in women). RESULTS: As for sex, prodromal constipation was associated with greater odds of attention/memory complaints and apathy symptoms in women only. As for age, prodromal constipation was associated with lower cognitive and higher apathy scores in older patients only. CONCLUSIONS: Prodromal constipation anticipates lower cognitive performances and more severe apathy since the earliest stages in women and older patients. Sex- and age-related heterogeneity of prodromal markers of Parkinson's disease may impact disease phenotype.

BACKGROUND AND PURPOSE: Data suggest a relationship between sexual dysfunction, mainly erectile dysfunction in men, and worse disease progression in Parkinson's disease (PD). There is scant evidence on the correlates of sexual activity in PD patients. By involving a subgroup of 355 patients from the PRIAMO (Parkinson Disease Non Motor Symptoms) study, the present 24-month longitudinal prospective analysis aims to demonstrate that the presence of active sexual life is associated with disease progression in early PD. METHODS AND RESULTS: Multivariable mixed-effect logistic regression models showed that gastrointestinal symptoms [odds ratio 0.56, 95% confidence interval (CI) 0.39-0.82, P = 0.003] and apathy (odds ratio 0.42, 95% CI 0.29-0.63, P < 0.001) were less likely to be associated with sexual activity in men. Analysis also demonstrated that sexual activity in men was associated with lower motor disability (coefficient -2.881, 95% CI -4.732 to -1.030, P = 0.002), better quality of life (coefficient -24.196, 95% CI -44.884 to -3.508, P = 0.022; coefficient 0.083, 95% CI 0.023-0.143, P = 0.006) and lower depression scores (coefficient -1.245, 95% CI -2.104 to -0.387, P = 0.004). No association was shown in women. CONCLUSIONS: This is the first prospective longitudinal study involving a large cohort of PD patients suggesting that sexual activity is associated with lower motor and non-motor disability as well as with better quality of life in men. These findings should prompt movement disorders specialists to periodically inquiry about their patients' sexual life

Background: Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. Methods: In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1–6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden. Findings: Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceable binding potential in the ventral (p

Marina Picillo,1 Marcello Moccia,2 Emanuele Spina,2 Paolo Barone,1 Maria Teresa Pellecchia1 1Department of Medicine and Surgery, Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, University of Salerno, Salerno, Italy; 2Department of Neuroscience, Reproductive and Odontostomatologic Sciences, Federico II University, Naples, Italy Abstract: A biomarker represents a tool possibly helping physicians in predicting onset, diagnosis, and progression of a disease as well as evaluating the response to disease-modifying treatments. Currently, there is no biomarker fulfilling all such ideal criteria for Parkinson's disease (PD). In this article, we have critically reviewed the literature searching for the most reliable and reproducible clinical, biochemical, and imaging biomarkers for prodromal phase, diagnosis, and progression of PD. Different comprehensive batteries of biomarkers have been proposed as a sensitive approach to predict the onset of PD during the prodromal phase. There is a discussion about the redefinition of the clinical diagnosis of PD, including clinical biomarkers as non-motor symptoms; however, on the other hand, we have also observed that imaging biomarkers support the differential diagnosis from other causes of parkinsonism. Various clinical (eg, freezing of gait or cognitive impairment), biochemical (eg, epidermal growth factor, insulin-like growth factor 1, uric acid, etc), and imaging (eg, functional magnetic resonance imaging, voxel-based morphometry, etc) biomarkers may help envisaging disease progression of PD. To conclude, given the lack of a single biomarker that could track the entire course of the disease, our challenge is to find the best combinations of biomarkers for the different stages of the disease. Keywords: biomarkers, Parkinson's disease, progression, motor, imaging , staging, non motor

Cognitive deficits are common in Parkinson’s disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.

To assess over a period of 9 months in a sample of Italian Parkinson’s disease (PD) patients reasons leading the neurologist to modify dopaminergic treatment and patients’ causes of dissatisfaction with ongoing therapy. To evaluate the influence of disease severity on therapy persistence. A disease severity balanced sample of PD patients with stable anti-parkinsonian drugs (APD) treatment was enrolled and evaluated every 3 months. Patients requiring APD treatment modifications were discontinued from the study. The probability to modify APD treatment is greater for higher motor (UPDRS scores) and non-motor symptoms (NMSS score) severity. Both from neurologist’s and patient’s perspective, motor symptoms were the main determinants underlying APD treatment modifications. Non-motor symptoms were cause of dissatisfaction with ongoing APD treatment for 52 % of the patients, while only 36 % of the neurologists considered these as valid reasons for therapy change. REASON is the first study in PD patients that prospectively examined reasons driving APD treatment changes. Results show that the disease severity significantly increases the probability of APD treatment change. Patients attribute greater relevance than neurologists to non-motor symptoms as reason requiring treatment changes. This confirms that patient and neurologist perceptions only partially overlap.

Information about patients' adherence to therapy represents a primary issue in Parkinson's disease (PD) management. To perform the linguistic validation of the Italian version of the self-rated 8-Item Morisky Medical Adherence Scale (MMAS-8) and to describe in a sample of Italian patients affected by PD the adherence to anti-Parkinson drug therapy and the association between adherence and some socio-demographic and clinical features. MMAS-8 was translated into Italian language by two independent Italian mother-tongue translators. The consensus version was then back-translated by an English mother-tongue translator. This translation process was followed by a consensus meeting between the authors of translation and investigators and then by two comprehension tests. The translated version of the MMAS-8 scale was then administered at the baseline visit of the "REASON" study (Italian Study on the Therapy Management in Parkinson's disease: Motor, Non-Motor, Adherence and Quality Of Life Factors) in a large sample of PD patients. The final version of the MMAS-8 was easily understood. Mean ± SD MMAS-8 score was 6.1 ± 1.2. There were no differences in adherence to therapy in relationship to disease severity, gender, educational level or decision to change therapy. The Italian version of MMAS-8, the key tool of the REASON study to assess the adherence to therapy, has shown to be understandable to patients with PD. Patients enrolled in the REASON study showed medium therapy adherence.

OBJECTIVES: To assess the association between clinical and socio-demographic features and anti-Parkinson drug (APD) treatment modifications in patients with PD and to describe neurologist and patient opinions regarding the need for changes in APD therapy. METHODS: Subjects with PD with stable APD treatment over ≥3 months prior to baseline were enrolled and evaluated for socio-demographic data, disability, disease severity and neurologist and patient views on the need to modify APD treatment. RESULTS: 775 Patients were included, 51% with Hoehn and Yahr (HY) stage 1-2 (early PD) and 49% with HY stage 2.5-4 (advanced PD). Neurologists modified APD treatment in 255 patients, 97 (25%) early PD and 158 (41%; p < 0.0001) advanced PD. APD modification was strongly associated with a low educational level and UPDRS part IV score. The most common reasons behind the APD therapy changes among neurologists were presence/worsening of motor or non-motor symptoms (88% and 37% of subjects respectively). Out of 216 patients, 92% and 51% were willing to undergo APD changes to therapy because of the presence/worsening of motor or non-motor symptoms. CONCLUSIONS: Neurologist decision to change APD therapy and patients reasons for dissatisfaction with it can be prevalently attributed to the presence/worsening of motor symptoms and motor fluctuations in the advanced stages. Non-motor symptoms were considered more often by patients. The patient educational level played a key role in treatment decision.

Objective: To find out hearing ability and speech discrimination of progressive supranuclear palsy (PSP) patients, we performed audiological evaluation by means of Pure Tone (PTA) and Speech Audiometry (SA) of patients with PSP as compared with both normative values and sex-age matched Parkinson’s disease (PD) patients and healthy controls. Background: Hearing impairment (HI) and altered speech discrimination abilities have been previously demonstrated in patients with PD. Despite its high prevalence in elderly, HI has never been investigated in patients with PSP. Methods: We screened a series of PSP outpatients attending our movement disorders unit. Severity of motor symptoms, disease staging and ongoing therapy were recorded at baseline. Audiometric evaluation consisted of a standardized audiological examination, PTA and SA. PD patients and healthy age- and sexmatched subjects were selected as controls. Results: 15 PSP patients, 45 PD patients and 45 healthy controls were enrolled. PTA showed severe agedependent sensorineural HI in PSP patients as compared with both normative values and controls. PTA also confirmed our previous finding of high-frequency HI in PD patients. The mean values for the Speech Recognition Threshold were higher in PSP patients as compared with both PD patients and controls. Finally PSP patients showed a significant speech-tone dissociation and rollover phenomenon thus suggesting retro-cochlear pathology and pointing to a central rather than a peripheral origin of HI in PSP. Conclusions: Our results showed the presence of severe age-dependent sensorineural hearing impairment in PSP patients as compared with both normative values and controls. Moreover, SA showed impaired speech discrimination abilities in PSP patients as compared with both PD patients and healthy controls thus expanding the non-motor panel of PSP

The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non- English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English- language MDS-UPDRS could be confirmed in data col- lected using the Italian translation. To be designated an 'Official MDS translation,' the Comparative Fit Index (CFI) had to be C0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was C0.94. Exploratory factor analyses revealed some differ- ences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now avail- able for use. This protocol will serve as outline for further validation of this in multiple languages.

INTRODUCTION: Apathy is a neuropsychiatric symptom in Parkinson's Disease (PD) which has a negative impact on quality of life and might be related in part to damage of presynaptic dopaminergic system. Little is known about relationship between striatal dopamine levels and apathy in PD patients without dementia and/or depression. The aim of the present study was to investigate the relationship between "pure apathy" and striatal dopamine uptake in untreated, drug-naïve PD patients without clinically significant dementia and/or depression. METHODS: Fourteen PD patients with pure apathy and 14 PD patients without apathy, matched for age, side of motor symptoms at onset, motor disability and disease duration, underwent both neuropsychological and behavioral examination including self-rated version of the Apathy Evaluation Scale (AES-S). All patients underwent 123 I-FP-CIT (DaT-SCAN) SPECT to assess dopamine transporter (DAT) striatal uptake. RESULTS: PD patients with apathy showed lower DAT levels in the striatum than non-apathetic patients. After Bonferroni correction the difference between groups was significant in the right caudate. CONCLUSIONS: Apathy is associated with reduced striatal dopamine transporter levels, independent of motor disability and depression in non-demented PD patients. These findings suggest that dysfunction of dopaminergic innervation in the striatum and particularly in the right caudate may contribute to development of apathy in early PD.