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Background: Functional motor disorders (FMD) are highly disabling neurological conditions in which postural control deficits increase the risk of falls and disability in performing daily living activities. Scattered evidence suggests that such disturbances may depend on abnormal attentional focus and might improve with distraction., Research Question: How do motor and cognitive dual tasks performed under two different sensory conditions shape postural control in patients with FMD., Methods: This posturographic study involved 30 patients with FMD (age, 45.20 ± 14.57 years) and 30 healthy controls (age, 41.20 ± 16.50 years). Postural parameters were measured with eyes open, and eyes closed in quiet stance (single task) and on a motor dual task (m-DT) and a calculation (cognitive) dual task (c-DT). The dual task effect (DTE, expressed in percentage) on motor and cognitive performance was calculated for sway area, length of Center of Pressure (CoP), and velocity of CoP displacement., Results: There was a statistically significant three-way interaction between task, condition, and group for the DTE on sway area (p = 0.03). The mean sway area DTE on the motor task in the eyes-closed condition was increased by 70.4 % in the healthy controls, while it was decreased by 1% in the patient group (p = 0.003). No significant three-way interaction was observed for the DTE on length of CoP and velocity of CoP displacement., Significance: This study provides novel preliminary evidence for the benefit of a simple motor dual task in the eyes closed condition as a way to improve postural control in patients with FMD. These findings are relevant for the management of postural control disorders in patients with FMD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Progressive supranuclear palsy (PSP) is a rare and rapidly progressing atypical parkinsonism. Albeit existing clinical criteria for PSP have good specificity and sensitivity, there is a need for biomarkers able to capture early objective disease-specific abnormalities. This study aimed to identify gait patterns specifically associated with early PSP. The study population comprised 104 consecutively enrolled participants (83 PD and 21 PSP patients). Gait was investigated using a gait analysis system during normal gait and a cognitive dual task. Univariate statistical analysis and binary logistic regression were used to compare all PD patients and all PSP patients, as well as newly diagnosed PD and early PSP patients. Gait pattern was poorer in PSP patients than in PD patients, even from early stages. PSP patients exhibited reduced velocity and increased measures of dynamic instability when compared to PD patients. Application of predictive models to gait data revealed that PD gait pattern was typified by increased cadence and longer cycle length, whereas a longer stance phase characterized PSP patients in both mid and early disease stages. The present study demonstrates that quantitative gait evaluation clearly distinguishes PSP patients from PD patients since the earliest stages of disease. First, this might candidate gait analysis as a reliable biomarker in both clinical and research setting. Furthermore, our results may offer speculative clues for conceiving early disease-specific rehabilitation strategies.

To evaluate intraocular pressure (IOP) and choroidal thickness (ChT) postural changes in multiple system atrophy (MSA), Parkinson's disease (PD) patients and healthy controls (HC). 20 MSA patients, 21 PD patients and 14 HC, were examined. All subjects underwent a complete examination, including corneal thickness, ChT, IOP and axial length (AL) measurements. IOP measurement was performed in supine, sitting, and standing positions, whereas ChT in sitting and standing positions. Supine to standing IOP variations were significantly higher in MSA vs PD(p = 0.01) and in MSA vs HC (p < 0.0001), whereas no significant differences were observed between PD and HC (p = 0.397). Mean sub-foveal ChT in MSA was 240 ± 92 μm in sitting position, and 215 ± 94 μm in standing position with a significant reduction (p = 0.008). Mean sub-foveal ChT in PD was 258 ± 79 μm in sitting position, and 259 ± 76 μm in standing position (p = 0.887). In HC it was 244 ± 36 μm in sitting position, and 256 ± 37 μm in standing position with a significant increase (p = 0.007). The significant IOP and ChT postural changes can be considered additional hallmarks of autonomic dysfunction in MSA and further studies are needed to consider them as biomarkers in the differential diagnosis with PD.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which environmental (lifestyle, dietary, infectious disease) factors as well as genetic make-up play a role. Metabolomics, an evolving research field combining biomarker discovery and pathogenetics, is particularly useful in studying complex pathophysiology in general and Parkinson's disease (PD) specifically. PD, the second most frequent neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of intraneural inclusions of α-synuclein aggregates. Although considered a predominantly movement disorder, PD is also associated with number of non-motor features. Metabolomics has provided useful information regarding this neurodegenerative process with the aim of identifying a disease-specific fingerprint. Unfortunately, many disease variables such as clinical presentation, motor system involvement, disease stage and duration substantially affect biomarker relevance. As such, metabolomics provides a unique approach to studying this multifactorial neurodegenerative disorder., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Parkinson's disease is the second most frequent neurodegenerative disorder. Its diagnosis is challenging and mainly relies on clinical aspects. At present, no biomarker is available to obtain a diagnosis of certainty in vivo., Objective: The present review aims at describing machine learning algorithms as they have been variably applied to different aspects of Parkinson's disease diagnosis and characterization., Methods: A systematic search was conducted on PubMed in December 2019, resulting in 230 publications obtained with the following search query: "Machine Learning" "AND" "Parkinson Disease"., Results: The obtained publications were divided into 6 categories, based on different application fields: "Gait Analysis - Motor Evaluation", "Upper Limb Motor and Tremor Evaluation", "Handwriting and typing evaluation", "Speech and Phonation evaluation", "Neuroimaging and Nuclear Medicine evaluation", "Metabolomics application", after excluding the papers of general topic. As a result, a total of 166 articles were analyzed after elimination of papers written in languages other than English or not directly related to the selected topics., Conclusion: Machine learning algorithms are computer-based statistical approaches that can be trained and are able to find common patterns from big amounts of data. The machine learning approaches can help clinicians in classifying patients according to several variables at the same time., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Anxiety is a common neuropsychiatric symptom in Parkinson's disease (PD). Until now, anxiety has been consistently related to cognitive deficits and severity of motor symptoms, whereas the association between anxiety and motor subtypes (TD-PD, tremor dominant and PIGD-PD, postural instability/gait disturbances dominant) revealed contrasting results. The present study aims to investigate the relationship between PD motor subtypes and anxiety and to explore whether the relationship between anxiety and cognitive deficits occurs in a specific PD motor subtype. Consecutive PD outpatients were recruited and divided into TD-PD and PIGD-PD groups according to Jankovic et al.'s criteria. All participants underwent a neuropsychological battery to evaluate anxiety, apathy, the global cognitive functioning, memory abilities, executive and visuo-constructional functions. Thirty-six patients with TD-PD and 35 patients with PIGD-PD were enrolled. The two groups did not differ on demographical and clinical variables. As for the severity of anxiety, no significant difference between the two groups was found. Regression analysis revealed that higher anxiety score was associated with poorer performance on constructional visuospatial test in both TD-PD and PIGD-PD. Clinical variables were not associated with anxiety in the two groups. Our findings indicated that the severity of anxiety was not associated with any PD motor subtypes. Moreover, regression analysis revealed that impaired visuo-constructional abilities are related to anxiety independently of PD motor subtypes. Since altered fronto-parietal network might be one of the pathogenetic mechanisms underpinning anxiety and constructional visuospatial deficits, the treatment of cognitive dysfunctions might reduce anxious symptoms.

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

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world, while Progressive Supranuclear Palsy (PSP) is an atypical Parkinsonism resembling PD, especially in early stage. Assumed that gait dysfunctions represent a major motor symptom for both pathologies, gait analysis can provide clinicians with subclinical information reflecting subtle differences between these diseases. In this scenario, data mining can be exploited in order to differentiate PD patients at different stages of the disease course and PSP using all the variables acquired through gait analysis., Methods: A cohort of 46 subjects (divided into three groups) affected by PD patients at different stages and PSP patients was acquired through gait analysis and spatial and temporal parameters were analysed. Synthetic Minority Over-sampling Technique was used to balance our imbalanced dataset and cross-validation was applied to provide different training and testing sets. Then, Random Forests and Gradient Boosted Trees were implemented., Results: Accuracy, error, precision, recall, specificity and sensitivity were computed for each group and for both algorithms, including 16 features. Random Forests obtained the highest accuracy (86.4%) but also specificity and sensitivity were particularly high, overcoming the 90% for PSP group., Conclusion: The novelty of the study is the use of a data mining approach on the spatial and temporal parameters of gait analysis in order to classify patients affected by typical (PD) and atypical Parkinsonism (PSP) based on gait patterns. This application would be helpful for clinicians to distinguish PSP from PD at early stage, when the differential diagnosis is particularly challenging., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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

Introduction: About 90% of cases of Parkinson's disease (PD) are idiopathic and attempts to understand pathogenesis typically assume a multifactorial origin. Multifactorial diseases can be studied using metabolomics, since the cellular metabolome reflects the interplay between genes and environment., Objective: The aim of our case-control study is to compare metabolomic profiles of whole blood obtained from treated PD patients, de-novo PD patients and controls, and to study the perturbations correlated with disease duration, disease stage and motor impairment., Methods: We collected blood samples from 16 drug naïve parkinsonian patients, 84 treated parkinsonian patients, and 42 age matched healthy controls. Metabolomic profiles have been obtained using gas chromatography coupled to mass spectrometry. Multivariate statistical analysis has been performed using supervised models; partial least square discriminant analysis and partial least square regression., Results: This approach allowed separation between discrete classes and stratification of treated patients according to continuous variables (disease duration, disease stage, motor score). Analysis of single metabolites and their related metabolic pathways revealed unexpected possible perturbations related to PD and underscored existing mechanisms that correlated with disease onset, stage, duration, motor score and pharmacological treatment., Conclusion: Metabolomics can be useful in pathogenetic studies and biomarker discovery. The latter needs large-scale validation and comparison with other neurodegenerative conditions.

Introduction : Impulse control disorders (ICDs) in Parkinson's disease (PD) are a group of impulsive behaviors most often associated, but not limited to, dopamine replacement therapy (DRT), particularly the use of dopamine agonists (DA). ICDs can impair activities of daily living and have a strong negative impact on quality of life of patients and their families. Areas covered : This review mainly focusses on the most common ICDs in the context of currently accepted management strategies for PD and emphasizes areas of controversy in need of further research. The authors further describe the concept of dopamine agonist withdrawal (DAWS) syndrome and its implication for the treatment of ICDs, the role of recently available antiparkinsonian drugs and routes of delivery, and non-pharmacological treatments. Expert opinion : When ICDs develop, proper management mainly consists of reducing, discontinuing or switching dopaminergic agents, especially of DA. In these scenarios, patients should be closely followed up as their motor condition may deteriorate along with occurrence of DAWS. Assessment of the presence and intensity of ICDs should be carried throughout the course of the disease and not only when a particular treatment is started or when the dosage is increased, since their occurrence is not linearly related to DRT alone.

Cognition and gait appear to be closely related. The chronological interplay between cognitive decline and gait dysfunction is not fully understood. The aim of the present prospective study is investigating whether the dysfunction of specific gait parameters, during specific task and medication conditions, may predict subsequent cognitive impairment in Parkinson's disease (PD). We evaluated cognition and gait in 39 Parkinsonian patients at an initial assessment and after 3 years. Cognitive performance was evaluated with a neuropsychological battery designed to assess memory, executive/attention, and visuospatial domains. Gait was investigated using a gait analysis system during both the off and on states in the following conditions: (1) normal gait; (2) motor dual task; and (3) cognitive dual task. We used regression models to determine whether gait predicts subsequent cognitive dysfunction. Overall, the cognitive test scores were stable over time with the exception of the executive/attention scores, whereas all gait parameters declined. The step length during the cognitive dual task during the on state at the initial evaluation was the only significant predictor of executive/attention domain dysfunction at follow up. The results were confirmed when executive/attention dysfunction at the initial assessment evaluation was included in the regression model as a covariate. Our longitudinal study offers additional insight into the progression of gait dysfunction, and its chronological relationship with cognitive dysfunction in PD patients. In particular, the present study indicates that step length during a cognitive task when on medication is an independent predictor of future executive/attention decline.

Introduction: Previous studies exploring the association between apathy and cognitive deficits in Parkinson's disease (PD) employed scales and questionnaires for apathy, which did not control for the possible confounding effect of motor symptoms. Here we investigated the cognitive correlates of "pure apathy" by the Dimensional Apathy Scale, which allows us to assess apathy minimizing the influence of motor symptoms., Methods: Consecutive PD outpatients referred to our centre were screened. All participants underwent a neuropsychological battery to assess verbal memory, executive functions and visuospatial abilities, apathy and depressive symptoms., Results: We enrolled 56 non-depressed and non-demented PD patients, of whom 28 were apathetic and 28 were not. The two groups did not differ on demographic and clinical aspects; apathetic PD patients performed worse than non-apathetic PD patients on the part A, B and B-A of Trail Making Test and the interference task of Stroop test. No significant differences were found on memory and perceptual visuospatial tasks., Conclusions: Our results demonstrated that "pure apathy" is associated with more severe executive dysfunctions such as alteration of set-shifting and inhibitory control, which are mediated by prefrontal cortex and subcortical regions (i.e. basal ganglia). Our findings also supported the hypothesis that co-occurrence of apathy and executive deficits may be the epiphenomenon of damage in prefrontal-striatal cortical circuitries connecting dorsolateral prefrontal cortex, anterior cingulate cortex and basal ganglia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Non-motor symptoms in Parkinson's disease (PD), such as cognitive, emotional, autonomic and somatosensory alterations, are not ubiquitous but vary between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes of the syndrome. Non-motor phenomena (e.g., anxiety, depression and apathy) have been related to representation of autonomic and somatosensory sensations (interoception), and recent findings suggest interoceptive deficits in PD., Objectives: To test whether interoceptive processing is differently affected in TD and PIGD phenotypes, by assessing both interoceptive accuracy and sensibility in PD patients with TD and PIGD subtypes, and in healthy controls., Methods: Interoceptive accuracy was measured by the heartbeat perception task requiring participants to count their own heartbeats in a given time interval. A time-estimation, control task was also administered asking participants to count the seconds in a set period of time. Interoceptive sensibility was assessed by a questionnaire of subjective interoception. Finally, the patients underwent measures of anxiety, depression, apathy and anhedonia, and impulsive-compulsive disturbances., Results: The main results showed reduced interoceptive accuracy and sensibility in TD patients relative to both PIGD patients and healthy controls. Reduced interoceptive accuracy of TD group was a reliable result since their performance on the time estimation control task was comparable to that of both PIGD patients and healthy controls., Conclusions: These findings demonstrate that the behavioural assessment of different aspects of interoceptive processing can provide with a further marker for subtyping patients with PD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Apathy is a state of diminished goal-directed speech, motor activity and emotions. The prevalence of apathy in Parkinson's disease (PD) ranges from 16 to 62%. Several studies have investigated the relationships between apathy and other dimensions of PD, but little is known about possible discrepancies between self-evaluation (SE) and caregiver reporting (CR) of this symptom. The aim of this study is twofold: 1) to investigate the differences in apathy evaluations according to the point of view from which apathy is reported (SE vs CR); 2) to identify the possible relationships between each of the two evaluations (SE and CR) and cognitive and affective dimensions of PD. Forty-eight patients with PD were assessed using the Apathy Evaluation Scale (AES) in its SE and CR versions (AES-SE and AES-CR); cognitive, affective and behavioral symptoms were also assessed. AES-SE scores were significantly higher than AESCR ones. Neither AES version correlated with depression, whereas both correlated with motor impairment, disease stage and behavioral symptoms. Mini-Mental State Examination and Frontal Assessment Battery scores showed significant negative correlations only with AES-SE scores. Our findings suggest that the point of view from which apathy is seen can lead to significant discrepancies, even when using the same tool. This should be taken into account in order to obtain correct assessment of this disabling and distressing symptom.

Background: Bisphenol A (BPA) is a widely distributed estrogen-mimetic molecule, with well-established effects on the dopaminergic system. It can be found in canned food, dental sealants, thermal paper, etc. BPA undergoes liver conjugation with glucuronic acid and is subsequently excreted in the urine., Objectives: In the present study we quantified the concentration of free and conjugated Bisphenol A in blood of patients affected by Parkinson Disease, using their spouses as controls., Methods: An interview was performed to determine possible confounders in BPA exposure. Free and conjugated BPA were quantified by gas chromatography coupled with mass spectrometry., Results: Parkinson's Disease patients carried a statistically significant lower amount of conjugated Bisphenol A compared to controls. The two populations were mostly homogeneous in terms of exposure to possible Bisphenol A sources. The only exceptions were exposure to canned tuna and canned tomatoes PD patients consumed significantly more of both (p<0.05). Moreover, no difference in Bisphenol A glucuronidation was found after stratification by typology of anti-Parkinson's drug taken and after conversion to the Levodopa Equivalent Daily Dose., Conclusion: BPA glucuronidation was decreased in patients with Parkinson disease. The possible unique mechanisms underlying Bisphenol A metabolism in PD patients deserve further elucidation. Moreover, further study is needed to assess a possible BPA role in Parkinson's Disease pathogenesis, due to its documented dopaminergic toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Cognitive deficits are common in Parkinson's disease (PD) since the early stages and many patients eventually develop dementia. Yet, occurrence of dementia in PD is unpredictable. Evidence supports the hypothesis that insulin-like growth factor-1 (IGF-1) is involved in cognitive deficits. Our aim was to evaluate the relationship between serum IGF-1 levels and neuropsychological scores in a large cohort of drug-naïve PD patients during the earliest stages of the disease., Methods: Serum IGF-1 levels were determined in 405 early, drug-naïve PD patients and 191 healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI). The association between serum IGF-1 levels and neuropsychological scores was evaluated with linear regression analysis., Results: IGF-1 levels were similar in PD and HC. In PD patients the lowest IGF-1 quartile was a predictor of lower performances at the Semantic Fluency task (β = -3.46, 95%CI: -5.87 to -1.01, p = 0.005), the Symbol Digit Modalities Score (β = -2.09, 95%CI: -4.02 to -0.15, p = 0.034), and Hopkins Verbal Learning Test Retention (β = -0.05, 95%CI: -0.09 to -0.009, p = 0.019)., Conclusions: Lower serum IGF-1 levels are associated to poor performances in cognitive tasks assessing executive function, attention and verbal memory in a large cohort of early PD patients. Follow-up studies are warranted to assess if IGF-1 is related to the development of dementia in PD.

Introduction: Parkinson's disease (PD) is characterized by a wide spectrum of non-motor symptoms that may impact negatively on the activities of the patient's daily life and reduce Health-related quality of life (HRQoL). The present study explored the impact of specific non-motor symptoms on the HRQoL in PD., Methods: Eighty-four outpatients underwent the Montreal Cognitive Assessment (MoCA) assessing global functioning and several questionnaires to assess depression, apathy, impulse control disorders (ICD), anxiety, anhedonia and functional impact of cognitive impairment. The perceived QoL was assessed by Parkinson's Disease Questionnaire (PDQ-8). The PD sample was divided into patients with high and low HRQoL around the median of PDQ-8 and compared on clinical features, cognitive and neuropsychiatric variables. A linear regression analysis, in which the global functioning, apathy, depression, anxiety, anhedonia, ICD and the functional autonomy scores were entered as independent variables and PDQ-8 score as dependent variable, was applied., Results: Patients with lower HRQoL were more depressed, apathetic, anxious and showed more severe reduction of functional autonomy and global functioning than patients with high HRQoL. The regression analysis revealed that higher level of anxiety, executive apathy and more reduced functional autonomy were significantly associated with higher score on PDQ-8., Conclusions: The finding indicated that anxiety, apathy associated with impaired planning, attention and organization (i.e., executive apathy evaluated by the Dimensional Apathy Scale) and reduced functional autonomy contribute significantly to reduce the HRQoL in PD. Therefore, early identification and management of these neuropsychiatric symptoms should be relevant to preserve HRQoL in PD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: To investigate intrinsic neural networks connectivity changes in Parkinson's disease (PD) patients with and without impulse control disorders (ICD)., Methods: Fifteen patients with PD with ICD (ICD+), 15 patients with PD without ICD (ICD-) and 24 age and sex-matched healthy controls (HC) were enrolled in the study. To identify patients with and without ICD and/or punding, we used the Minnesota Impulsive Disorders Interview (MIDI) and a clinical interview based on diagnostic criteria for each symptom. All patients underwent a detailed neuropsychological evaluation. Whole brain structural and functional imaging was performed on a 3T GE MR scanner. Statistical analysis of functional data was completed using BrainVoyager QX software. Voxel-based morphometry (VBM) was used to test whether between-group differences in resting-state connectivity were related to structural abnormalities., Results: The presence of ICD symptoms was associated with an increased connectivity within the salience and default-mode networks, as well as with a decreased connectivity within the central executive network (p < .05 corrected). ICD severity was correlated with both salience and default mode networks connectivity changes only in the ICD+ group. VBM analysis did not reveal any statistically significant differences in local grey matter volume between ICD+ and ICD- patients and between all patients and HC (p < .05. FWE)., Conclusions: The presence of a disrupted connectivity within the three core neurocognitive networks may be considered as a potential neural correlate of ICD presence in patients with PD. Our findings provide additional insights into the mechanisms underlying ICD in PD, confirming the crucial role of an abnormal prefrontal-limbic-striatal homeostasis in their development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Apathy is associated with motor symptoms in Parkinson's disease (PD); therefore, its evaluation could be influenced by motor disability. The Dimensional Apathy Scale (DAS) evaluates apathy excluding confounding effects of motor symptoms. The present study had three major aims: (a) to explore the psychometric properties of the DAS in non-demented PD patients; (b) to determine an optimal cut-off score of the DAS to identify apathetic PD patients; and (c) to determine a specific apathy profile in PD patients as compared to healthy controls (HC)., Methods: One hundred and seven PD patients and 100 HC completed the DAS. To explore convergent and divergent validity of the DAS in PD, patients underwent the Apathy Evaluation Scale and tools for assessing depressive symptoms, anxiety and cognition. Clinical aspects were recorded. Receiver operating characteristic curve analyses were carried out to estimate the optimal cut-off score to identify clinically significant apathy., Results: The DAS scores showed high internal consistency and good evidence for convergent and discriminant validity. Maximum discrimination between apathetic and non-apathetic patients was obtained with a cut-off score of 28.5 (total score range: 0-72 with higher score indicating more severe apathy). Comparison between PD and HC groups revealed significant differences on total DAS, behavioural/cognitive initiation and emotional subscales., Conclusions: The DAS is a valid and reliable tool to assess multidimensional apathy in PD, independently of severity of motor symptoms. Reduced initiation of thought and behaviour and emotional blunting characterised PD patients, without confounding effects of motor disability.

Objectives: To explore the relationships between nigrostriatal dysfunction and neuropsychiatric symptoms (including anxiety, depression and apathy) in a large cohort of newly diagnosed, drug-naïve Parkinson disease (PD) patients compared to a cohort of healthy controls (HC)., Methods: This is a cross-sectional analysis of the Parkinson's Progression Markers Initiative (PPMI) cohort at baseline, including 405 PD patients and 187 HC. Nigrostriatal degeneration was evaluated by means of SPECT DAT scan. Relationships between neuropsychiatric symptoms and DAT uptakes were analysed by means of stepwise multiple regression analysis., Results: In the PD group, lower DAT uptake in the right caudate was associated with higher STAI trait subscore (β = -2.939, 95%CI: -4.634 to -1.254, p = 0.001). Depression and apathy scores were not related with DAT uptakes. No associations were found in the HC group., Conclusions: Our cross-sectional analysis of the PPMI data shows that lower caudate DAT uptake is associated with higher level of anxiety. The data strengthens the relationship between dopaminergic dysfunction and neuropsychiatric symptoms in early PD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

Introduction: Higher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD., Methods: 79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models., Results: The average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382-0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = -0.01; 95%CI = -0.02 to 0.00), with 50% reduced LEDD (Coef = -0.01; 95%CI = -0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = -0.01; 95%CI = -0.01 to 0.00), but not with UPDRS part IV total score (Coef = -0.00; 95%CI = -0.00 to 0.00)., Conclusion: Caffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD., (Copyright © 2016. Published by Elsevier Ltd.)

Pisa syndrome is defined as a reversible lateral bending of the trunk with a tendency to lean to one side. It is a frequent and often disabling complication of Parkinson's disease, and has also been described in several atypical forms of parkinsonism and in neurodegenerative and psychiatric disorders after drug exposure and surgical procedures. Although no consistent diagnostic criteria for Pisa syndrome are available, most investigations have adopted an arbitrary cutoff of at least 10° of lateral flexion for the diagnosis of the syndrome. Pathophysiological mechanisms underlying Pisa syndrome have not been fully explained. One hypothesis emphasises central mechanisms, whereby Pisa syndrome is thought to be caused by alterations in sensory-motor integration pathways; by contrast, a peripheral hypothesis emphasises the role of anatomical changes in the musculoskeletal system. Furthermore, several drugs are reported to induce Pisa syndrome, including antiparkinsonian drugs. As Pisa syndrome might be reversible, clinicians need to be able to recognise this condition early to enable prompt management. Nevertheless, further research is needed to determine optimum treatment strategies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Anxiety disorders are common in Parkinson's Disease (PD) and their identification is relevant even at early stages. The Parkinson Anxiety Scale (PAS) evaluates anxiety in PD; it was used only in the original validation study in PD patients mainly at 2-3 stages of Hoehn & Yahr system (H&Y). The study aimed to investigate psychometric properties of observer-rated version of the PAS (OR-PAS), prevalence rate of anxiety and its features, compared with diagnostic criteria in early PD patients., Methods: A sample of 101 PD patients with H&Y:1-2 underwent the OR-PAS. To assess convergent and divergent validity, PD patients underwent Beck Anxiety Inventory, and scales assessing depression, apathy, anhedonia and cognition. To diagnose anxiety disorders, Mini International Neuropsychiatric Inventory was used as gold standard. A "receiver operating characteristics" curve was obtained; positive and negative predictive values were calculated for different cut-off points of the OR-PAS and its subscales., Results: There was no missing data, no floor and ceiling effects; mean score was 12.2±10.1; Cronbach's alpha was 0.899. The OR-PAS showed good convergent and divergent validity. Maximum discrimination was obtained with a cut-off score of 8.5. The anxiety occurred in 59 patients (58.4%)., Conclusion: The OR-PAS is a reliable and valid screening instrument for assessing anxiety in patients at early PD. Anxiety was found in 58.4% of PD patients, demonstrating that anxiety occurs even at early stages., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The heterogeneity of PD suggests the existence of different subtypes. While some motor clusters have been consistently identified, little is known about non-motor PD subtypes and motor-non-motor interplay. Research in this regard has produced somewhat contradictory results, which might be biased by the inclusion of treated patients., Patients and Methods: We performed a non-hierarchical cluster analysis using both motor and non-motor data on 398 newly diagnosed untreated PD patients enrolled in the Parkinson's Progressive Marker Initiative (PPMI) study. We further evaluated whether dopaminergic dysfunction, as measured by (123)[I]-FP-CIT SPECT scan, could explain, at least partially, the observed difference between the clusters., Results: Three clusters were identified. Group 1 was characterized by the lowest motor and non-motor burden, whereas group 2 and 3 had similar motor disability, but different non-motor involvement, especially with regards to apathy and hallucinations. (123)[I]-FP-CIT binding values paralleled motor disability burden among the 3 clusters, but further multivariate analyses also revealed a negative correlation with depression., Discussion: Our results confirm the motor as well as non-motor heterogeneity of PD, suggesting the existence of 3 different subtypes. Dopaminergic dysfunction only marginally explains the non-motor variability of PD. Identification of such clusters can have important implications for generating novel pathophysiological hypotheses and therapeutic strategies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: In Parkinson's disease (PD), non motor symptoms can fluctuate either along or irrespective to motor on/off phenomena. Prospective studies suggest that higher motor scores and levodopa dosage, younger age at onset and female gender represent risk factors for motor fluctuations' development. Yet, the predictors of development of non motor fluctuations (NMF) are less clear. In this prospective study, we aimed to assess the relationship between NMF and gender along with other potential risk factors., Methods: Forty-seven (16 women/31 men) de novo, drug-naïve PD patients have been followed for 4 years since diagnosis. Motor and non motor fluctuations were evaluated with the 19-item Wearing off Questionnaire (WOQ-19). The association between gender and NMF was explored with multivariable regression models adjusted for age at onset, motor and non motor symptoms at diagnosis and levodopa intake at follow up., Results: Female gender was more likely associated with a diagnosis of NMF (adjusted odds ratio, AOR = 5.33,95%CI = 1.21-23.4, p = 0.027), but not with a diagnosis of generic wearing off at follow up (OR = 3.66, 95%CI = 0.8-16.8, p = 0.097). Women had greater likelihood of developing higher WOQ-19 Non motor scores (AOR = 4.58, 95%CI = 1.23-17.03, p = 0.023), but not higher WOQ-19 Total scores (AOR = 2.88, 95%CI = 0.86-9.71, p = 0.087) compared to men. Notwithstanding, no gender differences were detected in medication intake., Conclusions: We showed that female gender represents a major risk factor for the development of NMF. There were no gender differences in medication intake, thus NMF in women remain mostly underestimated and not properly treated. From a practical standpoint, clinicians should take into account the role of gender in the management of NMF in PD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naïve PD patients. Forty-nine early, drug-naïve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA ≤ 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naïve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis.

Introduction: To investigate gray matter (GM) and cortical thickness (CTh) changes in patients with Parkinson's disease (PD) with and without Impulse Control Disorders (ICDs)., Methods: Fifteen patients with PD with ICDs (ICD+), 15 patients with PD without ICDs (ICD-) and 24 age and sex-matched healthy controls (HCs) were enrolled in the study. Patients were screened for ICDs by the Minnesota Impulsive Disorders Interview (MIDI) and underwent an extensive neuropsychological evaluation. Whole brain structural imaging was performed on a 3T GE MR scanner. Surface-based investigation of CTh was carried out by using Freesurfer Software. We also used voxel-based morphometry to investigate the pattern of GM atrophy., Results: The voxel-wise analysis of the regional differences in CTh revealed that ICD+ patients showed a statistically significant (p<0.01 FDR) thicker cortex when compared to both ICD- patients and HCs in the anterior cingulate (ACC) and orbitofrontal (OFC) cortices. Moreover, cortical thickness abnormalities were positively correlated with ICD severity (p<0.05 FDR). VBM data did not reveal any statistically significant differences in local GM., Conclusions: Our results demonstrate that ICD+ patients have an increased CTh in limbic regions when compared with ICD- patients at the same disease stage and with an equal daily levodopa equivalent dose. These corticometric changes may play a role in the lack of inhibition of compulsive behaviors. The presence of such structural abnormalities may result from a synergistic effect of dopaminergic therapy in patients with a pre-existing vulnerability to develop an abnormal behavioral response to external stimuli., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Freezing of gait (FOG) is one of the most common gait disturbances in patients with Parkinson's disease (PD). Recently, a PET study has documented that PD patients with FOG display cholinergic deficits selectively driven by nucleus basalis of Meynert (nbM)-neocortical denervation and not by peduncolopontine nucleus (PPN)-thalamic degeneration. Short-latency afferent inhibition (SAI) is a neurophysiological technique that allows evaluating major cholinergic sources in the central nervous system in vivo. We sought to determine whether central cholinergic circuits, evaluated by means of SAI testing, are impaired in patients with PD with FOG (FOG+) as compared to those without (FOG-). SAI and neuropsychological data were collected in 14 FOG+ and 10 FOG-. SAI was also performed in 11 healthy control subjects. Demographic, clinical, and cognitive data were compared by using non-parametric tests. Parametric tests were used to compare electrophysiological results among groups. FOG+ and FOG- had similar SAI without significant differences with controls (p = 0.207). None of the PD patients had SAI values outside the normal range (>72 %). FOG+ presented poorer executive and visuospatial performances as compared to FOG-. Despite the presence of cognitive deficits, SAI failed to detect any significant decrease of cholinergic activity in FOG+. However, nbM-related cholinergic dysfunction cannot be ruled out. In fact, integrity or even increased activation of PPN-related cholinergic circuits may mask an eventual nbM dysfunction thus resulting in normal SAI findings. Indeed, selective PPN cholinergic neurons sparing maybe a distinctive features of FOG. Alternatively or complementary, FOG pathophysiology is underpinned by non-cholinergic neurotransmitters dysfunction.

Introduction: In PD, Mild Cognitive Impairment (PD-MCI) occurs since early stages of disease. The aims were to assess presence of PD-MCI in untreated, drug-naive PD patients, and to follow-up the sample over 4 years to ascertain evolution of neurocognitive profile., Methods: Seventy-six patients underwent neuropsychological testing at baseline (T0), and after 2 (T1:n = 62) and 4 years (T2:n = 55). Diagnosis of PD-MCI and PD-associated dementia (PDD) was made according to current consensus criteria., Results: PD-MCI occurred in 25/76 patients (32.9%) at baseline, and 4 of them reverted from PD-MCI to Normal Cognition (Reverters), 7 remained stable (Non-Reverters) and 2 developed PDD at T2; 12 patients were lost to the follow-up. Among the 51 patients with normal cognition (PD-CN) at T0, 27 had normal cognition at T2 (5 of them were Reverters with respect to diagnosis at T1), 5 had MCI at T1 and T2 (Non-Reverters), 9 had MCI at T2 only, whereas 1 developed PDD; 9 patients were lost to the follow-up. At baseline, Reverters (n = 9) had younger age at onset and better performance on constructional visuospatial task than Non-Reverters (n = 12). Compared to patients without PD-MCI at all evaluations (n = 19), Reverters had poorer performance on verbal immediate recall and attention tasks and higher level of apathy at T0. Reduced performance on the Stroop Test at baseline predicted PD-MCI at T2., Conclusion: Executive dysfunctions predicted development of PD-MCI after few years from onset. Reversal from PD-MCI to PD-CN was related to young age at onset and high level of apathy at baseline evaluation., (Copyright © 2015. Published by Elsevier Ltd.)

The variability in the clinical phenotype of Parkinson's disease (PD) suggests the existence of several subtypes of the disease. Motor heterogeneity of PD is well established, but not nonmotor heterogeneity. At present, we are unable to predict the rate of progression of PD based on robust biomarkers. We aimed to examine the heterogeneity of PD by attempting to identify nonmotor factors associated with the rate of motor progression and functional decline, as measured by the time to reach the need for levodopa therapy during the first 4 years from diagnosis in a cohort of de novo PD patients. The median time to introduction of L-dopa for patients with urinary symptoms was significantly shorter than that for those without (20 vs. 37 months; P = 0.001). Cox's regression models showed that the urinary domain was associated with a higher probability of starting L-dopa (hazard ratio: 2.1; P = 0.002). There was no influence of such confounders as sex, age, baseline motor features, use of dopamine agonists and/or monoamine oxidase B inhibitors, and total L-dopa equivalent daily dosage. Patients with urinary symptoms had higher baseline and follow-up motor and nonmotor disturbances than those without. Our study suggests the existence of a subgroup of patients who show urinary symptoms along with an overall higher motor and nonmotor burden. Such patients are prone to manifest a rapid functional decline over the first 4 years of the disease. Urinary symptoms might be a clinical marker of severity as well as a possible nonmotor subtype of PD., (© 2015 International Parkinson and Movement Disorder Society.)

Introduction: Epidemiological studies report a 60-70% reduced risk of Parkinson's disease (PD) in smokers as compared to non-smokers. However, relationships between former smoking and PD have been poorly investigated., Methods: We recruited 116 de novo PD subjects, and investigated current, former and never smoking, and reasons for smoking cessation among former smokers. Two hundred and thirty-two controls were matched by Propensity Score., Results: PD subjects and controls were found to be current smokers (7.7 vs. 39.6%), former smokers (43.9 vs. 6.5%) and never smokers (48.2 vs. 53.9%). Logistic regression showed that current smokers were less likely to have PD (p < 0.001; OR: 0.22; 95% CI: 0.10-0.46), while former smokers were more likely to have PD (p < 0.001; OR: 7.6; 95% CI: 4.09-15.75), as compared to never smokers. Fifty-one PD patients reported quitting smoking before PD diagnosis (mean time since cessation 9.4 ± 7.3 years). Most important reasons to quit smoking in PD group were illness different from PD (26 subjects, 51.0%), knowledge of the harmful effects of smoking (24 subjects, 47.0%), and physician's advice (1 subject, 2.0%)., Conclusion: The reduced prevalence of current smokers among PD subjects as compared to healthy controls is consistent with previous findings, suggesting a possible neuroprotective effect of smoking. However, it could be due, at least in part, to the increased prevalence of former smokers among PD patients, that were more prone to quit smoking as compared to healthy controls. We suggest that smoking cessation could be an early preclinical condition occurring in PD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cognitive impairment is common in PD, even in early stages. The construct of mild cognitive impairment has been used to identify clinically evident cognitive impairment without functional decline in PD patients (PD-MCI). The aim of the present study was to investigate brain connectivity associated with PD-MCI through RS-fMRI. RS-fMRI at 3T was collected in 42 PD patients and 20 matched healthy controls. Among PD patients, 21 were classified as having MCI (PD-MCI) and 21 as cognitively unimpaired (PD-nMCI) based on criteria for possible PD-MCI (level I category). Single-subject and group-level ICA was used to investigate the integrity of brain networks related to cognition in PD patients with and without MCI. Image data processing and statistical analysis were performed in BrainVoyager QX. In addition, we used VBM to test whether functional connectivity differences were related to structural abnormalities. PD-nMCI and PD-MCI patients compared with controls showed decreased DMN connectivity. PD-MCI patients, but not PD-nMCI, compared with controls, showed decreased functional connectivity of bilateral prefrontal cortex within the frontoparietal network. The decreased prefrontal cortex connectivity correlated with cognitive parameters but not with clinical variables. VBM analysis did not reveal any difference in local gray matter between patients and controls. Our findings suggest that an altered DMN connectivity characterizes PD patients, regardless of cognitive status, whereas a functional disconnection of the frontoparietal network could be associated with MCI in PD in the absence of detectable structural changes.

Apathy is a behavioural disturbance occurring alone or in concomitance with depression in Parkinson's disease (PD). Here we present a validation study for the self-report version of the Apathy Evaluation Scale (AES-S), carried out in a sample of 60 non-demented, non-depressed untreated, drug-naïve, de novo PD patients; 20 patients of the sample (33.3%) were classified as apathetic according to current clinical criteria. All enrolled patients completed the AES-S and a neurological and cognitive assessment. Mean AES-S score was 34.43. AES-S did not show floor or ceiling effect. Cronbach's alpha was 0.872. Principal component analysis revealed three factors: the first (34.4% of the variance) represented constitutive aspects of the construct of apathy; the second (8.5% of the variance) represented a social dimension; the third factor (7.9% of the variance) represented a dimension related to insight. With respect to clinical criteria for apathy considered as the gold standard, receiver operating characteristics curve analysis showed that a cut-off of 36/37 has the maximum discrimination power. High sensitivity and negative predictive values were obtained with cut-off scores of 33/34 or lower; high specificity and positive predictive values were obtained with cut-off scores of 38/39 or higher. AES-S score correlated with scores on frontal tasks, but not on Beck Depression Inventory, Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale. The AES-S is a reliable and valid questionnaire for detecting apathy in PD. For screening purposes a 33/34 cut-off score is indicated, but a 38/39 cut-off score is necessary when a high specificity is desired.

Background: Longitudinal studies on healthy participants have shown that subjective memory impairment (defined as subjective cognitive complaints with normal cognitive objective performance) might be a strong predictor of mild cognitive impairment (MCI). Parkinson disease (PD) also manifests cognitive disturbances, but whether subjective memory complaints may predict the development of MCI in PD has not yet been explored., Methods: We prospectively screened newly diagnosed, untreated patients with PD in order to evaluate whether subjective memory complaints may predict development of MCI over a 2-year follow-up evaluation., Results: We enrolled 76 de novo untreated patients with PD. Of the 76 patients, 23 (30.3%) complained memory issues. Among the patients cognitively unimpaired at baseline, those with subjective complaints were more likely to develop MCI at follow-up. The regression model confirmed that presence of subjective memory complaints at baseline was an independent predictor of development of MCI at follow-up., Discussion: This is the first prospective study to explore the relationship between subjective and objective cognitive deficits in newly diagnosed, untreated patients. Our results provide preliminary evidence that subjective memory complaints might predict future development of MCI., (© The Author(s) 2014.)

Tremor dominant (TD) and akinetic-rigid type (ART) are two motor subtypes of Parkinson's disease associated with different disease progression and neurochemical/neuropathological features. The role of presynaptic nigrostriatal dopaminergic damage is still controversial, poorly explored, and only assessed in medicated patients. In this study, we investigated with FP-CIT SPECT the striatal dopamine transporter (DAT) availability in drug-naïve PD patients with ART and TD phenotypes. Fifty-one de novo, drug-naïve patients with PD underwent FP-CIT SPECT studies. Patients were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) part III and Hoehn and Yahr scale (H&Y) and divided into ART (24/51) and TD (27/51) according to UPDRS part III. ART and TD patients were not different with regard to age, gender, and disease duration. However, compared to TD, ART patients presented higher UPDRS part III (p = 0.01) and H&Y (p = 0.02) and lower DAT availability in affected and unaffected putamen (p = 0.008 and p = 0.007, respectively), whereas no differences were found in caudate. Moreover, in the whole group of patients, rigidity and bradykinesia, but not tremor scores of UPDRS part III were significantly related to FP-CIT binding in the putamen. These results suggest that in newly diagnosed drug-naïve PD patients DAT availability might be different between ART and TD in relation to different disease severity.

Background: We recently showed specific sex-related patterns of non motor symptoms (NMS) in early, drug-naïve PD patients. However, to date studies investigating gender-related effects of dopaminergic treatment on NMS in early PD are lacking., Methods: In the present study, we first report a prospective assessment of gender-related differences in the spectrum of NMS before (baseline) and after starting dopaminergic therapy (2-year follow-up) in a large cohort of newly diagnosed PD patients. Differences in NMS frequency between baseline and follow-up were evaluated by McNemar test. Spearman's rank test was employed to explore interactions between NMS and drug treatment., Results: One-hundred and thirty four PD patients (86M and 48W) were included in the present study. At 2-year follow-up, Sadness/blues presented a significant percentage reduction as compared to baseline in both sexes, while Urgency, Daytime sleepiness, Weight change and Sex drive presented a significant percentage increase only in men. At follow up men complained of a greater number of NMS as compared to women. Occurrence of Weight change was related to therapy in both sexes. Male gender was found to be a risk factor for developing Dribbling and Nocturia, irrespective of therapy and clinical features., Conclusions: In conclusion, our study showed that mood symptoms improved after the introduction of therapy in both sexes, while men appeared to be more prone to develop some NMS possibly linked to dopaminergic treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Low serum uric acid (UA) has been consistently shown to be associated with increased risk of Parkinson's disease (PD), and to predict faster motor and cognitive decline in established PD. The aim of the present study is to evaluate the relationship between serum UA and non-motor symptoms (NMS) in de novo PD., Methods: Serum UA was measured in consecutively recruited, early drug-naïve PD patients. Exclusion criteria were: treatment with UA modifying drugs; current smoking status; metabolic or cardiac morbidity. All patients completed the NMS Questionnaire (NMSQuest). The relationship between UA levels and NMSQuest domains was explored by logistic regression, subsequently adjusted for age, gender, disease duration (months since reported motor onset) UPDRS part III, H&Y scale, and MMSE. Regression analysis studied the overall relationship between UA levels and total NMS score, and was subsequently adjusted for age, gender, disease duration UPDRS part III, H&Y scale and MMSE., Results: Eighty PD patients were recruited. At logistic regression, higher UA levels were related to lower involvement of Attention/Memory (p = 0.004), Cardiovascular (0.009) and Sleep (p = 0.028) domains of NMSQuest. UA levels showed a significant negative correlation with total NMSQuest score at regression analysis (p = 0.001; Adjusted R-squared = 0.319)., Discussion: The present study investigated, for the first time, the relationship between NMSQuest and UA in de novo PD. Lower UA was related to higher NMSQuest total score and in particular to Attention/Memory, Cardiovascular and Sleep domains. Thus, UA seems to be a major candidate to be a valuable biomarker of such early features of PD as NMS., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Smoke-induced upper airway damage and Parkinson's disease (PD) can be considered independent risk factors for smell impairment. Interestingly, cigarette smoking has been strongly associated with reduced risk of PD and, therefore, has been suggested to have neuroprotective effects. Our pilot study aimed to evaluate the relationship between smoking and olfaction in PD patients and matched controls. Sixty-eight PD patients and 61 healthy controls were categorized in relation to PD diagnosis and current smoking status, and evaluated by means of the Italian version of the University of Pennsylvania 40-item Smell Identification Test (UPSIT-40). ANOVA analysis with post-hoc Bonferroni correction showed that non-smoker controls presented a higher UPSIT-40 total score than smoker controls (p<0.001), non-smoker PD patients (p<0.001) and smoker PD patients (p<0.001). In this view, smoking seems to affect olfaction in controls but not in PD patients, and no significant differences were found when comparing smoker controls, smoker PD patients and non-smoker PD patients. Several epidemiological studies showed a negative effect of smoking on olfaction in the general population. Otherwise the sense of smell is similar in smoker and non-smoker PD patients. These results suggest that PD and smoking are not independent risk factors for impairment of sense of smell, but they might variably interact., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Little is known about the anatomical progression over the body segments of extrapyramidal signs in Parkinson's disease (PD); furthermore a great unmet need is the availability of instruments able to detect disease progression, even in the early phase. The purpose of this study is to demonstrate that assessing topographical distribution of the cardinal motor features of PD may significantly improve the evaluation of disease progression in the early stages. Forty-four drug-naïve PD patients were included in the study. Presence or absence of bradykinesia, rest tremor and rigidity was derived from Unified Parkinson's disease rating scale part III (UPDRS-III) in five different anatomical segments: axial, right and left upper- and lower-limbs. Based on this approach, four new scores were computed evaluating the anatomical spread of the cardinal motor symptoms of PD on the five body segments over a 18-month follow-up period. The four new scores included: the Bradykinesia Segmental Score, the Tremor Segmental Score, the Rigidity Segmental Score, measuring the occurrence of each motor symptom in different segments and the Combined Segmental Score evaluating the occurrence of any motor symptom in different anatomical regions. Data were analyzed using a repeated measures analysis of variance. The Combined Segmental Score showed a significant progression over time whereas the Hoehn and Yahr and the UPDRS-III scores did not. We suggest that a simple approach evaluating the anatomical distribution of motor symptoms and their progression over the body segments may be a useful complement to the classical rating tools to assess progression in early PD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

Dementia and gait impairments often coexist in older adults and patients with neurodegenerative disease. Both conditions represent independent risk factors for falls. The relationship between cognitive function and gait has recently received increasing attention. Gait is no longer considered merely automated motor activity but rather an activity that requires executive function and attention as well as judgment of external and internal cues. In this review, we intend to: (1) summarize and synthesize the experimental, neuropsychological, and neuroimaging evidence that supports the role played by cognition in the control of gait; and (2) briefly discuss the implications deriving from the interplay between cognition and gait. In recent years, the dual task paradigm has been widely used as an experimental method to explore the interplay between gait and cognition. Several neuropsychological investigations have also demonstrated that walking relies on the use of several cognitive domains, including executive-attentional function, visuospatial abilities, and even memory resources. A number of morphological and functional neuroimaging studies have offered additional evidence supporting the relationship between gait and cognitive resources. Based on the findings from 3 lines of studies, it appears that a growing body of evidence indicates a pivotal role of cognition in gait control and fall prevention. The interplay between higher-order neural function and gait has a number of clinical implications, ranging from integrated assessment tools to possible innovative lines of interventions, including cognitive therapy for falls prevention on one hand and walking program for reducing dementia risk on the other., (© 2013 Movement Disorder Society.)

Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis., (© 2013 WILEY PERIODICALS, INC.)