Oxidative stress and synaptic dysfunction in rodent models of Parkinson's disease.

Parkinson's disease (PD) is a multifactorial disorder involving a complex interplay between a variety of genetic and environmental factors. In this scenario, mitochondrial impairment and oxidative stress are widely accepted as crucial neuropathogenic mechanisms, as also evidenced by the identification of PD-associated genes that are directly involved in mitochondrial function. The concept of mitochondrial dysfunction is closely linked to that of synaptic dysfunction. Indeed, compelling evidence supports the role of mitochondria in synaptic transmission and plasticity, although many aspects have not yet been fully elucidated. Here, we will provide a brief overview of the most relevant evidence obtained in different neurotoxin-based and genetic rodent models of PD, focusing on mitochondrial impairment and synaptopathy, an early central event preceding overt nigrostriatal neurodegeneration. The identification of early deficits occurring in PD pathogenesis is crucial in view of the development of potential disease-modifying therapeutic strategies.

Alpha-Synuclein is Involved in DYT1 Dystonia Striatal Synaptic Dysfunction.

BACKGROUND: The neuronal protein alpha-synuclein (α-Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1 dystonia, has been found to accumulate in Lewy bodies and to interact with α-Syn. Both proteins act as molecular chaperones and control synaptic machinery. Despite such evidence, the role of α-Syn in dystonia has never been investigated. OBJECTIVE: We explored whether α-Syn and N-ethylmaleimide sensitive fusion attachment protein receptor proteins (SNAREs), that are known to be modulated by α-Syn, may be involved in DYT1 dystonia synaptic dysfunction. METHODS: We used electrophysiological and biochemical techniques to study synaptic alterations in the dorsal striatum of the Tor1a+ /Δgag mouse model of DYT1 dystonia. RESULTS: In the Tor1a+/Δgag DYT1 mutant mice, we found a significant reduction of α-Syn levels in whole striata, mainly involving glutamatergic corticostriatal terminals. Strikingly, the striatal levels of the vesicular SNARE VAMP-2, a direct α-Syn interactor, and of the transmembrane SNARE synaptosome-associated protein 23 (SNAP-23), that promotes glutamate synaptic vesicles release, were markedly decreased in mutant mice. Moreover, we detected an impairment of miniature glutamatergic postsynaptic currents (mEPSCs) recorded from striatal spiny neurons, in parallel with a decreased asynchronous release obtained by measuring quantal EPSCs (qEPSCs), which highlight a robust alteration in release probability. Finally, we also observed a significant reduction of TA striatal expression in α-Syn null mice. CONCLUSIONS: Our data demonstrate an unprecedented relationship between TA and α-Syn, and reveal that α-Syn and SNAREs alterations characterize the synaptic dysfunction underlying DYT1 dystonia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia.

BACKGROUND: Acetylcholine-mediated transmission plays a central role in the impairment of corticostriatal synaptic activity and plasticity in multiple DYT1 mouse models. However, the nature of such alteration remains unclear. OBJECTIVE: The aim of the present work was to characterize the mechanistic basis of cholinergic dysfunction in DYT1 dystonia to identify potential targets for pharmacological intervention. METHODS: We utilized electrophysiology recordings, immunohistochemistry, enzymatic activity assays, and Western blotting techniques to analyze in detail the cholinergic machinery in the dorsal striatum of the Tor1a+/- mouse model of DYT1 dystonia. RESULTS: We found a significant increase in the vesicular acetylcholine transporter (VAChT) protein level, the protein responsible for loading acetylcholine (ACh) from the cytosol into synaptic vesicles, which indicates an altered cholinergic tone. Accordingly, in Tor1a+/- mice we measured a robust elevation in basal ACh content coupled to a compensatory enhancement of acetylcholinesterase (AChE) enzymatic activity. Moreover, pharmacological activation of dopamine D2 receptors, which is expected to reduce ACh levels, caused an abnormal elevation in its content, as compared to controls. Patch-clamp recordings revealed a reduced effect of AChE inhibitors on cholinergic interneuron excitability, whereas muscarinic autoreceptor function was preserved. Finally, we tested the hypothesis that blockade of VAChT could restore corticostriatal long-term synaptic plasticity deficits. Vesamicol, a selective VAChT inhibitor, rescued a normal expression of synaptic plasticity. CONCLUSIONS: Overall, our findings indicate that VAChT is a key player in the alterations of striatal plasticity and a novel target to normalize cholinergic dysfunction observed in DYT1 dystonia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia.

Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (Gαolf), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous Gαolf -deficient mice (Gnal+/-) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnal-/-) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnal+/-) with a 13 base pair deletion in the first exon of the rat Gnal splicing variant 2, a major isoform in both human and rat striatum. Gnal+/- rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnal+/- rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating Gαolf function and finding a suitable treatment for dystonia associated with deficient dopamine transmission.

Association between physical activity and dementia's risk factors in patients with Parkinson's disease.

Evidence suggests that physical activity (PA) exerts beneficial effects on neurodegenerative processes, either as symptomatic relief or disease-modifying strategy. Actually, it may represent a viable neuroprotective intervention in Parkinson's disease dementia (PDD), a severe, frequent, and untreatable complication of Parkinson's disease (PD). According to such hypothesis, this cross-sectional study tested, in PD patients, the association between levels of PA and well-known risk factors for PDD, such as mood disorders and amyloid-ß42 CSF content. Amount of PA was measured by the International Physical Activity Questionnaires-Short Form (IPAQ-SF) in 128 cognitively intact PD patients and correlated with the Hamilton-Depression (HAM-D) and the Hamilton-Anxiety (HAM-A) scores; in a homogenous subgroup of 40 patients, it was further correlated with a panel of CSF biomarkers, including amyloid-ß42, total α-synuclein, total, and phosphorylated tau. The statistical model was corrected for the main potential confounding factors (motor impairment, dopaminergic treatment, disease duration, age, and sex). Both the HAM-A and HAM-D scores, as well as the Aß42 CSF content, improved in parallel with the increase of the total week amount of PA. Although with several limitations, we preliminarily demonstrated that a high level of PA is associated with a more favourable profile of PDD risk factors, in terms of both mood disturbances and CSF markers of neurodegeneration. However, confirmative studies are necessary to validate the efficacy of PA as protective intervention for PDD.

Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease.

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson's disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

Cerebrospinal fluid biomarkers profile of idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a disabling neurological disorder whose potential treatability is significantly limited by diagnostic uncertainty. In fact, typical clinical presentation occurs at late phases of disease, when CSF shunting could be ineffective. In recent years, measurement of different CSF proteins, whose concentration directly reflects neuropathological changes of CNS, has significantly improved both diagnostic timing and accuracy of neurodegenerative disease. Unfortunately iNPH lacks neuropathological hallmarks allowing the identification of specific disease biomarkers. However, neuropathology of iNPH is so rich and heterogeneous that many processes can be tracked in CSF, including Alzheimer's disease core pathology, subcortical degeneration, neuroinflammation and vascular dysfunction. Indeed, a huge number of CSF biomarkers have been analyzed in iNPH patients, but a unifying profile has not been provided yet. In this brief survey, we thus attempted to summarize the main findings in the field of iNPH CSF biomarkers, aimed at outlining a synthetic model. Although defined cut-off values for biomarkers are not available, a better knowledge of CSF characteristics may definitely assist in diagnosing the disease.

Clinical value of CSF amyloid-beta-42 and tau proteins in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is a four-repeat tauopathy with high phenotypic and neuropathological variability, highlighting the urgent need for effective disease biomarkers. Quantitative analysis of cerebrospinal fluid (CSF) proteins reflecting pathological changes of CNS is currently used as biomarkers of multiple neurodegenerative disorders for both early differential diagnosis and prognostic clustering of patients. In this study, we thus assessed the clinical usefulness of a panel of CSF biomarker in PSP patients presenting with Richardson's Syndrome. CSF levels of 42-beta-amyloid, total-tau, phosphorylated-tau, and both 42-beta-amyloid/phosphorylated-tau and phosphorylated-tau/total-tau ratios were comparatively evaluated in 39 PSP patients, 31 patients with Parkinson's Disease (PD) and 58 gender-/age-matched healthy controls. Specific gold-standard clinical scores were obtained. Diagnostic accuracy and clinical correlates of each biomarker were measured with receiver operating curve analysis and Spearman's test/linear regression, respectively. In PSP, 42-beta-amyloid was lower than either controls or PD; total-tau and phosphorylated-tau were instead reduced compared to controls, but similar to PD. At the cut-off value of 623 pg/ml, 42-beta-amyloid significantly distinguished PSP from controls and PD. Likewise, phosphorylated-tau/total-tau ratio also supported differential diagnosis between PSP and PD (cut-off = 0.185). 42-beta-amyloid was inversely associated with PSP severity, as measured with PSP Rating Scale. Our study demonstrates that CSF 42-beta-amyloid is reduced in PSP patients, proportionally to clinical severity, thus suggesting a potential use as disease biomarker. Moreover, phosphorylated-tau/total-tau ratio resulted helpful in the early differential diagnosis between PSP and PD.

Assessment of serum uric acid as risk factor for tauopathies.

Low levels of serum uric acid (UA) are a risk factor for many neurodegenerative diseases but the role of UA in tauopathies has not been yet fully evaluated. In this study, we assessed the risk associated with serum UA levels in a large group of patients with tauopathies, either primary or secondary. The mean serum UA concentrations of 111 patients with tauopathies (TAU), including 41 with progressive supranuclear palsy (PSP), 45 with Alzheimer's disease (AD) and 25 with frontotemporal dementia (FTD) were compared to that of 130 controls (CTL). The association between serum UA and TAU condition, PSP, AD and FTD was calculated as odd ratio (OR) adjusted for age and gender. A cut-off value of serum UA was finally obtained to predict subjects at risk for TAU. The serum UA levels in TAU and PSP, AD and FTD subgroups were similar, and significantly lower than CTL. Linear regression revealed inverse relationships between UA and TAU (OR = 0.610), PSP (OR = 0.626), AD (OR = 0.685) and FTD (OR = 0.577). The cut-off value of 4.35 mg/dl (AUC = 0.655) discriminates TAU from CTL, although with poor specificity and sensitivity. Low concentrations of serum UA represent a common risk factor for different tauopathies (PSP, FTD and AD). These findings may represent a starting point for preventive strategies or novel therapeutic approaches in this group of severe neurodegenerative diseases.

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1-deficient mice.

Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease.

Heidenhain variant in two patients with inherited V210I Creutzfeldt-Jakob disease.

OBJECTIVE: To report two members of the same family carrying the valine to isoleucine point mutation of the prion protein gene (PRNP) and presenting with visual symptoms as initial manifestation as in the "Heidenhain variant" of sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Patients underwent neurological examination, electroencephalogram (EEG), brain magnetic resonance images (MRI) and cerebrospinal fluid (CSF) analysis including the Real Time Quaking Induced Conversion (RT-QuIC) test. Disease-specific mutations and polymorphism at codon 129 of the PRNP gene were also studied. RESULTS: Isolated visual symptoms characterized disease onset of both patients followed by progressive neurological signs, dementia and death in 3 (proband) and 9 (his aunt) months. RT-QuIC analysis of CSF samples of both patients revealed the presence of the pathological prion protein and DNA analysis the V210I point mutation of the PRNP and methionine homozygosity at the polymorphic codon 129. CONCLUSIONS: This report suggests to consider the diagnosis of V210I genetic CJD in patients presenting with the Heidenhain form of CJD and highlights the importance of genetic testing in all patients with isolated visual manifestations at onset followed by progressive neurological signs and dementia.

[Primary headache and work: concepts of pathophysiology, occupational risk factors, health monitoring and criteria for judging causation]. / Cefalea primaria e lavoro: nozioni di fisiopatologia, fattori occupazionali di rischio, sorveglianza sanitaria e criteri per la formulazione del giudizio di idoneità.

Primary headaches account for 90% of all the forms of headache. The disease is characterized by high occurrence in the working-age population and by significant impact in countries with high economic and social development. These two epidemiological aspects carry significant economic costs that can be estimated calculating loss of working days due to illness and appreciable loss of labour productivity. In an occupational setting several circumstances are known to cause the onset of attacks in workers who already suffer from primary headache. In this sense, the following factors have an important role: interruption of the circadian sleep-wake rhythm, sleep deprivation, physical/mental distress, not ergonomic postures (mainly those involving the cervical-brachial district), prolonged use of display screen, acoustic discomfort. Among chemicals, in the current conditions of exposure, the olfactory characteristics seem of primary importance rather than the more "conventional" mechanism of toxicity. The main aim of this study is to provide useful information to occupational physicians on the management of workers suffering from primary headache, with regard either to the formulation of the judgement of suitability, or to their auxiliary role in the planning and organization of work. A second aim involves the identification of specific preventive measures in order to reduce the probability of occurrence of a headache attack. This also minimizes the risk of accidents and injuries and ensures workers' efficiency. After these considerations, we suggest guidelines for a flow chart (aimed to understand worker's suitability for his/her specific task). This guarantees not only safety and health of workers who suffer from the illness, but also safeguards any third worker from a possible consequence due to less working capacity and reduction of attention of employees working with a headache attack. In conclusion we also identify three critical factors: the diagnosis of the form of primary headache, the characteristics of the work and the effects due to pharmacological therapy. The study and characterization of these elements are a crucial step for a proper formulation of the judgement of suitability to work. We report a decision process for judgement formulation at the end of this article. It is organized with a hierarchical model, the first steps are the clinical examination and history, the last step, if necessary or advisable, is the neurological visit and a periodic verification of the adherence to treatment prescribed and the follow-up.

Successful subthalamic stimulation, but levodopa-induced dystonia, in a genetic Parkinson's disease.

Recently, it is under scrutiny the possibility to anticipate the stereotactic implantation of the subthalamic nucleus (STN) even in relatively mild Parkinson's disease (PD) patients with an unsatisfying response to drugs. In addition, it is debated whether levodopa (LD) and deep brain stimulation (DBS) are congruent or, instead, mutually exclusive. A 56-year-old LRRK2-positive PD patient, with 7 years of disease history, dominated by severe left resting tremor, was submitted to bilateral implantation of the subthalamic nucleus (STN). Before surgery, the combination of LD and dopamine agonists failed to handle tremor unless administered at doses, which induced undesirable adverse events. STN deep brain stimulation (DBS) abolished tremor but did not provide satisfying control of hypokinetic-rigid symptoms. The condition STIM-ON plus LD, albeit transiently beneficial, installed a painful dystonia developing slowly after 24-36 h. Only a chronic therapy combining rotigotine plus STN-DBS proved effective without side effects. This case report, based upon the surprising difference between the therapeutic response to the combination of LD and dopamine agonist (before surgery) and the combination of DBS and agonist after surgery, emphasizes how STIM and LD target different motor domains through mechanisms with differential plasticity and confirms the efficacy of STN-DBS in LRKK2 patients.

Beyond the Microbiota: Understanding the Role of the Enteric Nervous System in Parkinson's Disease from Mice to Human.

The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of these connections appears to be involved in the pathophysiology of Parkinson's disease (PD). Alterations in the ENS have been shown to occur very early in PD, even before central nervous system (CNS) involvement. Post-mortem studies of PD patients have shown aggregation of α-synuclein (αS) in specific subtypes of neurons in the ENS. Subsequently, αS spreads retrogradely in the CNS through preganglionic vagal fibers to this nerve's dorsal motor nucleus (DMV) and other central nervous structures. Here, we highlight the role of the ENS in PD pathogenesis based on evidence observed in animal models and using a translational perspective. While acknowledging the putative role of the microbiome in the gut-brain axis (GBA), this review provides a comprehensive view of the ENS not only as a "second brain", but also as a window into the "first brain", a potentially crucial element in the search for new therapeutic approaches that can delay and even cure the disease.

Synaptic effects of ethanol on striatal circuitry: therapeutic implications for dystonia.

Alcohol consumption affects motor behavior and motor control. Both acute and chronic alcohol abuse have been extensively investigated; however, the therapeutic efficacy of alcohol on some movement disorders, such as myoclonus-dystonia or essential tremor, still does not have a plausible mechanistic explanation. Yet, there are surprisingly few systematic trials with known GABAergic drugs mimicking the effect of alcohol on neurotransmission. In this brief survey, we aim to summarize the effects of EtOH on striatal function, providing an overview of its cellular and synaptic actions in a 'circuit-centered' view. In addition, we will review both experimental and clinical evidence, in the attempt to provide a plausible mechanistic explanation for alcohol-responsive movement disorders, with particular emphasis on dystonia. Different hypotheses emerge, which may provide a rationale for the utilization of drugs that mimic alcohol effects, predicting potential drug repositioning.

[Accidents and headache]. / Infortuni e cefalee.

Work accidents are a major cause of morbidity and mortality by creating a loss not only for the individual affected but also for society given the high number of absences from work that follows. Many have been efforts since the early 60 'to minimize the number of accidents but, although it is known a steady downward trend in recent years, in Italy in 2010 there were still 775,000 cases of accidents and 980 deaths. The study examined a population of 192 persons injured of which 41 have proven to be headache and data collected showed that the frequency of headache among the workers who suffer an injury is equal to 26.2%. Finally, it is conceivable that the reduction of attention, "disability" or the effect induced headache post-pharmacological risk factors are important in causing accidents at work and would therefore be appropriate to continue the study recorded the presence/absence of headache at the time of the event accidents.

[Metabolic syndrome and shift work: study of the relationship in workers of a chemical plant]. / Sindrome metabolica e lavoro a turni: studio dell'associazione in uno popolazione di lavoratori di un'industria chimica.

Metabolic syndrome is defined by several metabolic factors, related to one another, which induce atherosclerotic pathology. These factors are: visceral obesity, atherogenic dyslipidemia, high blood pressure, hyperglycemia, proinflammatory and prothrombotic state. Shift work is known to be related to a series of organic changes, including increased cardiovascular risk independent factors. The aim of our study is to assess if shift work might be a cofactor inducing metabolic syndrome. 119 workers of a chemical industry have been examinated and been divided in two groups: shift workers and daytime workers. We checked if workers were affected by metabolic syndrome, following the ATP III criteria. The results have been statistically compared. The prevalence of metabolic syndrome is significantly higher in night shift workers comparing to other workers. Among night shift workers metabolic syndrome was found in 28 out of 77 (36,36%); in daytime workers the syndrome was observed in 8 workers out of 42 (19,05%) (DR: 2, 43; 95% CI 0,99 - 5,98; p=0,049). This difference is stronger when only over 40 years old subjects were considered. Our results show an association between metabolic syndrome and night shift work. It is therefore necessary, as primary health safety measure, to verify the presence of metabolic syndrome in night shift workers. All aspects of the syndrome should be studied to prevent disease and its clinical complications. The primary prevention activity should be based on specific information and education programs, particulary aimed at learning about a correct lifestyle.

A Dual Centre Study of Pain in Parkinson's Disease and Its Relationship with Other Non-Motor Symptoms.

BACKGROUND: Pain is a disabling and often underestimated non-motor symptom (NMS) detrimentally affecting the quality of life of patients with Parkinson's disease (PD). OBJECTIVE: Here, we conducted a cross-sectional, observational international study on 167 patients with idiopathic PD in order to analyze the potential relationship between pain and other NMS. METHODS: Subjects were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III, Hoehn and Yahr (H&Y) stage, King's Parkinson's Disease Pain Scale (KPPS), Brief Pain Inventory (BPI), Non-Motor Symptoms Scale (NMSS), and Beck Depression Inventory (BDI). Spearman's rank correlation coefficient, multiple regression and multiple index-based clustering algorithms were used for data analysis. RESULTS: The prevalence of pain was 88.6%, was not correlated with age, motor severity (UPDRS part III) or disease duration, whereas a weak correlation with female gender and H&Y stage >2.5 was found. Multiple NMS correlated significantly with pain. Specifically, sleep disturbance had the strongest correlation with pain, followed by depression, gastrointestinal and cardiovascular disturbances. Further analyses showed that sleep and cardiovascular disturbance were independently associated with pain, and that these symptoms clustered together in a subset of PD patients. The relationship between pain, sleep and dysautonomia persisted independently from dopamine replacement therapy. CONCLUSION: Our study suggests that sleep disruption and cardiovascular disturbance are associated with pain in PD, and possibly identifies a specific subtype within PD patients with pain. Our data also indicate that sleep disruption, pain and dysautonomia may have a common pathophysiology, possibly involving non-dopaminergic pathways.

Ischemic injury precipitates neuronal vulnerability in Parkinson's disease: Insights from PINK1 mouse model study and clinical retrospective data.

INTRODUCTION: Increasing evidence demonstrates the relevant association between Parkinson's disease (PD) and vascular diseases/risk factors, as well as a worse clinico-pathological progression in those patients with vascular comorbidity. The mechanisms underlying this relationship have not been clarified yet, although their comprehension is critical in a perspective of disease-modifying treatments development or prevention. METHODS: We performed an experimental protocol of ischemic injury (glucose-oxygen deprivation, OGD) on PTEN-induced kinase 1 knockout (PINK1-/-) mice, a well-established PD model, looking at both electrophysiological and morphological changes in basal ganglia. In addition, 253 PD patients were retrospectively analysed, to estimate the prevalence of vascular risk factors. RESULTS: In PINK1-/- mice, the OGD protocol induced electrophysiological (prolonged depolarization) and morphological alterations (picnotic cells, cellular loss and swelling, thickening of nuclear chromatin) in striatal medium spiny neurons and nigral dopaminergic neurons. Vascular comorbidity occurred in 75% of PD patients. CONCLUSIONS: The ischemic injury precipitates neuronal vulnerability in basal ganglia of PINK1-/- mice, probably through an impairment of mitochondrial metabolism and higher oxidative stress. These experimental data may provide a potential mechanistic explanation for both the association between vascular diseases and PD and their reciprocal interactions in determining the clinico-pathological burden of PD patients.

Long-term treatment with rotigotine in drug-naïve PSP patients.

Progressive supranuclear palsy (PSP) is a severe neurodegenerative disease still lacking of alleviating treatments for either cognitive or motor disturbances. Aimed at widening the spectrum of therapeutic options, here, we describe efficacy and safety of a long-term treatment with Rotigotine, a non-ergolinic dopamine agonist, in PSP. Seven PSP drug-naïve patients, presenting with Richardson's syndrome, received up to 6 mg/24 h transdermal patch for 42 weeks as unique therapy. Adverse effects were recorded; efficacy was measured by comparing baseline and final treatment scores of Montreal Cognitive Assessment (MoCA), Unified Parkinson Disease Rating Scale part3, and PSP rating scale (PSP-RS). At the end of our observation, no significant adverse events occurred; the cognitive item of PSP-RS was improved and MoCA score was similar at baseline. Contrariwise, motor disturbances worsened according to disease progression. Our observation thus suggests that long-term treatment with low doses of rotigotine is well tolerated and may support cognitive functions of PSP patients.