Studies In Parkinson's Disease Patients Research Articles

Mild Behavioral Impairment in Parkinson's Disease: An Updated Review on the Clinical, Genetic, Neuroanatomical, and Pathophysiological Aspects.

Neuropsychiatric symptoms (NPS), including depression, anxiety, apathy, visual hallucinations, and impulse control disorders, are very common during the course of Parkinson's disease (PD), occurring even at the prodromal and premotor stages. Mild behavioral impairment (MBI) represents a recently described neurobehavioral syndrome, characterized by the emergence of persistent and impactful NPS in later life, reflecting arisk of dementia. Accumulating evidence suggests that MBI is highly prevalent in non-demented patients with PD, also being associated with an advanced disease stage, more severe motor deficits, as well as global and multiple-domain cognitive impairment. Neuroimaging studies have revealed that MBI in patients with PD may be related todistinct patterns of brain atrophy, altered neuronal connectivity, and distribution of dopamine transporter (DAT) depletion, shedding more light on its pathophysiological background. Genetic studies in PD patients have also shown that specific single-nucleotide polymorphisms (SNPs) may be associated with MBI, paving the way for future research in this field. In this review, we summarize and critically discuss the emerging evidence on the frequency, associated clinical and genetic factors, as well as neuroanatomical and neurophysiological correlates of MBI in PD, aiming to elucidate the underlying pathophysiology and its potential role as an early "marker" of cognitive decline, particularly in this population. In addition, we aim to identify research gaps, and propose novel relative areas of interest that could aid in our better understanding of the relationship of this newly defined diagnostic entity with PD.

Temporal Muscle Thickness Correlates with Sarcopenia in Parkinson's Disease.

Sarcopenia is characterized by a progressive loss of muscle mass, strength, and function resulting in adverse health outcomes. Current assessment strategies are bothersome and means to simplify the diagnosis are an unmet medical need in Parkinson's disease (PD). To evaluate temporal muscle thickness (TMT) obtained on routine cranial MRI as a surrogate marker of sarcopenia in PD patients. We correlated TMT from axial non-contrast-enhanced T1-weighted sequences of MRI close (±12 months) to an outpatient visit including sarcopenia (EWGSOP1, EWGSOP2, SARC-F), frailty (Fried's criteria, clinical frailty scale), and disease characteristics of Parkinson's patients (Hoehn and Yahr-scale, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, quality of life with the Parkinson's Disease Questionnaire-8) assessments. Cranial MRI was available in 32 patients with a mean age of 73.56±5.14 years, mean disease duration of 11.46±5.66 years, and median Hoehn and Yahr stage of 2.5. The mean TMT was 7.49±2.76 (7.15) mm. Mean TMT was significantly associated with sarcopenia (EWGSOP2, p = 0.018; EWGSOP1, p = 0.023) and frailty status (physical phenotype; p = 0.045). Moreover, there were significant moderate to strong correlations between TMT measurement and appendicular skeletal muscle mass index (r: 0.437, p = 0.012), as well as handgrip strength (r: 0.561, p < 0.001). Reduced TMT seems to be a promising surrogate marker for sarcopenia (EWGSOP2) and muscle strength in this pilot study in PD patients.

Učestalost i prediktori potencijalnih interakcija između lekova kod hospitalizovanih pacijenata sa Parkinsonovom bolešću

Introduction: Patients with Parkinson's disease are exposed to higher number of drugs on average than other elderly persons. Levodopa, of the mainstay of Parkinson's disease therapy, is frequently interacting with numerous drugs. Aim: The aim of this study was to identify predictors of potential drug-drug interactions (pDDIs) in hospitalized patients suffering from Parkinson's disease (PD). Material and Methods: This was a academic retrospective cross-sectional study in PD patients hospitalized at the Clinic of Neurology, Clinical Center Kragujevac. Medical records of hospitalized patients during the period 1.1.2017 - 31.12.2019 were analysed. The pDDIs were identified by means of Micromedex andLexi-Interact online softwares, and multivariate regression methods were used to reveal potential predictors of number of pDDIs per patient. Results: Micromedex detected 160 different pDDIs in 77.8% of 72 patients with PD. The most frequent pDDIs were those that involved aspirin (with bisoprolol, sertraline and perindopril). Predictors of pDDIs in general was total number of drugs, while use of antidepressants presented a significant risk factor for major pDDIs. Lexi-Interact revealed 310 pDDIs in 98.6% of patients. The three most common pDDIs were with levodopa (bisoprolol, clonazepam, perindopril). Total number of drugs, number of co-morbidities, hospitalization at the neurodegenerative ward, and use of antipsychotics were identified as the relevant predictors of pDDIs. Lexi-interact software detected significantly more pDDIs than Micromedex (p&lt;0.001). Conclusion: Neurologists should pay special attention when deciding whether to administer new drug to a PD patient with multiple comorbidities, hospitalized in a neurodegenerative ward and/or taking antidepressant or antipsychotic drugs.

Amyloid-β and Parkinson's disease.

Parkinson's disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded α-synuclein is considered to be a key underpinning mechanism. Amyloid-β (Aβ) and tau deposition are also comorbid associations and especially Aβ deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Aβ42 is predictive of future cognitive impairment in PD. Recent studies also show that CSF Aβ is associated with the postural instability and gait difficulties (PIGD) or the newly proposed cholinergic subtype of PD, a possible risk factor for cognitive decline in PD. The glial-lymphatic system, responsible for convective solute clearance driven by active fluid transport through aquaporin-4 water channels, may be implicated in brain amyloid deposition. A better understanding of the role of this system and more specifically the role of Aβ in PD symptomatology, could introduce new treatment and repurposing drug-based strategies. For instance, apomorphine infusion has been shown to promote the degradation of Aβ in rodent models. This is further supported in a post-mortem study in PD patients although clinical implications are unclear. In this review, we address the clinical implication of cerebral Aβ deposition in PD and elaborate on its metabolism, its role in cognition and motor function/gait, and finally assess the potential effect of apomorphine on Aβ deposition in PD.

Latency of re-emergent tremor in Parkinson's disease is influenced by levodopa

IntroductionRe-emergent tremor (RET) is a common form of postural tremor observed in Parkinson's disease (PD) patients. Recent studies have shown that administration of levodopa decreases RET amplitude. However, drug effects on tremor pause duration are less clear. MethodsWe performed a prospective observational study in PD patients with RET, subjected to acute levodopa challenge. Tremor activity was measured during OFF and ON states both clinically, as well as by using accelerometers taped to the back of both hands. Correlation between RET amplitude and pause duration, as well with MDS-UPDRS scores were investigated. The slope of gradual increase of postural tremor after the pause was also measured in the OFF and ON states. ResultsSignificant inverse correlation between tremor amplitude and RET pause duration was observed in OFF (rs = −0.474, p = 0.030) and ON (rs = −0.569, p = 0.006) states. Levodopa reduced tremor amplitude (26%, p = 0.004) dampening slope gradient (22%, p = 0.029). Tremor pause duration also showed inverse correlation with postural tremor amplitude measured by MDS-UPDRS in OFF (rs = −0.311, p = 0.048) and ON (rs = −0.503, p = 0.020) states, as well as with total MDS-UPDRS Part III score (rs = −0.295, p = 0.009). Finally, accelerometric analysis proved to be more sensitive than visual inspection for detecting tremor pauses. ConclusionOur results suggest RET pause duration is amplitude related, since levodopa-induced amplitude decrease led to pause prolongation, associated with decreased tremor intensity and slope gradient dampening.

Lesions causing freezing of gait localize to a cerebellar functional network.

Freezing of gait is a disabling symptom in Parkinson disease and related disorders, but the brain regions involved in symptom generation remain unclear. Here we analyze brain lesions causing acute onset freezing of gait to identify regions causally involved in symptom generation. Fourteen cases of lesion-induced freezing of gait were identified from the literature, and lesions were mapped to a common brain atlas. Because lesion-induced symptoms can come from sites connected to the lesion location, not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has been recently shown to identify regions involved in symptom generation across a variety of lesion-induced disorders. Lesion location was heterogeneous, and no single region could be considered necessary for symptom generation. However, > 90% (13 of 14) of lesions were functionally connected to a focal area in the dorsal medial cerebellum. This cerebellar area overlapped previously recognized regions that are activated by locomotor tasks, termed the cerebellar locomotor region. Connectivity to this region was specific to lesions causing freezing of gait compared to lesions causing other movement disorders (hemichorea or asterixis). Lesions causing freezing of gait are located within a common functional network characterized by connectivity to the cerebellar locomotor region. These results based on causal brain lesions complement prior neuroimaging studies in Parkinson disease patients, advancing our understanding of the brain regions involved in freezing of gait. ANN NEUROL 2017;81:129-141.

An Update on the Role of Nitric Oxide in the Neurodegenerative Processes of Parkinson's Disease.

The pathogenesis of Parkinson's disease (PD) is not fully understood. Together with some important physiological functions in the Central Nervous System (CNS), nitric oxide (NO) can have both, neuroprotective or neurotoxic actions, depending on its redox state. An important body of evidence suggests the involvement of NO in many of the processes leading to neurodegeneration in several neurological disorders including PD. The main aim of this review is to update the data regarding the possible involvement of NO in the pathogenesis of PD. We performed a literature review on neuropathological, biochemical and genetic studies in PD patients and in several experimental models of parkinsonism and role of NO in these models. Results: Both studies in humans and in experimental models of parkinsonism give support to the contribution of NO in excitotoxicity, inflammation, oxidative stress, mitochondrial function impairment, DNA damage, and Snitrosylation of diverse proteins. The interaction of these mechanisms leads finally to neuronal death. The fact that selective of specific inhibitors of NO synthase (NOS, the enzyme responsible of NO synthesis) should prevent neuronal death through their actions of these pathogenic mechanisms supports the role of NO on PD as well. NO participates in the pathogenesis of PD by multiple mechanisms described in this review.

Anxiety in early Parkinson's disease: Validation of the Italian observer-rated version of the Parkinson Anxiety Scale (OR-PAS)

IntroductionAnxiety 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. MethodsA 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. ResultsThere 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%). ConclusionThe 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.

Aiming for Study Comparability in Parkinson's Disease: Proposal for a Modular Set of Biomarker Assessments to be Used in Longitudinal Studies.

Parkinson's disease (PD) is an example for a complex field of research, which is driven by the multifactorial etiology, the heterogeneity in phenotype and the variability in disease progression, as well as the presence of a long pre-diagnostic period, called prodromal PD, lasting up to decades (Postuma et al., 2010). The very slow, so far inevitably progressive, neurodegenerative process and the multidimensional heterogeneity of symptoms in kind (motor and non-motor), time of onset and speed of progression call for prediction markers and progression markers to understand the onset of neurodegeneration and its course. These markers would also help to establish endpoints for neuroprotective treatment strategies aiming to modify disease progression. Because of the complexity, heterogeneity, and the progressive nature of PD, such predictive and progression markers can only be identified in large cohorts and in studies with a longitudinal design. A considerable number of longitudinal cohort studies in PD patients, as well as in individuals at risk, are currently being performed, and extensive effort has gone into the characterization of the individuals assessed. Although each study has its own value and merits, many important research questions cannot be answered as the numbers of participants are too small (e.g., when studying conversion to PD in at-risk populations). Moreover, the pivotal combination of data and findings across studies is hampered by the lack of comparability of symptoms/factors that are being assessed and the specific assessments that are being applied. Therefore, a common approach is needed to enable harmonization and combination of data across studies to define and validate predictive and progression markers. Based on the need for harmonized assessments of symptoms/markers in PD, the working group: Harmonization of biomarker assessment in longitudinal cohort studies in Parkinson's Disease (BioLoC-PD) of the Joint Programme for Neurodegenerative Diseases (JPND), set out to develop an assessment battery that includes the most useful clinical, laboratory, and brain imaging assessments for (longitudinal) studies in PD. We here describe the result of the process to find a way to harmonize assessments across studies and propose a modular set of biomarker assessments agreed upon by the group of experts who were included in the working group (all authors of this manuscript).

Clinical variables associated with treatment changes in Parkinson’s disease: results from the longitudinal phase of the REASON study

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

Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases

Recently, it has been shown that in patients with AD (Alzheimer's disease) and, to some degree, in patients with PD (Parkinson's disease) insulin signalling is impaired. This finding has initiated a range of research projects that showed remarkable improvements using treatments that initially had been developed to treat diabetes. Pre-clinical studies showed good neuroprotective effects when applying insulin or long-lasting analogues of incretin peptides. In transgenic animal models of AD and PD, analogues of the incretin GLP-1 (glucagon-like peptide 1) prevented neurodegenerative processes and improved neuronal and synaptic functionality in AD and PD. Amyloid plaque load and synaptic loss as well as cognitive impairment had been ameliorated in AD models, and dopaminergic loss of transmission and motor function was reversed in models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results being published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for Type 2 diabetes also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients. The present review summarizes the range of neuroprotective effects that these drugs have demonstrated and emphasizes the great promise that this approach has in providing novel treatments that have protective and even restorative properties that no current drug treatment can offer.

The neurobiology of the spinal cord in experimental parkinsonism and Parkinson's disease.

The neurobiology of non-motor symptoms in Parkinson's disease (PD) reveals a number of unexpected areas which once were not recognized a priori as part of the neuropathology underlying PD. These areas may belong either to central nervous system or periphery. Among central areas major efforts in the last decade led to recognize a number of brain nuclei as part of the disease spreading or disease onset in PD patients. Unexpectedly recent evidence deriving from pathological studies in PD patients and corroborated by experimental models of PD provided clear evidence that the spinal cord is often recruited in PD pathology. Such an involvement is intriguing since the major degenerative disease of the spinal cord (amyotrophic lateral sclerosis) features the involvement of dopaminergic neurons of the substantia nigra pars compacta, while some environmental (parkinsonism, ALS, and dementia of Guam) and genetic (Kufor-Rakeb syndrome) diseases are known to be characterized by mixed degeneration of pyramidal and extrapyramidal regions. Thus, the clear-cut between degeneration of dopaminergic neurons in the substantia nigra and the loss of pyramidal motor system appears now more as a continuum of degeneration which converge in abnormal activity and cell pathology of motor neurons as a final common pathway. Among motor neurons, visceral efferent cells of the spinal cord are involved and provide a robust neurobiological findings which may justify a variety of non-motor autonomic symptoms which characterize PD. Neurodegeneration in the spinal cord extends to the dorsal horn of the grey matter posing an intriguing link between PD and sensory alterations. The present manuscript reviews the involvement of multiple regions of the spinal cord in PD and experimental parkinsonism in the attempt to provide both a neurobiological background to understand non motor symptoms and to provide the anatomical basis for disease spreading.

Effects of Sleep Disorders on the Non-Motor Symptoms of Parkinson Disease

To evaluate the impact of sleep disorders on non-motor symptoms in patients with Parkinson disease (PD). This was a cross-sectional study. Patients with PD were evaluated for obstructive sleep apnea (OSA), restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and REM sleep behavior disorder (RBD). Cognition was assessed with the Montreal Cognitive Assessment and patients completed self-reported questionnaires assessing non-motor symptoms including depressive symptoms, fatigue, sleep complaints, daytime sleepiness, and quality of life. Sleep laboratory. 86 patients with PD (mean age = 67.4 ± 8.8 years; range: 47-89; 29 women). N/A. Having sleep disorders was a predictor of overall non-motor symptoms in PD (R(2) = 0.33, p < 0.001) while controlling for age, PD severity, and dopaminergic therapy. These analyses revealed that RBD (p = 0.006) and RLS (p = 0.014) were significant predictors of increased non-motor symptoms, but OSA was not. More specifically, having a sleep disorder significantly predicted sleep complaints (ΔR(2) = 0.13, p = 0.006), depressive symptoms (ΔR(2) = 0.01, p = 0.03), fatigue (ΔR(2) = 0.12, p = 0.007), poor quality of life (ΔR(2) = 0.13, p = 0.002), and cognitive decline (ΔR(2) = 0.09, p = 0.036). Additionally, increasing number of sleep disorders (0, 1, or ≥ 2 sleep disorders) was a significant contributor to non-motor symptom impairment (R(2) = 0.28, p < 0.001). In this study of PD patients, presence of comorbid sleep disorders predicted more non-motor symptoms including increased sleep complaints, more depressive symptoms, lower quality of life, poorer cognition, and more fatigue. RBD and RLS were factors of overall increased non-motor symptoms, but OSA was not.

Implications of Parkinson’s Disease Pathophysiology for the Development of Cell Replacement Strategies and Drug Discovery in Neurodegenerative Diseases

Parkinson's disease (PD) is a progressive neurodegenerative disorder traditionally characterized by the loss of dopaminergic neurons in the substantia nigra (SN) at the midbrain. The potential use of adult or embryonic stem cells, induced pluriputent stem (iPS) cells and endogenous neurogenesis in cell replacement strategies has lead to numerous studies and clinical trials in this direction. It is now possible to differentiate stem cells into dopaminergic neurons in vitro and clinical trials have shown an improvement in PD-related symptoms after intra-striatal embryonic transplants and acceptable cell survival rates on the mid term. However, clinical improvement is transitory and associated with a strong placebo effect. Interestingly, recent pathological studies in PD patients who received embryonic stem cells show that in PD patients, grafted neurons show PD-related pathology. In this manuscript we review the latest findings regarding PD pathophysiology and give an outlook on the implications of these findings in how cell replacement strategies for PD treatment should be tested. These include changes in the type of animal models used, the preparation/conditioning of the cells before intracerebral injection, specially regarding backbone chronic diseases in iPS cells and determining the optimal proliferation, survival, differentiation and migration capacity of the grafted cells.

Bedside cognitive assessments and falls risk in Parkinson’s disease

Cognitive deficits may contribute to falls in Parkinson's disease (PD) and these deficits may be risk factors for falls. However, their association with falls has been generally studied in patients with continuous gait problems. There have been few studies in PD patients without postural instability. In addition, the effectiveness of various simple bedside cognitive tests in predicting falls has not been established. In this study, we investigated the effectiveness of three bedside cognitive tests in consecutive patients with PD without postural instability. Of the 119 patients, 39 experienced falls during the follow-up period. Of the bedside cognitive assessment methods examined, only the Montreal Cognitive Assessment (MoCA) score was significantly lower in the group of fallers than in the group of non-fallers. This result suggests that the MoCA is effective as a bedside test for evaluating the risk of falls.

Body weight gain and deep brain stimulation

Deep brain stimulation (DBS) is a neurosurgical technique that has now been available for some 25years. It is used in the treatment of various motor disorders, e.g. Parkinson's disease (PD), essential tremor and dystonia, and neuropsychiatric illnesses, e.g. obsessive–compulsive disorder and Tourette syndrome. The surgical targets of DBS include the thalamic ventralis intermedius nucleus (Vim), the globus pallidus internus (GPi) and more recently the subthalamic nucleus (STN), currently considered as the reference target in the treatment of PD. In the last ten years, most studies in PD patients have described a rapid and marked weight gain in the months following DBS of the STN. This weight gain sometimes induces obesity and can have metabolic repercussions. The physiopathological mechanisms responsible for the weight gain are multifactorial (changes in energy metabolism and eating behaviour, reduction of motor complications, etc.).This review reports current knowledge concerning weight changes in patients treated by DBS with different surgical targets. It also describes the mechanisms responsible for weight gain and the health outcome for the patients.

Levetiracetam for levodopa-induced dyskinesia in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial

The aim of this study was to assess the efficacy, safety and tolerability of the antiepileptic compound levetiracetam (LEV) for the treatment of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). We thus performed a randomized, double-blind, placebo-controlled, parallel-group pilot study in PD patients with moderate-to-severe LID on stable dopaminergic therapy. Placebo or LEV was administered twice daily (titrated from 250 to 2,000mg/day) as add-on therapy. Subjects underwent evaluation of the unified-PD-rating scale (UPDRS) and the modified abnormal involuntary movement scale (AIMS). The primary outcome variable was the change of the AIMS score between baseline and end-of-treatment visit. Secondary variables included total UPDRS score and response to levodopa challenge. Of 32 randomized patients (mean age 65.2years, 62.5% women), 17 received LEV and 15 placebo. After 11weeks of treatment, mean changes of the modified AIMS from baseline were -1.5 (-26%) for LEV (p=0.332) and +0.9 (+13%) for placebo (p=0.588) without significant differences between groups. Mean changes of the UPDRS item 32/33 sum score from baseline showed significant improvement of dyskinesia in the LEV group [-1.0 (-20%); p=0.012], but not in the placebo group [-0.4 (-8%); p=0.306]. Treatment had no effects on UPDRS motor score or levodopa response. Frequency and quality of adverse events were similar in both treatment groups. Together, LEV showed only mild antidyskinetic effects without worsening of Parkinsonian symptoms or compromising levodopa efficacy. LEV was well tolerated in doses up to 2,000mg/day. Further large controlled studies are warranted to evaluate the impact of LEV on LID in PD patients.

RTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: Searching for effective cortical targets

Long-term therapy with levodopa and dopamine agonists in Parkinson's disease (PD) patients is complicated by the development of fluctuations in motor response, such as levo-dopa induced dyskinesia (LID). Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently put forward as a possible therapeutic tool able to LID in PD. Trains of 1 Hz rTMS applied either over the supplementary motor area (SMA) or the primary motor cortex (M1) were able to induce a transient reduction in the severity of LID, confirming that an over-activity of these areas plays a crucial role in the pathophysiology of LID. However, repeated sessions of rTMS were not effective in inducing persistent beneficial clinical effects. Functional or metabolic changes have been reported in the cerebellum in studies in PD patients treated with procedures known to alleviate LID, such as deep brain stimulation. Therefore, the effects of rTMS applied over the lateral cerebellum has been recently tested in patients with LID. A two-week course of bilateral cerebellar rTMS induced persistent clinical beneficial effects, reducing peak-dose LID for up to four weeks after the end of the daily stimulation period. These findings demonstrate that rTMS is a potential tool in individuating the best cortical targets and the optimal parameters of stimulation able to improve LID in dyskinetic PD patients.

Long half-life and prolonged-release dopamine receptor agonists: a review of ropinirole prolonged-release studies

Our review summarizes the five main studies conducted to evaluate the efficacy and pharmacokinetics of ropinirole prolonged release (PR) in Parkinson's disease (PD). The PR formulation was developed with Geomatrix coating technology in order to obtain constant pharmacokinetics throughout 24 hours. The areas under the curve were not significantly different from those observed with similar doses of ropinirole immediate-release (IR) formulation, administered 3 times a day, but concentration fluctuations were less for ropinirole PR (2-fold vs 5-fold). The efficacy study of the PR versus IR formulations showed non-inferiority of the PR formulation, similar tolerability and feasibility of overnight switches, and indicated that the optimal doses of ropinirole in patients with de novo PD is in the range of 8–12 mg/day. The efficacy study in PD patients with motor fluctuations treated with l-dopa showed that adding ropinirole PR significantly reduced “off” time and increased “on” time in comparison with placebo. The study with ropinirole as an add-on to l-dopa showed a reduced incidence of dyskinesias.

How do cognitive and axial motor signs correlate in Parkinson’s disease? A 6-year prospective study

Impairment of Parkinson's disease (PD) axial motor signs (AMS) has been described as a risk factor for dementia. Executive dysfunction is an important feature in recently proposed clinical diagnostic criteria for PD dementia. To clarify the relationship between AMS progression and executive cognitive performance, we conducted a 6-year prospective study in PD patients without AMS impairment at baseline. A hospital-based cohort of PD patients (n = 24) without dementia, in the initial motor stage (Hoehn-Yahr < or = 2), and matched controls (n = 20) were followed prospectively over a 6-year period. Neuropsychological tests were performed in both groups, and motor function (including AMS: speech, gait, postural instability) was evaluated in the PD group. The PD group had a significantly higher decline in neuropsychological test scores than did the controls. Most of the neuropsychological and motor decline occurred in the last 4 years. In UPDRS III, progression of AMS and especially speech were the most important motor variables related to dementia. There was a correlation between speech impairment progression and declines in MMSE (r = -0.598, p = 0.002), Clock Drawing (r = -0.671, p < 0.001), Semantic Verbal Fluency (r = -0.435, p = 0.034), Alternating Sequences (r = 0.497, p = 0.014), and Raven's Coloured Progressive Matrices (r = -0.735, p < 0.001). PD patients with higher speech impairment progression showed more rapid declines in some neuropsychological tests. Further studies are needed to clarify the different roles of speech, gait and postural instability on the initial phases of cognitive dysfunction.