A dynamic brain network decomposition method discovers effective brain hemodynamic sub-networks for Parkinson's disease.

Objective.Dopaminergic treatment is effective for Parkinson's disease (PD). Nevertheless, the conventional treatment assessment mainly focuses on human-administered behavior examination while the underlying functional improvements have not been well explored. This paper aims to investigate brain functional variations of PD patients after dopaminergic therapy.Approach.This paper proposed a dynamic brain network decomposition method and discovered brain hemodynamic sub-networks that well characterized the efficacy of dopaminergic treatment in PD. Firstly, a clinical walking procedure with functional near-infrared spectroscopy was developed, and brain activations during the procedure from fifty PD patients under the OFF and ON states (without and with dopaminergic medication) were captured. Then, dynamic brain networks were constructed with sliding-window analysis of phase lag index and integrated time-varying functional networks across all patients. Afterwards, an aggregated network decomposition algorithm was formulated based on aggregated effectiveness optimization of functional networks in spanning network topology and cross-validation network variations, and utilized to unveil effective brain hemodynamic sub-networks for PD patients. Further, dynamic sub-network features were constructed to characterize the brain flexibility and dynamics according to the temporal switching and activation variations of discovered sub-networks, and their correlations with differential treatment-induced gait alterations were analyzed.Results.The results demonstrated that PD patients exhibited significantly enhanced flexibility after dopaminergic therapy within a sub-network related to the improvement of motor functions. Other sub-networks were significantly correlated with trunk-related axial symptoms and exhibited no significant treatment-induced dynamic interactions.Significance.The proposed method promises a quantified and objective approach for dopaminergic treatment evaluation. Moreover, the findings suggest that the gait of PD patients comprises distinct motor domains, and the corresponding neural controls are selectively responsive to dopaminergic treatment.

Estimulación cerebral profunda subtalámica en un caso de enfermedad de Parkinson idiopática y esquizofrenia / Subthalamic deep brain stimulation in a case of idiopathic Parkinson’s disease and schizophrenia

Introducción La enfermedad de Parkinson (EP) y la esquizofrenia pueden coexistir. Los antipsicóticos bloquean los receptores D2 estriados, lo que inevitablemente agrava las manifestaciones de la EP. Caso clínico Presentamos el caso de un paciente con enfermedad de Parkinson idiopática y esquizofrenia, con pobre tolerancia a dosis mínimas de levodopa, que presentó una gran mejoría tras la estimulación cerebral profunda subtalámica bilateral (ECP-NST). La ECP-NST se consideró aquí, debido a la gravedad de este caso particular, como la única posibilidad de lograr una mejoría motora. Conclusiones El diagnóstico de EP idiopática se confirmó pese al tratamiento antidopaminérgico. La ECP-NST puede considerarse como una opción de tratamiento para las manifestaciones de la EP invalidantes, siempre y cuando la selección del paciente sea cuidadosa. (AU)

Introduction. Parkinson’s disease (PD) and schizophrenia can coexist. Antipsychotics block striatal D2 receptors, which inevitably aggravates the manifestations of PD.Case report. We report the case of a male patient with idiopathic Parkinson’s disease and schizophrenia, with poor tolerance to minimal doses of levodopa, who underwent a dramatic improvement after bilateral subthalamic deep brain stimulation (DBS-STN). DBS-STN was taken into consideration here, due to the severity of this particular case, as the only possible way to achieve motor improvement.Conclusions. The diagnosis of idiopathic PD was confirmed despite antidopaminergic treatment. DBS-STN can be considered a treatment option for disabling manifestations of PD, provided that a careful selection of patients is carried out. (AU)

Delayed-onset posttraumatic stress disorder with response to methylphenidate / Trastorno por estrés postraumático de expresión retardada con respuesta a metilfenidato

Introduction: Posttraumatic stress disorder (PTSD) is extremely frequent in war veterans and has been widely studied. However, the efficacy of currently available pharmacological and psychotherapeutic treatments of war PTSD and other causes of PTSD is very limited. Method We present a case of war PTSD with delayed expression, with a good response to complementation with methylphenidate after a failed treatment with venlafaxine and risperidone. Results We review the role of dopamine in the pathophysiology of PTSD and the scarce studies in the treatment of PTSD with dopaminergic drugs that show an improvement in re-experimentation and in affective symptoms, especially anhedonia and cognitive impairment. Conclusions We conclude that the use of methylphenidate and other dopaminergic drugs can be a promising treatment for PTSD, a high prevalent disease with a high resistance to treatment, for which we encourage the use of large sample studies. (AU)

Introducción: El trastorno por estrés postraumático (TEPT) es extremadamente prevalente en veteranos de guerra y ha sido ampliamente estudiado. Sin embargo, la eficacia de los tratamientos farmacológicos y psicoterapéuticos disponibles es aún muy limitada, tanto en el TEPT de guerra como en el TEPT por otras causas. Método Presentamos un caso de TEPT de guerra con expresión retardada, con una buena respuesta al metilfenidato a su tratamiento con venlafaxina y risperidona, que había resultado ineficaz. Resultados Revisamos el rol de la dopamina en la psicopatología del TEPT y los pocos estudios del tratamiento del TEPT con fármacos dopaminérgicos, en los que se muestra una mejoría en los síntomas de reexperimentación y los síntomas afectivos, especialmente la anhedonia y los déficits cognitivos secundarios. Conclusiones Consideramos que el uso del metilfenidato y de otros fármacos dopaminérgicos podrían ser prometedores el tratamiento del TEPT, un trastorno altamente prevalente y con alta resistencia al tratamiento habitual. Por esto, animamos a realizar estudios con muestras amplias. (AU)

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

The effect of mitragynine on extracellular activity of brain dopamine and its metabolites.

Kratom, derived from the plant Mitragyna speciosa (M. speciosa) Korth is a traditional psychoactive preparation widely used in Southeast Asia and increasingly in the rest of the world. Use and abuse of Kratom preparations can be attributed to mitragynine (MIT), the main psychoactive compound isolated from its leaves. While MIT may have beneficial effects as a recreational drug, for pain management, and for opiate withdrawal, it may have an addiction potential at higher doses. However, its action in the reward system of the brain is currently unknown. This study investigated how mitragynine (10 mg/kg, i.p.) affects extracellular activity of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of the brain, compared to morphine (MOR; 10 mg/kg, i.p.) and methamphetamine (METH; 10 mg/kg, i.p.). Using in-vivo microdialysis in freely moving rats, we found a significant increase of extracellular DA after MOR and METH, but not after MIT in all three brain regions. MIT led to a significant increase of DOPAC and/or HVA in these brain regions while MOR and METH had only moderate effects. These findings suggest a strong and prolonged effect of MIT on DA synthesis/metabolism, but not on extracellular DA activity, which may limit the addiction risk of MIT, in contrast to MOR and METH.

New dopaminergic therapies for PD motor complications.

BACKGROUND: Motor complications, characterized by "off" periods - when anti-parkinsonian medications are ineffective - and dyskinesia, are the hallmark of advanced Parkinson's disease (PD). While levodopa is the gold standard PD medication in terms of efficacy, its short duration of effect coupled with progressive loss of dopaminergic neurons leads to motor complications and fails to treat off periods. PURPOSE OF REVIEW: This review focuses on novel dopaminergic therapies that were recently made clinically available or are currently in development for the treatment of motor complications. First, it will discuss rescue therapies for the treatment of off episodes, including novel apomorphine and levodopa formulations. Second, it will highlight adjunctive dopaminergic medications approved to reduce total daily off time. Third, it will discuss longer-acting levodopa formulations in development and introduce a novel selective dopamine agonist under study. Finally, it will cover novel dopaminergic delivery mechanisms, with specific focus on continuous subcutaneous infusions in development. SUMMARY: The breadth of dopaminergic therapies recently approved or in development for motor complications, and specifically off time reduction, evokes cautious optimism. Gains in reducing off time with rescue therapies, adjunctive medications or longer-acting levodopa formulations are modest, and underscore the need for more continuous dopaminergic delivery to address the underlying pathophysiology and translate to clinically meaningful improvement in motor complications.

Current concepts in treating mild cognitive impairment in Parkinson's disease.

Impairment in various aspects of cognition is recognized as an important non-motor symptom of Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) is common in non-demented PD patients and is often associated with severity of motor symptoms, disease duration and increasing age. Further, PD-MCI can have a significant negative effect on performance of daily life activities and may be a harbinger of development of PD dementia. Thus, there is significant interest in developing therapeutic strategies to ameliorate cognitive deficits in PD and improve cognitive functioning of PD patients. However, due to significant questions that remain regarding the pathophysiology of cognitive dysfunction in PD, remediation of cognitive dysfunction in PD has proven difficult. In this paper, we will focus on PD-MCI and will review some of the current therapeutic approaches being taken to try to improve cognitive functioning in patients with PD-MCI.

Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization.

OBJECTIVE: It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. METHODS: Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. RESULTS: Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. CONCLUSIONS: These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

Rotigotine-loaded microspheres exerts the antinociceptive effect via central dopaminergic system.

Rotigotine-loaded microspheres (RoMS), a sustained-release formulation with a continuous release of rotigotine for more than 7 days in vivo, have been conducted a clinical trial for the treatment of Parkinson's disease (PD). Previous work from our laboratory showed that RoMS exerted an antinociceptive effect in rat models of inflammatory pain. The purpose of this study was to investigate the mechanisms of action underlying the antinociceptive effect of RoMS. A rat model of inflammatory pain was prepared by an intraplantar injection of carrageenan. The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D2 receptor antagonist), D2D3 shRNA, and naloxone (nonselective opioid receptor antagonist) on RoMS-mediated antinociceptive efficacy. The expressions of D2 and D3 receptors in the striatum and periaqueductal gray were measured by Western blotting. Intracerebroventricular injection of domperidone abated the antinociceptive effect of RoMS. However, intraperitoneal injection of domperidone had no significant effect on the antinociceptive action of RoMS. Intracerebroventricular injection with D2D3 shRNA significantly attenuated the expressions of D2 and D3 receptors in the striatum and the periaqueductal gray. D2 and D3 receptors silence significantly weakened RoMS-mediated antinociceptive effect. Intracerebroventricular injection of naloxone also alleviated the antinociceptive effect of RoMS. The results suggest that RoMS-mediated antinociceptive efficacy is associated with activating central dopamine D2 and D3 receptors. Opioid receptors play a role in the antinociceptive effect of RoMS.

Dopamine-loaded lipid based nanocarriers for intranasal administration of the neurotransmitter: A comparative study.

Both dopamine (DA) loaded Solid Lipid Nanoparticles (SLN) and liposomes (Lip), designed for intranasal administration of the neurotransmitter as an innovative Parkinson disease treatment, were already characterized in vitro in some extent by us (Trapani et al., 2018a and Cometa et al., 2020, respectively). Herein, to gain insight into the structure of SLN, X-ray Photoelectron Spectroscopy Analysis was carried out and DA-SLN (SLN 1) were found to exhibit high amounts of the neurotransmitter on the surface, whereas the external side of Glycol Chitosan (GCS) containing SLN (SLN 2) possessed only few amounts. However, SLN 2 were characterized by the highest encapsulation DA efficiency (i.e., 81%). Furthermore, in view of intranasal administration, mucoadhesion tests in vitro were also conducted for SLN and Lip formulations, evidencing high muchoadesive effect exerted by SLN 2. Concerning ex-vivo studies, SLN and Lip were found to be safe for Olfactory Ensheathing Cells and fluorescent SLN 2 were taken up in a dose-dependent manner reaching the 100% of positive cells, while Lip 2 (chitosan-glutathione-coated) were internalised by 70% OECs with six-times more lipid concentration. Hence, SLN 2 formulation containing DA and GCS may constitute interesting formulations for further studies and promising dosage form for non-invasive nose-to-brain neurotransmitter delivery.

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice.

Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.

ATP13A2 levels in serum and cerebrospinal fluid in patients with idiopathic Parkinson's disease.

BACKGROUND: The enzyme ATP13A2 holds promise as biomarker in Parkinson's disease (PD). No study has examined the content of ATP13A2 in serum and cerebrospinal fluid (CSF) in idiopathic PD cohorts, or how ATP13A2 relates to the clinical features of the disease. METHODS: ATP13A2 concentration was evaluated with ELISA and immunoblotting. Correlations of serum and CSF ATP13A2 with clinical parameters were examined. The antiparkinsonian medication regimen was expressed as levodopa equivalent dose (LED, mg/day). RESULTS: Serum ATP13A2 concentration was similar in patients and controls, and it correlated with LED and MDS-UPDRS part-IV score (p < .0001), a scale which allows evaluating motor complications. LED also correlated with MDS-UPDRS part-IV score (p < .0001). Serum ATP13A2 concentration and LED were higher in patients with motor complications than in patients without motor complications (p < .0001). The ratio of serum ATP13A2 concentration versus LED was calculated, and mean value was similar in patients with or without motor complications. ATP13A2 concentration in the CSF was undetectable in many subjects because the ELISA assay was hampered by its detection limit. Immunoblotting indicated that CSF ATP13A2 content was higher in patients relative to controls (p = .0002), and no clinical correlations were found. CONCLUSIONS: Increasing LED enhanced serum ATP13A2 concentration and facilitated the development of motor complications. There is a direct relationship between serum ATP13A2 level and the dose intensity of the antiparkinsonian dopaminergic medication. The associations between serum ATP13A2 and LED suggest that serum ATP13A2 content might be a marker of dopamine replacement therapy.

Should we start integrating genetic data in decision-making on device-aided therapies in Parkinson disease? A point of view.

Parkinson disease (PD) is a complex heterogeneous neurodegenerative disorder. Association studies have revealed numerous genetic risk loci and variants, and about 5-10% suffer from a monogenic form. Because the presentation and course of PD is unique to each patient, personalized symptomatic treatment should ideally be offered to treat the most disabling motor and non-motor symptoms. Indeed, clinical milestones and treatment complications that appear during disease progression are influenced by the genetic imprint. With recent advances in PD, more patients live longer to become eligible for device-aided therapies, such as apomorphine continuous subcutaneous infusion, levodopa duodenal gel infusion, and deep brain stimulation surgery, each with its own inclusion and exclusion criteria, advantages and disadvantages. Because genetic variants influence the expression of particular clinical profiles, factors for better or worse outcomes for device-aided therapies may then be proactively identified. For example, mutations in PRKN, LRRK2 and GBA express phenotypes that favor suitability for different device therapies, although with marked differences in the therapeutic window; whereas multiplications of SNCA express phenotypes that make them less desirable for device therapies.

CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders.

Perinatal alcohol exposure can lead to fetal alcohol spectrum disorders (FASD), usually first diagnosed in childhood, that are characterized by hyperactivity, impulsivity and learning and memory disability, among others. To test the hypothesis that dopamine signaling is one of the main factors underlying these impairments, a new atypical dopamine transporter (DAT) inhibitor, CE-123 (1, 3 or 10 mg/kg) was assessed for its potential to overcome the ethanol-induced behavioral effects in a rat model of FASD. In the present study, neonatal rats were exposed to alcohol intubations across the neonatal period (postnatal day (PND)4-9, the third trimester equivalent of human gestation) and, after weaning, the animals (male rats) were assigned randomly to three groups. The first group was tested at PND21 (hyperactivity test). A second group was tested at PND45 (anxiety test), at PND47 (locomotor activity test), at PND49 (spatial cognitive test in the Barnes maze) and PND50 (reversal learning in the Barnes maze). The third group was tested at PND50 (dopamine receptor mRNA expression). Our results support the hypothesis that dopamine signaling is associated with FASD because the dopamine (D1, D2 and D5) receptor mRNA expression was altered in the striatum, hippocampus and prefrontal cortex in adult rats exposed to ethanol during neonatal period. CE-123 (3 and 10 mg/kg) inhibited the hyperactivity and ameliorated (10 mg/kg) the impairment of reversal learning in alcohol-exposed rats. Thus, these findings provide support that CE-123 may be a useful intervention for same of the deficits associated with neonatal ethanol exposure.

Novel Pharmacotherapies in Parkinson's Disease.

Parkinson's disease (PD), an age-related progressive neurodegenerative condition, is associated with loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which results in motor deficits characterized by the following: akinesia, rigidity, resting tremor, and postural instability, as well as nonmotor symptoms such as emotional changes, particularly depression, cognitive impairment, gastrointestinal, and autonomic dysfunction. The most common treatment for PD is focused on dopamine (DA) replacement (e.g., levodopa = L-Dopa), which unfortunately losses its efficacy over months or years and can induce severe dyskinesia. Hence, more efficacious interventions without such adverse effects are urgently needed. In this review, following a general description of PD, potential novel therapeutic interventions for this devastating disease are examined. Specifically, the focus is on nicotine and nicotinic cholinergic system, as well as butyrate, a short chain fatty acid (SCFA), and fatty acid receptors.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS: We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01). CONCLUSIONS: This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

Coadministration With Carbidopa Enhances the Antimyopic Effects of Levodopa in Chickens.

Purpose: Topical application of levodopa inhibits the development of form-deprivation myopia (FDM) and lens-induced myopia (LIM) in chicks. Here we examine whether coadministration with carbidopa enhances this protection and compare the effectiveness of topical versus systemic administration. We also investigate the degree to which topical and systemic administration of these compounds alters retinal dopamine release and examine whether this is the mechanism by which they inhibit experimental myopia. Methods: Levodopa and levodopa:carbidopa (at a 4:1 ratio) were administered as twice-daily eye drops or once-daily intraperitoneal injections to chicks developing FDM or LIM over an ascending dose range. Axial length and refraction were measured following 4 days of treatment. Dopamine levels in the vitreous and blood were analyzed using liquid chromatography-mass spectrometry following topical or systemic administration of levodopa or levodopa:carbidopa. Finally, chicks receiving topical or systemic levodopa or levodopa:carbidopa were cotreated with the dopamine antagonist spiperone. Results: Levodopa:carbidopa inhibited the development of FDM and LIM to a greater extent than levodopa alone (P < 0.05). Topical application was more effective than systemic administration (P < 0.001). Vitreal dopamine levels were increased to the greatest extent by topical application of levodopa:carbidopa (P < 0.001). Systemic but not topical administration significantly increased dopamine levels within the blood (P < 0.01). Cotreatment with spiperone inhibited the antimyopic effects (P < 0.05) of levodopa and levodopa:carbidopa. Conclusions: The presence of carbidopa increases the bioavailability of levodopa within the eye, enhancing its antimyopic effects, with topical application showing the greatest efficacy. Thus levodopa:carbidopa may be a promising treatment for controlling the progression of human myopia.

Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice.

RATIONALE: Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/-) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/- on innate and MA-modulated reward sensitivity are not known. OBJECTIVES: We examined innate reward sensitivity and facilitation by MA in H1+/- mice via intracranial self-stimulation (ICSS). METHODS: We used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5-4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. RESULTS: H1+/- mice displayed reduced normalized maximum response rates in response to MA. H1+/- females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. CONCLUSIONS: H1+/- mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/- females (lower normalized M50 values).

Motor blocks during bilateral stepping in Parkinson's disease and effects of dopaminergic medication.

INTRODUCTION: Freezing of gait (FOG) is a complex symptom in Parkinson's disease (PD) that manifests during walking as limited forward progression despite the intention to walk. It is unclear if lower limb motor blocks (LLMB) that occur independently from FOG are related to overground FOG and the effects of dopaminergic medications. METHODS: Nineteen patients with PD were tested on two separate days in the dopaminergic medication "on" and "off" states. The patients completed a series of freezing-provoking tasks while videotaped. Raters assessed videos for FOG presence using Movement Disorders Society Unified Parkinson's Disease Rating Scale item 3.11 score greater than or equal to 1 and FOG severity using the standardized FOG score. Whilst seated in a virtual environment, patients and 20 healthy controls stepped in right-left sequence on foot pedals. Frequency and percent time in LLMB were assessed for accurate classification of FOG presence and correlation to the FOG score. RESULTS: Frequency and percent time spent in LLMB predicted the presence of FOG in both medication states. Percent time spent in LLMB correlated with FOG severity in both medication states. LLMB frequency predicted FOG severity in the "off" state only. CONCLUSIONS: LLMB during bilateral stepping in a virtual environment predicted the presence and severity of FOG in PD in both "on" and "off" medication states. These findings support the use of this non-walking paradigm to detect and assess FOG in PD patients unable or unsafe to walk.