Anxiety-provoked gait changes are selectively dopa-responsive in Parkinson's disease.

In order to understand how dopamine modulates the effect of anxiety on gait, the goal of this study was to use virtual reality to provoke anxiety in Parkinson's disease (PD) (in both ON and OFF states) and quantify its effect on gait. Seventeen participants with PD and 20 healthy age-matched controls were instructed to walk in a virtual environment in two anxiety-provoking conditions: (i) across a plank that was located on the GROUND and (ii) across an ELEVATED plank. All participants with PD completed this experiment in both the ON and OFF states, and were then striated into groups based on baseline trait anxiety scores for further analyses. Anxiety (skin conductance and self-report) and spatiotemporal aspects of gait were measured. Overall, the ELEVATED condition resulted in greater skin conductance levels and self-reported anxiety levels. Additionally, all participants demonstrated slower gait with increased step-to-step variability when crossing the ELEVATED plank compared with the plank on the GROUND. The results showed that dopaminergic treatment selectively improved gait in only the highly anxious PD group, by significantly improving velocity, step length, step time and step-to-step variability specifically when walking across the ELEVATED plank (ON vs. OFF comparison). In conclusion, only highly trait anxious participants with PD benefitted from dopaminergic treatment, specifically when walking in the anxiety-provoking environment. Improvements to gait during anxious walking might be a result of dopaminergic medication acting in two ways: (i) improving the basal ganglia's capacity to process information and (ii) reducing the load from anxiety and subsequently making more resources available to effectively process other competing inputs.

Cardiovascular actions of DOPA mediated by the gene product of ocular albinism 1.

l-3,4-Dihydroxyphenylalanine (DOPA) is the metabolic precursor of dopamine, and the single most effective agent in the treatment of Parkinson's disease. One problem with DOPA therapy for Parkinson's disease is its cardiovascular side effects including hypotension and syncope, the underlying mechanisms of which are largely unknown. We proposed that DOPA is a neurotransmitter in the central nervous system, but specific receptors for DOPA had not been identified. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. It was unknown, however, whether or not OA1 is responsible for the actions of DOPA itself. Immunohistochemical examination revealed that OA1 was expressed in the nucleus tractus solitarii (NTS). OA1-positive cells adjacent to tyrosine hydroxylase-positive cell bodies and nerve fibers were detected in the depressor sites of the NTS. OA1 knockdown using oa1-specific shRNA-adenovirus vectors in the NTS reduced the expression levels of OA1 in the NTS. The prior injection of the shRNA against OA1 suppressed the depressor and bradycardic responses to DOPA but not to glutamate in the NTS of anesthetized rats. Thus OA-1 is a functional receptor of DOPA in the NTS, which warrants reexamination of the mechanisms for the therapeutic and untoward actions of DOPA.

Efficacy and safety of standardized extract of Trigonella foenum-graecum L seeds as an adjuvant to L-Dopa in the management of patients with Parkinson's disease.

The objective of this study is to evaluate disease modifying efficacy and safety of a standardized extract of Trigonella foenum-graecum L, Fenugreek (IBHB) (family Fabaceae) as a nutritional adjuvant to Levo-dopa (L-Dopa) in Parkinson's disease (PD) patients. We conducted double-blind placebo-controlled proof of concept clinical study of IBHB capsules (300 mg, twice daily) with matching placebo for 6 months of period in 50 patients of PD stabilized on L-Dopa therapy. The efficacy outcome measures were the scores of Unified Parkinson's Disease Rating Scale (UPDRS - total and its subsections), and Hoehn and Yahr (H&Y) staging at baseline and end of 6-months treatment duration. Safety evaluation included haematology, biochemistry, urinalysis parameters and adverse event monitoring. Total UPDRS scores in IBHB treatment (0.098%) showed slower rise as opposed to steep rise (13.36%) shown by placebo. Further, Clinically Important Difference for total UPDRS scores and scores of motor subsection of UPDRS was found to be 5.3 and 4.8, respectively, in favour of IBHB treatment. Similar improvement was shown by IBHB in terms of H&Y staging as compared with placebo. IBHB was found to have excellent safety and tolerability profile. In conclusion, IBHB can be useful adjuvant treatment with L-Dopa in management of PD patients.

The combination of oral L-DOPA/rimonabant for effective dyskinesia treatment and cytological preservation in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia.

Parkinson's disease is the second most prevalent neurodegenerative disease in the world. Its treatment is limited so far to the management of parkinsonian symptoms with L-DOPA (LD). The long-term use of LD is limited by the development of L-DOPA-induced dyskinesias and dystonia. However, recent studies have suggested that pharmacological targeting of the endocannabinoid system may potentially provide a valuable therapeutic tool to suppress these motor alterations. In the present study, we have explored the behavioral (L-DOPA-induced dyskinesias severity) and cytological (substantia nigra compacta neurons and striatum neuropil preservation) effects of the oral coadministration of LD and rimonabant, a selective antagonist of CB1 receptors, in the 6-hydroxydopamine rat model of Parkinson's disease. Oral coadministration of LD (30 mg/kg) and rimonabant (1 mg/kg) significantly decreased abnormal involuntary movements and dystonia, possibly through the conservation of some functional tyrosine hydroxylase-immunoreactive dopaminergic cells, which in turn translates into a well-preserved neuropil of a less denervated striatum. Our results provide anatomical evidence that long-term coadministration of LD with cannabinoid antagonist-based therapy may not only alleviate specific motor symptoms but also delay/arrest the degeneration of striatal and substantia nigra compacta cells.

DOPA pheomelanin is increased in nigral neuromelanin of Parkinson's disease.

Neuromelanin (NM) in dopaminergic neurons of human substantia nigra (SN) has a melanic component that consists of pheomelanin and eumelanin moieties and has been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). While eumelanin is considered as an antioxidant, pheomelanin and related oxidative stress are associated with compromised drug and metal ion binding and melanoma risk. Using postmortem SN from patients with PD or Alzheimer's disease (AD) and unaffected controls, we identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to controls. Eumelanins derived from both DOPA and DA were reduced in PD group. In addition, we report an increase in DOPA pheomelanin relative to DA pheomelanin in PD SN. In AD SN, we observed unaltered melanin markers despite reduced DOPA compared to controls. Furthermore, synthetic DOPA pheomelanin induced neuronal cell death in vitro while synthetic DOPA eumelanin showed no significant effect on cell viability. Our findings provide insights into the different roles of pheomelanin and eumelanin in PD pathophysiology. We anticipate our study will lead to further investigations on pheomelanin and eumelanin individually as biomarkers and possibly therapeutic targets for PD.

Neuroleptic Malignant Syndrome in Patients With Dementia: Experiences of A Single Memory Clinic.

OBJECTIVES: Neuroleptic malignant syndrome (NMS) is a life-threatening condition that occurs as an adverse reaction to antipsychotic and antiemetic agents or sudden withdrawal of dopaminergic medications. Given the metabolic and functional reserves and the comorbidities in older adults, NMS may show an atypical course. METHODS: The medical records of patients with neurodegenerative diseases leading to dementia between 2013 and 2020 were reviewed for the diagnosis of NMS. Demographic and clinical characteristics of the patients were obtained from the records of laboratory parameters, management, and length of stay. RESULTS: Fifteen older adults (19 episodes) diagnosed with NMS were included. The median age was 76 years, and 5 were female. Ten of 15 NMS patients were atypical. Most of them had an infection accompanying NMS. Neuroleptic malignant syndrome was caused by antidopaminergic agents (5 antipsychotics, 1 metoclopramide) in 6 episodes and discontinuation of a dopaminergic agent, l -DOPA, in 12 episodes. In 1 patient, it was associated with simultaneous use of domperidone and amantadine withdrawal. Rigidity in NMS due to l -DOPA discontinuation was higher than in those due to antipsychotic use ( P = 0.027). Two of our patients needed intensive care, and 1 died. CONCLUSIONS: This study highlights the high frequency of atypical NMS and the importance of early recognition of this potentially fatal syndrome, which can accompany neurodegenerative diseases and infections in older adults.

Dopamine transporter imaging (123)I-FP-CIT (DaTSCAN) SPET in differential diagnosis of dopa-responsive dystonia and young-onset Parkinson's disease.

Dopa-responsive dystonia (DRD) is a genetic disorder characterized by childhood onset dystonia, dominant inheritance, diurnal symptoms fluctuation and positive levodopa response. Adult-onset DRD is frequently combined with parkinsonism and can be mistaken with young onset Parkinson's disease (YOPD). Both conditions are caused by dopamine deficiency, due to nigral cells' loss in YOPD, and due to enzymatic defects in dopamine synthesis in DRD. Single photon emission tomography (SPET) with (123)I-N--fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane ((123)I-FP-CIT)-DaTSCAN is a sensitive neuroimaging method for the assessment of nigrostriatal dopaminergic system integrity and degeneration. Our aim was to evaluate the usefulness of (123)I-FP-CIT( DaTSCAN) SPET in the differential diagnosis of DRD and YOPD in clinical practice. Brain SPET with (123)I-FP-CIT was performed in 13 patients (7 males, 6 females), age 20-58 years, with mean age of onset of their disease, 29 years, eleven patients with early onset parkinsonian symptoms and 2 with genetically proved DRD. The images were evaluated by visual and semiquantitative analyses (ROI). The ratio of specific-striatal to non specific-occipital binding was calculated. Ten out of 11 patients with YOPD had decreased accumulation of DaTSCAN in striatum, especially in putamen, that is typical findings for Parkinson's disease. In three patients DaTSCAN was normal with symmetric tracer uptake in both striata, caudate nucleus and putamen and the diagnosis of DRD was suspected. Two patients with initial dystonic symptoms and genetically proved DRD had normal DaTSCAN. In one patient after normal DaTSCAN findings the initial diagnosis of YOPD was changed to the diagnosis of DRD. Region of interest (ROI) analyses have shown significantly lower(123)I-FP-CIT binding ratios in YOPD than in DRD in all 3 regions of interest: striatum (1.95±0.32) vs (2.76±0.10) P<0.001, putamen (1.76±0.25) vs (2.84±0.14) P<0.0001 and caudate nucleus (2.37±0.51) vs (3.27±0.14) P<0.01. In conclusion, our results indicate that DaTSCAN is an objective neuroimaging method able to distinguisch neurodegenerative disease YOPD from DRD and clarify a clinical dilemma, which is important for the treatment, prognosis and genetic counseling of patients and their families.

Manganese Dioxide-Based Nanocarrier Delivers Paclitaxel to Enhance Chemotherapy against Orthotopic Glioma through Hypoxia Relief.

Chemotherapy plays an important role in treating cancers in clinic. Hypoxia-mediated chemoresistance remains a major hurdle for effective tumor chemotherapy. Herein, a new class of tLyP-1-modified dopamine (DOPA)-ß-cyclodextrin (CD)-coated paclitaxel (PTX)- and manganese dioxide (MnO2 )-loaded nanoparticles (tLyP-1-CD-DOPA-MnO2 @PTX) is developed to enhance glioma chemotherapy. The nanomedicine delivered to the tumor site decomposes in response to the weak acidity and high hydrogen peroxide in the tumor microenvironment (TME), resulting in collapse of the system to release PTX and generates Mn2+ and O2 . In a rat model of intracranial glioma, tLyP-1-CD-DOPA-MnO2 @PTX can efficiently pass through the blood-brain-barrier to accumulate in tumor sites. The hypoxia in TME can be relieved via O2 generated by MnO2 and the reactive oxygen species produced by Mn2+ can kill tumor cells. The tLyP-1-CD-DOPA-MnO2 @PTX nanoparticles exert a remarkable antitumor effect by promoting apoptosis and inhibiting proliferation of tumor cells in addition to enabling real-time tumor monitoring with magnetic resonance imaging. This MnO2 -based theranostic medicine will offer a novel strategy to simultaneously enhance chemotherapy and achieve real-time imaging of therapeutic process in glioma treatment.

The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [18F]-FDOPA imaging in schizophrenia.

BACKGROUND: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [18F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test-retest reliability of [18F]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery. METHODS: Twenty patients with schizophrenia received symptom measures and [18F]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment. RESULTS: AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Kicer) and reduction in symptoms, in the AUT00206 group (r = 0.58, p = 0.03). This was not observed in the placebo group (r = -0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [18F]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions. CONCLUSIONS: The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [18F]-FDOPA PET imaging showed very good test-retest reliability in patients with schizophrenia.

[Functional imaging: role for the diagnosis and therapeutic evaluation of Parkinson's disease]. / Imagerie fonctionnelle: quelle place dans le diagnostic et l'évaluation thérapeutique de la maladie de Parkinson ?

Functional imaging is a tool that has been long restricted to research programs. However, the availability of ¹²³I-Ioflupane SPECT imaging has developed its' clinical utilization with a risk of misuse. There is room for improvement for the differential diagnosis between idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes and the measure of brain glucose metabolism with PET might fill this gap in the future. Conversely, functional imaging is still a major tool for the evaluation of new experimental therapeutic strategies in PD, especially for those aiming at restoring or protecting striatal dopaminergic innervation.

Two in the hand, an essential lesson in tremor management.

Dopa responsive dystonia results from abnormalities in the dopamine synthesis pathway which produces an array of phenotypic presentations with equally numerous genotypes. First documented in children in 1971, the 'classic' phenotype is childhood onset, predominantly lower limb dystonia which gradually progresses to generalised dystonia. Other hallmarks of 'classical' dopa responsive dystonia include marked diurnal variation in symptom severity (worse in the evening), subsequent development of parkinsonism and an excellent, sustained response to levodopa. More recently, adult onset variants have been reported. Here we discuss two siblings with dopa responsive dystonia caused by a mutation in the GTP cyclohydrolase 1 gene. Both presented in adulthood with tremor rather than the 'classic' phenotype. A video is presented (available online) followed by a brief discussion of the literature.

Renin-aldosterone system in Parkinson's disease.

Low blood pressure is frequent in the akinetic form of Parkinson's disease. A low renin activity in plasma as well as a low rate of aldosterone secretion is demonstrated in these patients. Renin activity in the plasma is further decreased by treatment with L-dihy-droxyphenylalanine, thus partially accouinting for the hypotensive episodes seen with this form of therapy.

Dopamine: stimulation-induced release from central neurons.

Dopamine, synthesized in rat brain slices from labeled L-tyrosine or L-dopa, can be released by electrical stimulation of a type known to induce neuronal depolarization. Pretreatment of the animals with 6-hydroxydopamine, which destroys central catecholamine-containing nerve terminals, substantially reduced the release of dopamine synthesized from [(14)C]tyrosine or from a low concentration of [(3)H]dopa, whereas the release of dopamine formed from a high concentration of [(3)H]dopa remained essentially unchanged. The observations that at high concentrations L-dopa may enter noncatecholaminergic cells, undergo decarboxylation to dopamine, and subsequently be liberated in response to depolarization suggest that dopamine may act as a substitute central transmitter, possibly in serotonergic neurons. This mechanism may contribute to L-dopa's clinical effects in parkinsonian patients.

Dopamine protects mice against whole-body irradiation.

Injection of dopamine before whole-body x-irradiation of mice resulted in 80 percent survivors whereas no irradiated controls survived; injection after exposure had no effect. D,L-Dihydroxyphenylalanine, the precursor of dopamine, had no effect on survival when injected either before or after irradiation.

Tremor and involuntary movements in monkeys: effect of L-dopa and of a dopamine receptor stimulating agent.

Either L-dopa, in combination with 1-alpha-methyldopa hydrazine (MK-486), or 1-(2''-pyrimidyl)-4-piperonylpiperazine, an agent that stimulates dopamine receptors, relieves surgically induced tremor in monkeys and concomitantly evokes involuntary movements. These results indicate that tremor and involuntary movements are associated with a common mechanism and that the activity of the dopamine receptors is involved in the regulation of these dysfunctions.

Uneventful electroconvulsive therapy in a patient with dopa-responsive dystonia (Segawa syndrome).

BACKGROUND: The Segawa syndrome is an autosomal dominant form of guanosine triphosphate cyclohydrolase deficiency, resulting in decreased dopamine and serotonin levels, typically presenting as a dopa-responsive dystonia. METHOD: Case presentation of a 56-year-old man with dopa-responsive dystonia, treated with electroconvulsive therapy for a psychotic depression. RESULTS: Scores on the Inventory of Depressive Symptomatology dropped from 35 before treatment to 3 after the eighth treatment session. Etomidate and succinylcholine were used as anesthetics. Apart from 2 sessions with postictal agitation, the course of electroconvulsive therapy was finished uneventfully. Electroconvulsive therapy and anesthesia had no untoward effects on motor function. CONCLUSIONS: Electroconvulsive therapy can be administered safely and effectively in a patient with dopa-responsive dystonia (Segawa syndrome).

Peripheral aromatic L-amino acids decarboxylase inhibitor in Parkinsonism. I. Effect on O-methylated metabolites of L-dopa-2- 14 C.

The effects of MK-486, an inhibitor of peripheral aromatic L-amino acids decarboxylase, on the urinary metabolites derived from orally administered L-Dopa-2-(14)C were studied in three Parkinsonian patients. Treatment with MK-486 before L-Dopa-2-(14)C markedly reduced radioactivity found in catecholamines fraction by 70-80% during 48 hr, but increased 3-O-methyldopa fraction by threefold, as compared with a nonpretreated base line value. Pretreatment with MK-486 for a period of 1 wk resulted in less inhibition of O-methylated amine and acid metabolite fractions than that measured after a single dose of the inhibitor.

Functional evaluation of prolactin secretion: a guide to therapy.

Stimulation and inhibition tests are proposed for evaluating prolactin secretion. Thyrotropin-releasing hormone (TRH) stimulates the release of prolactin from the pituitary. Chlorpromazine acts presumably at the hypothalamic level to increase prolactin secretion. L-Dopa (D,L-alpha-hydrazino-alpha-methyl-beta-[3,4-di-hydroxyphenyl]) has the opposite effect; it inhibits prolactin secretion and may be effective in suppressing galactorrhea.

[Mutation analysis of GCH1 gene in Chinese patients with dopa responsive dystonia].

OBJECTIVE: To detect mutations of guanosine triphosphate cyclohydrolase I (GCH1) gene in Chinese patients with dopa responsive dystonia (DRD). METHODS: Six sporadic patients with DRD were examined. GCH1 gene mutations were detected using polymerase chain reaction (PCR), DNA sequence analysis and restriction enzyme digestion analysis. One hundred normal people were detected using PCR and restriction enzyme digestion analysis. RESULTS: A new point mutation, 151(G-->A) in exon one was found in a patient. It lead to substitution of a methionine for isoleucine at amino acid 1(M1I). This mutation was not found in normal control people. CONCLUSION: The authors report a new heterozygotic point mutation 151(G-->A) in GCH1 gene. There are GCH1 gene mutations in Chinese sporadic patients with DRD.

Anxiety provokes balance deficits that are selectively dopa-responsive in Parkinson's disease.

Previous research has suggested that balance impairments may be linked to anxiety in PD, yet there is little empirical evidence to support this link in PD. This study aimed to evaluate the influence of anxiety on balance, and also examine whether dopaminergic treatment modulates the influence of anxiety on balance. Forty-two participants (10 high anxious PD [HA-PD]; 11 low anxious PD [LA-PD], 21 controls [HC]) performed 10 quiet standing trials on a force platform in two virtual environments: LOW threat; on a plank located on the ground; HIGH threat; on an elevated plank. After each 30-s trial, participants rated their anxiety. PD participants were tested both ON and OFF dopaminergic medication, and center of gravity (COG) deviations in anterior-posterior (AP) and medio-lateral (ML) directions were recorded. Results showed that all groups reported significantly greater levels of anxiety when standing in the HIGH condition compared to the LOW and HA-PD reported greater levels of anxiety compared to both other groups. All participants significantly reduced their COG position to be closer to center in the ML plane during the HIGH compared to LOW threat condition. HA-PD participants were the only group to reduce their lean significantly in the AP plane while standing in the HIGH compared to the LOW condition. HA-PD participants also had significantly greater variability in the COG displacement in both the AP and ML planes compared to LA-PD participants. Although dopaminergic medication significantly reduced self-reported anxiety, it had limited effects on balance. In conclusion, this study provides strong evidence that anxiety does influence balance control in PD, especially those who are highly anxious. Dopamine appears to modulate anxiety, but further research is needed to evaluate whether dopaminergic treatment is optimal for anxiety induced balance deficits.