Treating Malignant Catatonia With Liquid Amantadine: A Case Report and Literature Review.

Malignant catatonia (MC) is a complex, life-threatening condition characterized by motor dysregulation and autonomic instability, which requires prompt and effective treatment. There are some limitations to the current recommendations for treating MC, including barriers to receiving ECT, failure to respond to benzodiazepines, or benzodiazepine intolerance. To the authors' knowledge, there are 3 case reports in the literature describing the use of amantadine in the treatment of MC. We present the case of a 51-year-old female with a history of multiple medical and psychiatric conditions who was admitted to the hospital for altered mental status. During her admission, she developed symptoms that raised concern about MC, which was initially managed with lorazepam. However, due to concerns about severe respiratory compromise, lorazepam was discontinued, and the patient was started on liquid amantadine. She showed marked reduction in the symptoms of malignant catatonia, and the autonomic instability resolved after she was started on amantadine. The patient was eventually discharged home with outpatient follow-up scheduled. Our case report shows successful treatment of MC with liquid amantadine in a patient who was unable to tolerate escalating doses of benzodiazepines. The positive response to amantadine suggests that it may be a useful treatment option for MC. While further studies are needed, clinicians should consider the use of amantadine in the treatment of MC, especially in patients who are unable to tolerate benzodiazepines, who have failed to respond to treatment with benzodiazepines, or who are being treated in institutions where the availability of ECT is limited. Amantadine may be more readily accessible given its multiple formulations and wide availability.

Effectiveness of Continuous Dopaminergic Therapies in Parkinson's Disease: A Review of L-DOPA Pharmacokinetics/Pharmacodynamics.

Background: Parkinson's disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa (L-DOPA), remains the mainstay of treatment. However, the significant pharmacokinetic (Pk) and pharmacodynamic (Pd) limitations of L-DOPA, combined with the severity of PD, may trigger motor and non-motor complications, for which continuous dopaminergic delivery therapies have been developed. Objective: The aim of this study was to review the literature on the Pk/Pd limitations of L-DOPA and how current treatments of continuous dopaminergic administration ameliorate these problems, in order to identify the need for new therapeutic avenues. Methods: A comprehensive literature search was carried out using PubMed and 75 articles were initially extracted. Following independent screening by two reviewers and consideration of eligibility, 10 articles were chosen for further analysis. Information concerning the Pk/Pd of L-DOPA was classified for each article. Results: Pk/Pd problems notably include: (i) restricted digestive and cerebral absorption; (ii) unnecessary peripheral distribution; (iii) short half-life; (iv) age- and PD-induced decline of central aromatic L-amino acid decarboxylase; (v) misdistribution in many cells; and (vii) pulsatile stimulation of dopaminergic receptors. Current treatments only slightly ameliorate some of these problems. Conclusions: Many Pk/Pd constraints are not resolved by existing continuous dopaminergic delivery therapies. This highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation.

Rethinking Parkinson's disease: could dopamine reduction therapy have clinical utility?

Following reports of low striatal dopamine content in Parkinson's disease, levodopa was shown to rapidly reverse hypokinesis, establishing the model of disease as one of dopamine deficiency. Dopaminergic therapy became standard of care, yet it failed to reverse the disease, suggesting the understanding of disease was incomplete. The literature suggests the potential for toxicity of dopamine and its metabolites, perhaps more relevant given the recent evidence for elevated cytosolic dopamine levels in the dopaminergic neurons of people with Parkinson's. To understand the relevance of these data, multiple investigations are reviewed that tested dopamine reduction therapy as an alternative to dopaminergic agents. The data from use of an inhibitor of dopamine synthesis in experimental models suggest that such an approach could reverse disease pathology, which suggests that cytosolic dopamine excess is a primary driver of disease. These data support clinical investigation of dopamine reduction therapy for Parkinson's disease. Doing so will determine whether these experimental models are predictive and this treatment strategy is worth pursuing further. If clinical data are positive, it could warrant reconsideration of our disease model and treatment strategies, including a shift from dopaminergic to dopamine reduction treatment of the disease.

Effects of dopaminergic therapy on sleep quality in fluctuating Parkinson's disease patients.

BACKGROUND: Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients. METHODS: Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness-EDS). Binary logistic regression analysis, adjusting for age, sex, disease duration, motor impairment, and sleep drugs, was employed to evaluate the association between dopaminergic therapy and PDSS-2 and ESS scores. Analysis of covariance assessed differences in PDSS-2 and ESS scores between patients without DA, and between patients treated with low or high doses of DA (cut-off: DA-LEDD = 180 mg). RESULTS: In a cohort of 281 patients, 66.2% reported poor sleep quality, and 34.5% reported EDS. DA treatment demonstrated twofold lower odds of reporting relevant sleep disturbances (OR 0.498; p = 0.035), while DA-LEDD, levodopa-LEDD, total LEDD, and extended-release levodopa were not associated with disturbed sleep. EDS was not influenced by dopaminergic therapy. Patients with DA intake reported significant lower PDSS-2 total score (p = 0.027) and "motor symptoms at night" domain score (p = 0.044). Patients with higher doses of DA showed lower PDSS-2 total score (p = 0.043). CONCLUSION: Our study highlights the positive influence of DA add-on treatment on sleep quality in this group of advanced fluctuating PD patients.

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

BACKGROUND: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa. METHODS: Levodopa/carbidopa (4:1) was started at age 11 to 13 months, aiming at escalating to 5 to 6 mg/kg levodopa per day. Follow-up focused on dystonia severity and whether self-injury occurred. In addition, the literature was reviewed to delineate the age at onset of self-injury for all reported cases to date. RESULTS: During long-term follow-up, self-injury appears to have been prevented in two patients (now aged 14 and 15.5 years), as their HPRT1 gene mutations had been invariably associated with self-injury before. Future self-injury is unlikely, as only 1.1% of 264 published cases had self-injury onset later in life than these patients' current ages. The third patient started self-injury at age 1.5 years, while on a substantially lower levodopa dose. A clear effect of levodopa on dystonia could not be determined. CONCLUSIONS: Our observations suggest that levodopa, given early enough and sufficiently dosed, might be able to prevent self-injury in LND. Therefore, levodopa could be considered in patients with LND as early as possible, at least before the self-injury appears. Further research is needed to establish very early levodopa as an effective treatment strategy in LND, and to optimize timing and dosing.

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.

Assessing the benefits and risks of amantadine for irritability and aggression after traumatic brain injury.

OBJECTIVE: To quantify the benefits versus harms of amantadine in the treatment of irritability and aggression following traumatic brain injury. METHODS: Secondary outcome data from a randomized controlled multisite trial of amantadine 100 mg twice daily were used to calculate number-needed-to-treat (NNT). Given prior findings of positive clinician-perceived effects and low incidence of adverse events, we hypothesized low number-needed-to-treat for benefit (NNTB; high benefit) and high number-needed-to-treat for harm (NNTH; low risk) based on the clinician ratings, supporting the use of amantadine in clinical practice. Specifically, NNTB values were calculated using number of individuals with improvement on the Clinician Global Impressions-Global Improvement scale (GI). NNTH values were computed using number of individuals with worsening on the GI and experiencing serious and any adverse events. RESULTS: Based on clinician ratings, on average for every six patients treated with amantadine rather than placebo, one extra patient would be expected to improve (NNTB = 6.4; 95% confidence interval [CI]: [3.3-76.8]). More participants in the placebo group worsened than in the amantadine group, but the result was not statistically significant (NNTH = -92.4; 95% CI: [NNTB -32.9 to infinity to NNTH -19.2]). The amantadine and placebo groups did not differ on the numbers of adverse events experienced during the trial. CONCLUSION: Clinician ratings suggest modest benefit of amantadine 100 mg twice daily with low risk to appropriately selected patients with adequate renal clearance. Thus, amantadine should be considered a treatment option for the experienced brain injury clinician. These data may support treatment decisions when a pharmaceutical agent is being considered to control irritability/aggression.

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.).

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.

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.

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.

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.

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.

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.

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.

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.