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Current Neuropharmacology 2023Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its... (Review)
Review
Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.
Topics: Humans; Antiparkinson Agents; Dopamine; Dyskinesias; Levodopa; Parkinson Disease; Serotonin; Zonisamide
PubMed: 35193486
DOI: 10.2174/1570159X20666220222150811 -
Neurology India 2020Deep brain stimulation (DBS) is the most commonly used surgical treatment for drug-refractory movement disorders such as tremor and dystonia. Appropriate patient... (Review)
Review
Deep brain stimulation (DBS) is the most commonly used surgical treatment for drug-refractory movement disorders such as tremor and dystonia. Appropriate patient selection along with target selection is important to ensure optimal outcome without complications. This review summarizes the recent literature regarding the mechanism of action, indications, outcome, and complications of DBS in tremor and dystonia. A comparison with other modalities of surgical interventions is discussed along with a note of the recent advances in technology. Future research needs to be directed to understand the underlying etiopathogenesis of the disease and the way in which DBS modulates the intracranial abnormal networks.
Topics: Deep Brain Stimulation; Dystonia; Dystonic Disorders; Humans; Movement Disorders; Tremor
PubMed: 33318349
DOI: 10.4103/0028-3886.302472 -
Journal of Neural Transmission (Vienna,... Jun 2023Parkinson's disease (PD) is the second most common neurodegenerative disorder, with increasing numbers of affected patients. Many patients lack adequate care due to... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder, with increasing numbers of affected patients. Many patients lack adequate care due to insufficient specialist neurologists/geriatricians, and older patients experience difficulties traveling far distances to reach their treating physicians. A new option for these obstacles would be telemedicine and wearables. During the last decade, the development of wearable sensors has allowed for the continuous monitoring of bradykinesia and dyskinesia. Meanwhile, other systems can also detect tremors, freezing of gait, and gait problems. The most recently developed systems cover both sides of the body and include smartphone apps where the patients have to register their medication intake and well-being. In turn, the physicians receive advice on changing the patient's medication and recommendations for additional supportive therapies such as physiotherapy. The use of smartphone apps may also be adapted to detect PD symptoms such as bradykinesia, tremor, voice abnormalities, or changes in facial expression. Such tools can be used for the general population to detect PD early or for known PD patients to detect deterioration. It is noteworthy that most PD patients can use these digital tools. In modern times, wearable sensors and telemedicine open a new window of opportunity for patients with PD that are easy to use and accessible to most of the population.
Topics: Humans; Parkinson Disease; Hypokinesia; Gait Disorders, Neurologic; Tremor; Wearable Electronic Devices
PubMed: 36609737
DOI: 10.1007/s00702-022-02575-5 -
Seminars in Neurology Feb 2023A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be...
A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.
Topics: Humans; Cerebellar Ataxia; Ataxia; Genetic Testing; Multiple System Atrophy; Neuroimaging
PubMed: 36828010
DOI: 10.1055/s-0043-1763511 -
European Journal of Paediatric... Jan 2022The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the... (Review)
Review
BACKGROUND
The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network.
METHODS
In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia.
RESULTS
In a clinical EOA cohort, the prevalence of dystonia was over 60%. Both human and animal studies converge on the underlying role for the cortico-basal-ganglia-ponto-cerebellar network. Genetic -clinical and -in silico network studies reveal underlying biological pathways for energy production and neural signal transduction.
CONCLUSIONS
EOA-dystonia phenotypes are attributable to the cortico-basal-ganglia-ponto-cerebellar network, instead of to the cerebellum, alone. The underlying anatomic and pathogenetic pathways have clinical implications for our understanding of the heterogeneous phenotype, neuro-metabolic and genetic testing and potentially also for new treatment strategies, including neuro-modulation.
Topics: Animals; Ataxia; Basal Ganglia; Cerebellum; Dystonia; Dystonic Disorders; Humans
PubMed: 34954622
DOI: 10.1016/j.ejpn.2021.12.001 -
Neurology Apr 2023In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease.
METHODS
We enrolled carriers of a pathologic or expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls.
RESULTS
We enrolled 200 participants: 45 carriers of a pathologic expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in or . Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [ < 0.0001], SCA3: 19.8 pg/mL [ < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 = 0.0003, SCA3 = 0.003) and by the presence of sensor impairment and diplopia in SCA3 ( = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia.
DISCUSSION
READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.
TRIAL REGISTRATION INFORMATION
ClinicalTrials.gov NCT03487367.
Topics: Humans; Prospective Studies; Spinocerebellar Ataxias; Cerebellar Ataxia; Cerebellum; Biomarkers; Machado-Joseph Disease
PubMed: 36797067
DOI: 10.1212/WNL.0000000000207088 -
Journal of Psychopharmacology (Oxford,... Jan 2021Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is... (Review)
Review
Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.
Topics: Antipsychotic Agents; Cholinergic Antagonists; Cholinergic Neurons; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Extrapyramidal Tracts; Humans; Interneurons; Muscarinic Antagonists; Neuronal Plasticity; Receptors, Dopamine D2
PubMed: 32900259
DOI: 10.1177/0269881120944156 -
European Neurology 2022Diabetic striatopathy (DS), coined as a generic term, has been defined as a hyperglycemic condition associated with either one of the two following conditions:... (Review)
Review
BACKGROUND
Diabetic striatopathy (DS), coined as a generic term, has been defined as a hyperglycemic condition associated with either one of the two following conditions: chorea/ballism or striatal hyperdensity on computed tomography or striatal hyperintensity on T1-weighted magnetic resonance imaging. This review highlights those "gray areas," which need further exploration to understand better hyperglycemia-induced striatal changes and diverse movement disorder phenotypes associated with these changes.
RESULTS AND DISCUSSION
We searched in PubMed and Google Scholar the terms "diabetes mellitus," "movement disorders," "diabetic striatopathy," "chorea," "hemichorea," "ballism," "hemichorea-hemiballism," and "neuroradiology" in various combinations (time range from 1980 to March 2022). We selected the publications about our topic of discussion.
SUMMARY
Hemichorea-hemiballismus is the most commonly associated movement disorder in DS, and the putamen is the most frequently affected anatomical region. The exact pathophysiological mechanisms remain elusive. Clinical-radiological discordance is not rare. Complete reversal of symptoms with the resolution of the imaging findings is the most prevalent outcome in patients with DS. Dramatic improvement of chorea can be achieved by either insulin monotherapy or combination therapy of insulin and D2-blocker or, in some cases, even spontaneously.
CONCLUSION
The term "diabetic striatopathy" is ambiguous and controversial. Pathological mechanisms behind clinical-radiological discordance in hyperglycemia-induced striatopathy need further exploration through well-designed studies. We propose a classification of DS that includes symptomatic DS (striatal neuroimaging lesions in association with a clinically evident movement disorder and hyperglycemia), clinically isolated DS (clinically evident movement disorders without striatal changes in neuroimaging), and radiologically isolated DS.
Topics: Chorea; Diabetes Mellitus; Dyskinesias; Humans; Hyperglycemia; Insulins; Magnetic Resonance Imaging; Movement Disorders; Neuroimaging
PubMed: 35717942
DOI: 10.1159/000524936 -
Drug Design, Development and Therapy 2022Cancer is one of the deadliest diseases in the world. In 2020, 19.3 million cancer cases and 10 million deaths were reported in the world. It is supposed that the... (Review)
Review
Cancer is one of the deadliest diseases in the world. In 2020, 19.3 million cancer cases and 10 million deaths were reported in the world. It is supposed that the prevalence of cancer cases will rise to 28.4 million by 2040. Chemotherapy-based regimens have a narrow therapeutic index, severe adverse drug reactions, and lack metabolic stability. Besides, the metabolism of anticancer produces several non-active and toxic metabolites that reduce exposure of the target site to the parent drug. Therefore, developing better-tolerated and effective new anticancer drugs and modification of the existing anticancer drugs to minimize toxicity and increase efficacy has become a very urgent need. Deuterium incorporation reduces the metabolism of certain drugs that are breakdown by pathways involving hydrogen-carbon bond scission. For example, CYP450 mediated oxidative metabolism of drugs that involves the breakdown of a hydrogen-carbon bond affected by deuteration. Deuterium incorporation into the drug increases the half-life and reduces the dose, which provides better safety and efficacy. Deutetrabenazine is the first deuterated form of tetrabenazine approved to treat chorea associated with Huntington's disease and tardive dyskinesia. The study revealed that Deutetrabenazine has fewer neuropsychiatric side effects with favorable safety than tetrabenazine. The current review highlights the deuterium kinetic isotope effect on drug metabolism, deuterated compound pharmacokinetic property, and safety profile. Besides, this review explains the deuterated anticancer drug development update status.
Topics: Carbon; Deuterium; Humans; Huntington Disease; Neoplasms; Tardive Dyskinesia; Tetrabenazine
PubMed: 36217450
DOI: 10.2147/DDDT.S379496 -
Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation.Science Immunology Apr 2024The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the...
The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3 progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator.
Topics: Cell Differentiation; Chorea; Cytokines; Dendritic Cells
PubMed: 38608038
DOI: 10.1126/sciimmunol.adi1023