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Frontiers in Neurology 2022Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well... (Review)
Review
Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well understood that every pathologic tauopathy may present with various clinical phenotypes based on the primary site of involvement and the spread and distribution of the pathology in the nervous system making clinicopathological correlation more and more challenging. The clinical spectrum of tauopathies includes syndromes with a strong association with an underlying primary tauopathy, including Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA)/apraxia of speech, pure akinesia with gait freezing (PAGF), and behavioral variant frontotemporal dementia (bvFTD), or weak association with an underlying primary tauopathy, including Parkinsonian syndrome, late-onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), and amnestic syndrome. Here, we discuss clinical syndromes associated with various primary tauopathies and their distinguishing clinical features and new biomarkers becoming available to improve diagnosis. Although the typical phenotypic clinical presentations lead us to suspect specific underlying pathologies, it is still challenging to differentiate pathology accurately based on clinical findings due to large phenotypic overlaps. Larger pathology-confirmed studies to validate the use of different biomarkers and prospective longitudinal cohorts evaluating detailed clinical, biofluid, and imaging protocols in subjects presenting with heterogenous phenotypes reflecting a variety of suspected underlying pathologies are fundamental for a better understanding of the clinicopathological correlations.
PubMed: 35911892
DOI: 10.3389/fneur.2022.944806 -
Journal of Parkinson's Disease 2022Parkinson's disease (PD) is defined by its motor symptoms rigidity, tremor, and akinesia. However, non-motor symptoms, particularly autonomic disorders and sleep... (Review)
Review
Parkinson's disease (PD) is defined by its motor symptoms rigidity, tremor, and akinesia. However, non-motor symptoms, particularly autonomic disorders and sleep disturbances, occur frequently in PD causing equivalent or even greater discomfort than motor symptoms effectively decreasing quality of life in patients and caregivers. Most common sleep disturbances in PD are insomnia, sleep disordered breathing, excessive daytime sleepiness, REM sleep behavior disorder, and sleep-related movement disorders such as restless legs syndrome. Despite their high prevalence, therapeutic options in the in- and outpatient setting are limited, partly due to lack of scientific evidence. The importance of sleep disturbances in neurodegenerative diseases has been further emphasized by recent evidence indicating a bidirectional relationship between neurodegeneration and sleep. A more profound insight into the underlying pathophysiological mechanisms intertwining sleep and neurodegeneration might lead to unique and individually tailored disease modifying or even neuroprotective therapeutic options in the long run. Therefore, current evidence concerning the management of sleep disturbances in PD will be discussed with the aim of providing a substantiated scaffolding for clinical decisions in long-term PD therapy.
Topics: Humans; Parkinson Disease; Quality of Life; REM Sleep Behavior Disorder; Sleep; Sleep Wake Disorders
PubMed: 35938257
DOI: 10.3233/JPD-212749 -
Movement Disorders : Official Journal... Aug 2019Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the... (Review)
Review
Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the basal ganglia on the function of the basal ganglia/thalamocortical circuit(s). Changes of firing rates of individual nodes within these circuits were originally considered central to parkinsonism. However, this view has now given way to the belief that changes in firing patterns within the basal ganglia and related nuclei are more important, including the emergence of burst discharges, greater synchrony of firing between neighboring neurons, oscillatory activity patterns, and the excessive coupling of oscillatory activities at different frequencies. Primarily focusing on studies obtained in nonhuman primates and human patients with Parkinson's disease, this review summarizes the current state of this field and highlights several emerging areas of research, including studies of the impact of the heterogeneity of external pallidal neurons on parkinsonism, the importance of extrastriatal dopamine loss, parkinsonism-associated synaptic and morphologic plasticity, and the potential role(s) of the cerebellum and brainstem in the motor dysfunction of Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
Topics: Animals; Basal Ganglia; Brain Stem; Brain Waves; Cerebellum; Cerebral Cortex; Dopamine; Electroencephalography; Globus Pallidus; Haplorhini; Humans; Neostriatum; Neural Pathways; Neuronal Plasticity; Parkinson Disease; Parkinsonian Disorders; Pars Compacta; Thalamus
PubMed: 31216379
DOI: 10.1002/mds.27741 -
Neurotoxicity Research Aug 2021Parkinson's disease (PD), an age-related progressive neurodegenerative condition, is associated with loss of dopaminergic neurons in the substantia nigra pars compacta... (Review)
Review
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.
Topics: Animals; Antiparkinson Agents; Brain; Butyrates; Dopamine Agents; Dopaminergic Neurons; Drug Therapy, Combination; Humans; Levodopa; Nicotine; Parkinson Disease
PubMed: 34003454
DOI: 10.1007/s12640-021-00375-5 -
Revue Medicale de Liege Mar 2020Psychomotor disadaptation syndrome (PDS) was first described by the Geriatrics School of Dijon (France), three decades ago, under the name «psychomotor regression...
Psychomotor disadaptation syndrome (PDS) was first described by the Geriatrics School of Dijon (France), three decades ago, under the name «psychomotor regression syndrome». Over time, the original clinical features remained unchanged. However, progress has been made in its pathophysiology understanding and care, hence the new name, PDS, appeared in the 1990s. The PDS is also called sub-cortico-frontal dysfunction syndrome since the 2000s. It corresponds to a decompensation of posture, gait and psychomotor automatisms, related to an alteration of the postural and motor programming, which is a consequence of sub-cortico-frontal lesions. The clinical features of PDS associate backward disequilibrium, nonspecific gait disorders and neurological signs (akinesia, reactional hypertonia, impaired reactive postural responses and protective reactions, etc.). Psychological disorders of PDS are a fear of standing and walking in its acute form (the post-fall syndrome), or a bradyphrenia and anhedonia in its chronic form. The PDS occurrence results from the combination of three factors implicated in the reduction in functional reserves related to the alteration of the sub-cortico-frontal structures: ageing, chronic afflictions and acute situations, which induce a decrease in cerebral blood flow. The PDS management must be multidisciplinary, including the physician, the physiotherapist, the psychologist, nurses and care assistants.
Topics: Accidental Falls; Adaptation, Physiological; France; Gait; Humans; Postural Balance; Posture; Sensation Disorders; Syndrome
PubMed: 32157844
DOI: No ID Found -
International Journal of Molecular... Feb 2022Takotsubo syndrome (TTS) is identified as an acute severe ventricular systolic dysfunction, which is usually characterized by reversible and transient akinesia of walls... (Review)
Review
Takotsubo syndrome (TTS) is identified as an acute severe ventricular systolic dysfunction, which is usually characterized by reversible and transient akinesia of walls of the ventricle in the absence of a significant obstructive coronary artery disease (CAD). Patients present with chest pain, ST-segment elevation or ischemia signs on ECG and increased troponin, similar to myocardial infarction. Currently, the known mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, genetic predisposition and thyroidal dysfunction. However, the real etiologic link remains unclear and seems to be multifactorial. Currently, the elusive pathogenesis of TTS and the lack of optimal treatment leads to the necessity of the application of experimental models or platforms for studying TTS. Excessive catecholamines can cause weakened ventricular wall motion at the apex and increased basal motion due to the apicobasal adrenoceptor gradient. The use of beta-blockers does not seem to impact the outcome of TTS patients, suggesting that signaling other than the beta-adrenoceptor-associated pathway is also involved and that the pathogenesis may be more complex than it was expected. Herein, we review the pathophysiological mechanisms related to TTS; preclinical TTS models and platforms such as animal models, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) models and their usefulness for TTS studies, including exploring and improving the understanding of the pathomechanism of the disease. This might be helpful to provide novel insights on the exact pathophysiological mechanisms and may offer more information for experimental and clinical research on TTS.
Topics: Animals; Humans; Myocytes, Cardiac; Receptors, Adrenergic; Signal Transduction; Takotsubo Cardiomyopathy
PubMed: 35216067
DOI: 10.3390/ijms23041951 -
Journal of Neural Transmission (Vienna,... May 2020Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions... (Review)
Review
Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.
Topics: Animals; Humans; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Parkinson Disease; Selegiline
PubMed: 31562557
DOI: 10.1007/s00702-019-02082-0 -
Handbook of Clinical Neurology 2024New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis... (Review)
Review
New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis is one of the more important causes of new onset movement disorders, and movement disorders are a common feature (~25%) of all encephalitis. However, all encephalitides are not the same, and movement disorders are a key diagnostic feature that can help the clinician identify the etiology of the encephalitis, and therefore appropriate treatment is required. Movement disorders are a characteristic feature of autoimmune encephalitis such as anti-NMDAR encephalitis, herpes simplex virus encephalitis-induced autoimmune encephalitis, and basal ganglia encephalitis. Other rarer autoantibody-associated encephalitis syndromes with movement disorder associations include encephalitis associated with glycine receptor, DPPX, and neurexin-3 alpha autoantibodies. In addition, movement disorders can accompany acute disseminated encephalomyelitis with and without myelin oligodendrocyte glycoprotein antibodies. Extremely important infectious encephalitides that have characteristic movement disorder associations include Japanese encephalitis, dengue fever, West Nile virus, subacute sclerosing panencephalitis (SSPE), and SARS-CoV-2 (COVID-19). This chapter discusses how specific movement disorder phenomenology can aid clinician diagnostic suspicion, such as stereotypy, perseveration, and catatonia in anti-NMDAR encephalitis, dystonia-Parkinsonism in basal ganglia encephalitis, and myoclonus in SSPE. In addition, the chapter discusses how the age of the patients can influence the movement disorder phenomenology, such as in anti-NMDAR encephalitis where chorea is typical in young children, even though catatonia and akinesia is more common in adolescents and adults.
Topics: Adolescent; Child; Child, Preschool; Humans; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Catatonia; Chorea; Movement Disorders; Subacute Sclerosing Panencephalitis
PubMed: 38494280
DOI: 10.1016/B978-0-12-823912-4.00018-9 -
Movement Disorders : Official Journal... Oct 2023Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID)....
BACKGROUND
Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID.
OBJECTIVE
The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model.
METHODS
We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation.
RESULTS
Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation.
CONCLUSIONS
Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Mice; Animals; Pars Reticulata; Levodopa; Halorhodopsins; Parkinson Disease; GABAergic Neurons; Dyskinesia, Drug-Induced; Substantia Nigra
PubMed: 37461292
DOI: 10.1002/mds.29558 -
Journal of Neural Transmission (Vienna,... Jun 2022Neurodegenerative disorders involving preferentially the globus pallidus, its efferet and afferent circuits and/or related neuronal systems are rare. They include a... (Review)
Review
Neurodegenerative disorders involving preferentially the globus pallidus, its efferet and afferent circuits and/or related neuronal systems are rare. They include a variety of both familial and sporadic progressive movement disorders, clinically manifesting as choreoathetosis, dystonia, Parkinsonism, akinesia or myoclonus, often associated with seizures, mental impairment and motor or cerebellar symptoms. Based on the involved neuronal systems, this heterogenous group has been classified into several subgroups: "pure" pallidal atrophy (PPA) and extended forms, pallidonigral and pallidonigrospinal degeneration (PND, PNSD), pallidopyramidal syndrome (PPS), a highly debatable group, pallidopontonigral (PPND), nigrostriatal-pallidal-pyramidal degeneration (NSPPD) (Kufor-Rakeb syndrome /KRS), pallidoluysian degeneration (PLD), pallidoluysionigral degeneration (PLND), pallidoluysiodentate atrophy (PLDA), the more frequent dentatorubral-pallidoluysian atrophy (DRPLA), and other hereditary multisystem disorders affecting these systems, e.g., neuroferritinopathy (NF). Some of these syndromes are sporadic, others show autosomal recessive or dominant heredity, and for some specific gene mutations have been detected, e.g., ATP13A2/PARK9 (KRS), FTL1 or ATP13A2 (neuroferritinopathy), CAG triple expansions in gene ATN1 (DRPLA) or pA152T variant in MAPT gene (PNLD). One of the latter, and both PPND and DRPLA are particular subcortical 4-R tauopathies, related to progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal lobe degeneration-17 (FTLD-17), while others show additional 3-R and 4-R tauopathies or TDP-43 pathologies. The differential diagnosis includes a large variety of neurodegenerations ranging from Huntington and Joseph-Machado disease, tauopathies (PSP), torsion dystonia, multiple system atrophy, neurodegeneration with brain iron accumulation (NBIA), and other extrapyramidal disorders. Neuroimaging data and biological markers have been published for only few syndromes. In the presence of positive family histories, an early genetic counseling may be effective. The etiology of most phenotypes is unknown, and only for some pathogenic mechanisms, like polyglutamine-induced oxidative stress and autophagy in DRPLA, mitochondrial dysfunction induced by oxidative stress in KRS or ferrostasis/toxicity and protein aggregation in NF, have been discussed. Currently no disease-modifying therapy is available, and symptomatic treatment of hypo-, hyperkinetic, spastic or other symptoms may be helpful.
Topics: Atrophy; Basal Ganglia Diseases; Humans; Iron Metabolism Disorders; Neuroaxonal Dystrophies; Parkinson Disease; Parkinsonian Disorders; Syndrome; Tauopathies
PubMed: 34363531
DOI: 10.1007/s00702-021-02392-2