In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament ...light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.
The basal ganglia are subcortical nuclei controlling voluntary actions and have been implicated in Parkinson's disease (PD). The prevailing model of basal ganglia function states that two circuits, ...the direct and indirect pathways, originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different output structures. These circuits are believed to have opposite effects on movement. Specifically, the activity of direct pathway MSNs is postulated to promote movement, whereas the activation of indirect pathway MSNs is hypothesized to inhibit it. Recent findings have revealed that this model might not fully account for the concurrent activation of both pathways during movement. Accordingly, we propose a model in which intrastriatal connections are critical and the two pathways are structurally and functionally intertwined. Thus, all MSNs might either facilitate or inhibit movement depending on the form of synaptic plasticity expressed at a certain moment. In PD, alterations of dopamine-dependent synaptic plasticity could alter this coordinated activity.
Although the discovery of the critical role of α-synuclein (α-syn) in the pathogenesis of Parkinson's disease (PD) is now twenty-five years old, it still represents a milestone in PD research. ...Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of α-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting α-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.
Background: Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine
(levodopa) has represented the gold standard for the treatment of Parkinson’s Disease (PD). However,
long-term ...levodopa (LD) treatment is frequently associated with fluctuations in motor response
with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic
properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life,
poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the
last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications.
Methods: Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing
the progressive improvements of LD treatment.
Results: Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to
achieve proper LD concentration in the central nervous system reducing systemic adverse events.
Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts
are still being made to achieve a continuous dopaminergic stimulation, with the combination of
oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/
carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration
routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as
well as on novel ER formulations, including IPX066, which recently concluded phase III trial.
Conclusion: New LD formulations, oral compounds as well as routes have been tested in the last
years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver
route for LD.
Summary Parkinson's disease is a common progressive neurodegenerative disease, of which the main neuropathological hallmark is dopaminergic neuronal loss. Increased attention has been directed ...towards non-motor symptoms in Parkinson's disease, such as cognitive impairment and behavioural disorders. Clinical and experimental findings support the view that the hippocampus, a temporal lobe structure involved in physiological learning and memory, is also implicated in the cognitive dysfunction seen in some patients with Parkinson's disease. Moreover, emerging data suggest interactions between the dopaminergic systems and the hippocampus in synaptic plasticity, adaptive memory, and motivated behaviour. This structure is also implicated in the pathophysiology of other non-motor symptoms, such as impulse control disorders, anosmia, and fatigue. Evidence from clinical observations and experimental studies suggest a complex hippocampal cross-talk among the dopaminergic and other transmitter systems. Furthermore, neurotrophic factors might interact with the hippocampal dopaminergic system having possible implications on the non-motor symptoms seen in patients with Parkinson's disease.
Over the last two decades, many experimental and clinical studies have provided solid evidence that alpha-synuclein (α-syn), a small, natively unfolded protein, is closely related to Parkinson's ...disease (PD) pathology. To provide an overview on the different roles of this protein, here we propose a synopsis of seminal and recent studies that explored the many aspects of α-syn. Ranging from the physiological functions to its neurodegenerative potential, the relationship with the possible pathogenesis of PD will be discussed. Close attention will be paid on early cellular and molecular alterations associated with the presence of α-syn aggregates.
Dystonia and levodopa-induced dyskinesia (LID) are both hyperkinetic movement disorders. Dystonia arises most often spontaneously, although it may be seen after stroke, injury, or as a result of ...genetic causes. LID is associated with Parkinson's disease (PD), emerging as a consequence of chronic therapy with levodopa, and may be either dystonic or choreiform. LID and dystonia share important phenomenological properties and mechanisms. Both LID and dystonia are generated by an integrated circuit involving the cortex, basal ganglia, thalamus and cerebellum. They also share dysregulation of striatal cholinergic signaling and abnormalities of striatal synaptic plasticity. The long duration nature of both LID and dystonia suggests that there may be underlying epigenetic dysregulation as a proximate cause. While both may improve after interventions such as deep brain stimulation (DBS), neither currently has a satisfactory medical therapy, and many people are disabled by the symptoms of dystonia and LID. Further study of the fundamental mechanisms connecting these two disorders may lead to novel approaches to treatment or prevention.
•Levodopa-induced dyskinesia (LID) and dystonia share important phenomenological properties and mechanisms.•Both LID and dystonia are generated by an integrated circuit involving the cortex, basal ganglia, thalamus and cerebellum.•LID and dystonia share dysregulation of striatal cholinergic signaling, and abnormalities of striatal synaptic plasticity.•The long duration nature of both LID and dystonia suggests that there may be underlying epigenetic dysregulation as a proximate cause.
Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in ...serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797–811