Striatal signaling in L-DOPA-induced dyskinesia: common mechanisms with drug abuse and long term memory involving D1 dopamine receptor stimulation
Parkinson’s disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-L-alanine (L-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brain’s response to L-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias. L-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless L-DOPA dosages are reduced to below therapeutic levels. Thus, controlling LID is one of the major challenges in Parkinson’s disease therapy. LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons. Through increased coupling to Gαolf, resulting in greater stimulation of adenylyl-cyclase, D1 receptors phosphorylate DARPP-32 and other protein kinase A targets. Moreover, D1 receptor stimulation activates ERK and triggers a signaling pathway involving mTOR and modifications of histones that results in changes in translation, chromatin modification and gene transcription. In turn, sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID. Importantly, different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation. Here we review evidence implicating D1 receptor signaling in the genesis of LID, analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements, and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinson’s disease brain (Abstract and Full text).
|MRI illustrating pertinent findings during the attack of headache and right homonymous hemianopsia (A and B) and at 2-week follow-up (C and D)|
The baseline MRI is done at 1.5 T and the follow-up MRI at 3 T. (A) At 150 minutes after symptom onset, axial isotropic diffusion-weighted imaging (b = 1,000 s/mm2) (a) is normal without ischemic injury. The circle of Willis on the time-of-flight magnetic resonance angiogram (MRA) (b) 155 minutes after symptom onset is also normal with symmetric arterial calibers. Axial fluid-attenuated inversion recovery (FLAIR) sequence at 170 minutes (c) is also normal. At 205 minutes, the T1 postcontrast “equilibrium” sequence (d) shows pial vessels dilatation (arrow), overlying the left occipital area. (B) Perfusion images at 210 minutes after symptom onset show symmetric relative cerebral blood volume (rCBV) map (a) and relative cerebral blood flow (rCBF) map (b) through the occipital lobes. The mean transit time (MTT) map (c) and the maximal time to peak of the residue function (Tmax) map (d) show mild delay in contrast arrival time in the left occipital pole. Using the RAPID automated software, the post-processed thresholded and segmented Tmax map (e) highlights 9.5 mL of tissue in blue with Tmax >4 seconds, indicating mild tissue hypoperfusion (benign oligemia). Only scattered and patchy areas within the area of mild hypoperfusion have a Tmax ≥6 seconds (currently accepted threshold2,7 for significant tissue ischemia) on the Tmax map (d) and these represented less than 3 mL of volume per RAPID (e). This pattern of normal rCBV, rCBF, mildly prolonged MTT and Tmax indicates only mild hypoperfusion without risk of progressing to infarction.2,7 Similar perfusion changes were seen in 3 additional contiguous slices through the left occipital pole. (C) Follow-up MRI at day 12 shows a normal axial isotropic diffusion-weighted imaging (b = 1,000 s/mm2) (a), normal time-of-flight MRA (b), and normal axial FLAIR (c), without any resultant tissue injury. The improved conspicuity of arteries on this MRA is due to higher magnet strength (3T). The T1 postcontrast sequence (d) shows complete resolution of the prior pial vasodilation. (D) On perfusion imaging, the rCBV (a) and rCBF (b) maps continue to be normal. MTT (c), Tmax (d), and RAPID (e) maps show complete resolution of the left occipital hypoperfusion.
Spongiform degeneration in humans and animals is characterized by vacuolar change in the central nervous system
Coma resulting from brain injury or illness usually is a transient state. Within a few weeks, patients in coma either recover awareness, die, or evolve to an eyes-open state of impaired responsiveness such as the vegetative or minimally conscious state. These disorders of consciousness can be transient stages during spontaneous recovery from coma or can become chronic, static conditions. Recent fMRI studies raise questions about the accuracy of accepted clinical diagnostic criteria and prognostic models of these disorders that have far-reaching medical practice and ethical implications (Full text).
As the profession of neurology becomes increasingly subspecialized, it becomes more and more difficult for general neurologists to feel comfortable with every category of disease. At no time is this felt more keenly than when an imaging procedure has been performed on a patient for a seizure, headache, or focal neurologic complaint and a brain tumor is discovered. In contrast to consulting with a patient with a movement disorder or neuromuscular disease, there is no time to craft the discussion and discuss a differential diagnosis. As with demyelinating disease or stroke, the scan result dictates an immediate conversation with the patient, but in contrast to those disorders this takes place from the perspective of a provider who understands that the eventual outcome for the patient is likely to be guarded. How to give that message with tact, candor, and some optimism could be the sole topic of this article but, instead, we focus on 5 new ideas that are changing the management of brain tumor patients in the hopes that these points might prove useful during those times (Full text).
Care of the patient with multiple sclerosis (MS) is becoming increasingly complex, with new symptomatic therapies (e.g., dalfampridine), enhanced use of disease-modifying therapies that are potentially both more efficacious and more risky (e.g., natalizumab, rituximab) than “standard” immunomodulators, the advent of oral disease-modifying therapies (DMTs) (e.g., fingolimod, cladribine, teriflunomide, laquinimod), and the possibility of regenerative or reparative therapies (e.g., stem cells, neuroprogenitor cells, antibodies to leucine-rich repeat and immunoglobulin (Ig) domain containing NOGO receptor interacting protein-1, i.e., anti-LINGO therapies). All of this is happening in the context of a suggestion that MS may fundamentally result from aberrant venous flow, so-called chronic cerebrospinal venous insufficiency (CCSVI), and a similarly fundamental pathologic discussion of the relationship between inflammation and degeneration over time in patients with MS. Noting the difficulty of choosing among many options, we present discussions of 5 new topics relevant to patients with MS and their neurologists in 2010 (Full text).
It has been almost 15 years since the publication of the landmark National Institute of Neurological Disorders and Stroke tissue plasminogen activator (NINDS-tPA) trial. The findings of the NINDS-tPA trial soon led to Food and Drug Administration (FDA) approval for IV alteplase (tPA) in the treatment of acute ischemic stroke (AIS) that transformed the way neurologists approach this devastating disease. Unfortunately, 15 years removed from the NINDS-tPA trial, IV tPA remains the only FDA-approved drug for the treatment of AIS. Although no major clinical breakthrough has occurred in the AIS treatment front, newer trials have increased the spectrum of patients who can be treated, but failed to find better lytic drugs or ways to identify treatable patients using advanced imaging. Major advancements have transpired in the arena of stroke prevention, especially in endovascular therapy and management of atrial fibrillation (AF). This article aims to summarize 5 new topics in stroke treatment, prevention, and poststroke care that have or will soon affect clinical treatment of stroke patients, and to offer critiques and commentary on how the results of the trials presented can be applied to the care of individual stroke patients (Full text).