The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is ...protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label (3)Hdihydrotetrabenazine were profoundly reduced in PD by 87-90% and 71-80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.
Abstract One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with ...Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state.
The transition from the Semail ophiolite mantle to the underlying metamorphic sole was drilled at ICDP OmanDP Hole BT1B. We analyzed the bulk major, volatile and trace element compositions of the ...mantle‐derived listvenite series and metamorphic rocks, with the aim to constrain chemical transfers associated with peridotite carbonation along the ophiolite basal thrust. The listvenite series comprise variously carbonated serpentinites and (fuchsite‐bearing) listvenites. They have high CO2 (up to 43 wt.%) and variable H2O (0–12 wt.%). Yet, they have compositions close to that of the basal banded peridotites for most major and lithophile trace elements, with fuchsite‐bearing listvenites overlapping in composition with amphibole‐bearing basal lherzolites (e.g., Al2O3 = 0.1–2.2 wt.%; Yb = 0.05–1 x CI‐chondrite). The protolith of the listvenite series was likely similar in structure and composition to serpentinized banded peridotites which immediately overlie the metamorphic sole elsewhere in Oman. The listvenite series are enriched in fluid mobile elements (FME) compared to Semail peridotites (up to ∼103–104 x Primitive Mantle), with concentrations similar to the underthrusted metabasalts and/or metasediments for Cs, Sr and Ca and sometimes even higher for Pb, Li, As, and Sb (e.g., Li up to 130 μg/g; As up to 170 μg/g). We also observe a decoupling between Sr‐Ca enrichments and other FME, indicating interactions with several batches of deep CO2‐rich fluids transported along the basal thrust. These results suggest that peridotite carbonation could represent one of the major trap‐and‐release mechanisms for carbon, water and FME along convergent margins.
Plain Language Summary
Ophiolites are sections of oceanic lithosphere emplaced on‐land as tectonic plates converge. The faults developed at their base are analogues to plate interfaces in subduction zones, where mass transfers occur and play a key role in the global cycling of elements. A core was drilled at the base of the Semail Ophiolite, where variously hydrated and carbonated mantle rocks known as serpentinites and listvenites witnessed major fluid fluxes. Reactions with CO2‐bearing fluids (carbonation reaction) enhanced the mobility of elements during mass transfers along the basal thrust. We measured the elemental composition of 84 samples spaced along this core. Results indicate that CO2‐bearing fluids derive from at least two sources or pathways. As peridotites reacted, their volume increased, causing cracking, helping the ingress of reactive fluids and allowing (almost) complete carbonation of the basal ophiolite mantle. Carbon as well as many elements such as cesium, arsenic, antimony, lead, became enriched in these rocks. If forming in subduction zones, listvenites may act as temporary storage for these elements and impact global chemical cycles.
Key Points
BT1B listvenite series and metamorphic sole derive from partially serpentinized basal banded peridotites and alkaline basalts respectively
Chemical redistribution suggests reactions with several batches of CO2‐rich fluids over various flow paths parallel to the basal thrust
Listvenitization due to CO2 metasomatism could represent a major trap‐and‐release mechanism for CO2, fluid mobile elements and H2O along convergent margins
Abstract Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms ...underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET (18 F-DOPA Ki and11 C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features.
Abstract Objective The observation of a voluntary movement executed by another person is associated with an alpha and beta EEG desynchronization over the motor cortex, thought to reflect activity ...from the human “mirror neuron” system. The aim of our work was to study the changes in local field potentials (LFP) recorded from the subthalamic nucleus (STN) and their relationship with cortical activity, during movement observation. Methods Bilateral EEG and STN LFP recordings were acquired in 18 patients with Parkinson’s disease, through surgically implanted electrodes for deep brain stimulation. Oscillatory changes during movement execution and movement observation were compared with two different control conditions (simple stimulus and rotating stimulus observation), in “off” and “on” motor states. Time–frequency transforms and event-related coherence were used for the analysis. Results Movement observation was accompanied by bilateral beta reduction in subthalamic power and cortico-STN coherence, which was smaller than the decrease observed during movement execution, but significant when compared with the two control conditions. Conclusions Movement observation is accompanied by changes in the beta oscillatory activity of the STN, similar to those observed in the EEG. Significance These changes suggest that the basal ganglia might be engaged by the activity of the human mirror system.
The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinson's disease is not well understood. We have recorded local field potentials (LFP) from macroelectrodes implanted in the ...subthalamic nucleus (STN) of 14 patients with Parkinson's disease following surgical treatment with deep brain stimulation. Patients were studied in the ‘Off’ medication state and in the ‘On’ motor state after administration of levodopa–carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power spectrum of the LFP in selected frequency bands (4–10, 11–30 and 60–80 Hz) was compared between the ‘Off’ and ‘On’ medication states. A peak in the 11–30 Hz band was recorded in the ‘Off’ medication state and reduced by 45.2% (P < 0.001) in the ‘On’ state. The ‘On’ was also associated with an increment of 77. 6% (P < 0.001) in the 4–10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60–80 Hz band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4–10 Hz peak was only recorded in the contralateral STN. These findings suggest that the 4–10 Hz oscillation is associated with the expression of LID in Parkinson's disease.
Functional neuroanatomy of the basal ganglia Lanciego, José L; Luquin, Natasha; Obeso, José A
Cold Spring Harbor perspectives in medicine,
12/2012, Letnik:
2, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The "basal ganglia" refers to a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions. ...Proposed more than two decades ago, the classical basal ganglia model shows how information flows through the basal ganglia back to the cortex through two pathways with opposing effects for the proper execution of movement. Although much of the model has remained, the model has been modified and amplified with the emergence of new data. Furthermore, parallel circuits subserve the other functions of the basal ganglia engaging associative and limbic territories. Disruption of the basal ganglia network forms the basis for several movement disorders. This article provides a comprehensive account of basal ganglia functional anatomy and chemistry and the major pathophysiological changes underlying disorders of movement. We try to answer three key questions related to the basal ganglia, as follows: What are the basal ganglia? What are they made of? How do they work? Some insight on the canonical basal ganglia model is provided, together with a selection of paradoxes and some views over the horizon in the field.
Summary The basal ganglia were originally thought to be associated purely with motor control. However, dysfunction and pathology of different regions and circuits are now known to give rise to many ...clinical manifestations beyond the association of basal ganglia dysfunction with movement disorders. Moreover, disorders that were thought to be caused by dysfunction of the basal ganglia only, such as Parkinson's disease and Huntington's disease, have diverse abnormalities distributed not only in the brain but also in the peripheral and autonomic nervous systems; this knowledge poses new questions and challenges. We discuss advances and the unanswered questions, and ways in which progress might be made.
Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6–12 months of treatment. Long-term results in a ...large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3–4 years after surgery. The primary outcome measure was the change in the ‘off’ medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3–4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the ‘off’ medication UPDRS-III score at 3–4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the ‘on’ time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3–4 years showed a significant worsening in the ‘on’ medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3–4 years in a large cohort of patients with severe Parkinson's disease.
PDF
