96 research outputs found
Clinical features, pathophysiology, and treatment of levodopa-induced dyskinesias in Parkinson's disease
Dyskinetic disorders are characterized by excess of motor activity that may interfere with normal movement control. In patients with Parkinson's disease, the chronic levodopa treatment induces dyskinetic movements known as levodopa-induced dyskinesias (LID). This paper analyzed the pathophysiology, clinical manifestations, pharmacological treatments, and surgical procedures to treat hyperkinetic disorders. Surgery is currently the only treatment available for Parkinson's disease that may improve both parkinsonian motor syndrome and LID. However, this paper shows the different mechanisms involved are not well understood
Thalamic innervation of the direct and indirect basal ganglia pathways in the rat: Ipsi- and contralateral projections
The present study describes the thalamic innervation coming from the rat parafascicular nucleus (PF) onto striatal and subthalamic efferent neurons projecting either to the globus pallidus (GP) or to the substantia nigra pars reticulata (SNr) by using a protocol for multiple neuroanatomical tracing. Both striatofugal neurons targeting the ipsilateral SNr (direct pathway) as well as striatal efferent neurons projecting to the ipsilateral GP (indirect pathway) were located within the terminal fields of the thalamostriatal afferents. In the subthalamic nucleus (STN), both neurons projecting to ipsilateral GP as well as neurons projecting to ipsilateral SNr also appear to receive thalamic afferents. Although the projections linking the caudal intralaminar nuclei with the ipsilateral striatum and STN are far more prominent, we also noticed that thalamic axons could gain access to the contralateral STN. Furthermore, a small number of STN neurons were seen to project to both the contralateral GP and PF nuclei. These ipsi- and contralateral projections enable the caudal intralaminar nuclei to modulate the activity of both the direct and the indirect pathway
Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinsonâs disease
Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinsonâs disease receive
dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded
local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to
the predominant clinical features of each patient, their Parkinsonâs disease was associated with impulse control disorders
(n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained
during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical
coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined
in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each
patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients
with impulse control disorders displayed theta-alpha (4â10 Hz) activity (mean peak: 6.71 Hz) that was generated 2â8mm below
the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency
(mean: 8.38 Hz) and was generated 0â2mm below the intercommissural line. No such activity was detected in patients that
displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the
4â7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with
dyskinesia it was in the 7.5â10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus,
dopaminergic side effects in Parkinsonâs disease are associated with oscillatory activity in the theta-alpha band, but at different
frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations.
These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the
associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in
patients with L-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent
with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural
complications associated with dopaminergic drugs in Parkinsonâs disease, specifically engaging different anatomo-functional
territories
Slow oscillatory activity and levodopa-induced dyskinesias in Parkinsonâs disease
The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinsonâs disease is not well understood.
We have recorded local field potentials (LFP) from macroelectrodes implanted in the subthalamic nucleus
(STN) of 14 patients with Parkinsonâs disease following surgical treatment with deep brain stimulation. Patients
were studied in the âOffâ medication state and in the âOnâ motor state after administration of levodopaâ
carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power
spectrum of the LFP in selected frequency bands (4â10, 11â30 and 60â80 Hz) was compared between the
âOffâ and âOnâ medication states. A peak in the 11â30 Hz band was recorded in the âOffâ medication state
and reduced by 45.2% (P < 0.001) in the âOnâ state. The âOnâ was also associated with an increment of 77. 6%
(P < 0.001) in the 4â10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60â80 Hz
band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4â10 Hz peak was
only recorded in the contralateralSTN. These findings suggest that the 4â10 Hz oscillation is associated with the
expression of LID in Parkinsonâs disease
Terapia celular âneuro-restauradoraâ en la enfermedad de Parkinson: un debate pendiente
Existe en la actualidad un gran entusiasmo sobre las perspectivas derivadas de la denominada terapia
celular en la enfermedad de Parkinson. Este entusiasmo ha sobrepasado la esfera de la comunidad médica,
llegando hasta el pĂșblico general, y se ha venido alimentando de un considerable debate Ă©tico y polĂtico,
hurtĂĄndose en todo momento la necesidad de un anĂĄlisis realmente cientĂfico sobre las cualidades y limitaciones reales del tratamiento con cĂ©lulas madre en las enfermedades neurodegenerativas. La enfermedad de Parkinson con frecuencia se observa desde una perspectiva simplista, como una mera neurodegeneraciĂłn de la vĂa dopaminĂ©rgica nigroestriada, punto de vista bajo el que se colocan diferentes diseños tendentes a reemplazar la falta de dopamina en el estriado, mediante el empleo de distintos tipos de terapia celular. En este sentido, es necesario señalar por un lado la naturaleza multisistĂ©mica y generalizada de la enfermedad, y por otro lado el carĂĄcter progresivo del proceso neurodegenerativo de la enfermedad de Parkinson. Bajo este enfoque, pretender que el mero reemplazo de la dopamina estriatal mediante terapia celular sustitutiva, pueda corregir el carĂĄcter generalizado y progresivo de la enfermedad es una aspiraciĂłn quimĂ©rica, que Ășnicamente contribuye a generar expectativas infundadas en el pĂșblico general. Este artĂculo pretende argumentar desde un punto de vista puramente cientĂfico las dudas sobre las expectativas creadas con estos nuevos diseños terapĂ©uticos.At present there is great enthusiasm over the perspectives deriving from so-called cell therapy in
Parkinsonâs disease. This enthusiasm has spread beyond the ambit of the medical community, reaching
the general public, and has been fuelled by a considerable ethical and political debate, sidestepping
the need for a really scientific analysis of the real qualities and limitations of treatment with stem-cells in
neurodegenerative diseases. Parkinsonâs disease is frequently observed from a simplistic perspective, as a
mere neurodegeneration of the nigrostriatal dopaminergic pathway. This viewpoint encompasses
different designs that tend to replace the lack of dopamine in the striatum through the use of different
types of cell therapy. In this respect, it is important to indicate, on the one hand, the multisystemic and
generalised nature of the disease and, on the other, the progressive character of the neurodegenerative
process of Parkinsonâs disease. With this approach, to claim that the mere replacement of striatal dopamine
through replacement cell therapy can correct the generalised and progressive character of the disease is
a fanciful aspiration, which can only contribute to generating unfounded expectations in the general
public. This article attempts to set out from a purely scientific point of view the doubts over the
expectations created by these new therapeutic designs
New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification
Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of
interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a
high quality template image. The aim of this study was to create new MRI and PET templates of 18F-DOPA
and 11C-(+)-α-dihydrotetrabenazine (11C-DTBZ) of the Macaca fascicularis brain, an important animal
model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15
healthy animals, previously transformed into the space of one representative MRI. In order to create the PET
templates, 18F-DOPA and 11C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET
scanner and transformed to the created MRI template space. To validate these templates for PET
quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to
each template were statistically compared to results computed using individual VOIs drawn for each animal.
The high correlation between both procedures validated the utilization of all the templates, improving the
reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine
striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) was assessed by SPM analysis of 11C-DTBZ PET. A symmetric reduction in striatal 11C-DTBZ uptake
was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have
been constructed and validated for reproducible and automated PET quantification. All templates are
electronically available via the internet
Influence of microRNA deregulation on chaperone-mediated autophagy and α-synuclein pathology in Parkinson's disease
The presence of α-synuclein aggregates in the characteristic Lewy body pathology seen in idiopathic Parkinson's disease (PD), together with α-synuclein gene mutations in familial PD, places α-synuclein at the center of PD pathogenesis. Decreased levels of the chaperone-mediated autophagy (CMA) proteins LAMP-2A and hsc70 in PD brain samples suggests compromised α-synuclein degradation by CMA may underpin the Lewy body pathology. Decreased CMA protein levels were not secondary to the various pathological changes associated with PD, including mitochondrial respiratory chain dysfunction, increased oxidative stress and proteasomal inhibition. However, decreased hsc70 and LAMP-2A protein levels in PD brains were associated with decreases in their respective mRNA levels. MicroRNA (miRNA) deregulation has been reported in PD brains and we have identified eight miRNAs predicted to regulate LAMP-2A or hsc70 expression that were reported to be increased in PD. Using a luciferase reporter assay in SH-SY5Y cells, four and three of these miRNAs significantly decreased luciferase activity expressed upstream of the lamp-2a and hsc70 3'UTR sequences respectively. We confirmed that transfection of these miRNAs also decreased endogenous LAMP-2A and hsc70 protein levels respectively and resulted in significant α-synuclein accumulation. The analysis of PD brains confirmed that six and two of these miRNAs were significantly increased in substantia nigra compacta and amygdala respectively. These data support the hypothesis that decreased CMA caused by miRNA-induced downregulation of CMA proteins plays an important role in the α-synuclein pathology associated with PD, and opens up a new avenue to investigate PD pathogenesis
Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease
Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action
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