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PARKINSON'S DESEASE, Screenshot (35), Screenshot (37), Screenshot (39)…
PARKINSON'S DESEASE
INTRODUCTION
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. it is now recognized as a complex and heterogeneous disorder that encompasses the classic motor features, as well as early and late non-motor manifestations
Dopaminergic drugs, especially levodopa therapy, provide symptomatic benefit and improvement of quality of life but are typically associated with motoefluctuations, dyskinesias and non motor complications
The pathognomonic hallmark of PD is the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) leading to striatal dopamine depletion, which in turn is causally responsible for the cardinal motor features, particularly rigidity and bradykinesia.
PD evolves into a multi-systems disorder that extends beyond
the SNc, affecting both central and peripheral nervous systemsaccompanied by a widevariety of non-motor symptoms, some of which may be present before the onset of the motor features.
Lewy pathology as an essential pathogenic feature and on the propagation of alpha-synuclein toxic species from the peripheral nervous system and olfactory bulb through the brain in a bottom-up caudo-rostral direction up to the neocortex. the neocortex is not necessarily the final stage of a bottom-up sequence, but could also be an initial top-down contributor for‘‘pushing over the edge’’ the vulnerable dopaminergic neurons.
SUMMARY
In Parkinson’s disease, the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) is associated with classic motor features, which typically have a focal onset.
this focal motor onset is unexplained and hardly justified by current pathogenic theories of bottom-up disease progression. this study proposes that corticostriatal activity may represent a critical somatotopic.‘stressor’’ for nigrostriatal terminals, ultimately driving retrograde nigrostriatal degeneration and leading to focal motor onset and progression of Parkinson’s disease
This cortical pathogenesis may co-exist with bottom-up mechanisms, adding an integrative top-down perspective to the quest for the factors that impinge upon the vulnerability of dopaminergic cells in the onset and progression of Parkinson’s disease
CONCLUSION
A cortical pathogenesis of Parkinson’s disease offers a viable solution to this anatomo-clinical dissociation. the theory is built upon of cortical involvement in the early and
prodromal stages of Parkinson’s disease. it is in fact fully
compatible with Braak’s experimental data.
These experiments will be necessary to establish
whether the cortex may be a realistic target for future diseasemodifying therapies.
IMAGES
this image shows (A) asymmetric dopamine depletion in the posterior putamen of a patient recently diagnosed with Parkinson’s disease (right) compared to a normal subject (left). (B) Topographic organization of corticostriatal circuits and rostrocaudal transition of goal-directed to habitual actions in motor learning. (C) Somatopic organization of corticostriatal projections from the primary motor cortex (MI) and the supplementary motor area (SMA) to the putamen of the monkey (Macaca fuscata). (D) Diagram of corticostiratal inputs inducing striatal dopamine release by activating cholinergic interneurons (ChI)
this image shows (A) Alpha-synuclein expression in the striatum. (B) Specific localization of striatal alpha-synuclein at corticostriatal terminals. The Pearson’s coefficients represent the co-localization of alpha-synuclein with synaptic and neuronal markers. (C) Secretion of corticostriatal alpha-synuclein through K+ (evoked depolarization using microdialysis in transgenic mice in vivo). (D) Striatal staining of vesicular monoamine transporter (VMAT2) in non-transgenic mice (NonTg) and in transgenic mice overexpressing alpha-synuclein
this image shows (A) Cortical activity is somatotopically transmitted to the striatum, acting as a focal top-down ‘‘stressor’’ that drives retrograde nigrostratal neurodegeneration, thereby leading to focal onset and somatotopic progression of motor signs. (B) Excessive corticostriatal activity increases presynaptic intracellular levels of Ca2+, leading to secretion of alpha synuclein in the striatal extracellular space.
this image shows (A) Representative pyramidal tract neurons reconstructed after injection of biotinylated dextran amine in the rat motor cortex. (B) Corticospinal and corticobulbar projections forming the pyramidal tract
originate from a vast set of cortical regions
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