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51 Cards in this Set
- Front
- Back
What is the current theory of why neurodegeneration occurs?
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A combination of events causes selective degeneration of some neurons; not just one single factor.
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What does Selective Vulnerability refer to?
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The increased vulnerability of some neurons to toxic insult than others.
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What is a clinical example of this selective vulnerability of neurons to toxic degeneration?
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Huntington's disease - all neurons HAVE the huntingtin gene, but not all neurons degenerate in this disease.
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What are 3 types of insults that can induce neurodegeneration?
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-Environmental toxins
-Neuronal metabolism -Aging |
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How do environmental toxins often induce neurodegeneration?
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By affecting mitochondrial function which results in low ATP and more oxidative stress.
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Why does neuronal metabolism cause neurodegeneration?
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Because it is an oxidative process, so oxidative stress on neurons is high - even normally.
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What are 3 ways that Aging contributes to neurodegeneration?
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-Affects mitochondrial function
-Loss in protective enzymes and molecules -Progressive hits |
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What are 3 major outcomes of the combined Environmental toxins, Neuronal metabolism, and Aging?
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-Free radical formation
-Oxidative stress -Excitotoxicity |
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What is excitotoxicity?
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Excessive intracellular calcium
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How do free radicals form?
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From dysfunctional, inefficient mitochondria which leak out electrons and oxygen radicals; caused by aging/environm. toxins
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What do the free radicals do?
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Cause lipid peroxidation
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What part of the mitochondria is particularly vulnerable to free radical injury?
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Complex 1
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What are 3 results of Complex 1 injury?
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-Loss of ATP synthesis
-Inability to extrude Ca2+ dt no energy -Loss of ability for membrane to maintain resting potential |
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What are the 2 main molecules that cause oxidative stress?
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-H2O2 and Superoxide
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What does oxidative stress precipitate?
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-Excitotoxicity
-Mitochondrial dysfunction |
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And what is excitotoxicity?
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Excessive intracellular calcium
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What does Excitotoxicity result from?
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A vicious cycle:
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What are the 6 steps in the vicious cycle of excitotoxicity?
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1. Depletion of ATP for pumps
2. Cell death 3. Excessive glutamate release 4. Persistant activation of NMDA receptors 5. Excess intracellular Ca 6. More ATP depletion |
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What is another factor that can cause persistant activation of NMDA receptors, other than excessive glutamate?
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Superoxide - so oxidative stress is linked to excitotoxicity too.
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What are 4 mechanisms that neuronal cells have for dealing with radicals?
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-Ascorbate (vit C)
-Glutathione -Superoxide dismutase -Catalase |
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When does degeneration due to free radicals occur?
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-When too many radicals are produced
-When cells lose the ability detoxify |
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What is the main thing to remember about neurodegeneration?
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There is SELECTIVE VULNERABILITY - not all neurons undergo degeneration even though the factors are present among them all
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What is Parkinson's disease?
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A movement disorder
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What is Parkinson's disease due to?
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Selective loss of the Dopaminergic neurons in Substantia nigra that project to the striatum
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What is the Striatum?
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Caudate + Putamen
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What are 4 pathologic findings in Parkinson's disease?
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-Neurodegeneration in basal ganglia and substantia nigra
-Lewy bodies -Loss of nigrostriatal Dopamine neurons -Decreased Dopamine levels in Substantia nigra |
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What other level is decreased by decreased Dopamine in Substantia nigra?
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CSF levels of HVA - the DA metabolite
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What does the loss of Dopamine in nigrostriatal circuits result in overall?
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Dysregulation of the basal ganglia
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What does the dysregulation of the basal ganglia in Parkinson's disease result in?
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Not enough excitation of the motor cortex; decrease in movement.
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What are the 4 Major symptoms of Parkinsons disease?
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-Cogwheel rigidity
-Resting Tremor -Bradykinesia -Postural reflex loss |
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What is the cogwheel rigidity in Parkinson's due to?
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Dysregulation of gamma motor neurons
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What does the loss of postural reflexes result in?
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Shuffling gait and unsteadiness
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What it the resting tremor seen in Parkinson's also called?
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Pill-rolling tremor
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What is Brady/Hypokinesia?
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Brady = slow movements
Hypo = fewer movements |
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What are 4 physical manifestations of the brady/hypokinesia seen in Parkinson's?
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-Mask-like facial expression
-Muffled speech -Sialorrhea (drool) -Freezing |
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What are the slower/fewer movements due to?
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The effect of decreased thalamic input to the cortex, so loss of alpha motor neuron stimulation.
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Is Parkinson's strictly a movement disorder?
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NO - there are also intellectual problems
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What are 3 intellectual changes in Parkinson's?
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-Changes in personality
-Loss of drive/curiosity -Memory loss - ultimate dementia |
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What are 2 more common personality changes seen in PD?
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-Irritibility
-Impulsivity |
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What are the intellectual changes in PD due to?
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Effects on the ventral striatum - dopamine is part of several cerebral circuits
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What is the etiology of Parkinson's Disease?
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SELECTIVE VULNERABILITY of the dopaminergic cells of the substantia nigra
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Why are SN dopaminergic cells selectively vulnerable to degeneration?
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Because when MAO metabolizes Dopamine to DOPAC, H2O2 gets produced at the same time.
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What happens to the H2O2 product of Dopamine metabolism?
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It undergoes Fenton chemistry where Fe2+ reduces H2O2 to OH- and Hydroxy radicals + Fe3+
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What happens over the years as MAO and Fe2+ in dopaminergic neurons of SN continue to be produced?
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The accumulation of free radical damage over the years causes death and reduced # of DA cells
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Is the accumulation of free radicals and loss of DA neurons the same in everyone?
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No, the slope of DA loss down to a threshold where PD symptoms manifest varies btwn patients.
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What are 7 factors that can change the rate of how soon symptoms of Parkinson's disease will develop?
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ABCEING
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What is ABCEING?
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-Arteriosclerosis
-Brain trauma -Chemicals -Encephalitis -Iatrogenic -Neuroinflammation -Genetic factors |
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What are 6 chemicals that can increase the rate of development of parkinsons symptoms?
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-CO
-CN -Methanol -Manganese -MPTP -Insecticides |
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Who developed PD due to brain injury?
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Muhammad ali
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What is an iatrogenic cause that has been linked to PD?
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Antipsychotics - block DA receptors
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What is a gene that may be related to the rate of PD manifestation?
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Parkin
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