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Neurobiology of Disease > Exam 1: Parkinson's > Flashcards

Exam 1: Parkinson's Flashcards

1
Q

Lateral corticospinal tract

A

3/4 axons
cross MEDULLA
originate in cortex for LIMBS

terminate Lateral alpha-MN

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2
Q

Ventral Corticospinal tract

A

1/4 axons
axons don’t cross
originate cortex represents neck shoulder trunk
terminate MEDIAL alpha-MN

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3
Q

Transected pyramid tract

A

can stand walk run but can’t use hands/pick up objects

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4
Q

Motor cortex

A

collateral sent to

1) vestibular nuclei
2) superior colliculus
3) Reticular formation
4) Red nuceus
5) Cranial motor nuclei

to alpha MN

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5
Q

Local circuit neurons

A

reflex coordination
local grey matter spine circuit

to lower motor neuron pools to skeletal muscle

where sensory input comes in

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6
Q

upper motor neurons

A

essential for voluntary movement

integration of sensory and adjust reflex activity of spinal cord

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7
Q

basal ganglia

A

getting initiation of movement

no direct to local circuit and LMN

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8
Q

Cerebellum

A

sensory motor coordination

detects differences between actual and intentional movement

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9
Q

What does the globus pallidus and SN par reticulta inhibit? What is it in feedback loop with?

A

Superior colliculus and thalamus

Subthalamic nuc (feedback)

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10
Q

Basal ganglia structures: INPUT

A

1) Frontal cortex - primary and secondary motor association areas
2) Parietal cortex - secondary visual and somatic sensory
3) Temporal Cortex - visual auditory

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11
Q

Basal Ganglia: incoming axons

A

cortical glutaminergic

synapse on medium spiny neurons in striatum

Also receive DA input from SN pars compacta

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12
Q

Basal ganglia: medium spiny neuron projections

A

GABA projections

to GP and SN pars reticula

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13
Q

Basal ganglia: GP and SNpr projections

A

inhibitory

through thalamic relay, directly to collicular N.

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14
Q

What is the pathway:

Striatum
GP
Thalamus
Cortex

A

Striatum: INhibits GP: Inhibits: Thalamus: Activates: crotex

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15
Q

BG: direct pathway

A

D1 receptors from SN pars compacta

Caudate/putamen: inhibits INTERNAL GP

disinhibiting thalamus = INCREASED motor output

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16
Q

BG: indirect pathway

A

D2 receptors in SN pars compacta

EXTERNAL SEGMENT

GP inhibit Subthalamic nuc which activates internal segment (plot twist)

Now internal GP can inhibit Thalamus!
Decreased motor output

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17
Q

Parkinson’s cause and demographics

A

2nd leading neurodegenerative disorder 1,000,000 in US, 5,000,000 worldwide

age is the greatest risk factor, typically 5th-7th decade

99% idiopathic (no known cause) some rare family forms

More common in Caucasian males

higher rise in rural areas (environment)
nicotine and caffeine protective.

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18
Q

Parkinson’s symptoms

A

tremor (resting)
rigidity: hands/feet
bradykinesia- slow movement, can’t start/stop movement
postural instability- balance/coordination

micrographia, sleep issue, dementia

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19
Q

Parkinson’s disease: premotor stage

A 
constipation
loss of smell
bad sleep 
acting out dreams
anxiety
executive function and attention issues
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20
Q

Parkinson’s: early stage

A

resting tremor, postural instability, bradykinesic, rigidity, levodopa typically effective at this point.

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21
Q

Parkinson’s: moderate

A

on/off periods, constipation, and depression common

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22
Q

Parkinson’s: advanced

A

gait worse, instability, falling issues, dementia and behavioral issues.

Residential nursing required. Life expectancy is near normal.

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23
Q

Incidence/prevalence parkinson’s

A

inconsistent prevalence (environment factors)

age major risk factor, rare before 50

males more

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24
Q

Brain of Parkinson’s: normal, but wait!

A

loss of pigmented dopaminergic in SN pars compacta, replaced by phagocytic cells, gliosis and astrocytes

Lewy bodies= aggregates of tau protein, alpha-synuclein, ubiquitin, etc.

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25
alpha-syn
charperoning vesicles if it can't protein accumulation. SNCA involved too.
26
what controls accumulation of protein?
ubiquitin and proteasome system and LAS system
27
Parkinson's is overactivation of the
INDIRECT pathway. thalamus inhibited. little motor output.
28
Pathogenesis: neuromelanin
interactions between melanin and metals may produce free radical formation, resulting in mitochondrial function Autoxidation, polymer pigment
29
Pathogenesis: alpha-synuclein
mutations in presynaptic protein associated with microtubule dysfunction and amyloid fibril formation through interaction with tau A3OP gene, 5% family
30
Pathogenesis: Neurofilament
mutations in neurofilament proteins other than tau have been found in PD patients
31
Pathogenesis: ubiquitin/proteasome pathway
ubiquitin tags misfolded or nonfunctioning proteins for degradation by proteasomes. Disruption of this pathway may result in intracellular protein accumulation. Heat shock proteins
32
D1
direct, increase cAMP
33
D2
indirect decrease cAMP
34
DA neurons have intrinsic rhythm which needs frequent depolarization. High energy consumption, active mitochondria. So what?
Lots of ROS, damages mitochondria membranes and DA
35
Parkinson's pathogenesis (stages)
Stage 1-2 Lewy bodies medulla and pons Stage 3 aggregated alpha-syn in SN Stages 4-6 supratentorial compartment in graded fashion Substantial neocrotical pathology in stage 6 (cortex) Pathology caudal --> Rostral loss of 80%+ DA neurons in SN before symptoms
36
What is main point of Parkinson genetics?
gradient of genes and environmental factors LRRK2 (leucine) alpha-synuclein SNCA 4q21 GBA: lysosomal enzyme Microtubule-associated protein tau (MAPT)
37
alpha-synuclein genetics
early on set. dominant inheritance SNARE complex issues- can't assembly SNARE
38
LRRK2 gene
arabs/Ashkenazi autosomal dominant late onset protein-protein interaction
39
Parkin gene
autosomal RECESSIVE PD. encodes for ubiquitin ligase in protein degradation and recycling along ubiquitin-proteasome pathway reduced protein degradation
40
PINK1
abundant protein kinases degrades failing mitochondria recruits parkin to label for autophagic clearance by lysosomes. Recessive.
41
Parkinson treatment list (4 different ones)
1) Thalamic DBS 2) Dopamine replacements anticholinergics, trophic factors cell transplants 3) Subthalmonotomy STN DBS (Gene therapy (GAD)) 4) Gpi DBS pallidotomy
42
Deep brain stimulation
in GP or Thalamus Complication: executive function issues. relieve tremor/dyskinesia no effect on rigidity and bradykinesia
43
Paper: Bilateral Deep Brain stimulation vs. Best medical therapy for patients with advance Parkinson disease
results: again 4.6 hours a day without dyskinesasia motor function improvements great ! of L-scale improvements did have adverse effects and risk Conclusion: good, but risk Better motor control (handwriting)
44
Levodopa
front line drug for parkinsons' | Combined with carbidopa, which reduces side effects, stops levodopa from getting in blood stream
45
Dopamine agonists
supplement levodopa may interact with other drugs
46
anticholinergics
secondary meds (benzotropine mesylate)
47
MAO =-B inhibitor and COMT
so DA not degraded supplementary med MAO: selegiline COMT: entacapone
48
problems with DA agonists?
unintended movement | hallucinations
49
Physical therapy
exercise stretching and strengthening patterned movements (high stepping)
50
Occupational Therapy
orthotic and adaptive equipment home and workplace modification speech therapy
51
Neural grafting: rat paper in neostraitum
animal unilateral lesions, spin when given amphetamine, but grafts stop it lesioned in niagral-striatal DA pathway with 6-OHDA treated symptomatically, not curable
52
Neural grafting: TH staining in striatum shows what? Problem with placing grafts?
TH-immunoreactive cell-bodies in striatum G1,3,4 cell bodies show TH-immune fiber network SN graft fail to send axons to striatum
53
MPPP vs. MPTP what is going on?
MPTP is impure, makes MPP+, DA neurotoxin. Animal model
54
Neural grafting: monkey
MPTP lesion in SN Fetal monkey tissue TH+ cells found after VM tissue engraphed
55
Neural grafting: clinical trials
decreased rigidity, but mixed results better in younger patients trends, but no significant effect some developed dyskinesia
56
Gene therapy for Parkinson's
adenvirus-free recombinant adeno-associated virus. Tranfected using 3 plasmids 1) plasmid with transgene 2) replication and capside genes 3) plasmid with adenovirus helper genes generating Ad-free rAAV
57
What is most common viral vector in parkinson's
rAAV
58
Types of gene therapy trials in progress for parkinsons'
1) enzyme replacement 2) BG circuit modification 3) Protection form disease with trophic factors
59
Experiment: Primate Parkinson's AAVV with dopamine synthesizing enzyme
genes for TH, AADC, GTP-cyclo in 3 different rAAV to MPTP Result? Improvement
60
Clinical Trials: Dopamine replacement
levtiviral prep (HIV): packaging ability tropism= cells a virus can attach to and infect pseudotyping- envelope characteristics Some improvement
61
Clinical trials: AAV to deliver AADC
inject to striatum moderate improvement

Neurobiology of Disease (8 decks)

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