Exam 1: Parkinson's Flashcards
Lateral corticospinal tract
3/4 axons
cross MEDULLA
originate in cortex for LIMBS
terminate Lateral alpha-MN
Ventral Corticospinal tract
1/4 axons
axons don’t cross
originate cortex represents neck shoulder trunk
terminate MEDIAL alpha-MN
Transected pyramid tract
can stand walk run but can’t use hands/pick up objects
Motor cortex
collateral sent to
1) vestibular nuclei
2) superior colliculus
3) Reticular formation
4) Red nuceus
5) Cranial motor nuclei
to alpha MN
Local circuit neurons
reflex coordination
local grey matter spine circuit
to lower motor neuron pools to skeletal muscle
where sensory input comes in
upper motor neurons
essential for voluntary movement
integration of sensory and adjust reflex activity of spinal cord
basal ganglia
getting initiation of movement
no direct to local circuit and LMN
Cerebellum
sensory motor coordination
detects differences between actual and intentional movement
What does the globus pallidus and SN par reticulta inhibit? What is it in feedback loop with?
Superior colliculus and thalamus
Subthalamic nuc (feedback)
Basal ganglia structures: INPUT
1) Frontal cortex - primary and secondary motor association areas
2) Parietal cortex - secondary visual and somatic sensory
3) Temporal Cortex - visual auditory
Basal Ganglia: incoming axons
cortical glutaminergic
synapse on medium spiny neurons in striatum
Also receive DA input from SN pars compacta
Basal ganglia: medium spiny neuron projections
GABA projections
to GP and SN pars reticula
Basal ganglia: GP and SNpr projections
inhibitory
through thalamic relay, directly to collicular N.
What is the pathway:
Striatum
GP
Thalamus
Cortex
Striatum: INhibits GP: Inhibits: Thalamus: Activates: crotex
BG: direct pathway
D1 receptors from SN pars compacta
Caudate/putamen: inhibits INTERNAL GP
disinhibiting thalamus = INCREASED motor output
BG: indirect pathway
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
Parkinson’s cause and demographics
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.
Parkinson’s symptoms
tremor (resting)
rigidity: hands/feet
bradykinesia- slow movement, can’t start/stop movement
postural instability- balance/coordination
micrographia, sleep issue, dementia
Parkinson’s disease: premotor stage
constipation loss of smell bad sleep acting out dreams anxiety executive function and attention issues
Parkinson’s: early stage
resting tremor, postural instability, bradykinesic, rigidity, levodopa typically effective at this point.
Parkinson’s: moderate
on/off periods, constipation, and depression common
Parkinson’s: advanced
gait worse, instability, falling issues, dementia and behavioral issues.
Residential nursing required. Life expectancy is near normal.
Incidence/prevalence parkinson’s
inconsistent prevalence (environment factors)
age major risk factor, rare before 50
males more
Brain of Parkinson’s: normal, but wait!
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.
alpha-syn
charperoning vesicles
if it can’t protein accumulation. SNCA involved too.
what controls accumulation of protein?
ubiquitin and proteasome system and LAS system
Parkinson’s is overactivation of the
INDIRECT pathway. thalamus inhibited. little motor output.
Pathogenesis: neuromelanin
interactions between melanin and metals may produce free radical formation, resulting in mitochondrial function
Autoxidation, polymer pigment
Pathogenesis: alpha-synuclein
mutations in presynaptic protein associated with microtubule dysfunction and amyloid fibril formation through interaction with tau
A3OP gene, 5% family
Pathogenesis: Neurofilament
mutations in neurofilament proteins other than tau have been found in PD patients
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
D1
direct, increase cAMP
D2
indirect decrease cAMP
DA neurons have intrinsic rhythm which needs frequent depolarization. High energy consumption, active mitochondria. So what?
Lots of ROS, damages mitochondria membranes and DA
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
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)
alpha-synuclein genetics
early on set.
dominant inheritance
SNARE complex issues- can’t assembly SNARE
LRRK2 gene
arabs/Ashkenazi
autosomal dominant
late onset
protein-protein interaction
Parkin gene
autosomal RECESSIVE PD.
encodes for ubiquitin ligase in protein degradation and recycling along ubiquitin-proteasome pathway
reduced protein degradation
PINK1
abundant protein kinases
degrades failing mitochondria
recruits parkin to label for autophagic clearance by lysosomes. Recessive.
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
Deep brain stimulation
in GP or Thalamus
Complication: executive function issues.
relieve tremor/dyskinesia
no effect on rigidity and bradykinesia
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)
Levodopa
front line drug for parkinsons’
Combined with carbidopa, which reduces side effects, stops levodopa from getting in blood stream
Dopamine agonists
supplement levodopa
may interact with other drugs
anticholinergics
secondary meds (benzotropine mesylate)
MAO =-B inhibitor and COMT
so DA not degraded
supplementary med
MAO: selegiline
COMT: entacapone
problems with DA agonists?
unintended movement
hallucinations
Physical therapy
exercise
stretching and strengthening
patterned movements (high stepping)
Occupational Therapy
orthotic and adaptive equipment
home and workplace modification
speech therapy
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
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
MPPP vs. MPTP what is going on?
MPTP is impure, makes MPP+, DA neurotoxin.
Animal model
Neural grafting: monkey
MPTP lesion in SN
Fetal monkey tissue
TH+ cells found after VM tissue engraphed
Neural grafting: clinical trials
decreased rigidity, but mixed results
better in younger patients
trends, but no significant effect
some developed dyskinesia
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
What is most common viral vector in parkinson’s
rAAV
Types of gene therapy trials in progress for parkinsons’
1) enzyme replacement
2) BG circuit modification
3) Protection form disease with trophic factors
Experiment: Primate Parkinson’s AAVV with dopamine synthesizing enzyme
genes for TH, AADC, GTP-cyclo in 3 different rAAV to MPTP
Result? Improvement
Clinical Trials: Dopamine replacement
levtiviral prep (HIV): packaging ability
tropism= cells a virus can attach to and infect
pseudotyping- envelope characteristics
Some improvement
Clinical trials: AAV to deliver AADC
inject to striatum
moderate improvement
