Parkinson's Flashcards
1
Q
typical age of diagnosis
A
over 60
2
Q
Young-onset PD
A
symptoms before age 50, 4-10% of PD population, mainly caused by genetics, progression is slower
3
Q
which gender and race is more likely to get it?
A
men are more likely, whites are 2x more likely than Black or Asians
4
Q
risk factors
A
increasing age, family history (30% w/PD have a known family history), male, caucasian, personality (intorverted, shy, nervous, strong sense of responsibility), environmental (pesticides, herbicides, heavy metals, well water, repeated head injury)
5
Q
primary movement symptoms
A
resting tremor
bradykinesia
rigidity
postural instability
6
Q
rigidity
A
inflexibility of the limbs, neck, truck
decreased range of motion
7
Q
postural instability
A
later in disease progression
unstable to stand upright
reflexes needed to maintain upright posture are lost
may fall backwards if pushed
8
Q
what two primary motor symptoms must be present for a diagnosis to be considered
A
bradykinesia and either tremor or rigidity
9
Q
resting tremor
A
most common symptom
starts in hand (finger) or foot, sometimes uncommonly in the jaw or face
shaking movement when muscles are relaxed
can be enhanced by stress
starts on 1 side and then spreads to the other
10
Q
bradykinesia
A
slow voluntary movement
difficulties with repetitive movements
decrease in facial expressions
11
Q
secondary symptoms
A
freezing (differs from rigidity and bradykinesia, during walking, increases risk of falling)
micrographia (shrunken handwriting)
unwanted accelerations ( gait and speech)
reduced sense of small
mask-like expression
11
Q
secondary symptoms
A
freezing (differs from rigidity and bradykinesia, during walking, increases risk of falling)
micrographia (shrunken handwriting)
unwanted accelerations ( gait and speech)
reduced sense of small
mask-like expression
12
Q
what is the autonomic NS?
A
part of the peripheral NS that regulates involuntary physiological processes (digestion, respiration, blood pressure, heart rate, etc)
13
Q
autonomic dysfunctions
A
constipation
low blood pressure- when changing positions
sweating problems- excessive perspiration even when not hot
urine problems- frequent urination or involuntary urine loss
14
Q
stage 1
A
symptoms on one side of body
little loss of function
15
Q
stage 2
A
symptoms on both sides
balance is normal
16
Q
stage 3
A
symptoms on both sides
balance impairment
physically independent
17
Q
stage 4
A
severe impairment in movement and balance
able to walk or stand unassisted
18
Q
stage 5
A
severe impairment of movement
wheelchair bound
increase risk of choking, pneumonia and deadly falls
19
Q
can we predict disease progression?
A
no
20
Q
how long do symptoms take to progress
A
at least 20 years, or more quickly
21
Q
What is the MDS-Unified PD Rating Scale?
A
better measures PD progression
22
Q
what are the 4 parts to the MDS scale?
A
non-motor aspects of daily living- cognitive impairment, hallucinations, depression, sleep. etc. (13 items)
motor aspects of daily living- speech, swallowing, use of utensils, handwriting, etc. (13 items)
motor examination (18 items) - facial expression, tremor at rest, posture, gait, body bradykinesia, hand movements
motor complications ( 6 items)
23
Q
scoring for MDS
A
healthy- 0
severe-4
24
how is PD diagnosed?
based on medical history and neurological exam
no blood or lab tests for non-genetic
CT and MRI appear normal but can rule out other diseases
25
what is Post-encephalitic Parkinsonism
unknown causes, but thought to be viral in nature
bradykinesia, rigidity, posture instability, gait disorders with falls, facial masking
present w/ NFTs in hippo and cortical areas
26
Drug-induced Parkinsonism
manganese dust, carbon monoxide
dopamine inhibitors including metoclopramide
MPTP
27
what is tardive dyskinesia
involuntary, repetitive body movements
28
what is multiple system atrophy w/ predominant Parkinsonism (MSA-P)
no known cause
progressive neurodegenerative disorder
nigrostriatal degeneration
alpha synuclein inclusions in neurons and oligodendrocytes (only in neurons In PD and LWD)
29
symptoms of MSA-P
rigid muscles
difficulty bending your arms and legs
bradykinesia
tremors (rare in MSA compared to Parkinsons)
problems w/ posture and balance
autonomic dysfunction
faster rate of symptom progression, more autonomic dysfunction, poorer response to LDOPA treatment than PD
30
MSA-P
similar to PD (w/ moving slowly, stiffness, and tremor) along w/ more mild problems of balance, coordination, and autonomic NS dysfunction
31
MSA-C
ataxia (problems w/balance and coordination) difficulty swallowing, speech abnormalities, abnormal eye movements
32
normal pressure hydrocephalus
blockage causes abnormal increase of CSF in ventricles
ventricle enlarge which puts pressure on the brain
problems with walking, general slowing movements and cognitive problems
cognitive problems caused from pressure put on hippo since it is close to ventricles
33
corticobasal syndrome (CBS)
atrophy of cortex and basal ganglia
rigidity, impaired balance and coordination, dystonia
no treatment
loss of cortical tissue
caused from genetics
34
LWD
build up of leeway bodies in motor and cognitive areas
difficult to diagnosis
loss of memory, confusion, poor attention, muscle stiffness, postural instability
dementia first then motor
35
structures involved in motor control
cerebral cortex
basal ganglia
cerebellum
thalamus
36
Major regions of basal ganglia
caudate nucleus
putamen
nucleus accumbent
globus pallidus
subthalamic nucleus
substantia nigra
37
region of caudate nucleus
head
body
tail
38
what is the striatum
the putamen and caudate nucleus accumbent are collectively referred to as the striatum
39
what is the substantia nigra
black substance
contains neuromelanin synthesized from dopamine
two subregions:
pars compacta- contains dopamine cell bodies
pars reticulate
40
what are the 4 dopamine system pathways
nigrostriatal
mesolimbic
mesocortical
tuberoinfundibulnar
41
nigrostriatal
where dopamine is vs. axon terminals, regulates movement
-substantia nigra
-striatum- made of caudate and putamen, anterior to midbrain
42
mesolimbic
in midbrain, addiction pathways (drugs, sex)
-ventral tegmentum
-nucleus accumbens- where axon terminals end
43
mesocortical
axons to frontal cortex, regulates decision making, executive functions etc
-ventral tegmentum
-frontal cortex
44
tuberoinfundibular
hypothalamus
pituitary
45
dopamine neurotransmission
synthesis
release
receptors (D1-D5)
Uptake (DAT)
Metabolism
46
what is an auto receptor
dopamine binds and auto regulates what is happening in the receptor by increasing or decreasing synthesis and changing dopamine binding in the membrane
47
what is dopamine transporter(DAT)
If dopamine doesn't bind to receptors, transported recycles it to release it again
48
about how much of the substantia nigra dopamine neurons lost before symptoms occur
60-80%
49
what are lewy bodies
aggregates of the protein alpha synuclein protein
found in cell bodies
they are not the cause of PD, there are an outcome
50
what are lewy neuritis
neuronal processes with alpha synuclein polymers
mainly found in axons and dendrites (extensions of cell bodies)
51
amphipathic N-terminal
hydrophobic
interacts with neuronal membrane
found in membrane
52
NAC region
non-amyloid component prone to aggregation
imbedded in membrane or hanging off outside membrane
where aggression occurs
53
acidic c-terminal
interacts w/ other proteins and metals in neuron
54
why dopamine neurons?
dopamine appears to interact w/ alpha synuclein and stabilize oligomers
55
proteosomal
gets rid of misfiled proteins
56
oligomers
clusters of alpha synuclein, larger structures found in Lewy bodies and neurites
57
what does dopamine do with oligomers
dopamine binds to the oligomers and the oligomers stay around longer because they become more stable, dopamine is the only transmitter known to bind to oligomers
58
what do oligomers do?
form their own pores by pushing aside phospholipids which allows ions to pass through which changes the ion concentrations and their balance
59
what is the alpha syn cascade hypothesis?
the formation of aggregating alpha-syn species precede synaptic dysfunction and subsequent neuronal death
increased levels of differently sized alpha-syn oligomers have been measured in brains w/ Lewy pathology compared to brains from non-diseased individuals
elevated levels of olihpmeric alpha-syn in CSF in PD patients compared to control subjects
60
non-motor symptoms in PD
impaired cognition (dopamine, acetylcholine, serotonin, glutamate)
depression (serotonin, glutamate, GABA)
attention dysfunction (dopamine and acetylcholine)
sleep disorders (dopamine, acetylcholine, serotonin, glutamate, GABA)
treated with drugs that target neurotransmitter systems
61
monogenic forms
controlled by a single gene
10% of PD cases
highly penetrant, rare gene mutations in families
age of onset tends to be younger
62
idiopathic
sporadic
unknown cases
likely multi-factorial, interactions between several genes and environmental
63
penetrance
number of people w/ a particular gene that express an associated trait
64
autosomal dominant genes
SNCA-alpha synuclein
LRRK2- leucine-rich repeat kinase2
65
autosomal recessive gene
PRKN-parkin
66
what were the first genes reported w/ mutations to cause autosomal dominant PD? and characteristics?
SNCA-PARK1/PARK4
young onset PD <50 yrs
immediate response to LDOPA
Lewy bodies present at autopsy
rapid progression of motor symptoms
dementia and seizures
67
missense mutations
DNA mutation that results in a change in amino acid
likely reduces interaction w/ lipid membrane
lead to increased aggregation of alpha syn
68
what chromosome does duplicate and triplicate SNCA gene repeats of the wild type on?
chromosome 4
69
what do triplications lead to?
a 10 year earlier age of PD onset and faster progression compared to duplication
increased concentrations of alpha-syn increase likelihood of misfiling
the more copies= the more chances of being diagnosed and faster progression
70
LRRK2-PARK8
mutated gene reported to cause autosomal dominant PD
most common, known genetic contributor to PD (1-2% of all cases)
present in dopamine-rich regions
mutations enhance kinase activity
encodes for LRRK2
mutations appear to increase SNCA transcription
71
characteristics of LRRK2-PARK8
LO PD >50 yrs
response to LDOPA
inconsistent Lewy bodies presence at autopsy
slow progression of symptoms
dementia is NOT a symptom
72
what can oxidative stress activate?
non-mutated LRRK2 in idiopathic PD
73
role of LRRK2 in end-lysosomal trafficking
shows how proteins come off membrane and then go back on
If early endoscope gets recycled back to membrane=recycling endosome which then fuses w/ membrane and protein comes back
or earl endoscopes can pair w/ lysosomes which helps degrade proteins on the late end
74
what is an endosome
modified vesicle, intracellular so makes protein intracellular
75
what does LRRK2 do?
increased activity in protein function
inhibits late endoscope binding to lysosomes
stresses lysosome so the lysosome breaks down
76
what does reactive oxygen species do to LRRK2?
increases activity, implications for idiopathic PD
mitochondrial dysfunction can also increase activity
77
what does overactivity of LRRK2 do?
increased caspase-dependent apoptosis
78
what is Parkin-PARK2
first gene identified causing autosomal recessive PD
protein is part of ubiquitin proteasome system
most common, known cause of young onset PD
if age of first symptoms is <30 years, there is a 25% chance the person has the Parkin mutation
most common cause of juvenile PD <21 yrs
mutated prawn results in protein not being tagged, which causes folded and nonfunctional proteins
79
what do organohalogen industrial contaminants contain?
F, Cl, B
electrical insulating coatings, flame-retardant oils, adhesives, plastics
highly stable
80
what are the 2 types of organohalogen contaminants linked to PD?
PCBs
PBDEs
81
what are PCBs (polychlorinated biphenyls)
209 chemicals
used as fire preventive and insulator in the manufacture of electrical devices because of their ability to withstand exceptionally high temps.
other uses: solvents in paints
hydraulic fluids
window caulking
preferentially accumulate lipid-rich regions of the body
82
how can you be exposed to PCBs?
food- bottom feeders and predators b/c PCBs are found in sediment
surface soils- eat or skin exposure (barefoot)
drinking water- not as common, not water soluble
workplace- old fluorescent light transformers that fail, electrical fires, increased incidence of PD in plant workers
83
what are PBDEs (polybrominated biphenyl ethers)?
replaced PCBs
commonly used in flame retardants in carpeting, furniture cushions and insulation
lipophilic, resistant to degradation like PCBs (increasing levels in serum and breast milk, penta and exa forms are more frequently detected in humans and wildlife)
84
what are oxygen free radicals?
they can damage proteins, lipids, DNA, RNA
85
where is increased PCB desposition?
in caudate and substantia nigra
86
Herbicides in PD
paraquat- common herbicide in US
maneb- fungicide
ziram- fungicide, widely used on fruits
combined exposure over 25 years increases PD risk
ziram and paraquat exposure increases PD risk by 80%
Agent Orange
87
how does paraquat affect dopamine
it can gain access to dopamine neurons by passing through DAT, it then messes with the mitochondrial function
88
what does ziram do
prevents misfiled proteins from being broken down
89
how does genes affect paraquat
some gene mutations cause more DAT so more paraquat can get in
90
what are dioxins
group of chemically related compounds that are environmental pollutants, can cause cancer and increase risk of neurological diseases
91
LDOPA
first medication that has proven to treat PD
helps manage motor symptoms
corrects the dopamine deficit
however, it does not reduce the rate of dopaminergic cell loss
92
what is LDOPA given with? and what does it do?
carbidopa
inhibits AADC and prevents conversion to DA in periphery
increases the amount of LDOPA that enters brain ( from 1-10%)
product name-sinemet
93
sinemet
works for shorter periods of time after years of treatment (2-10 years)
taken 3-8x times a day
94
rasagiline
MAO-B inhibitor. FDA approved
taken in early stages, coupled with LDOPA or dopamine agonists to boost effects
95
COMT inhibitors
not effective on their own and must be combined with LDOPA
96
stalevo
contains LDOPA/carbidopa and entacapone in one pill
97
symptoms unresponsive to LDOPA
freezing
posture instability
mental changes (dementia and depression)
speech abnormalities
98
side effects of LDOPA
diarrhea, dizziness, drowsiness, dry mouth, increased sweating, loss of appetite, nausea, UTI, vomiting, etc.
LDOPA induced dyskinesias (affects > 50% of patients), after several years of chronic use
99
LDOPA-induced dyskinesia
presence of involuntary movements- most commonly observed in uncontrolled movements of the upper body, sometimes In lower body
related to fluctuating LDOPA
100
apokyn (apomorphine)
non selective dopamine receptor agonist
helps improve "off" episodes during LDOPA treatment in advanced PD
administered subcutaneously
drug binds to dopamine receptors to mimic dopamine
can work in about 15-20 min
duodenum absorbs it, it enters the bloodstream and is broken down by stomach acid
side effects: nausea and vomiting (may be prescribed Tigamn to suppress)
101
ropinerole (requip) and pramipexole (mirapex)
acts at D2, D3, and D4 receptors and some serotonin and norepinephrine receptors
take during LDOPA "off episodes"
more severe side effects: compulsive behaviors, nausea, hypotension, extreme drowsiness
mood disorders: depression, hallucinations, paranoia, and psychosis
102
how does apomorphine, ropinerole, and pramipexole work?
act by bypassing the degenerating dopamine neurons and directly stimulate the postsynaptic dopamine receptors in striatum, cortex and other regions
103
depression
in 40-70% of patients
tricyclic antidepressants
selective serotonin reuptake inhibitors (SSRIs)-paroxetine (Paxil)
104
dementia
estimated in 30-40% of patients
acetylcholinesterase inhibitors; only rivastigmine (Exelon) is FDA approved to treat mild-moderate dementia
105
sleep attacks
excessive sleep associated w/ dopamine agonists
can lead to-accidents while driving and falling while standing
106
REM sleep behavior disorder
treat w/ clonazepam
acting out of dreams that are vivid
107
psychosis management
delusions and hallucinations affect 20-40% of patients
linked to dopamine receptor agonists
108
psychosis treatments
pimavanzserin (Nuplazid)- blocks serotonin 2A receptor (FDA approved)
clozapine- causes granulocytes in 1% and requires weekly monitoring of WBC count
quetiapine- no major side effects but may be less effective than clozapine
109
medications in pipeline
anle138b- alpha synuclein aggregation inhibitor (MODAG, Pase 1 trial)
immunotherapy (phase 1/2 trials), targets alpha synuclein
DNL201- LRRK2 inhibitor (Denali, Phase 1 trial)
Inosine - precursors of urate, a natural metabolite and major antioxidant in humans (Phase 3 trials)
110
deep brain stimulation
most common treatment
electrodes are connected by wires (leads) to a battery (pulse generator, IPG) implanted under the skin below the collarbone
blocks electrical signals from targeted areas of the brain
approved for PD patients who have had PD for at least 4 years and still have motor symptoms
improves stiffness, slowness and tremor
doesn't work well for imbalance, freezing, or non-motor symptoms
most people can decrease their intake of PD drugs
111
neural transplantation in PD
fetal ventral midbrain intrastriatal transplantations (produce dopamine)
humans embryonic dopamine neurons
no signifcant difference in movement
produced non-medication induced dyskinesias in 15% of patients
implanted into nigrostriatal tract
112
early biomarkers
about >60% of dopamine neurons lost in striatum before motor symptoms appear
loss of smell appears to occur before motor symptoms in 50-90% of patients (about 4 years before)
113
UPSIT
people w/ normal sense of smell can identify about 35 odors correctly
PD patients can only identify 20 or less
114
University of PA Smell Idenifitication Test (UPSIT)
original- 40 smells
shorter 12 smell test
115
problems with UPSIT
age and allergies can affect performance
females have a better sense of smell
some meds can affect smell
some can't remember substance names
116
problems with UPSIT
age and allergies can affect performance
females have a better sense of smell
some meds can affect smell
some can't remember substance names
117
purines
in DNA and ATP
118
urate (uric acid)
antioxidant end product of purine metabolism, eliminated in urine
don't give as a treatment because it is easily excreted, lots of uric acid can lead to problems
119
why is inosine a better treatment than urate
helps create uric acid so the levels of the acid are more controlled and progressive so that way you don't get a lot at once
120
urate as PD biomarker
low levels- linked to higher risk of PD
high levels- lowers risk in men, but not women
121
biomarkers imaging
PET and SPECT can be used to monitor changes in DAT levels
PET-expensive
SPECT- used more
122
where is DAT most present
on axon terminals in the striatum
123
common DAT ligands
123I-beta-CIT (SPECT)
18F-beta-CFT(PET)
18F-FDOPA (PET)
124
why developing alpha syn radiotracers are so difficult
18F-ACI-12589= leading contender
increased binding in some patients w/ MSA compared to controls
no differences between PD and controls
they bind in areas that they shouldn't be binding (lack of specificity)
not FDA approved because 1) needs to cross BBB and be lipiphilic- needs a transporter to pass membrane 2) structure similar to other proteins could be binding to other aggregates (tau and amyloid -not only alpha) 3) we have to get them into neurons to bind to oligomers, Lewy bodies, etc.
