Exam 4 Flashcards
1
Q
primary motor symptoms of PD
A
- bradykinesia: slowness and lack movement
- tremor at rest
- rigidity
- flexed posture and postural instability
2
Q
cardinal feature of PD
A
bradykinesia
almost all have
3
Q
secondary motor symptoms of PD
A
- freezing of gait
- micrographia
- mask-like expression
4
Q
why do PD patients have micrographia
A
difficult to concetrate on the size of the writing and the thing they are writing
5
Q
non motor features of PD
A
- sleep disorders
- autonomic function
- sensation loss
- cognitive impairment
- mood
6
Q
autonomic function problems in PD are likely due to
A
denervation
7
Q
main neuropathological hallmarks of PD
A
- loss of dopamenergic neurons in the SNpc
- loss of pigmented neurons in the SNpc
- lewy bodies
8
Q
The motor symptoms of PD result from the loss of which neurotransmitter?
A
dopamine
9
Q
Which neurons are most severely lost in PD patients?
A
Neurons in the Substantia nigra Pars Compacta
10
Q
if dopamine is lost in PD, why do treatments use L-Dopa?
A
- dopamine is too big to cross the BBB
- dopamine broken down too quickly
- L-Dopa does not do these things
11
Q
therapeutic targets to improve dopamine neurotransmission in PD
A
- viral expression of tyrosine hydroxylase (makes L-Dopa)
- expression of AADC (makes dopamine)
- MAO/COMT inhibitors
- DAT inhibitors
- DA receptor agonists
12
Q
MAO/COMT does what
A
breaks down dopamine
13
Q
PD treatment by using DA receptor agonists helps because
A
dopamine is relased more since the receptors don’t signal that it is not needed anymore
14
Q
PD treatment by using DAT inhibitors helps because
A
DAT not there to uptake dopamine
15
Q
critical advancements in discovering PD
A
- DA recognized as a neurotransmitter
- MPTP usage by addicts causing parkinson’s like symptoms
- genetic causes discovery
16
Q
MPTP is
A
a prototypical DAergic toxin
* causes degeneration of DAergic neurons
17
Q
how does MPTP cause loss of DA neurons
A
- MPTP crosses BBB
- MPTP turned into MPP+ by MOA-B in astrocytes
- MPP is uptaked via DAT into mitochondria
- oxygen free redicals and energetic failure in mitchondria = cell death
18
Q
current therapies for basal ganglia circuit in PD
A
- DA or cell therapy replacement
- surgical pallidotomy
- DBS
19
Q
Deep brain stimulation treats the motor symptoms of Parkinson’s Disease patients by:
A
interfering with signals in the basal ganglia circuit in the brain
20
Q
PD has loss of D1 or D2 neurons
A
D1
21
Q
Mutations in which of the following genes is not considered a monogenic cause of PD?
SNCA
PINK1
GBA
LRRK2
A
GBA
22
Q
Which genetic mutations is the most common cause of PD?
IMPORTANT - MIGHT BE ON EXAM
A
LRRK2
IMPORTANT - MIGHT BE ON EXAM
22
Q
Which genetic mutations is the most common cause of PD?
IMPORTANT - MIGHT BE ON EXAM
A
LRRK2
IMPORTANT - MIGHT BE ON EXAM
23
Q
According to Braak, where does alpha-synuclein pathology (Lewy Bodies) first appear in the CNS of PD cases?
A
Dorsal Motor Nucleus of Vagus
24
10% of PD cases are
genetic
25
Parkin mutations are _ _
autosomal dominant
26
genes involved in PD that mutate
* SNCA
* PINK1
* DJ-1
27
parkin is a _ that is important in _
E3 ligase important for Ub tagged degredation
28
PINK1 mutations are
autosomal recessive
29
PINK1 normally has a _ and function to _
mitochondrial targetting motif and localizes to mitochondria
30
PINK1 regulates
mitochondrial fussion/fission
31
in animals, deletion of PINK1 led to
muscle atrophy
32
in animals, deletion of PINK1 was corrected by
overexpression of Parkin
33
PINK1 normally _ parkin
recruits and activates parkin
34
parkin/pink 1 mutations have:
* onset
* symptoms
* degeneration
* pathologies
* onset before 40
* slow or no symptoms
* selective degeneration of SNpc and locus coeruleus neurons
* no lewy bodies or tau pathologies
35
Parkin/PINK1 knockout mice features
* no neurodegeneration
* loss of DA neurons sometimes
* no increase of vunerability of DA neurons ot MPTP or synuclein toxicity
* overexpression of parkin protexted DA neurons from MPTP and alpha synuclein toxicity
36
overexpression of parkin...
protected DA neurons from MPTP and alpha synuclein toxicity
37
DJ-1 is what type of mutation
point mutation
38
L166P mutant is in what gene
DJ-1
39
DJ-1 knockout mice have severe or mild phenotype
mild
40
SNCA mutations are _ _
autosomal dominant
41
synuclein normally functions
as a synaptic chaperone
* important to inhibition of vesicle release (inhibit neurotransmitter release)
42
alpha synuclein antibodies...
recognize lewy bodies
43
lewy bodies are composed of
fibrillar alpha synuclein
44
alpha synuclein aggregates form
lewy bodies
45
two other types of alpha synucleinpathies
* dementia with lewy bodies
* multiple system atrophy (MSA)
46
what parts of the brain show Lewy Bodies in PD
Hippocampus
Locus Coeruleus
Vagal Nerve
## Footnote
IMPORTANT
47
Toxic conversion of alpha-synuclein is thought to involve:
formation of beta sheet structures
## Footnote
IMPORTANT
48
Which of the following are genetic risk factors for sporadic PD?
APP
PINK1
Parkin
MAPT
MAPT
## Footnote
IMPORTANT
49
synucleins inhibit
neurotransmitter release
50
alpha synuclein antibodies recognize
lewy bodies, lew neurites and GCIs
51
in SMA and dementia in lewy bodies, alpha synucleinopathies occur in
oligodendricytes
52
in SMA and dementia in lewy bodies, alpha synucleinopathies occur in
oligodendricytes
53
alpha synuclein pathology in PD initiates from _ and moves _
the brainstem and moves anteriorally
54
expression of A53T Hu alpha syn leads to
fatal neurological disease in Tg mice
55
human alpha synuclein transgenic mice features
1. sudden onset
2. rapid progession
3. within 10 days, catatonic
56
expression of A53T Hu alpha syn
causes neurodegeneration in DA neurons
57
LRRK2 is important to
innate immunity
membrane trafficking
other things
| gene important in PD
57
LRRK2 is important to
innate immunity
membrane trafficking
other things
| gene important in PD
58
homzygous loss of function in _ causes Gaucher disease
GBS
59
LRRK2 pathology
* lewy bodies
* alpha syn aggregates
* extran SN degeneration
60
LRRK2 mutation are _ inheritance
autosomal dominant
| PD
61
LRRK2 mutation PD has clinical pathology
* progressive
* common non motor abnormalities
* dementia
62
PRKN PINK 1 and DJ1 inheritance
autosomal recessive
63
PRKN PINK DJ 1 mutations pathologies
* no lewy bodies
* selective SNpc degeneration
64
clinical PRKN PINK1 DJ1
* slowly progressive
* limited non motoric abnormalities
65
lack of GBA causes dysfunction in
the lysosomes
| PD
66
lack of GBA causes dysfunction in
the lysosomes
| PD
67
genes that are heriditary PD
* LRRK2
* PRKN
* PINK1
* DJ-1
68
genes that are sporadic PD risk
* SNCA
* GBA
69
pathology of sporadic PD
* lewy bodies
* alpha syn aggregates
* SNpc and SN degeneration
70
clinical features of sporadic PD
* progressive
* common non motoric abnormalities
* dementia
71
targets for PD treatment
* alpha syn aggregates
* targets of alpha syn aggregates
72
many clinical defects of PD do not respond to
DA replacement therapy
73
LRRK2 mutation increases
alpha syn in glia (astrocytes, microglia)
74
if PD starts in the gut, alpha syn is carried ot the brain via
vagal nerve
75
a vagotomy _ in PD
decreases the risk of developing PD
76
injection of al[ha syn in the gut in animal models let to _ unless
led to alpha syn in the brain unless the vagal nerve was cut
77
CNS pathology after initiation of alpha syn in the gut is first seen in _ and leads to
DMV, leads to progressive loss of SNpc DA neurons
| PD
78
alpha syn pathology in the ER
* ERAD defect
* ER caspase 9 and 3 activation
**lack of P-eIF2a activation
**
79
P-eIF2a activation is important for
protecting the ER from stress
| PD
80
salubrinal
inhibits dephosphorylation of P-eIF2a
* protects cells from ER stress
81
ER derived alpha syn oligomers are
* highly pathogenic in animal models (very toxic)
82
a syn pathology activatives c-Abl which leads to
impairment of p53 dependent autophagy by inhibiting Mdm2
83
nilotinib
treatment that inhibits c-Abl so inhibits the inhibition of p53
* works to help a little in animal models
| PD
84
nilotinib
treatment that inhibits c-Abl so inhibits the inhibition of p53
* works to help a little in animal models
| PD
85
prion diseases can be
* aquired
* genetic
* sporadic
86
prion diseases manifest as
rapid progressive demtias with clinical visual or cerebellar signs and mutism
87
sporadic, iatrogenic and familial CJD symptoms
progressive dementia and neurological signs
88
variant CJD symptoms
early psychiatric symptoms, neurological deficits and cognitive decline
89
GSS symptoms
cerebellar dysfunction
90
pathological characteristics of prion diseases
* brain vacuolation (holes)
* astrogliosis
* neuronal cell death
* PrP amyloid plaques
91
general structure of prion
* 2 charged clusters
* octapeptide repeat protein
* hydrophobic domain
* glycosylations
* protein with GPI anchor
92
prion cleavage sites and when
* alpha - occurs normally
* beta and gamma - occurs during stress
93
sCJD has _ PrP plaques
little to none
94
kuru has _ Prp plaques
some/medium
95
vCJD has _ PrP amyloid plaques
a lot
96
list the types of CJD with little to alot plaques in order
sCJD, kuru, vCJD
97
prion strains affect/are different in
* shape of aggregates
* what brain regions they're in
* what disease they're involved in
98
prion strains affect/are different in
* shape of aggregates
* what brain regions they're in
* what disease they're involved in
99
sCJD has _ prion strains
no coexisting prion strains
100
sCJD has _ prion strains
coexisting prion strains
101
vCJD has _ prion strains
coexisting
102
statistics of prion diseases
* rare
* older incidence
* white people
103
entry sites of acquired prion diseases
* intracranial
* coreal
* airway
* ingestion
* intramuscular
* intravenous
104
the passage of prions from one species of the other is _
inefficient
105
species barrier
prion diseases dont pass easily between species, absolute or partial transmitssion
106
models for the confirmational conversion of PrPc into PrPsc
* template directed refolding
* seed nucleation
107
early change in PrP toxicity
removal of synapses
108
PrP overexpressing transgenic mice features
* neuronal loss
* PrP Sc deposits
* Gliosis
* Premature death
109
in Prion diseases, see _ in MRI DWI
cortical ribbons
110
PSWC in Prion diseases shows
??
| EEG
111
biomarkers in CSF in prion diseases
* 14-3-3
* Tau
112
CUrrent strategies of treatment of prion diseases
* Prnp knockdown (prion production)
* antibodies to prevent prion conversion
* antibodies to prevent prion aggregation
* compounds to interfere with neurotoxicity
113
the primary determinants of TSEs are
* primary sequence of PrPc
* route of entry of PrP Sc
114
_ are good noninvasive biomarkers of prion diseases
* cortical ribbons
* PSWC
115
which codon polymorphisms increase chance of prion infections
codon 129
116
familial CJD defined by
* CJD
* CJD in family member
* disease causing PRNP mutation
117
brain stroke is a condition that occurs when
there is not enough blood flow to the brain to meet metabolic demand
* leads to limited oxygen supply and death of brain tissue
118
_ strokes are more common
isochemic
119
ischemic strokes are due to
blockage of blood vessel
120
hemorrhagigc strokes are due to
bleeding around the brain
121
most common symtoms of stroke
all are sudden
* numbness of face arm or leg
* confusion
* trouble seeing
* dizziness
* severe headache
122
arteries bringing blood to the brain
* internal carotid artery
* vertebral artery
* the circle of willis
123
middle cerebral artery
* covers 80% of lateral surface of the brain
* common site of occlusion
124
anterior cerbral artery
* mostly supplies the midline of both cerebral hemispheres
125
posterior cerebral artery
* supplies the parietooccipital and temporal cortices
126
advantage of the circle of willis
* connects everything so if there is occulusion other branches can provide blood to the vital areas
127
the major arteries giving blood to the brain make up the
circle of willis
128
ischemic penumbra
outside part of affected region by stroke
* can recover after if treatment is fast enough
* will become core (dead) if not fast enough
129
in stroke, tissue outcome depends on
* severity of flow reduction
* duration of flow reduction
130
statistics of stroke
* very common cause of death
* aging is a risk factor
* leading cause of disability
131
CADASIL
* inherited form of cerbrovascular disease
* occurs when the thickening of blood vessel walls blocks the flow of blood to the brain
* genetic risk factor for stroke
132
CADASIL
* inherited form of cerbrovascular disease
* occurs when the thickening of blood vessel walls blocks the flow of blood to the brain
* genetic risk factor for stroke
133
imaging used to see stroke
FLAIR MRI
134
CADASIL mutation causes
* mutation in substrate for gamma secretase (NOTCH 3)
135
ischemic cascade in the core
1. ENergy failure (decrease in ATP)
2. decrease in Na/K ATPase
3. **anoxic deplarization** (constant APs)
4. increased glutamate release
5. excitotoxicity
136
penumbra ischemic cascade
stress increases glutamate release
* leads to excitotoxicity, apoptosis and necroptosis
137
temporal sequence of events in cerebral ischemia
1. excitotocity within minutes, falls at hours
2. release of GABA to inhibit glutamate during exocitocity
2. depolarization constant whole time
3. inflammation after hours
4. necroptosis and apoptosis increase as time goes on
138
mechanisms of ischemic cell death in the brain
* activation of cytokines, proteases
* cell swelling
* excitoxicity
* transmigration of immune cells
139
stages of excitotoxicity
* initiation: increase in glutamate
* amplification release of Ca and Ca up in cell
* expression: ROS, RNS, swelling, yeet cell
140
proinflammatory cytokines
* IL 1, 6, TNF
141
cell death and immune response in isochemic
* proinflammatory responses
* proinflammatory cytokines
* leukocyte infiltration
* tissue damage
142
resolution of inflammation and tissue repair
* clearing dead cells with "eat me" and "find me" signals
* releasing anti inflammatory cytokines (IL 10, TGF beta)
* brain repair (MMPs)
143
rt-PA (activase)
* clot buster
* drawback: need to administer within 3 hours and only worls for isochemic stroke
144
current strategies of stroke treatment target
* oxidative stress
* excitotoxicity
* apoptosis
* inflammation
* energy deficit
145
_ plays a key role in ischemic mechanisms
inflammation
146
cell death type in infarct core
necrosis
147
two broad groups of cerebrovascular disease
* ischemia
* hemorrhage
148
potential ways to harness the human microbiome
1. stool from two groups then analysis
2. put stool from patients in animal modes and behav anal
3. transfer healthy stool to patients and behav analy
4. control diet of patients
149
98% of the gut biome
* firmicutes
* bacteroidetes
150
estabilishment and maintainence of gut colony
* high variability in infancy
* higher diversity in species as we age
151
estabilishment and maintainence of gut colony
* high variability in infancy
* higher diversity in species as we age
152
the microbiota gut brain axis
bidirectional communication
* HPA axis
* bacteria release neurotransmitters and neuropeptides, microbial by products and metabolites, cytokines, bacterial debris
153
the microbiota gut brain axis
bidirectional communication
* HPA axis
* bacteria release neurotransmitters and neuropeptides, microbial by products and metabolites, cytokines, bacterial debris
154
microbiome and aging
* aging affects microbiomes and their products which effects intestinal properties
* which causes increased frailty, inflammaging, release of proinflammatory cytokines, increased blood pressure
155
microbiome and aging
* aging affects microbiomes and their products which effects intestinal properties
* which causes increased frailty, inflammaging, release of proinflammatory cytokines, increased blood pressure
156
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
157
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
158
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
159
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
160
centenarians have an
overall higher diversity in their microbiome, but not necessarily the same as the young microbiome
161
germ free mice never
develop mature microglia
| the microbiome affects microglial maturation and activation
162
microbiota secrete
ROS scavengers
* short chain fatty acids
* ferulic acid
163
microbial dysbiosis
leaky gut so increase in proinflammatory molecules which increases BBB ermeability which causes oxidative stress in CNS
164
_ shows lewy body pathology first in PD
dorsal motor nucleus of CN10
165
_ starts to show lewy body pathology in PD stage 3
substantia nigra
166
dual hit staging hypothesis
PD pathology originates from insults in the peripheral organs where alpha syn is seeded before translocating to the brain
167
patients with IBS show
an increased incidence of PD
| evidence for the dual hit staging hypothesis
168
evidence for dual hit staging hypothesis in animal models
* gut microbes promote alpha syn mediated motor deficits and brain pathology
* depletion of gut bacteria reduces microglia activation
* human gut microbiota from PD patients enhanced motor dysfunction in mice
169
limitations of microbiota research
* defing normal and healthy gut microbiota
* understand the effect of lifestyle
* define directionality between cause and effect
* understand the contribution of gene enviroment impacts
* understand the effect of lifestyle
170
gut microbiome
A collection of microorganisms, viruses, and fungi, their genes and genomes
171
There has been evidence for a role for the microbiome in which of the following disorders?
Parkinson's Disease
Alzheimer's Disease
Multiple Sclerosis
Amyotrophic Lateral Sclerosis
172
primary pathways by which the gut microbiome may modulate neurodegenerative diseases
* The immune system
* The vagus nerve
* Microbial metabolites in circulation
