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Applied Neuroanatomy > Parkinsons Disease > Flashcards

Parkinsons Disease Flashcards

1
Q

approx. how many PD patients in the UK?

A

120,000

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2
Q

What can PD be subdivided into?

A

young onset (5%), late onset, sporadic (95%) and familial

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3
Q

What are the typical PD symptoms?

A

muscle rigidity and stiffness
resting rhythmic tremor
bradykinesia
postural instability/abnormalities

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4
Q

What are the secondary PD symptoms?

A

depression, impotence, dizziness, drooling, dementia

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5
Q

What is the basal ganglia?

A

a collection of sub-cortical nuclei situated within each cerebral hemisphere and upper brain stem

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6
Q

What are the constituents of the BG?

A 
caudate
putamen
globus pallidus (internal and external)
STN
substantia nigra (pars compacta and reticulata)
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7
Q

What parts of the BG make up the striatum?

A

caudate and putamen

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8
Q

Where does the BG recieve inputs from ?

A

all cortical areas

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9
Q

Where does the BG project to?

A

the thalamus -> motor cortex

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10
Q

What is the major input to the striatum?

A

the cerebral cortex

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11
Q

Where is cortical information processed?

A

in the striatum -> BG out put nuclei (GP, SNpr)

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12
Q

What are the neuropathological hallmarks of PD?

A

loss of nigrostriatal DA neurons

formation of Lewy Bodies

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13
Q

What is lost in the nigrostriatum?

A

neuromelanin pigmented DA neurons in the pars compacta

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14
Q

Where are Lewy Bodies particularly found?

A

as intraneuronal cytoplasmic inclusions within the pars compacta

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15
Q

What are major constituents of Lewy Bodies?

A

a-synuclein

ubiquitin

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16
Q

How many nerve cells does the SNpc normally have?

A

400,000

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17
Q

When do PD symptoms onset from the SNpc?

A

when 80% of DA is lost in the putamen and 60% of SNpc neurons are lost

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18
Q

What does loss of the projection to the putamen cause?

A

loss of DA inhibition to the striatum - shaking and tremor at rest

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19
Q

What are the other neuronal losses in PD?

A
  • noradrenergic neurons in the locus coreulus
  • serotonergic neurons in the raphe nucleus
  • cholinergic neurons in the dorsal motor nucleus of vagus
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20
Q

What is the shape of a LB?

A

dense proteinacious core with a surrounding halo

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21
Q

What are LB composed of?

A

filaments of ubiquitin and neurofilament proteins

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22
Q

What are the sizes of filaments in the LB?

A

around 5-20nm

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23
Q

What is a key component of LB?

A

a-synuclein

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24
Q

What are the features of a-synuclein?

A

140aa protein
hydrophillic
natively unfolded

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25
Q

What is the structure of a-synuclein?

A

amphipathic region
a hydrophobic central region (non-amyloidogenic b-component)
acidic C-terminal region

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26
Q

Where are most mutations in a-synuclein found?

A

the amphipathic region

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27
Q

What gene is involved in a-synuclein mutations?

A

SNCA

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28
Q

Where is the SNCA gene mapped in PD?

A

4q21-q23

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29
Q

Which mutation was found to be a missense mutation?

A

A53T

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30
Q

What is found in a-synuclein in sporadic PD?

A

genetic variability in the promotor region of the gene - alters susceptibility to disease?

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31
Q

Where is a-synuclein normally expressed?

A

brain (mammalian) - particularly pre-synaptic nerve terminals

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32
Q

What do KO transgenic a-synuclein mice studies suggest about its function?

A
  • role in synaptic vesicle recycling as can bind acidic phospholipid vesicles
  • role in DA neurotransmission
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33
Q

What is found in mutant a-synuclein?

A

self-aggregates more readily than WT

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34
Q

How has mutant a-synuclein been shown to aggregate?

A

transgenic mice - have LB formation and neurodegeneration

mice over-expressing A53T develop LB, mitochondrial damage and apoptosis of neocortical brainstem and MNs

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35
Q

What occurs with a-synculein in vitro?

A

overexpression of mutant or WT leads to ROS production and enhanced cell death

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36
Q

How does a-synuclein form LB?

A

unfolded or mutant a-synuclein form b-sheet rich oligomers which give rise to more stable amyloid-like fibrils
fibrils aggregate and form LB

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37
Q

What are the features of Parkin ?

A

E3 ligase - tags proteins for degradation via lysine residues
465 aa protein
relatively common mutation in PD

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38
Q

What is the main feature of Parkin mutations?

A

usually loss of function and tend to impair E3 ligase acitvity

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39
Q

What does UCH-L1 stand for?

A

ubiquitin C-terminal hydrolase L1

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40
Q

What does UCH-L1 do?

A

hydrolysis of c-terminal ubiquityl esters -> recycling ubiquitin

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41
Q

What is the dominant mutation found in UCH-L1 in one family?

A

I93M

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42
Q

What is a protective polymorphism in UCH-L1?

A

S18Y

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43
Q

Where is DJ-1 localised and what does this suggest?

A

highly localised to mitochondria

suggests important modulator of mitochondrial function and a cellular monitor of oxidative stress

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44
Q

What have been found in DJ-1 mutations?

A

autosomal recessive with deletion or mis-sense mutations

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45
Q

What are the steps in the UPS?

A
  1. Ubiquitin monomers activated by E1 and transferred to Ub-conjugating E2 enzyme
  2. Added to proteins by E3
  3. form poly-ub chains by attaching at lysine residues
  4. poly-ub chains mark protein for degradation - small fragments
  5. Poly-ub chains recycled by UCH-L1 and other enzymes
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46
Q

What is the gene for LRRK2?

A

park 8

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47
Q

What is the common mutation in LRRK2?

A

G2019S - gain of function

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48
Q

What does LRRK2 do normally?

A

phosphorylates substrates i.e. MKK3/6 for activation of JNK and p38 MAPK

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49
Q

What is the additional substrate for mLRRK2?

A

moesin

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50
Q

What does moesin normally do?

A

regulates neurite outgrowth and cytoskeleton

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51
Q

What does mLRRK2 interact with in the hippocampus?

A

a/b-tubulin - parts of the cytoskeleton

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52
Q

what is the suggested role of LRRK2 mutations in PD?

A

interfering with cytoskeletal motility and vesicular trafficking events

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53
Q

What are the two main hypothesis in PD?

A

misfolding and aggregation of proteins -> death of SNpc DA neurons
mitochondrial dysfunction and consequent ROS lead to cell death

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54
Q

What is the evidence for misfolding and aggregation of proteins?

A

abnormal deposits of protein in the brain is a feature of multiple neurodegenerative disorders

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55
Q

What evidence is there for abnormal protein conformation in inherited PD?

A
  • pathogenic mutations directly inducing abnormal protein folding - a-synuclein
  • pathogenic mutations that interfere with processing of misfolded proteins - Parkin, UCH-L1
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56
Q

What evidence is there for abnormal protein conformation in sporadic PD?

A
  • direct protein damaging modifications ad indirect changes in processing of misfolded proteins have also been detected
  • oxidative stress thought to be a possible trigger
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57
Q

What is the evidence for mitochondrial dysfunction and oxidative stress in PD?

A
  • defects in oxidative phosphorylation suggested with MPTP block of complex I
  • complex I abnormalities identified in PD
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58
Q

What is the process which is inhibited in complex I abnormalities?

A
  • NADH binds to complex I and passes two electrons to FMN group
  • FMN is reduced to FMNH2
  • Electrons are passed to iron-sulphur proteins
  • Fe3+ -> Fe2+
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59
Q

What does inhibition of complex I cause?

A

increase in ROS production

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60
Q

What can be formed in complex I inhibition?

A

Hydroxy radicals or reaction with NO to form OONO-

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61
Q

How do hydroxy radicals cause damage?

A

damage by reacting with nucleic acids, proteins and lipids

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62
Q

What markers suggest increased ROS in PD?

A

decreased glutathione antioxidant

increased markers of oxidative damage

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63
Q

Why is it a suggestion of increased ROS -> neurodegeneration?

A

correlative - no data just yet

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64
Q

What happens to cause cell death in PD?

A

Programmed Cell Death

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65
Q

When in PCD crucial?

A

in normal development and as a homeostatic mechanism

66
Q

What is the evidence for PCD in PD?

A
  • increase in Bax-positive SNpc DA neurons
  • increased neuronal expression of Bax
  • presence of caspase-8, caspase-9 and Bcl-xL
67
Q

What are the Toxin based animal models of PD?

A

6-OH-Da
Paraquat
Rotenone
MPTP

68
Q

What are the gene based animal models of PD?

A

synuclein

parkin

69
Q

Why is 6-OH-DA induced toxicity efective?

A

selective for DA neurons - preferential uptake by DA transporter

70
Q

Where does 6OHDA accumulate in neurons and what is its effect?

A

in the cytosol -> ROS and inactivates various molecule by generating quinones

71
Q

What can be varied in 6OHDA model?

A

there are potentially different models depending on the location of injection into the brain

72
Q

What happens with 6OHDA injection into the medial forebrain bundle?

A

extensive DA depletion

73
Q

What happens with 6OHDA injection into the SNpc?

A

specific and more moderate DA depletion

74
Q

What occurs with 6OHDA injection into the caudate putamen?

A

specific DA depletion

75
Q

What form of rat are most appropriate for studying PD with 6OHDA model?

A

rats with partial lesions of the ventrolateral caudate for early and late PD

76
Q

What is the advantage of studying the 6oHDA model?

A

good for assessing anti-PD actions of new drugs as unilateral striatal lesions causes quantifaibly asymetric circling behaviour

77
Q

What are the disadvantages of the 6OHDA?

A
  • not clear if mechanisms of cell death is similar to PD
  • no LB and pathology differs to PD
  • pathology varies with injection site
78
Q

What does MPTP cause in humans and monkeys?

A

irreversible and severe PD syndrome characterised by tremor, rigidity, bradykinesia

79
Q

What similarities does MPTP have to PD?

A

low dose -> preferential degeneration of putamen vs caudate DA nerve terminals
regional pattern of damage is similar to PD?

80
Q

What are the difference of MPTP model to PD?

A

doesn’t affect other monoaminergic neurosn (i.e. locus coreleus)
no LBs

81
Q

What uses do MPTP models have?

A
  • monkey model - assess novel treatments of PD
    electrophys. showed hyperactivity of STN (key in PD) - lead to targeted DBS to reduce motor hyperactivity in patients
  • mouse model enhance understanding of possible neurodegeneration mechanisms
82
Q

What is the MPTP metabolism pathway?

A
  • crosses BBB where converted to MPDP+ and then into MPP+ by unknown mechanism
  • MPP+ released in to EC space and concentrated into DA neurons by DA transporter, DAT
83
Q

What does MPP+ do in neurons?

A
  • blocks complex I
  • reduces ATP
  • increases ROS
  • interacts with cytosolic enzymes TOXIC
  • sequesters into synaptic vesicles via VMAT - protective
84
Q

What is paraquat?

A

a herbicide that induces toxin model of PD similar in structure to MPP+ although does not easily cross BBB

85
Q

What is toxicity due to in paraquat model?

A

increased superoxide radicals - SNpc DA degeneration and a-synuclein inclusions

86
Q

What is the advantage of the paraquat model?

A

may be useful to study role of a-synuclein in neurodegeneration

87
Q

What is the disadvantage of the paraquat model?

A

not known if it is just DA neurons affected

88
Q

What is Rotenone?

A

cytotoxic compounds which are widely used as insecticides and fish poison

89
Q

What are the features of Rotenone?

A

highly lipophillic with access to most organs

binds to same site as MPP+ and inhibits complex I

90
Q

What is found in rotenone rats with IV?

A

selective DA degeneration and a-synuclein pos. inclusions

abnormal postures and slow movement

91
Q

What are the advantages of the rotenone model?

A

studying the relationship between aggregation formation and cell death

92
Q

What is the disadvantage of the rotenone model?

A

widespread neurotoxic actions which are not DA selective

93
Q

Why is it good to use genetic models of PD?

A

there is an expectation that the genetic and sporadic forms share similar pathogenic mechanisms - genetic models can focus on pathways

94
Q

What does the a-synuclein model severity depend on?

A

the region of promotor used to make the transgene

95
Q

What is found with overexpression of a-synuclein in mice?

A

causes neurochemical deficits in the nigrostriatal pathway, behavioural anomalies and a-synuclein accumulation
also accelerated age related loss of DA neurons

96
Q

What can be concluded from the a-synuclein mice?

A

that other factors probably contribute to the full human PD phenotype

97
Q

What have parkin models focussed on?

A

parkin KO as the PD mutations are loss of function

98
Q

What happens in quaking mouse mutant?

A

spontaneous deletion of parkin. myelin deficiency and enhanced DA metabolism. behavioural deficits and tremor in trunk and extremities

99
Q

What is the defect in the Parkin KO mouse?

A

defective exon 3

100
Q

What happens in parkin KO mouse?

A

progressive motor anomalies and deficits in sensori-motor integration
paradoxically have increased basal release of striatal DA and reduced striatal neuronal excitability
reduced levels of proteins in mitochondrial function
oxidative stress

101
Q

What is the disadvantage of the genetic models?

A

neither model has full spectrum of anomalies found in humans

102
Q

Where are highest levels of DA found?

A

corpus striatum (largest), limbic system and hypothalamus

103
Q

How is DA synthesised?

A

from tyrosine to dopa

decarboxylation to DA

104
Q

What metabolises DA?

A

MAO-B and COMT

105
Q

What are the products of DA metabolism?

A

Dopac

Homovanillate - HVA

106
Q

What are the two major classes of DA receptor?

A

D1

D2

107
Q

What are the subtypes and function of D1 class?

A

D1 and D5 - stimulate AC to produce cAMP

108
Q

What are the subtypes and function of D2 class?

A

D2,3,4 - inhibit AD activity

109
Q

Where are D1 class normally found?

A

brain and smooth muscle - mostly post-synaptic inhibition

110
Q

Where are D2 class normally found?

A

brain, CV system, presynaptic nerve terminals - pre/post synaptic inhibition

111
Q

How is DA release modulated?

A

D3 autoreceptors

112
Q

How is DA synthesis and metabolism modulated?

A

D2 autoreceptors

113
Q

What are the 3 main DA pathways in the brain?

A 
Nigrostriatal system (motor) - SN -> corpus striatum
Mesolimbocortical system - emotion and rewards
tuberohypophyseal system (endocrine control) - hypothalamus
114
Q

Which receptors are found on dynorphin neurons?

A

D1

115
Q

Where are dynorphin neurons?

A

in the striatum

116
Q

How does the SNc affect the dynorphin neurons?

A

stimulates the striatum -> direct pathway (voluntary movement)

117
Q

Which receptors are found on the enkephalin neurons?

A

D2

118
Q

Where are the enkephalin neurons found?

A

striatum

119
Q

What is the effect of the SNc on the enkephalin neurons?

A

inhibits the striatum -> indirect pathway (involuntary movement)

120
Q

What happens to the pathway in PD?

A

reduced inhibition of indirect pathway (tremor)

increased inhibition of direct pathway (bradykinesia)

121
Q

What are the current pharmacological therapy options in PD?

A
  • drugs that increase endogenous production
  • drugs that mimic DA action
  • drugs that prevent DA degradation endogenously (MAO-B Inhibitors) or exogenously (COMT-Is)
  • drugs that release DA
  • muscarinic cholinergic antagonists
122
Q

How does levodopa cross the brain?

A

as a precursor

123
Q

what is levodopa usually combined with and why?

A

a dopa decarboxylase inhibitor to reduce the dose needed and decrease side-effects

124
Q

what does the dopa decarboxylase inhibitor do in the periphery?

A

prevents levodopa conversion to DA but doesn’t cross the BBB so decarboxylation can occur rapidly

125
Q

What are the therapeutic features of levodopa?

A

well absorbed by small intestine via active transport

short plasma half life

126
Q

How do patients normally improve at the start of treatment?

A

80% improved motor function

20% motor function restored

127
Q

Why does levodopa effectiveness reduce?

A

natural progression of the disease
receptor downregulation
other compensatory mechanisms

128
Q

What are the slow-developing side-effects of levodopa?

A
  • dyskinesia (involuntary writing movements) in face and limbs (around 2 years of starting)
  • on-off effect - rapid fluctuations in clinical state - worsening then recovery ?due to plasma fluctuations
129
Q

What are the acute side-effects of levodopa?

A
  • nausea and anorexia
  • hypotension
  • pyschological i.e. hallucinations and delusions
130
Q

What is Selegine?

A

MAO-B inhibitor

131
Q

What does selegine do?

A

selective for MAO-B which predominates DA-containing neurons

132
Q

What is the advantage of selegine?

A

lacks unwanted peripheral side effects unlike unselective MAO-Is - can’t eat cheese because increase in tyrosine

133
Q

When choosing DA receptors agonists, why is it preferable to choose D2 selective than D1?

A

produces consistent anti-parkinsonism unlike D1 which may have broader effects

134
Q

Give an example of a D2 R agonist?

A

bromocryptine

long duration of action (t1/2 = 6-8 hours)

135
Q

Why may doses of DA-R agonists be limited?

A

similar side effects to levodopa

136
Q

How can ACh influence the brain stem?

A

SN-> DA-> ACh -> Brain stem

137
Q

Why is the ACh imbalance a problem?

A

lack of DA causes increase in ACh

138
Q

Give an example of an mAChR antagonist?

A

Benztropine

139
Q

What effects do mAChRs have?

A
  • excitatory on striatal neurons (opposite to DA)

- Presynaptic inhibition of DA terminals

140
Q

Why are mAChR antagonists limited in their use?

A

some bad side-effects : impaired vision and urinary retention, also dry mouth and constipation

141
Q

When are mAChR antagonists mainly used?

A

in parkinsonism caused by anti-psychotics

142
Q

Where are Adenosine A2A receptors found?

A

in the CNS, enriched in the striatum, high levels in D2R expressing GABAergic striatal pallidal neurons

143
Q

What does activation of the A2A Rs do?

A

opposes the effects of D2Rs - hence antagonists would be useful

144
Q

What are the issues with using A2AR antagonists?

A

have systemic and CNS side effects

145
Q

What are the systemic side effects of A2A R antagonists?

A

inflammation

ischemic tissue damage in heart, renal, liver

146
Q

What are the CNS side-effect of A2A R antagonists?

A

psychosis and insomnia

147
Q

What does the endocannabinoid system modulate?

A

GABAergic and glutamergic transmission in the BG

148
Q

What can be seen in PD patients re: CB?

A

decrease in CB1 Rs

149
Q

Where are CB2Rs expressed in brain?

A

expressed in BG - impairement linked to dyskinesia

150
Q

What was found in CSF of PD patients?

A

doubles AEA levels

151
Q

What do CB1agonists do?

A

reduce excitotoxicity - improve motor symptoms although results variable

152
Q

What does neural transplantation involve?

A

injection of dissociated fetal cells into the SNc

153
Q

What has been found in neural transplantation in humans?

A
  • success rate variable and benefits are usually short-lived
  • post-mortem studies show that transplants can survive and establish synaptic connections
  • can remain healthy and maintain function for 15-18 years
154
Q

For whom, is DBS an alternative for?

A

patients with intractable tremor and/or affected by complications of levodopa

155
Q

What is targeted in DBS treatment?

A

STN and GPi

156
Q

Which area is superior to target in DBS?

A

STN as it produces a more pronounced anti-kinetic effect

157
Q

Why is gene-therapy appropriate in PD?

A

has specific neuro-anatomical pathology

158
Q

Why is GAD an ideal target in gene therapy for PD?

A

the STN is disinhibited causing the tremor and bradykinesia however inhibiting it with GABA is a good idea
GAD helps synthesise GABA

159
Q

What has been found in the studies of GAD gene therapy so far?

A

no adverse affects in small studies

monkeys have small improvements in motor activity

160
Q

Why may GDNF be an ideal gene therapy for PD?

A

promotes DA neurons survival and regeneration in rodents and primates
variable success in humans

161
Q

What are the issues with gene therapy?

A
  • short term results meaning patients have to undergo therapy every few months
  • immune response may destroy viral vector
  • toxicity if viral vector mutates and becomes pathogenic

Applied Neuroanatomy (11 decks)

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