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Drugs and the Brain > Neurodegenerative Disorders > Flashcards

Neurodegenerative Disorders Flashcards

1
Q

At what age is Parkinsons disease most common and what is the rate between men and women having it

A

Parkinsons is most common in patients in their 80s or older and the rate in men is around 1.5x higher than in women

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2
Q

What are 7 factors that INCREASE the risk of developing PD

A

Male gender, Age, Hispanic heritage, Head trauma, Rural living, Genetics, Melanoma

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3
Q

What are 7 factors that DECREASE the risk of developing PD

A

Smoking, Caffeine use, High serum urate, Female gender, Physical activity, NSAID use, urban living

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4
Q

What changes can we see in the brain that provide evidence for PD

A

Clear loss of Dopaminergic neurons from a specific brain region, the substantia nigra pars compacta (SNpc).

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5
Q

What is the substantia nigra and what happens to it during PD

A

It is a black substance that appears in normal brains as a dark streak. In the brains of PD patients, the dark areas are lost. However, it may require loss of 50-70% of the SNpc dopaminergic neurons before the motor symptoms of PD become apparent.

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6
Q

What bodies begin to appear when PD patients brains change

A

Lewy bodies

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7
Q

What are Lewy bodies and what protein do they mainly consist of?

A

They are intracellular inclusions mostly consisting of protein a-synuclein.

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8
Q

Which protein is important in Proteasome and Mitochondrial function

A

Parkin

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9
Q

What happens if A-synuclein misfolds

A

It forms oligomers

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10
Q

How are ‘Proteasome’s not functioning’ linked to Parkinsons

A
  • Proteasome’s usually remove oligomers but if they are not functioning properly then you may get oligomers forming LEWY bodies.
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11
Q

How do Lewy bodies kill cells?

A

Lewy bodies kill cells via Neuroinflammation or mitochondrial dysfunction (cells wont have enough energy and will die)

PRKN, PINK1, PARK7 are all genes effected causing mitochondrial dysfunction

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12
Q

Is PD a homogenous disorder - why/why not? (3 reasons)

A

No - lots of ways to get it, lots of genes to make you high risk, and lots of environmental toxins that could lead to its development

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13
Q

What is MPTP

A

Its a uniquely selective toxin - its a prodrug

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14
Q

What are prodrugs

A

Prodrugs are medications that turn into an active form once they enter the body

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15
Q

Where is MPTP metabolised and what does it interfere with?

A

Metabolised in glial cells to MPP and then taken up by neurons where it interferes with mitochondrial electron transport.

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16
Q

What is MPTP used as

A

Its used in modern day to produce animal models of parkinsons

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17
Q

What animals are used for parkinsons models and why?

A

non human primates as rodents are immune to MPTP

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18
Q

What 4 features of PD define the disease?

A
  • Bradykinesia
  • Resting tremor
  • Rigidity
  • Postural instability
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19
Q

Whats Bradykinesia

A

Slowed movement - main defining feature of PD and is a major cause of disability.

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20
Q

What are examples of Bradykinesia (4)

A
  • Slowed walking
  • Reduced facial expressions
  • Decreased voice volume
  • Micrographia (reduction in writing size)
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21
Q

Whats the most visible sign of PD and what does it consist of?

A

Resting tremor - can consist of repetitive movements with their thumb and forefinger, mainly seen in the hands.

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22
Q

What is Rigidity and what are the 2 types?

A

Stiffness in mainly arms, legs, back and neck. 2 types: Lead pipe and cogwheel.

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23
Q

What is the difference between lead pipe rigidity and cogwheel rigidity?

A
  • Lead pipe is smooth resistance to movement
  • Cogwheel is resistance that momentarily gives way.
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24
Q

What is postural instability and how is treating it different from lots of other symptoms?

A
  • Its the loss of postural reflexes and having problems with balance.
  • Its different because its symptoms are not primarily due to loss of dopaminergic neurons in the substania nigra
  • So therapies that are based around this do very little for this symptom.
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25
Q

Why is postural instability particularly dangerous

A

It can lead to falling which is extremely dangerous even in healthy elderly people.

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26
Q

What are the main non-motor symptoms of PD (8 examples)

A
  • Depression
  • Apathy
  • Cognitive dysfunction (inc dementia)
  • Anxiety
  • Psychosis
  • Loss of sense of smell
  • Sleep disorders
  • Autonomic dysfunction
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27
Q

What Percentage of PD is idiopathic?

A

Around 85%

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28
Q

What Percentage of PD is familial?

A

Around 15%

This normally includes early onset

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29
Q

What is PINK1 and what does it do?

A
  • One of the 20 proteins involved in PD
  • Is PTEN induced putative kinase 1
  • Is important in mitochondrial function
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30
Q

What is PARK7 and what does it do?

A
  • Is one of the 20 proteins involved in PD
  • DJ-1 protein
  • Protects against oxidative stress
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31
Q

What is seeding?

A

Where oligomers cause other copies of the a-synuclein to misfold

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32
Q

What are 4 main structures the the Basal Ganglia consists of?

A
  • Striatum
  • Globus Pallidus
  • Substantia nigra
  • Sub-thalamic nucleus
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33
Q

What are the 4 major roles of the basal ganglia?

A
  • Motor
  • Learning
  • Mood/emotion
  • Links cerebral cortex back to the cerebral cortex through the thalamus
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34
Q

What is the classic motor loop?

A
  • Cerebral cortex
  • Cerebellum
  • through thalamus
  • Back to cerebral cortex
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35
Q

Which dopiminergic pathway is the primary focus of the basal ganglia?

A

Nigostriatal pathway

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36
Q

What are the two components of the dorsal striatum?

A
  • Putamen
  • Caudate nucleus
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37
Q

What is the globus palidus subdivided into?

A
  • Globus palidus externa
  • Globus palidus interna
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38
Q

What is the motor cortical-basal ganglia circuit?

A
  • Cortex
  • Striatum (putamen)
  • Globus palidus
  • Thalamus
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39
Q

What is the hyperdirect route of the basal ganglia?

A

Bypasses the striatum and the globus palidus externa

Goes straight to the STN (sub-thalamic nucleus) and then to the globus palidus interna- to the thalamus
(therefore it will be inhibitory)

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40
Q

What is the indirect pathway of the basal ganglia?

A
  • Excitatory input to striatum
  • Sends out inhibitory input to the globus palidus externa
  • Globus palidus externa sends a weak inhibitory input to the globus palidus interna and the STN
  • STN sends large excitatory signal to the globus palidus interna which then inhibits the thalamo-cortical drive
  • This inhibits movement
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41
Q

What is the direct pathway of the basal ganglia?

A
  • Excitatory output from the cortex to the striatum
  • Striatum sends an inhibitory signal to the globus palidus interna
  • Thr globus palidus interna synapses with an inhibitory interneuron and fires a weak inhibitory signal to the thalamus
  • This will excite the thalamo-cortical drive and therefore cause movement
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42
Q

What are the neurons in the striatum which first synapse with the cortex?

A

Medium spiny neurons (GABAergic)

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43
Q

What do the GABAergic neurons do?

A
  • The substantia nigra neurons are forming synapses with the necks of the dendritic spines
  • These have the potential to regulte the output from the cortex
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44
Q

What are the different populations of medium spiny neurons and what do they do?

A
  • Some have dopamine D1 and others D2 receptors
  • These have different influences on the dendritic dopamine substantia nigra spine
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45
Q

Which dopamine receptors are associated with the direct pathway?

A
  • Dopamine D1 receptors on medium spiny neurons
  • They are excitatory and facilitate the activation of neurons
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46
Q

Which dopamine receptors are associated with the indirect pathway?

A
  • Dopamine D2 receptors on medium spiny neurons
  • They are inhibitory, therefore if we inhibit this we will promote movement
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47
Q

How does less dopamine lead to less movement?

A
  • Dopamine promotes movement through the direct pathway
  • Therefore less dopamine means less promotion of movement
  • Dopamine also inhibits the indirect pathway
  • This means less activation of D2 receptors means the inhibition of movement will be strenghtened
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48
Q

What is the current hypothesis of how PD disrupts the cortical plan for movement?

A
  • There is no constant level of activity which is necessary for the basal ganglia to plan activity
  • Instead, there are bursts of high activity and periods of quiet
  • The change in pattern and frequency of activity may be what disrupts the cortical function as it is hard to interpret this activity
  • In turn disrupting the cortical plan
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49
Q

What is L-DOPA?

A
  • Substrate for DOPA decarboxylase
  • Can increase CNS dopamine levels
  • Metabolised in the periphery (side effects)
  • Can cross the blood brain barrier
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50
Q

What are 2 drugs used in conjunction with L-DOPA?

A
  • Carbidopa
  • Benserazide
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51
Q

Why are Carbidopa and benserazide used in co-combination therapies with L-DOPA?

A
  • 2 peripheral inhibitors of DOPA decarboxylase
  • Cannot cross the BBB
  • They reduce the side-effects of L-DOPA and increase CNS levels of L-DOPA
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52
Q

How is L-DOPA degraded in the periphery?

A
  • Can be catalysed by COMT
  • Catalysed by DOPA decarboxylase
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53
Q

Why do we want to prevent the amount of COMT degredation of L-DOPA?

A

COMT converts L-DOPA into 3-O-methyldopa not dopamine (unuseful in the treatment of PD)

Ca use a COMPT inhibitor

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54
Q

How is dopamine degraded in the CNS?

A
  • COMT
  • Monoamine oxidase A and B
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55
Q

How do we preserve dopamine in the CNS?

A
  • Block COMT using inhibitor: Tolcapone
  • Block monoamine oxidase using inhibitor: selegiline, rasagiline
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56
Q

What are some unwanted effects of L-DOPA treatment?

A
  • Dyskinesia (upregulation of RASGRP1 protein)
  • Rapid changes in clinical status (wearing off- hypokinesia followed by dyskinesia)
  • Nausea
  • Postural hypotension
  • Psychiatric effects (schizophrenia like, confusion, insomnia and nightmares in 20% of patients)
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57
Q

What is a benefit of dopamine agonists?

A
  • Don’t rely on DA neurons
  • So don’t have the L-DOPA on-off effect
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58
Q

Why are dopamine agonists use limited?

A
  • Due to side effects
  • Compulsive behaviour
  • Peripheral DA effects (cardiovascular)
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59
Q

What are Bromocriptine, pergolideand apomorphine?

A
  • Less selective dopamine agonists
  • Use limited by side effects (nausea/vomiting, lung fibrosis)
  • Can be co-administered with doperidone (cannot cross BBB)
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60
Q

What are Pramipexole and ropinirole?

A
  • Dopamine agonsits
  • more active at D2 and D3 receptors
61
Q

What are Benztropine and procyclidine?

A
  • Dopamine release enhancers/mAChR antagonists
  • Non-selective so diffilcult to manage side-effects
  • They regulate basal ganglia at multiple points
62
Q

What are recent studies swapping benztropine and procyclidine for?

A

M4 selective drugs

63
Q

What is amantadine?

A
  • Mechanisms not fully understood
  • Likely a non-competative inhibitor of NMDA receptor
  • Increases the release of dopamine but cannot be used alone (good add on therapy)
64
Q

What are the three possible states for L-DOPA treatment that a patient can be in (wearing off effect)?

A
  • On state (good therapeutic effect)
  • Off state (not enough effect to get out of bradykinesia)
  • Peak state (patient is at risk of dyskinesia)
65
Q

How can we manage the wearing off effect?

A
  • Administer L-DOPA in extended release, intestinal gel pump
  • Use adjunct medications like entacapone (stabalise L-DOPA levels)
  • Make the most of on periods
66
Q

What did a clinical study of L-DOPA effectiveness over time show?

A
  • Huge improvement on condition for 3 years
  • After 3 years, the patients condition is worse than when began treatment
  • Because more neurons are dying, so the baseline is changeing
67
Q

What is deep brain stimulation as a treatment for PD?

A
  • Implant electrodes into STN (or GPi)
  • Stimulation modifies abnormal firing patterns but mechanism not fully understood
  • Can produce dramatic improvements in function
68
Q

What are the risks of deep brain stimulation for PD?

A
  • Motor problems
  • Cognitive dysfunction
  • Mood
  • Behavioural abnormalities

(also does not improve non-dopamine problems)

69
Q

What are the NICE guidlines for the treatment of PD?

A
  • If motor symptoms not probelmatic: MAOi, L-DOPA (+DDCi), DA agonist
  • If motor symptoms are problematic: L-DOPA + DDCi
  • If not controlled by prior: Add MAOi, COMTi, DA agonist
  • If not controlled again: Consider amantadine
  • If still not controlled: Consider DBS
70
Q

What does DDCi stand for?

A

DOPA decarboxylase inhibitor

71
Q

What causes Huntington’s disease?

A

Dysfunction of the basal ganglia

72
Q

What is the main symptom of huntington’s?

A

Chorea- seems to be the opposite of PD (jerking movements)

73
Q

What are similarities between Huntongton’s and PD in the end stages?

A
  • Paucity of movement
  • L-DOPA is sometimes used to treat hypokinesia
74
Q

What do brain examinations of HD patients reveal?

A

Enlarged ventricles

Shrinkage of the cerebral cortex

Atrophy of the basal ganglia

75
Q

What gene is linked to Huntington’s disease?

A

Mutant Huntingin mHTT

76
Q

What causes cell death in HD?

A
  • mHTT is broken down differently resulting in fragments which contain extra glutamine repeats
  • These have the propensity to misfold
  • These molecules can aggregate to form inclusion bodies
77
Q

What do HD inclusions do?

A
  • Are not apparently toxic themselves
  • Represent an attempt by the cell to detoxift mHTT
  • The presence however, does cause mitochondrial dysfunction and neuroinflammation
78
Q

What percentage of HD sufferers experience juvinile HD?

A

10% (before 21)

79
Q

What causes juvenile HD?

A

Large number of CAG repeats in huntingtin (>50)

80
Q

How to juvenile HD sufferers symptoms differ?

A
  • Do not have the writhing movements
  • Instead have immobility symptoms very early
81
Q

How rare is Huntingon’s disease?

A

5-10 per 100,000

82
Q

What type of condition is Huntington’s?

A

Inherited (autosomal dominant) neurodegenerative disorder

83
Q

When do HD symtpoms normally start?

A

Usually middle life- AFTER children are born

84
Q

What are the cognitive symptoms associated with HD?

A

Dementia

85
Q

What are the motor symtoms associated with HD?

A
  • Involuntary writhing movements (chorea)
  • Later stages: immobility
86
Q

What are the psychiatric conditions associated with HD?

A
  • Depression, anxiety
  • Aggression, compulsive behaviour
87
Q

After how many years does one die from HD?

A

15-20 years after onset

88
Q

How many people with HD die from suicide?

A

30%

89
Q

What type of malfunction happens within the huntingtin protein?

A

Trinucleotide repeat disorder of CAG- the more repeats, the more severe the disease and the earlier the onset

90
Q

If a person has <27 CAG repeats what is their phenotype and risk for children?

A
  • Normal phenotype
  • No risk for children
91
Q

If a person has 27-35 CAG repeats what is their phenotype and risk for children?

A
  • Normal phenotype
  • Elevated risk for children
92
Q

If a person has 36-39 CAG repeats what is their phenotype and risk for children?

A
  • Possible HD with late onset and slow progression
  • 50% risk for children
93
Q

If a person has 40+ CAG repeats what is their phenotype and risk for children?

A
  • HD
  • 50% risk for children
94
Q

Outline Huntingtin

A
  • Ubiquitous
  • Function unclear
  • Mutant huntingtin seems to be toxic to cells
  • Whole brain is affected but basal ganglia is more sensitive
  • Indirect pathway medium spiny neurons
95
Q

What does the loss of inhibitory neuronsin the indirect pathway (HD) cause?

A
  • Inhibits movement normally
  • Therefore, we get excessive drive from the thalamus to the cortex
  • Leading to hyperkinesia and additional movement drive
96
Q

What is the best drug treatment for HD?

A
  • Tetrabenazine
  • Inhibitory of vesicular monoamine uptake (VMAT)
  • Decreases dopamine levels
97
Q

How are Chlorprozamine, haloperidol, olanzapine, risperidone and quetiapine used to treat HD?

A
  • Competative antagonists for the dopamine D2 receptor
  • Usually used as antipsychotics
98
Q

Whos silver stain method was used to visualise amyloid plaques and neurofibrillary tangles in Alzheimer’s?

A

Max Bielschowsky

99
Q

When do cases of Alzheimer’s normally arise?

A

In people’s 70s

100
Q

What are 4 symptoms of Alzheimer’s disease?

A
  • Loss of declarative memory (facts etc)
  • Loss of cognitive functions (reasoning, language, calculation etc)
  • Psychosis with hallucinations and delusions
  • Final stage sufferers can be mute, incontinent and bed-ridden
101
Q

What is the prevalence of Alzheimer’s at different ages?

A
  • 65-74: 1.6%
  • 75-84: 19%
  • 84+: 42%
102
Q

How many sufferers of Alzheimer’s were there in 2006 worldwide?

A

26.6 million

103
Q

What is the estimate of sufferers of Alzheimer’s by 2050?

A

> 100 million

104
Q

What is the annual care cost in the US for AD per year?

A

$236 billion

105
Q

What is the mean life expectancy of AD sufferers?

A

7 years (70% from AD)

106
Q

What are beta amyloid plaques?

A

Extracellular protein aggregates

107
Q

What are neurofibrillary tangles?

A

Intracellular aggregates of TAU

108
Q

What are the 13 risk factors for Alzheimer’s?

A
  • Age
  • Genetics
  • Down’s Syndrome
  • Obesity
  • Diabetes
  • Smoking
  • High alcohol intake
  • Sedentary lifestyle
  • Ethnicity
  • Female gender
  • Poor cardiovascular health
  • Head trauma
  • Poor sleep patterns
109
Q

What are 6 protective factors for AD?

A
  • Physical excercise
  • Cognitive activity
  • Social engagement
  • Mediterranean diet
  • Male gender
  • NSAID use
110
Q

What are two subsets of Alzheimer’s?

A

Early and Late onset

111
Q

What percentage of alzheimers cases are early onset?

A

10%

112
Q

What percentage of early onset alzheimer’s cases have a family history?

A

60%

113
Q

What is Amyloid precursor protein?

A

The precursor protein for amyloid beta, which is the protein responsible for forming amyloid plaques

114
Q

What are the two forms of amyloid beta found in alzheimers?

A
  • AB40
  • AB42 (more toxic)
115
Q

What does the presence of amyloid beta mutations cause?

A

Alters the breakdown of amyloid precursor protein so that the formation of the more toxic AB42 is favoured

116
Q

What is presenilin?

A

1 and 2- form part of the protease (gamma-secretase) that cleaves amyloid precursor protein to yield amyoid beta

117
Q

What to presenilin mutation cause?

A

Favour the formation of AB42

118
Q

What percentage of AD cases are late onset?

A

> 90%

119
Q

Are sporadic or familial cases of late onset AD more frequent?

A

Sporadic

120
Q

What gene is particulary important in AD?

A

APOE gene

121
Q

What does the APOE gene code for?

A
  • Apolipoprotein E
  • This is one of the adress markers found in LDL and other lipoprotein complexes
122
Q

What are the 3 different alleles for APOE and what do they mean?

A
  • Epsilon 2, 3, 4
  • The epsilon allele 4 is particularly bad news- it is associated with higher risk of a range of disorders
123
Q

What disorders is APOE allelee psilon 4 associated with?

A
  • Atherosclerosis
  • Alzheimer’s
  • Poor outcomes after a traumatic brain injury
  • Poorer outcome in COVID-19 infection
124
Q

What is the frequency of allele epsilon 4 in the normal population and those with AD?

A
  • Normal is 14%
  • Alzheimer’s is 40%
125
Q

For heterozygotes of APOE epsilon 4 what is the risk for developing AD?

A

15-20 fold higher

126
Q

What causes Down’s syndrome?

A

Trisomy of chromosome 21

127
Q

What do people with down syndrome also develop?

A

Almost always develop early onset AD by the age of 40

128
Q

Why are those with Down’s syndrome more likely to develop AD?

A
  • The gene for amyloid precurser protein is located on chromosome 21
  • People with Down’s syndrome therefore have an extra copy of the gene and are likely to produce higher amounts of amyloid beta protein
129
Q

Why are cholinesterase inhibitors used as an AAD treatment?

A
  • Loss of cholinergic neurons from the basal forebrain is marked, and early
  • Therefore increase the ACh availability
130
Q

What are 4 drugs for AD using AChEi means?

A
  • Tacrine
  • Donepezil
  • Rivastigmine
  • Galantamine
131
Q

What drug is used for AD when AChEi is not tolerated?

A

Memantine

132
Q

What antipsychotics are licenced for AD?

A
  • Risperidone
  • haloperidol
  • Short term and low dosage
133
Q

Outline how the microtubule disintegrates in AD

A
  • Tau becomes hyperphosphorylated and self-aggreagtes
  • It dissociates from the microtubules causing the tangles
  • The microtubule then becomes unstable and disintegrates
134
Q

What can activate the amyloid precursor protein?

A

3 proteases called secretases: alpha, beta and gamma

135
Q

What happens when amyloid precursor protein is cleaved by alpha and gamma secretase?

A

It becomes non-amyloidogenic

136
Q

What happens when amyloid precursor is cleaved by beta and gamma?

A

Leads to soluble extracellular and intracellular components as well as the amyloid beta component which comes as AB40 and 42

Amyloidogenic

137
Q

How can we target Tau therapeutically?

A
  • Initial studies on aggregation, kinases were a failure
  • Immunotherapies vs tau may hold promise
138
Q

How can Diabetes medication aid AD progression?

A
  • Insulin resistance (Type 2 diabetes) may compromise brain’s repair functions
  • GLP-1 agonist liraglutide works in animal models, now in clinical trials
139
Q

How can we target neuroinflammation to treat AD?

A
  • Epidemiological stuides: NSAID use
  • Clinical trials: more harm than good, little effect
140
Q

What is a proteopathy?

A

Where a protein has an abnormal structure, which misfolds and accumutales

141
Q

What are 5 examples of proteopathies?

A
  • Alzheimer’s (amyloid-beta, tau)
  • Parkinson’s (alpha-synuclein)
  • huntington’s (huntingtin)
  • ALS (Superoxide dismutase)
  • Creuzfeld-Jakob Disease (prion protein)
142
Q

What is a prion disease?

A
  • infectious agent is a protein (prion protein; PrP)
  • It folds abnormally and can induce other folded copies of the prion protein to take on the aberrant folding pattern
  • Because the misfolded protein has more beta-sheet structure, it has a greater tendency to stick together
  • The misfolded protein therefore forms aggregates in neurons leading to cell death
143
Q

What is mad cow disease?

A
  • bovine spongifrom ecephalopathy (BSE)
  • Is a neurodegenerative disease of cattle
  • Is classified as a prion disease
144
Q

How is mad cow disease thought to have arisen?

A

Feeding cattle with products derived from sheep or other cattle

It is possible that the original source of contamination was the sheep infected with another prion disease called scrapie

145
Q

What is BSE in humans called?

A

CJD

146
Q

What is the symptoms of CJD?

A
  • Psychiatric problems
  • Rapid progression into movement disorders and dementia
147
Q

What is the mean survival time after diagnosis of CJD?

A

1 year

148
Q

How is CJD transmited?

A
  • Organ tissue donation
  • Surgical equipment contamination
  • Cannabilism
149
Q

What disease was developed from the Fore people of Papau New Guinea?

A
  • Kuru- laughing sickness
  • Consumed the brains of the dead

Drugs and the Brain (9 decks)

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