Neurodegenerative Disorders Flashcards
(149 cards)
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
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
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
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).
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.
6
Q
What bodies begin to appear when PD patients brains change
A
Lewy bodies
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.
8
Q
Which protein is important in Proteasome and Mitochondrial function
A
Parkin
9
Q
What happens if A-synuclein misfolds
A
It forms oligomers
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.
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
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
13
Q
What is MPTP
A
Its a uniquely selective toxin - its a prodrug
14
Q
What are prodrugs
A
Prodrugs are medications that turn into an active form once they enter the body
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.
16
Q
What is MPTP used as
A
Its used in modern day to produce animal models of parkinsons
17
Q
What animals are used for parkinsons models and why?
A
non human primates as rodents are immune to MPTP
18
Q
What 4 features of PD define the disease?
A
- Bradykinesia
- Resting tremor
- Rigidity
- Postural instability
19
Q
Whats Bradykinesia
A
Slowed movement - main defining feature of PD and is a major cause of disability.
20
Q
What are examples of Bradykinesia (4)
A
- Slowed walking
- Reduced facial expressions
- Decreased voice volume
- Micrographia (reduction in writing size)
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.
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.
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.
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.
25
Why is postural instability particularly dangerous
It can lead to falling which is extremely dangerous even in healthy elderly people.
26
What are the main non-motor symptoms of PD (8 examples)
- Depression
- Apathy
- Cognitive dysfunction (inc dementia)
- Anxiety
- Psychosis
- Loss of sense of smell
- Sleep disorders
- Autonomic dysfunction
27
What Percentage of PD is idiopathic?
Around 85%
28
What Percentage of PD is familial?
Around 15%
This normally includes early onset
29
What is PINK1 and what does it do?
- One of the 20 proteins involved in PD
- Is PTEN induced putative kinase 1
- Is important in mitochondrial function
30
What is PARK7 and what does it do?
- Is one of the 20 proteins involved in PD
- DJ-1 protein
- Protects against oxidative stress
31
What is seeding?
Where oligomers cause other copies of the a-synuclein to misfold
32
What are 4 main structures the the Basal Ganglia consists of?
- Striatum
- Globus Pallidus
- Substantia nigra
- Sub-thalamic nucleus
33
What are the 4 major roles of the basal ganglia?
- Motor
- Learning
- Mood/emotion
- Links cerebral cortex back to the cerebral cortex through the thalamus
34
What is the classic motor loop?
- Cerebral cortex
- Cerebellum
- through thalamus
- Back to cerebral cortex
35
Which dopiminergic pathway is the primary focus of the basal ganglia?
Nigostriatal pathway
36
What are the two components of the dorsal striatum?
- Putamen
- Caudate nucleus
37
What is the globus palidus subdivided into?
- Globus palidus externa
- Globus palidus interna
38
What is the motor cortical-basal ganglia circuit?
- Cortex
- Striatum (putamen)
- Globus palidus
- Thalamus
39
What is the hyperdirect route of the basal ganglia?
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)
40
What is the indirect pathway of the basal ganglia?
- 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
41
What is the direct pathway of the basal ganglia?
- 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
42
What are the neurons in the striatum which first synapse with the cortex?
Medium spiny neurons (GABAergic)
43
What do the GABAergic neurons do?
- 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
44
What are the different populations of medium spiny neurons and what do they do?
- Some have dopamine D1 and others D2 receptors
- These have different influences on the dendritic dopamine substantia nigra spine
45
Which dopamine receptors are associated with the direct pathway?
- Dopamine D1 receptors on medium spiny neurons
- They are excitatory and facilitate the activation of neurons
46
Which dopamine receptors are associated with the indirect pathway?
- Dopamine D2 receptors on medium spiny neurons
- They are inhibitory, therefore if we inhibit this we will promote movement
47
How does less dopamine lead to less movement?
- 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
48
What is the current hypothesis of how PD disrupts the cortical plan for movement?
- 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
49
What is L-DOPA?
- Substrate for DOPA decarboxylase
- Can increase CNS dopamine levels
- Metabolised in the periphery (side effects)
- Can cross the blood brain barrier
50
What are 2 drugs used in conjunction with L-DOPA?
- Carbidopa
- Benserazide
51
Why are Carbidopa and benserazide used in co-combination therapies with L-DOPA?
- 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
52
How is L-DOPA degraded in the periphery?
- Can be catalysed by COMT
- Catalysed by DOPA decarboxylase
53
Why do we want to prevent the amount of COMT degredation of L-DOPA?
COMT converts L-DOPA into 3-O-methyldopa not dopamine (unuseful in the treatment of PD)
Ca use a COMPT inhibitor
54
How is dopamine degraded in the CNS?
- COMT
- Monoamine oxidase A and B
55
How do we preserve dopamine in the CNS?
- Block COMT using inhibitor: Tolcapone
- Block monoamine oxidase using inhibitor: selegiline, rasagiline
56
What are some unwanted effects of L-DOPA treatment?
- 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)
57
What is a benefit of dopamine agonists?
- Don't rely on DA neurons
- So don't have the L-DOPA on-off effect
58
Why are dopamine agonists use limited?
- Due to side effects
- Compulsive behaviour
- Peripheral DA effects (cardiovascular)
59
What are Bromocriptine, pergolideand apomorphine?
- Less selective dopamine agonists
- Use limited by side effects (nausea/vomiting, lung fibrosis)
- Can be co-administered with doperidone (cannot cross BBB)
60
What are Pramipexole and ropinirole?
- Dopamine agonsits
- more active at D2 and D3 receptors
61
What are Benztropine and procyclidine?
- Dopamine release enhancers/mAChR antagonists
- Non-selective so diffilcult to manage side-effects
- They regulate basal ganglia at multiple points
62
What are recent studies swapping benztropine and procyclidine for?
M4 selective drugs
63
What is amantadine?
- 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
What are the three possible states for L-DOPA treatment that a patient can be in (wearing off effect)?
- On state (good therapeutic effect)
- Off state (not enough effect to get out of bradykinesia)
- Peak state (patient is at risk of dyskinesia)
65
How can we manage the wearing off effect?
- 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
What did a clinical study of L-DOPA effectiveness over time show?
- 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
What is deep brain stimulation as a treatment for PD?
- Implant electrodes into STN (or GPi)
- Stimulation modifies abnormal firing patterns but mechanism not fully understood
- Can produce dramatic improvements in function
68
What are the risks of deep brain stimulation for PD?
- Motor problems
- Cognitive dysfunction
- Mood
- Behavioural abnormalities
(also does not improve non-dopamine problems)
69
What are the NICE guidlines for the treatment of PD?
- 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
What does DDCi stand for?
DOPA decarboxylase inhibitor
71
What causes Huntington's disease?
Dysfunction of the basal ganglia
72
What is the main symptom of huntington's?
Chorea- seems to be the opposite of PD (jerking movements)
73
What are similarities between Huntongton's and PD in the end stages?
- Paucity of movement
- L-DOPA is sometimes used to treat hypokinesia
74
What do brain examinations of HD patients reveal?
Enlarged ventricles
Shrinkage of the cerebral cortex
Atrophy of the basal ganglia
75
What gene is linked to Huntington's disease?
Mutant Huntingin mHTT
76
What causes cell death in HD?
- 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
What do HD inclusions do?
- Are not apparently toxic themselves
- Represent an attempt by the cell to detoxift mHTT
- The presence however, does cause mitochondrial dysfunction and neuroinflammation
78
What percentage of HD sufferers experience juvinile HD?
10% (before 21)
79
What causes juvenile HD?
Large number of CAG repeats in huntingtin (>50)
80
How to juvenile HD sufferers symptoms differ?
- Do not have the writhing movements
- Instead have immobility symptoms very early
81
How rare is Huntingon's disease?
5-10 per 100,000
82
What type of condition is Huntington's?
Inherited (autosomal dominant) neurodegenerative disorder
83
When do HD symtpoms normally start?
Usually middle life- AFTER children are born
84
What are the cognitive symptoms associated with HD?
Dementia
85
What are the motor symtoms associated with HD?
- Involuntary writhing movements (chorea)
- Later stages: immobility
86
What are the psychiatric conditions associated with HD?
- Depression, anxiety
- Aggression, compulsive behaviour
87
After how many years does one die from HD?
15-20 years after onset
88
How many people with HD die from suicide?
30%
89
What type of malfunction happens within the huntingtin protein?
Trinucleotide repeat disorder of CAG- the more repeats, the more severe the disease and the earlier the onset
90
If a person has <27 CAG repeats what is their phenotype and risk for children?
- Normal phenotype
- No risk for children
91
If a person has 27-35 CAG repeats what is their phenotype and risk for children?
- Normal phenotype
- Elevated risk for children
92
If a person has 36-39 CAG repeats what is their phenotype and risk for children?
- Possible HD with late onset and slow progression
- 50% risk for children
93
If a person has 40+ CAG repeats what is their phenotype and risk for children?
- HD
- 50% risk for children
94
Outline Huntingtin
- 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
What does the loss of inhibitory neuronsin the indirect pathway (HD) cause?
- Inhibits movement normally
- Therefore, we get excessive drive from the thalamus to the cortex
- Leading to hyperkinesia and additional movement drive
96
What is the best drug treatment for HD?
- Tetrabenazine
- Inhibitory of vesicular monoamine uptake (VMAT)
- Decreases dopamine levels
97
How are Chlorprozamine, haloperidol, olanzapine, risperidone and quetiapine used to treat HD?
- Competative antagonists for the dopamine D2 receptor
- Usually used as antipsychotics
98
Whos silver stain method was used to visualise amyloid plaques and neurofibrillary tangles in Alzheimer's?
Max Bielschowsky
99
When do cases of Alzheimer's normally arise?
In people's 70s
100
What are 4 symptoms of Alzheimer's disease?
- 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
What is the prevalence of Alzheimer's at different ages?
- 65-74: 1.6%
- 75-84: 19%
- 84+: 42%
102
How many sufferers of Alzheimer's were there in 2006 worldwide?
26.6 million
103
What is the estimate of sufferers of Alzheimer's by 2050?
>100 million
104
What is the annual care cost in the US for AD per year?
$236 billion
105
What is the mean life expectancy of AD sufferers?
7 years (70% from AD)
106
What are beta amyloid plaques?
Extracellular protein aggregates
107
What are neurofibrillary tangles?
Intracellular aggregates of TAU
108
What are the 13 risk factors for Alzheimer's?
- 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
What are 6 protective factors for AD?
- Physical excercise
- Cognitive activity
- Social engagement
- Mediterranean diet
- Male gender
- NSAID use
110
What are two subsets of Alzheimer's?
Early and Late onset
111
What percentage of alzheimers cases are early onset?
10%
112
What percentage of early onset alzheimer's cases have a family history?
60%
113
What is Amyloid precursor protein?
The precursor protein for amyloid beta, which is the protein responsible for forming amyloid plaques
114
What are the two forms of amyloid beta found in alzheimers?
- AB40
- AB42 (more toxic)
115
What does the presence of amyloid beta mutations cause?
Alters the breakdown of amyloid precursor protein so that the formation of the more toxic AB42 is favoured
116
What is presenilin?
1 and 2- form part of the protease (gamma-secretase) that cleaves amyloid precursor protein to yield amyoid beta
117
What to presenilin mutation cause?
Favour the formation of AB42
118
What percentage of AD cases are late onset?
>90%
119
Are sporadic or familial cases of late onset AD more frequent?
Sporadic
120
What gene is particulary important in AD?
APOE gene
121
What does the APOE gene code for?
- Apolipoprotein E
- This is one of the adress markers found in LDL and other lipoprotein complexes
122
What are the 3 different alleles for APOE and what do they mean?
- Epsilon 2, 3, 4
- The epsilon allele 4 is particularly bad news- it is associated with higher risk of a range of disorders
123
What disorders is APOE allelee psilon 4 associated with?
- Atherosclerosis
- Alzheimer's
- Poor outcomes after a traumatic brain injury
- Poorer outcome in COVID-19 infection
124
What is the frequency of allele epsilon 4 in the normal population and those with AD?
- Normal is 14%
- Alzheimer's is 40%
125
For heterozygotes of APOE epsilon 4 what is the risk for developing AD?
15-20 fold higher
126
What causes Down's syndrome?
Trisomy of chromosome 21
127
What do people with down syndrome also develop?
Almost always develop early onset AD by the age of 40
128
Why are those with Down's syndrome more likely to develop AD?
- 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
Why are cholinesterase inhibitors used as an AAD treatment?
- Loss of cholinergic neurons from the basal forebrain is marked, and early
- Therefore increase the ACh availability
130
What are 4 drugs for AD using AChEi means?
- Tacrine
- Donepezil
- Rivastigmine
- Galantamine
131
What drug is used for AD when AChEi is not tolerated?
Memantine
132
What antipsychotics are licenced for AD?
- Risperidone
- haloperidol
- Short term and low dosage
133
Outline how the microtubule disintegrates in AD
- Tau becomes hyperphosphorylated and self-aggreagtes
- It dissociates from the microtubules causing the tangles
- The microtubule then becomes unstable and disintegrates
134
What can activate the amyloid precursor protein?
3 proteases called secretases: alpha, beta and gamma
135
What happens when amyloid precursor protein is cleaved by alpha and gamma secretase?
It becomes non-amyloidogenic
136
What happens when amyloid precursor is cleaved by beta and gamma?
Leads to soluble extracellular and intracellular components as well as the amyloid beta component which comes as AB40 and 42
Amyloidogenic
137
How can we target Tau therapeutically?
- Initial studies on aggregation, kinases were a failure
- Immunotherapies vs tau may hold promise
138
How can Diabetes medication aid AD progression?
- Insulin resistance (Type 2 diabetes) may compromise brain's repair functions
- GLP-1 agonist liraglutide works in animal models, now in clinical trials
139
How can we target neuroinflammation to treat AD?
- Epidemiological stuides: NSAID use
- Clinical trials: more harm than good, little effect
140
What is a proteopathy?
Where a protein has an abnormal structure, which misfolds and accumutales
141
What are 5 examples of proteopathies?
- Alzheimer's (amyloid-beta, tau)
- Parkinson's (alpha-synuclein)
- huntington's (huntingtin)
- ALS (Superoxide dismutase)
- Creuzfeld-Jakob Disease (prion protein)
142
What is a prion disease?
- 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
What is mad cow disease?
- bovine spongifrom ecephalopathy (BSE)
- Is a neurodegenerative disease of cattle
- Is classified as a prion disease
144
How is mad cow disease thought to have arisen?
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
What is BSE in humans called?
CJD
146
What is the symptoms of CJD?
- Psychiatric problems
- Rapid progression into movement disorders and dementia
147
What is the mean survival time after diagnosis of CJD?
1 year
148
How is CJD transmited?
- Organ tissue donation
- Surgical equipment contamination
- Cannabilism
149
What disease was developed from the Fore people of Papau New Guinea?
- Kuru- laughing sickness
- Consumed the brains of the dead
