Neurodegeneration Flashcards
(103 cards)
1
Q
Describe the prevalence of Parkinson’s disease.
A
Age dependent (>65 years).
2
Q
Describe some of the symptoms of Parkinson’s disease.
A
Resting tremor, rigidity, bradykinesia, hypokinesia, akinesia, flexed posture, postural instability.
3
Q
What is thought to cause Parkinson’s disease?
A
It is thought to be multifactorial and heterogenous in aetiology but can be possibly caused by:
- Loss of dopaminergic neurones in the substantial nigra and noradrengeric neurones in the locus coeruleus.
- Lewy bodies develop in the neurones.
4
Q
What is the most common neurodegenerative movement disorder ?
A
Parkinson’s disease
5
Q
Describe the aetiology of Parkinson’s disease.
A
Thought to be multifactorial and heterogenous.
6
Q
For what people may Parkinson’s disease be incorrectly diagnosed?
A
People who have; essential tremor, multiple strokes, Alzheimer’s disease, drug induced conditions, post encephalitis, Parkinson’s plus syndrome.
7
Q
What are the risk factors for Parkinson’s disease?
A
- Increasing age
- 2 times more common in men than women.
- More common in caucasian’s
- 1.4x more common in families with relatives with PD (more common in siblings than in parents).
- Environmental factors (pesticides)
- Head trauma
- Infection
- Caffeine use
- Smoking
8
Q
Describe the resting tremor clinical feature of Parkinson’s disease.
A
This is the most common first symptom and is usually asymmetric and most evident in one hand with the arm at rest.
9
Q
Describe the Bradykinesia clinical feature of Parkinson’s disease.
A
- Difficulty with daily activities such as writing, shaving etc.
- Decreased blinking
- Slowed chewing and swallowing.
10
Q
Describe the depression clinical feature of Parkinson’s.
A
Mild to moderate in 50% of patients.
11
Q
Describe the rigidity clinical feature of Parkinson’s.
A
- Muscle tone increases in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stopped posture, anterioflexid head and flexed knees and elbows.
12
Q
Describe the cognitive impairment clinical feature of Parkinson’s.
A
Mild cognitive decline including impaired visual and spatial perception and attention.
Slowness in execution of motor tasks and impairment of concentration.
13
Q
Describe the how autonomic function is altered by Parkinson’s disease.
A
- Impotence
- Slower bowel motility
- Orthostatic hypotension
14
Q
Describe how cognition and mood is altered by Parkinson’s disease.
A
- Slow executive functions
- Depression
- Apathy
- Frustration
15
Q
What is apathy?
A
A lack of motivation and care about what is going on around you.
16
Q
Describe the olfactory deficiencies caused by Parkinson’s disease.
A
Senses of smell and taste are altered/ disturbed.
17
Q
Describe the postural instability caused by Parkinson’s disease.
A
Caused by loss of postural reflexes.
Leads to falls.
18
Q
Describe how Parkinson’s disease causes affects funtion of the autonomic nervous system.
A
- Impaired GI motility
- Bladder dysfunction
- Sialorrhea
- Excessive head and neck sweating
- Orthostatic hypotension
19
Q
What is Sialorrhea?
A
Poor facial and oral muscle control.
20
Q
What are lewy bodies and where are they found during Parkinson’s disease?
A
Eosinophillic, round intracytoplasmic inclusions.
There are a lot in the substantial nigra pars compacta but can also be found in the locus coeruleus, motor nucleus of the vagus nerve, the hypothalamus, the nucleus basalts of Meynert, the cerebral cortes, the olfactory bulb and the autonomic nervous system.
21
Q
What is the purpose of the Substantia nigra?
A
It is the main origin of the dopamingeric innervation of the striatum.
22
Q
What is the purpose of the Extrapyramidal system ?
A
Processes information coming from the cortex to the striatum, retuning it back to the cortex through the thalamus.
23
Q
What is the main function of the Striatum?
A
Regulation of posture and muscle tone.
24
Q
Outline the process of dopamine synthesis and how this leads to altered gene expression and excitability of cells.
A
- Tyrosine is converted to DOPA and then to Dopamine.
- Dopamine is stored in the vesicles where it can act on a range of receptors.
- D3 and D2 receptors on the nerve terminals that are secreting Dopamine trigger changes within the cell by an internal feedback loop.
- Dopaminergic producing cells have transporters that allow Dopamine to be retaken-up into vesicles for storage.
- When Dopamine hits the post synaptic neurone, it activates various receptors, triggering changes in the second messengers and ion channels.
- This alters gene expression and excitability of cells.
25
In Parkinson's disease, what causes inhibition of movement?
There is a reduction in the quantity of Dopamine produced by the substantial nigra. The net effect is that there is much less activation of the direct pathway and relatively more stimulation of the indirect pathway. The inhibition of movement is increased.
26
In terms of Hoehn and Yahr staging of Parkinson's disease, describe stage 0
No clinical signs evident
27
In terms of Hoehn and Yahr staging of Parkinson's disease, describe stage 1
Unilateral involvement
28
In terms of Hoehn and Yahr staging of Parkinson's disease, describe stage II
Bilateral involvement but no postural abnormalities.
29
In terms of Hoehn and Yahr staging of Parkinson's disease, describe stage III
Bilateral involvement with mild postural imbalance on examination or history of poor balance or falls; patient leads independent life.
30
In terms of Hoehn and Yahr staging of Parkinson's disease, describe stage IV
Bilateral involvement with postural instability; patient requires substantial help.
31
In terms of Hoehn and Yahr staging of Parkinson's disease, describe stage V
Severe, fully developed disease; patient restricted to bed or wheelchair.
32
When was the L-Dopa therapy for Parkinson's disease first used/discovered?
Late 1950s
33
How does L-Dopa work to treat Parkinson's disease?
It is a precursor of Dopamine that crosses the blood-brain barrier and could restore Dopamine levels and mortar functions in those treated with a Catecholamine depleting drug.
34
What are the problems with L-Dopa therapy for Parkinson's disease?
- It has a short half-life
| - Some L-Dopa will be converted to Dopamine before it reaches the brain.
35
What are the side effects of L-dopa therapy?
Nausea, vomiting, postural hypotension, hallucinations.
36
What is used to stop L-Dopa being converted to Dopamine before it reaches the brain?
L-dopa is always administered with an inhibitor of aromatic L-amino acid decarboxylase, so it doesn't get converted to dopamine before it crosses the blood brain barrier. (The inhibitor commonly used is Carbidopa, which doesn't cross the blood brain barrier).
37
What is L-Dopa degeneration and how is this helpful?
This is a secondary degeneration pathway using a COMT inhibition. L-Dopa metabolism is reduced and so L-Dopa half-life is increased. This reduced the dose of L-Dopa needed.
38
How do most treatments , other than L-dopa, generally work to treat Parkinson's ?
They mimic Dopamine
39
How do Oral Dopamine Agonists treat Parkinson's disease?
They act directly on Dopamine brain receptors.
| They may delay onset of dyskinesia.
40
What are the side effects of using oral dopamine agonists to treat Parkinson's ?
Nausea, vomiting, postural hypotension, hallucinations.
41
How do MAO-B inhibitors work to treat Parkinson's and how is this beneficial?
They reduce dopamine breakdown in the brain by inhibiting dopamine metabolism.
This may delay the need for L-Dopa.
42
How do Anticholingerics work to treat Parkinson's disease?
Restore the dopamine acetylcholine balance by antagonising acetylcholine activity.
43
What are the side effects of using anticholingerics to treat Parkinson's disease?
Dry mouth, constipation, sedation, neuropsychiatric.
44
What treatment can be specifically used to reduce dyskinesias in Parkinson's disease?
Amantadine
45
What are dyskinesias?
Muscle movements that people with Parkinson's can't control.
46
Describe the possible issues of L-Dopa treatment
- Efficacy of L-dopa wears off over time
- Delayed or no ON response
- Unpredictable ON-OFF phenomena
- Dyskinesia (affects nearly all patients after long term treatment with L-Dopa)
47
What are the possible non-drug treatments for Parkinson's disease?
Deep brain stimulation
| Ablative surgery
48
How does deep brain stimulation work to treat Parkinson's ?
Implantation of a wire into the Thalamus, globes pallid us or sub thalamic nucleus
High frequency stimulation can improve symptoms by creating a functional lesion.
49
How is ablative surgery used to treat Parkinson's disease?
| What are the issues with this treatment?
Creating a lesion on one or both sides of the brain. This addresses motor symptoms; particularly side effects of L-dopa such as dyskinesias.
This causes significant side effects and adverse events, particularly for bilateral surgery.
50
What are the different pathogenic cascades in Parkinson's disease?
- Protein aggregation
- Oxidative stress
- Mitochondrial impairment
51
What are the symptoms of Alzheimers disease?
- Memory Loss
- Synaptic Dysfunction
- Neurodegenration
52
What causes the synaptic dysfunction experienced in Alzheimers disease?
Decreased neurotransmitters
53
What causes the neurodegeneration experienced in Alzheimers disease?
- Cell death in memory regions of the brain
| - oxidative stress
54
Name the causes and pathology of Alzheimers.
- Appearance of neurofibrillary tangles.
| - Amyloid plaques
55
What is Alzheimers?
A progressive, irreversible disease that slowly destroys cognitive function.
56
Who does Alzheimers tend to affect?
The most common causes occur in the elderly but can occur in middle aged people (early-onset).
57
Describe the time frame of Alzheimers.
May take 10-20 years before symptoms become evident.
Death usually occurs within 3-10 years of being diagnosed, depending on the age of diagnosis.
58
Describe the 'Very Mild' stage of Alzheimers.
Occasional memory relapses, incidents go unnoticed by family and friends, taken as signs of getting old.
59
Describe the 'mild' stage of Alzheimers.
Memory lapses are more frequent, unable to concentrate, difficulty in remembering names of people or objects, misplacing personal items.
60
Describe the 'moderate' stage of Alzheimers.
Failure to recall recent events, unable to organise or plan events, individuals become withdrawn in certain situations.
61
Describe the 'moderately severe' stage of Alzheimers.
Difficulty in recalling address, date, season, performing mental arithmetic.
Usually remembers own name and those of close family members.
Difficulty choosing appropriate clothing.
62
Describe the 'severe' stage of Alzheimers.
May forget the name of spouse or carer, will remember their own name, may need help with dressing and personal hygiene, disruption of normal sleep/wake cycle,e, tendency to wander, may exhibit personal changes.
63
Describe the 'very severe' stage of Alzheimers
Speech lost, help needed for all aspects of daily life, doubly incontinent, unable to walk or sit down without support, muscles become rigid, swallowing impaired.
64
What is alpha secreatase?
A member of the a disintegrin and metalloprotease family of proteases.
65
What 'ADAM's' show a secretes activity?
10, 9, 17 and 19
66
What is beta-secratase?
A transmembrane aspartyl protease.
67
Where are the different forms of beta-secratase found?
BACE-1 expressed in CNS.
| BACE-2 expressed in periphery.
68
What is y-secratase?
An integral membrane complex comprised of 5 different proteins.
69
What is the purpose of the 'presenilin' protein in y-secratase?
An aspartyl protease, autocatalysis the generation of N- and C- terminal fragments.
70
What is the purpose of the 'Nicastrin' protein in y-secratase?
Involved in trafficking and stability of the assembled protein.
71
What is the purpose of the 'APH-1' protein in y-secratase?
Required for proteolytic activity
72
What is the purpose of the 'PEN-2' protein in y-secratase?
Stabilises complex after presenilin proteolysis.
73
What is the purpose of the 'CD147' protein in y-secratase?
A non-essential regulator. Absence increases activity.
74
Describe the genetics of early onset Alzheimers disease.
- Mutations on chromosome 1 and 1 lead to abnormal Presenilin's 2 and 1 respectively.
- Point mutations on chromosome 21 cluster around sites of secretes cleavage and lead to abnormal APP.
75
What causes Down's syndrome genetically?
Trisomy of chromosome 21.
76
What is a trisomy?
An extra copy of chromosomes present in the cell nuclei, causing developmental abnormalities
77
What amyloid protein is found the plaques in Alzheimer's brain?
Amyloid-beta
78
What Amyloid protein is deposited in type II diabetic pancreas ?
Amylin or islet amyloid polypeptide.
79
What Amyloid protein causes mad cow disease ?
Prion protein
80
In what form are amyloid proteins likely to be toxic ?
In their aggregated form.
81
What dye to amyloid proteins interact with?
Congo red dye
82
What % of Alzheimers patients have no known cause?
90%
83
Describe how atrophy levels alter in terms of Alzheimers.
Rates of cerebral atrophy are increased in Alzheimers and correlate with cognitive decline.
84
Describe how positron emission tomography is used to diagnose Alzheimers.
Uses radioactive materials to track specific aspects of brain function.
A radioisotope is then added to something the brain uses (glucose or water).
A neurotransmitter or precursor attaches to amyloid plaques.
85
Why is imaging important in terms of Alzheimers?
- Potential to detect preclinical stages meaning treatment will be more likely to slow or halt the disease.
- Identify an earlier time to intervene.
- Useful as a marker of change/ intervention of diseases.
86
Describe what Apo-E is and how is is used in terms of Alzheimers.
Apo-E is a risk factor for Alzheimers.
It is a gene found on chromosome 19 and is involved in transporting cholesterol, lipoproteins and fat soluble vitamins into the bloodstream via the lymph.
Those with the e4 form of Apo-E are at the highest risk of having Alzheimers disease.
87
Where is Apo-E synthesised?
In the astrocytes of the liver and microglia of the CNS.
88
What is the purpose of Apo-E in the CNS?
Involved in AB uptake and breakdown
89
Describe what cholingeric deficit is.
- Reduced choline acetyltransferase activity, acetylcholine release and choline uptake in neocortex.
- Reduced cholinergic neurones in basal forebrain (nucleus basalis of Meynert and medial septal nucleus).
- Reduced acetylcholinesterase levels but increased butyrylcholinesterase levels.
- Reduced muscarinic M2 and nicotinic receptors (primarily pre-synaptic). Post synaptic muscarinic M1 receptors remain largely unchanged.
90
What different therapies are used to treat cholingeric deficit?
- Donepezil – acetylcholinesterase inhibitor
- Galantamine – acetylcholinesterase inhibitor and nicotinic agonist
- Rivastigmine – acetylcholinesterase and butyrylcholinesterase inhibitor
- Memantine – NMDA receptor agonist
91
What type of disease is Creutzfeldt-Jakob disease?
A human prion disease
92
Describe the pathology of Creutzfeldt-Jakob disease.
Spongiform lesions
| Plaques
93
What are prion proteins?
A prion is a type of protein that can trigger normal proteins in the brain to fold abnormally.
94
When do prion diseases occur?
When normal prion proteins, found on the surface of many cells, become abnormal and clump in the brain, causing brain damage.
95
What form of the human prion protein leas to accumulation in deposits ?
PrP^(sc)
96
What is the cause of sporadic CJD?
The cause is unknown but the most common theory suggests that the normal prion protein in the brain undergoes a spontaneous change to an abnormal form, thereby resulting in disease.
97
What is the cause of Latrogenic CJD?
CJD which has been accidentally transmitted during the course of medical or surgical procedures.
98
What is the cause of familial CJD?
Caused by an inherited abnormal gene.
(The illness is usually known in the family history but occasionally genetic cases are seen in which no family history has been identified).
99
What causes new variant CJD?
Ingestion of infected meat converting normal prion protein into the pathogenic form.
100
What is fatal familial insomnia?
Autosomal disorder characterised by degeneration of the thalamus and progressive insomnia.
101
What sexes does fatal familial insomnia affect and who carries it?
Both sexes are affected and there are no carries.
102
What are the symptoms of fatal familial insomnia?
Vegetative state of sleep, inability to produce tears or feel pain, poor reflexes and dementia.
103
What is Kuru and what causes it?
"The laughing death" prion disease. This is caused by cannibalism - the disease is passed on by eating of infected brain tissue.
(Tribes ingested brain tissue from dead relatives for religious reasons).
