7- Neurodegenerative Diseases Flashcards
How is dementia defined?
A loss of cognitive functioning interfering with someone’s daily life and activities
What is the global prevalence of dementia?
About 46 million people in 2015
What is the expected trend of dementia?
To increase as the population ages
5 types of dementia
- Alzheimer’s Disease- most common
- Vascular dementia
- Posterior cortical atrophy
- Lewy body dementia
- Frontotemporal dementia
How many cases of dementia are Alzheimer’s Disease?
50-70%
What is the Alzheimer’s prevalence at 55 years?
0.5%
How does the risk of Alzheimer’s change as one ages?
Doubles every 5 years
How many new cases of Alzheimer’s each year?
About 7.7 million
How often is someone diagnosed globally with Alzheimer’s?
Every 4 seconds
What type of Alzheimer’s show a clear inheritance pattern?
Early-onset familial Alzheimer’s
How many studies have identified specific genes responsible for Alzheimer’s?
A minority
What is Alzheimer’s preceded by?
Mild Cognitive Impairment phase
Where are initial Alzheimer’s symptoms?
In the memory domain, but progress to other domains
What disturbances are observed in later stages of Alzheimer’s?
Mood and behavioural disturbances
How long can mild to severe Alzheimer’s progression take?
Up to 10 years
7 symptoms of mild Alzheimer’s
- Forgetfulness
- Word finding difficulty
- Apathy
- Poor attention
- Complex task difficulty
- Depression
- Work trouble
8 symptoms of moderate Alzheimer’s
- Disorientation
- Increased memory loss
- Confusion
- Insomnia
- Wandering
- Speech difficulty
- Restlessness
- Difficulty with everyday activities
7 symptoms in severe Alzheimer’s
- Agnosia
- Apraxia
- Aggression
- Agitation
- Incontinence
- Poor basic everyday activities
- Gait disturbance
What is the main drug therapy for Alzheimer’s and what is the aim?
Cholinesterase inhibitors, aim to increase acetylcholine in the brain
When were cholinesterase inhibitors discovered?
25 years ago
What functions is acetylcholine’s role established in?
Learning and memory
What happens to acetylcholine at the synapse?
It is broken down by acetylcholinesterase
How do acetylcholinesterase inhibitors (AChEIs) increase acetylcholine?
By blocking the enzyme
What does the cholinergic hypothesis suggest is the cause of Alzheimer’s?
Loss of cholinergic neurons
What did post-mortem studies in the mid-1970s find?
Reduced levels of the enzyme responsible for acetylcholine synthesis in the cortex
How do acetylcholinesterase inhibitors help compensate for cholinergic neurons?
By boosting Ach
How many cases do AChEIs offer symptomatic improvement in?
About 50%
How long are cognition improvements sustained for after treatment with AChEIs?
For about 2 years
2 limitations of AChEIs treatment
- Not ‘disease modifying’
- Modest and temporary symptom improvement only- doesn’t slow course of the disease
Why is the cholinergic hypothesis no longer favoured for treatment?
Treatment has limited effects
What might cholinergic system failure also be due to?
Accumulation of other pathology
Is Ach the only neurotransmitter affected by Alzheimer’s?
No, nor is it the only neurodegenerative disorder that shows cholinergic dyfunction
What 2 things occur in the brains of Alzheimer’s patients?
Amyloid-beta plaques and neurofibrillary tangles
What is brain shrinkage like in Alzheimer’s brain?
It begins in hippocampal formation and spreads, is consistent with symptoms
What is amyloid beta?
A fragment of larger protein called APP found in healthy neurons
What leads to higher levels of amyloid beta in Alzheimer’s?
Abnormal cleavage of APP
How are plaques created?
Amyloid beta 42 aggregates into ‘clumps’
What do plaques trigger?
An inflammatory response
What does the inflammatory response triggered by plaques lead to?
Synaptic dysfunction and neuronal death
How can the progression of amyloid plaques be detected in Alzheimer’s?
PET brain imaging can detect plaques
How do plaques follow a characteristic pattern?
As Alzheimer’s progresses
Where do amyloid plaques begin?
In hippocampal regions
How do amyloid plaques spread in Alzheimer’s?
Spreads to temporal lobe to frontal to eventually affecting the entire cortex
How is tau protein different to amyloid?
Seems to build up after amyloid
What is the amyloid cascade hypothesis?
Believes that amyloid beta is the initiating event in Alzheimer’s, which then triggers symptoms and other pathology
When are amyloid plaques detectable in Alzheimer’s?
Very early in the disease process
What has been the dominant theory of AD pathogenesis since the 90s?
Amyloid cascade hypothesis
What type of AD implicates genes involved in production of the precursor of beta-amyloid protein?
Familial AD
What is the problem with the amyloid cascade hypothesis?
Amyloid load doesn’t link well with AD symptom severity
What evidence shows that amyloid may not be predictive of AD?
30% of cognitively normal controls show elevated amyloid
What does high amyloid increase risk of?
Later cognitive decline
What does high amyloid predict?
Conversion from Mild Cognitive Impairment to AD
What are the 2 strategies of anti-amyloid drugs?
- Block/inhibit overproduction or aggregation of AB- inhibit enzymes which break down APP into AB
- Clearance of AB from brain
What does blocking overproduction of AB increase risk of?
Skin cancer and infections- significant negative effects on function and cognition
How do anti-amyloid drugs promote AB clearance from the brain?
Antibodies that bind to the AB peptide and speed up clearance
What do anti-amyloid drugs show evidence for but what not for?
Evidence for enhanced clearance, no effect on symptom progression
3 disadvantages of anti-amyloid drugs
Limited effects on symptoms
High costs
Risk of side-effects
What type of protein is tau protein?
An intracellular protein
What does tau protein do?
Stabilises microtubules that transport nutrients and molecules from the cell body to the axon and dendrites
How are neurofibrillary tangles formed?
By abnormal chemical changes that cause tau to become ‘hyperphosphorylated’ and clump together
What is the effect of neurofibrillary tangles?
Impair microtubule function
What is the second most common cause of dementia?
Vascular dementia
What happens in vascular dementia?
Loss of cognitive functioning due to a series of small ‘silent’ strokes
What is the main symptom of vascular dementia?
Progressive cognitive impairment after each stroke
5 risk factors of vascular dementia
Age
Hypertension
Smoking
High cholesterol
Diabetes
Why is early detection of vascular dementia essential?
Treatment involves reducing the risk factors
Why can diagnosis of vascular dementia be difficult?
Since features overlap with other dementias
What is PCA?
An atypical variant of Alzheimer’s
How is PCA characterised in the brain?
Focal, affecting posterior parietal cortex
5 symptoms of PCA
- Blurred vision, light sensitivity
- Progressive inability to recognise faces and objects
- Problems with spatial skills such as dressing and driving
- Impaired reading and writing
- Memory, spoken language and reasoning better preserved until later stages
