Alzheimers Flashcards
Neurodegeneration
‘Progressive damage or death of neurons leading to a gradual deterioration of the bodily functions controlled by the affected part of the nervous system.’
Acute neurodegeneration
Stroke
Chronic neurodegeneration
Alzheimers, parkinsons etc.
Natural degeneration
ageing
Dementia
An ‘umbrella’ term for a particular group of symptoms
Characteristic symptoms of dementia = memory, language, problem-solving, other cognitive abilities
Dementia has many causes
Alzheimer’s disease = most common cause of dementia
Prevalence
- 50 million worldwide
- 1 million UK
- 1 in 14 people aged over 65
- At current rate – over 1.5 million people in the UK by 2040
Non-modifiable risk factors
- Age
- Most important risk factor
- Ageing DOES NOT = Alzheimer’s disease
- 65-74 yrs – 3%; 75-84 yrs – 17%; over 85 – 32% of population
Biological sex
* x2 as many women over 65 with AD versus men
* Why? Women live longer than men? Links with loss of the hormone oestrogen post-menopause?
Genetics
Family history
Modifiable risk factors
- Cardiovascular disease risk factors – smoking, diabetes, obesity, hypertension, high cholesterol
Relationship between cardiovascular system and brain function
* Brain – consumes 20% of the blood’s oxygen and energy supplies
* Brain function – reliant on healthy heart and blood vessels
* Impaired blood flow = increases risk of dementia/AD
* Fatty plaques – cholesterol, salt, age, lack of exercise
Preventative factors/recommendations?
- Physical activity
- Healthy diet
- Social and cognitive engagement
○ Data support a relationship
Biological explanation?
Early stages symptoms
Changes in brain function aren’t sufficient to = symptoms
Compensatory mechanisms activated?
Some changes in brain function (e.g. beta-amyloid levels) may occur up to 20 years before symptoms
Early signs
- Normal ageing?
- ‘Blunting of emotional responses’
- Social withdrawal
- Memory Impairment
- Progressive memory loss (initially episodic and declarative)
- Impairment in function
- Memory, insight, judgement, language
- Changes in personality
Apathy, indifference, depression
Early Stage AD
Temporary memory lapses
Forgetting words/names
Difficulty performing complex tasks (e.g. at work)
Misplacing valuable objects
Difficulties with planning/organising
Middle-Stage AD
Forgetful of events/personal history
Confuse words
Unable to recall personal information
Frustration/anger
Confusion – surroundings/time
Sleep disturbances
Bladder/bowel problems
Personality/behavioural changes – delusions, paranoia, repetitive (stereotyped) behaviours.
Late Stage AD
Lose awareness – surroundings, time
Difficulties in communicating
Changes in physical abilities – walking, swallowing
Vulnerable to infections (especially pneumonia)
Presentation of symptoms dependent on;
- Stage of disease
- Age of individual
- Sex of individual
- Other underlying conditions/medication
- Patient vs carer reporting
- Access (real or perceived) to diagnosis
Advanced stages presentation of symptoms
- Gross disorientation in time and place
- Total dependence on carer for ‘everyday’ tasks
- Inability to comprehend/communicate
- Little awareness of past or future
- Little movement – difficulty in swallowing – infections (e.g. sepsis, pneumonia)
AD causes
- There is (most probably) not a single cause of Alzheimer’s disease.
○ Most likely develops from multiple factors - genetics, lifestyle and environment.
Majority of cases (99%) of Alzheimer’s disease are NOT hereditary
- What causes brain dysfunction associated with Alzheimer’s?
- The accumulation of the protein fragment beta‐amyloid (called beta‐amyloid plaques) outside neurons
- and the accumulation of an abnormal form of the protein tau (called tau tangles) inside neurons are the most prominent brain changes associated with Alzheimer’s.
Early onset AD
- Caused by gene mutations on chromosomes;
Chromosome Gene
1 Presenelin 1 (PS-1)
14 Presenelin 2 (PS-2)
21 Amyloid precursor protein (APP)
These genes possess the characteristic of Autosomal dominant inheritance
* If one of these mutated genes is inherited from a parent – person will almost always develop early onset AD
- Late onset AD
- Genetic risk factors involved
- e.g. Apolipoprotein E (apoE)
○ gylcoprotein, transports cholesterol in blood, plays a role in cellular repair
○ E4 = one allele of ApoE
Presence of E4 = increases risk of developing AD (does not cause AD)
- e.g. Apolipoprotein E (apoE)
- ApoE and b-amyloid
Normally – b-amyloid is soluble
* BUT… becomes insoluble when ApoE4 attaches to it
* Therefore, more likely to be deposited in plaques
* Presence of ApoE4
Increases deposits of b-amyloid and formation of plaques
Pathology
- Brain atrophy
- Cellular level features
- Senile plaques
- Neurofibrillary tangles
- Synaptic loss
- Selective depletion of neurotransmitter systems (e.g. Ach)
Brain atrophy
Severe degeneration of the hippocampus, cerebral cortex and ventricular enlargement
Cellular level features
Normal = is usually short form amyloid beta
AD = increase of long form amyloid beta which are less soluble > lead to accumulation of plaques
Normal = tau binds to and stabilizes microtubules
AD = tau detaches and sticks to other tau molecules, disrupts cell’s transport system
Synaptic loss
- Extensive
- Depletion of selective neurotransmitter systems
- Acetylcholine (Ach)
- Glutamate
- Serotonin
- Noradrenaline
Cholinergic hypothesis of AD
- Cholinergic neurones
- Learning, memory, certain aspects of sleep states
- Antagonists (e.g. scopolamine)
○ Deleterious effect on learning and memory
- Alzheimer’s Disease
- Degeneration of Ach producing neurones in forebrain
- Deficit in Ach producing enzyme (affecting learning and memory)
Treatment - existing and developing treatment
- Psychological
- For example: external memory aids, visual imagery, reality orientation
- Pharmacological
- Cholinesterase inhibitors
- Glutamate receptor antagonists
Psychological (non-pharmacological) approaches treatments
Does not stop Alzheimers development but does increase individual’s quality of life
- Memory Aids
- diaries, journals, lists,
- Cognitive Behavioural Therapy (CBT)
- aimed at reducing depression/anxiety (rather than specifically AD)
- Music Therapy
- to help engage and express feelings
- Structured social interaction
- Allows a carer to maintain an activity/contact with a patient for 10-15 mins/day
- Stimulated presence therapy
- Using reminders of events from their personal life
- Helps reduce agitation and restlessness
Caregiving
- Attending to another person’s health needs and well-being
- Assisting with activities of daily living
- Emotional and practical support
- Managing medications/health service interactions
- Informal/unpaid
- 2/3 = women
- 1/3 = over 65 yrs
- Caregiver wellbeing and burden
Reduce carer burden/stress and improve quality of lif
Pharmacological approaches
- Cholinergic drugs
- Nearly every drug currently licensed for AD = cholinesterase inhibitor (ChEI)
- Boosts activity at cholinergic synapses
- Examples include Aricept, donezepil, rivastigmine, galantamine
- Licensed (in UK) for mild to moderate AD, transiently improves clinical symptoms for 6-12 months
- Glutamate receptor antagonists
- E.g. Memantine
- NMDA receptor antagonist
- Protects brain cells from toxic effects of excessive levels of glutamate
- Licensed (in UK) for treatment of moderate-to-severe AD
- Shown to temporarily slow the progression of symptoms
- Helps behavioural symptoms such as aggression and agitation
- Treatment approaches in development
- Strategies to reduce b-amyloid accumulation
○ Anti-inflammatory agents
○ Enzyme inhibitors (decrease production of b-amyloid)- Strategies to reduce tau aggregation
○ Anti-inflammatory agents - Improving cardiovascular health
- Strategies to reduce tau aggregation
Biomarkers
- A naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified
- Found in blood, other body fluids, organs and tissues
Can track healthy functioning, diagnosis disease, monitor response to treatment, identify health risks (e.g. high cholesterol/high blood pressure for cardiac disease
Biomarkers specific to AD
- CSF levels/changes of B-amyloid and/or tau
- Blood tests of brain-derived products
- Brain imaging studies
○ MRI/CT – structural changes in brain (*need age comparison)
○ Amyloid or Tau PET scans – to examine accumulation of amyloid/tau
○ Fluorodeoxyglucose PET scans – to examine energy i.e. glucose, use in brain
