Alzheimer's Disease Flashcards
What is dementia?
Chronic/ persistent disorder of the mental processes caused by brain disease or injury and marked by memory disorders, personality changes and impaired reasoning.
What is used to identify if someone has Dementia?
and how does it work/ identify dementia?
Diagnostic and statistical manual of mental disorders (5th ed).
DSM-5 replaces the word “dementia” with “major cognitive disorder”
It states that symptoms include a decline in memory and a decline in AT LEAST one of the following:
1) Ability to generate coherent speech and/or understand spoken or written language
2) Ability to execute or carry out motor activities
3) Ability to recognise or identify objects, persons, sounds, shapes or smells
4) Ability to think abstractly, make sound judgements and plain and execute complex tasks
Alzheimer’s Association still use the term dementia.
Decline in cognitive ability must be severe enough to interfere with daily life.
What are the most common types of dementia?
- Alzheimers Disease- 62%
- Vascular dementia (multi infarct dementia)
- Dementia with Lewy bodies
- Frontotemporal dementia (inc. Pick’s disease)
- Mixed dementia
- Parkinsons disease dementia
- Creutzfeldt-Jakob disease
- Normal pressure hydrocephalus
- Korsakoff’s syndrome
- Other dementias
State the symptoms of Alzheimers
- Memory loss, important dates, repeated questioning
- Challenges in planning or problem solving
- Difficulty completing familiar tasks, games, locations
- Confusion with time or space (what day is it?)
- Difficulty understanding visual images
- Problems with words spoken/written
- Misplacing things/retracing steps
- Decreased or poor judgment
- Withdrawal from activities
- Changes in mood/personality
State what normal aging is like
- Sometimes forgetting names or appointments
- Making occasional errors
- Occasionally needing help with settings (TV etc)
- Getting confused which day of week but figuring it out
- Vision changes related to cataracts
- Sometimes having trouble finding the right word
- Misplacing things from time to time/retracing them
- Bad decision once in a while
- Feeling weary of work/family/socializing
- Becoming irritable when routine disrupted
Provide key facts about Alzheimers Disease
The Good
* Identified over 100 years ago by Alois Alzheimer and Oskar Fischer
* Research intensified over the last 30 years
* Great amount of knowledge about Alzheimer’s disease gained
The Bad
* Physiological changes that trigger Alzheimer’s disease are unknown
* Rare, inherited forms of disease caused by known genetic
mutations
* No treatment currently exists to slow or stop Alzheimer’s disease
The Ugly
* If you live long enough you will most likely develop Alzheimer’s
disease
* Alzheimer’s disease is fatal
* No strategy in place to deal with dementia
Define prevalence, incidence and life time risk.
- Prevalence: The number of existing cases of a disease in a population at a given time
- Incidence: The number of new cases of a disease in a given time period (1 year)
- Lifetime risk: The probability that someone of a given age develops a condition during their remaining life span. For 65 year old 1 in 5 for women, 1 in 10 for men.
How many people are estimated to be living with dementia in the UK?
850,000
how many people born in the UK this year will develop dementia in their lifetime
1 in 3
Alzheimers is the leading cause of death (Sept 2020)
11.2% in England
11.1% in Wales
Population-Attributable Fraction (PAF).
List potentially modifiable fraction.
Percentage reduction in new cases over a given, if a given risk factor was completely eliminated.
- Education attainment
- Midlife hypertension
- Midlife obesity
- Hearing Loss
- Diabetes
- Physical inactivity
- Depression
- Social isolation
- Smoking
After adjustment for association between risk factors
PAR falls to 35%
Clinical diagnosis of Alzheimers Disease.
National Institute of Neurological and Communicative Disorders/ Stroke & Alzheimer’s Disease and related Disorders Association (NINCDS/ADRDA).
Clinical criteria is used to identify patients that are likely to have developed AD
Sensitivity ~80% (ability to detect patients that have AD)
Specificity ~70% (differentiates between people with/without AD)
Criteria detects short term memory loss, difficulties with daily living & changes in personality
- Historical information from family/friends (timing & severity of symptoms, e.g. gradual onset suggests AD, sudden onset suggests vascular dementia)
- Physical examination (head injury, circulatory problems, stroke)
- Mental state examination
Name the 5 different cognitive assessments
- Mini-mental state examination (Folstein et al., 1975 J. Psych. Res.)
- Blessed Scale (Blessed et al., 1968 Brit. J. Psych.)
- ADAS-cog (Alzheimer’s disease assessment scale – cognitive)
- ADAS-noncog Alzheimer’s disease assessment scale –
(neuropsychomotor) - ADL (activities of daily living)
How is AD diagnosed?
If memory is impaired and two or more deficits in the following tests:
1) Cognitive function- questions e.g. what is todays date? where are we? 7 x table. spell ‘world’ backwards etc.
2) Global measures- measures memory, orientation, judgement, problem solving, community affairs, home and hobbies, personal care
3) Psycopathology- measures depression, behavioural disturbances, anxiety, irritability, comprised of observations from both clinician and informant
4) Functional ability- measures basic activities of daily living (e.g. feeding, eating, toilet) and more complex living activities (shopping, travelling, finances)
Name the different types of Physical and Neurological Assessment that can be done for AD patients?
- MRI (Magnetic Resonance Imaging)
- PET (Positron Emission Tomography)
Check slides 14 and onwards for images
What can an MRI show in patients with AD?
MRI provides detailed high resolution images (1mm)
Gross anatomical changes in ventricles/ sulci can be seen on brain scans.
All occur but not useful, as occur with many different causes of dementia, so no differential diagnostic info obtained. Can rule out tumours and stroke as cause of cognitive decline.
Check slides 14 for images
What can a PET show in patients with AD?
Functional neuroimaging detects metabolically active cells/ brain regions and cerebral blood flow (when the patient has been injected with 18^F-FDG or inhaled 15^O2)
Unfortunately medium resolution images (4mm) involve the use of radioisotopes. They can also be expensive and time consuming- therefore they’re mainly used for research.
Can distinguish AD from FTS; AD shows inactivity in the rear brain. Whereas with FTD the frontal part of the brain is inactive.
Newer agents may be developed (e.g. 18^F-florbetapir) that specifically bind to plaques.
Check slides 15 for images
State the diagnostic & guidelines for AD
Based on clinical judgement about the cause of a patients symptoms
Based on reports from the patient, family and friends
Results of cognitive testing and neurological assessment
Distinguished 3 stages of Alzheimer’s disease
1. Mild/ early stage
2. Moderate/ mid stage
3. Severe/ late stage
Describes Mild/ Early Stage Alzheimer’s
Memory loss is the first sign of AD however:
1. They appear healthy, have trouble making sense of surroundings
2. Commonly mistaken for normal ageing
3. Underlying pathology can occur up to 20 years before symptoms
Describes Moderate/ Mid Stage Alzheimer’s
AD spreads through the brain. The cerebral cortex begins to shrink due to death of neurons
Mild AD signs can include memory loss, confusion, trouble handling money, poor judgement, mood changes and increased anxiety
Moderate AD signs can include increased memory loss and confusion, problems recognising people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements
Describes Late/ Severe Stage Alzheimer’s
Extreme shrinkage occurs in the brain.
Patients become completely depended on others for care
Hospices/ Palliative care may be needed.
Symptoms include:
weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control
Cause of death usually: aspiration, pneumonia or other infections
What is the new diagnostic criteria and guidelines for Alzheimer’s Disease and what does it propose?
- 2011 National Institute on Ageing (NIS) recommend new diagnostic criteria
and guidelines for Alzheimer’s disease - New guidelines update, refine and broaden guidelines published in 1984
- Incorporate scientific advances in the last 3 decades
Three stages of Alzheimer’s Disease proposed
1. Preclinical Alzheimer’s disease
Measureable changes in biomarkers
2. Mild cognitive impairment (MCI) due to Alzheimer’s disease
Mild but measurable changes in thinking ability, but not enough to
impact on daily life
3. Dementia due to Alzheimer’s disease
Encompasses all stages of AD as previously described
Gross Anatomy- what is the difference between a normal and alzheimers brain?
- cerebral atrophy predominantly in the temporal and frontal lobes
- narrowed gyri
- widened sulci
- cortical atropy leads to compensatory dilation of ventricles
Name the 3 main researchers who looked into Alzheimers?
- Dr Alois Alzheimer
- Dr Auguste Deter
- Dr Oskar Fischer
What are Bielschowsky Stains used for?
- Beta-Amyloid Plaques
Insoluble aggregates of beta-amyloid proteins that form outside
neurons - Neurofibrillary Tangles
Insoluble aggreates of hyper-phosphorylated Tau protein that
form inside neurons
- Symptoms not sufficient for diagnosis
- Require presence and abundance of identifiable morphological
substrates - Plaques and Tangles
What are Tau Protein?
Predominantly expressed in the CNS
In neurons, predominantly found in axons
Co-purifies with tubulin/MT’s, stabilizes MT integrity, promotes MT assembly;
Microtubules are responsible for transport of molecules
(eg neurotransmitter receptors) within neurons
What are Amyloid Precursor Protein (APP)
Function: unknown? Maybe cell adhesion, neurite outgrowth, synaptogenesis, cell survival?
APP-null mice: are relatively normal (underweight, decreased locomotor activity, reactive gliosis)
APLP2-null mice: are relatively normal
APP/APLP2-null mice: 80% die 1 week after birth, deficits in balance and strength
Check slide 26 for diagram explanation
Production of beta-amyloid
The Aβ42 variant is more hydrophobic, more prone to fibril formation, and is the predominant isoform found in cerebral plaques.
Normally an individual would have Aβ40 at 50-70% and Aβ42 at 5-20%. However in people with Alzheimers, their Aβ42 is higher.
When the Aβ42 fragments are released from their secretory vesicles, these fragments fold to toxic form and aggregate.
Biomarkers
New criteria required as it doesn’t establish diagnostic criteria for preclinical AD. Additional research is required before this stage of AD can be diagnosed. New criteria recommend biomarker testing for MCI (Mild Cognitive Impairment).
- Total tau proteins increases to about 300%, probably as a result of
neuronal and axonal degeneration - Aβ decreases to about 50%, probably due to increased deposition in
plaques - Phosphorylated tau increases, owing to the hyperphosphorylation
associated with NFT - Combining the 3 increase sensitivity and specificity of diagnosis to
90%
What causes Alzheimers?
Cause/ causes of Alzheimers are not known.
Probs the result of many factors (rather than a single cause)
Factors include number of brain changes that begin as early as 20 years before clinical phenotype is even evident.
Brain functions normally (Initial brain changes) -> Subtle decline in congnitive function (Mild cognitive impairment) -> Obvious decline in cognitive function & memory changes (Advanced Alzheimers)
^this is according to the the 1984 criteria
Explain the continuum of Alzheimer’s Disease on a graph.
Preclinical -> MCI (Mild cognitive impairment) -> Dementia
Cognitive function decreases as the years goes on and the more the patient ages.
Check slide 30 for graph.
Describe the Hypothetical model of biomarkers graph.
Order in which biomarkers become abnormal in relation to the stage of disease progression:.
First:
(preclinical and plateaus)
1. Amyloid-β accumilation (CSF/PET)
(increasing towards the end of preclinical, then sharply & progressively increases during MCI until heightening in Dementia)
2. Synaptic dysfunction (FDG-PET/fMRI)
3. Tau-mediated neuronal injury (CSF)
4. Brain structure (volumetric MRI)
5. Cognition
(not affected in preclinical, only slightly increases towards the end of MCI but then sharply and steeply heightens and increases during the late stages of dementia)
Describe age as a risk factor.
- Biggest risk factor is age
- AD is not a normal part of aging
- Majority of cases are diagnosed after 65 years old. This is late-onset Alzheimers
- Minority of cases before 65 (early onset Alzheimers)
check slide 32 for details
Describe Apolipoprotein E (APOE) as a risk factor
- 34 kDa, 299 amino acid glycoprotein
- Gene found on chromosome 19
- Produced at high levels in liver and brain
- Synthesised by glia in brain (predominantly astrocytes)
- Present in lipoprotein particles in the CNS which are HDL-like (apoE
in the CNS comes from the CNS) - Binds to soluble and aggregated amyloid-
- Exists in 3 common isoforms in humans, e2, e3, e4
- We have 2 copies of each gene, one from each parent
- Six possible combinations e2/e2, e2/e3, e3/e3, e3/e4, e2/e4 or e4/e4
APOE4 e4 associated with higher risk. ~ ¼ population. Increases lifetime risk by up to 4
~2 % population gets a ‘double dose’ increases risk by 10
60 % population has a ‘double dose’ of e3. Approx half develop Alzheimer’s by late 80’s
APOE e2 is mildly protective. Carriers less likely to get Alzheimer’s. 11 % pop has e2/e3 and 0.5 % has e2/e2
Greatest impact on age of development.
Having gene does not guarantee a person will develop Alzheimer’s
