Lecture 25: Neurodegenerative diseases Flashcards
Describe the major features of Alzheimer’s disease:
- Symptoms, clinical progression, age structure
- Risk factors
- Gross brain regions affected
- Histopathology
- Components of lesions
Alzheimer’s disease accounts for 50-70% of all dementia cases and a n estimated 1/3 of people from 85-95 experience dementia
Symptoms
- No biological test, only confirmed after death
- Definitive diagnosis is post mortem, however the clinical assessment is now very accurate
- Insidious onset – slow – rather than abrupt or stepwise progression
- Duration is 5-12 years but likely long prodromal period
- Memory signs appear early – repetition, getting lost, inability to do calculations and follow conversations, trouble orienting to space and time, losing things, hiding this
- Other cognitive signs appear later – Early on activities are intact but may need instruction, breaking down tasks - Behavioural changes include Agitation and paranoia), aphasias, apraxias, activities of daily living (dressing, eating, bathing), agitation
Exclusion criteria for AD diagnosis
- Movement disorders
- Abrupt onset
- Delirium, seizures, focal signs (e.g. paralysis)
Risk factors
- Age - but people can also get alzheimers in their 30s and 40s
- Genetics
- Autosomal dominant mutations: amyloid precursor protein (APP), presenilin 1 presenilin 2 account for <1% of cases, involved in production of amyloid peptide Normally-occurring isoform of the apolipoprotein ApoE4 (a lipid transporter) associated with increased risk, but not determinate
- Cardiovascular risk factors
- Diabetes Type II
- Midlife hypertension
- Smoking
- Atrial fibrillation
- Previous stroke
- High cholesterol
- Head injury
- Low educational attainment (may be study bias, socioeconomic factors)
Neuropathology
Alzheimer’s disease early Anterograde memory dysfuncton - no NEW memories What was that conversation about? Where did I leave my car? Did we just have tea? Atrophy & senile plaques and neurofibrillary tangles in hippocampus/entorhinal cortex
Retrograde memory dysfunction - OLD memories lost Previously consolidated memories erode Who are you? Where am I? What is that called? What do I do with this? Atrophy & senile plaques and neurofibrillary tangles in neocortex, limbic and association areas
Describe the major features of frontotemporal dementia:
- Symptoms, clinical progression, age structure
- Risk factors
- Gross brain regions affected
- Histopathology
- Components of lesions
- FTD is a group of disorders / syndromes with different aetiologies*, frequencies, progression, symptoms and genetics
- Not a single disease – with a peculiar atrophy in frontal and temporal lobes
- FTD accounts for just ~10-15% of dementias overall (all ages)
- For persons under 50 years it accounts for 50% of dementias
- Usually starts with odd behaviour, “out of character” / people think it is a mental health problem’
- Massive imports of atrophy in frontal and temporal lobes
- Often people will have language problems due to problems in Wernicke’s area
- Aphasia / Not understanding language / Problems expressing themselves
- Can be frontal dominant or temporal dominant
Clinical features
Characterised by behavioural abnormalities
- Decreased initiative (less motivation
- Social disinhibition (telling inappropriate jokes, taking clothes off, gambling to much, talking back to people you should be respectful of)
- Poor planning (not thinking ahead)
- Impulsivity, loss of restraint
- Emotional blunting, difficulty regulating emotion (no longer respond to sadness)
- Stereotypical behaviours (repetitive behaviours, mimicking, compulsive behaviours)
Aphasias
- Some forms of FTD have primarily a language dysfunction, less behavioural or memory
Memory dysfunction (is minor compared to Alzheimer’s and appears later)
- usually appears later, can be a minor feature and often not as severe as Alzheimer’s disease
Movement disorders
- some subtypes of FTD (FTD 17 – a tau mutation) show parkinsonism
- more likely to have an early age of onset (midlife – 40-50 years)
- 2-15 year duration of symptoms
What causes neurofibrillary tangles and beta-amyloid plaques in alzheimers?
Neurofibrillary tangles
Tau is a cytoskeletal protein that binds to microtubules – it becomes hyper-phosphorylated in alzheimers disease
- Forms into tangles
- Neurons eventually die, leaving behind ghost tangles
- As these neurons die you are disconnecting the network – gradually each link is disconnected until the memory cant be recalled
Amyloid-beta (Ab)
- Ab is deposited extra neuronally (extracellular) in plaques
- Ab deposited within and around blood vessels
- Not well correlated with dementia symptoms compared to tangles
- Huge debate whether this is really the cause
- Anatomically it does not correlate with symptoms – doesn’t mean its not important.
- But you can have plaques without the symptoms
The symptoms related to the medial temporal lobe don’t relate to where the plaques are found.
