Alzheimer's disease and Current Treatment Flashcards
5 early signs of Alzheimer’s disease/dementia
- Amnesia.
- Disorientation in time.
- Disorientation in place.
- Abstract thinking impaired.
- Judgement impaired.
Five A’s of Alzheimer’s
• Amnesia. (dysmnesia “bad memory”)
• Aphasia. Impairment of language, affecting the production or comprehension of speech and the ability to read or write
• Apraxia. Difficulty with the motor planning to perform tasks or movements despite an intact motor system
• Agnosia. Inability to interpret sensations and hence to recognize things
• Associated features. Aggressivness, depression, anxiety, insomnia, hallucinations, personality changes. Delusions.
What other common conditions must be ruled out for the diangosis of AD
- Other forms of dementia, such as FTD, Lewy body (P.D.), Jakobs disease
- Delerium i.e., drug induced or some other acute state such as dehydration, UTI
- Pseudodementia (symptom of depression)
- Normal ageing. MCI
- Normal pressure hydrocephalus. Blocked CSF flow, usually caused by spinal obstruction
How is Alzheimer’s diagnosed?
- History / Informant history. In the case of cognitive impairment, informant history i.e., from relative may be more informative
- MMSE. Mental State examination (including surroundings).
- Physical examination.
- Investigations (Blood, Urine, Imaging).
- Diagnosis of exclusion. Previous two steps allow exclusion of other potential diagnoses.
Life style risk factors (10)
- APOE/4, APP or Presenelin SNPs
- Unhealthy diet
- Alcohol misuse
- Smoking
- Obesity
- Hypertension
- Hypercholesterolaemia
- Diabetes
- Vascular insults
- Neuronal damage
Protective life style factors
- APOE2
- Higher level of education
- More physical activity
- More mental and social activity in later life
All of these things also promote synaptogenesis and neurogenesis, which could be the mechanism of their protective effects.
How are neurotransmitters affected by AD
NTs showing the greatest decrease in post mortem AD cortex as a percentage of control in order of severity:
- Acetylcholine
- Noradrenaline
- Serotonin
-
Glutamate
It should be noted that this represents end stage disease after subjection to a battery of pharmacological interventions, and only depicts changes in the cortex. Pathology in subcortical structures like the hippocampus are extremely important in AD. Nonetheless, enhancing these NTs may (and does in some cases) provide symptomatic relief.
Which molecular cholinergic systems are most affected in AD?
- Choline-acetyl transferase activity (synthesis of ACh). 35-50% of control.
- ACh synthesis. 40-50% of controls.
- Choline reuptake. 60% of controls.
- AChe activity. 40-60%. This is interesting, as AChe inhibitors are a treatment. Perhaps AChE is downregulated in attempt to compensate for reduced presynaptic ACh activity.
The binding to post synaptic receptors is not affected - suggesting that it is the presynaptic activity which is most affected. The hippocampus and cortex are both under cholienergic control from the medial septum and nucleus basalis, respectively.
What are the changes in the glutamate–glutamine cycle?
- Reduced activity of glial reuptake transporter (50%). Levels of transporter remain unaffected, but there is less reuptake, increasing glutamate concentration in the synpatic cleft.
- Reduced staining for VGluT. This suggests less packaging of glutamate into vesicles, which may promote reduced peak glutamate concentration upon AP.
- Reduced NMDAR expression.
- Reduced staining for glutamate & glutamine. This suggests less hippocampal pyramidal neurons. They also have shorter dendrites and contain tangles.
How may glutamatergic changes affect cognition in Alzheimer’s?
Pathways for both storage and retreival between the cortex and the hippocampus are underpinned by glutamate (and the tone is modulated by ACh).
Glutamate becomes dysregulated in AD, resulting in both reduced glutamate recyling and increased concentration/longevity at the synpatic cleft. This decreases the signal-to-noise ratio of signalling.
How may cholinergic changes affect congnition in AD?
Acetylcholine is involved in modulating activity in the hippocampus and the cortex - overall increasing the tone of glutamatergic signalling. Reduced ACh results in weaker signals, which become lost in the increased noise due to extended NMDA activation at synpases.
What is the mechanism of action of mematine?
Memantine’s symptomatic improvement in AD was initially confusing, as it is an NMDA antagonist - but AD already shows reduced levels of glutamate within the brain.
However, it is reversible antagonist. It requires a higher depolarisation to be displaced from the pore than magnesium, but can still be displaced at high levels of activity. It therefore increases the signal to noise ratio, making glutamatergic signalling more efficient.
It shows mild benefits in symptomatic improvement. It may be most effective when given with ACh enhancers in early stages of AD.
How is the serotonergic system effect in AD?
H3 paroxetine binding assays show less binding to reuptake sites in depressed AD patients compared to non depressed AD patients. May suggest less reuptake sites OR less serotonergic synapses. Large studies have found that SSRIs do not benefit depression in dementia.
AD patients with anxiety have a higher density of 5HT2A receptors than non-anxious patients. Levels of 5HT2a receptors are similar to that of normal controls - but anxiety is common in elderly people with dementia. 5HT2A receptor antagonists could therefore show therapeutic benefit in anxious AD. Clinical trials have not shown benefit however.
One study has show signficant improvement in in the core symptoms of AD when combinding 5HT6 receptor antagonists with donezipil (AChEi).
Neuroleptics in AD
People with AD do not commonly show delusions or hallucinations (unlike lewy body dementia etc), but they are commonly disturbed and agitated. Neuroleptics are commonly prescribed to manage these patients within care homes, however they significantly increase mortality rate with chronic use (exceeding 12month) and may only show moderate benefit.
5-HT6 receptor antagonists in AD
Phase II has show signficant improvement in in the core symptoms of AD when combinding 5HT6 receptors with donezipil (AChEi). Unfortunately phase III failed.
