L7 Neuropathy of Dementia Flashcards
What is dementia and how is is diagnosed?
Dementia is a progressive loss of memory and cognition for which there is no cure.
It is diagnosed as a decline in memory with impairment in at least one other cognitive function.
What are the three types of clinical presentation and what are they dependant on?
1) Temporo-parietal e.g. Alzheimer’s disease. You see early memory symptoms.
2) Fronto-temporal e.g. FTD. You see behaviour and language disturbance.
3) Subcortical e.g. vascular dementia. You see reduced speed/efficiency of cognition.
These types are dependant on the anatomical location of of the region affected.
What is the biggest risk factor for dementia?
Age.
What are the causes of dementia?
- Neurodegeneration.
- Vascular.
- Infectious/inflammartory/immune.
- Toxic and metabolic.
What are the pathological hallmarks of AD?
- Extracellular aggregates of beta-amyloid peptides.
- Intracellular inclusions of neurofibrillary tangles.
- Neuritic plaques.
- Cerebral atrophy.
- Cerebral amyloid angiopathy (beta-amyloid is deposited in the walls of vascular structures in the CNS). This is a feature of AD, but also commonly occurs in the non-demented elderly.
- Synaptic and neuronal loss.
- Gliosis/microglial reaction.
What did genetic studies in the 1990s indicate regarding AD?
That beta-amyloid was the causitive factor in AD.
This was concluded because mutations in the gene APP (beta-amyloid precursor protein), PSEN1&2 (codes for the beta-amyloid processing pathway components) led to inherited, early-onset AD.
What is the amyloid cascade hypothesis?
This proposes that beta-amyloid accumulation initiates the pathophysiology of AD leading to neurofibrillary tangles and neurodegeneration, resulting in memory loss.
What did drug therapeutics aimed at plaque reduction show?
They were successful at reducing beta-amyloid plaques, but show no reversal in memory deficits nor halt in cognitive decline.
How are beta-amyloid peptides obtained?
Cleavage of APP.
APP contains a beta-amyloid domain that has cleavage sites for secretase enzymes.
What are the two pathways in which APP is cleaved?
1) Non-Amyloidogenic pathway. Cleavage by alpha-secretase releases C-terminal fragment-alpha (CTFa).
2) Amyloidogenic Pathway. Cleavage by beta-secretase releases CTF-beta.
The pathogenic effects of these fragments depends on the length of the fragments. The longer the fragments, the more likely they are to form aggregates.
What are neurofibrillary tangles?
These are formed by abnormal aggregation of the tau protein which usually associates with microtubules.
The levels of neurofibrillary tangles correlates strongly with the progression of AD and cognitive symptoms.
What happens in AD that causes dysfunction of Tau?
- Circuit hyperactivity and calcium influx triggers aberrant tau phosphorylation.
- Tau phosphorylation then leads to dysfunction of PP2A which then causes tau hyperphosphorylation, insolubility and aggregation.
What three pathological indicators does Braak Staging use?
1) Beta-amyloid plaques.
2) Tau inclusions.
3) Alpha-synuclein-positive Lewy pathology.
What is a downside of Braak Staging?
- Does not provide a threshold for dementia prediction.
- Often shows an overlap between the demented and non-demented elderly.
What is dementia with Lewy bodies?
This is the second most common neurodegenerative cause of dementia.
It leads to fluctuating cognitive decline, visual hallucinations, Parkinsonism and neuroleptic sensitivity.
