B1: WALLACE - neurobiology in DS adults w/ Dementia Flashcards
What is DS?
Congenital chromosomal abnormality associated with extra Chromosome 21 material
Ranges from above average intelligence to severe intellectual disability
May be associated with autism
Ages of early onset of dementia in DS patients
Especially AD
Uniquele vulnerable at >50yo
Average onset 52.8 years
Signs/symptoms of DS and healthy people developing AD is the same
Describe phenotype of AD: clinical course
Older or younger age onsets present the same way
Initial 1-5 years: Early stage = memory, orientation, communication, work and social skills dysfunction
Next 2-5 years: Middle Stage = Pronounces losses in language, comprehension, prientation, STM, daily living skills, confusion and personality changes - social withdrawal
Last 1-2 years: Almost complete loss of all higher functions, memory, mobility, social, personality, frequent incontinence, seizures
Describe end-point brain pathology of AD
Neuritic plaques: extracellular deposits of fibrillar Beta Amyloid surrounded by degenerating neuronal processes and terminals
Intra-neuronal neurofibrillary tangles: comprised mainly of abnormally phosphorylated Tau Protein
Vascular Beta Amyloisosis: associated with fibrillar amyloid deposition within the vascular wall -> inflammation -> oxidative damage
What are the two main features that contribute to the end-pont brain pathology of AD?
How are these features toxic to the brain?
Beta Amyloid Deposition
Abnormal/Hyperphosphorylation of Tau Protein
Interfere with cell-cell communication via energy failure, neurotransmitter failure, synaptic and neuronal loss, deterioration of neuronal networks, brain atrophy
*Also associated with immune responses, which exacerbate the situation
How is the pathway to end-point brain pathology proposed to be different between eary- and late-onset AD?
Early onset (inc. people with DS): Proposed mechanism is via overproduction of the toxic changes (too much deposition)
Older onset: Mechanisms failing to clear the amyloid deposition and tau phosphorylation (not enough clearance)
Early onset and late onset also have DIFFERENT GENOTYPE - despite presenting with same phenotype
Role of APP gene in DS patients developing AD
Those with DS (caused by trisomy 21) -> have extra copies of APP gene (precursor to beta amyloid), which is located on chromosome 21.
Overall, DS people have 55% increase in the APP gene product
This is why younger people with DS will have beta amyloid plaques and phosphorylised Tau Protein in their brains, even before onset of AD
What is the mechanism by which APP leads to toxic Beta Amyloid deposits?
APP undergoes processing by alpha, beta and gamma secretases.
These confer differing levels of toxicity - beta amylast is nost toxic and the longest amyoid deposit
Gene locations for beta secretase (which produces beta amyloid) is located on chromosome 21 - people with DS have extra copies of this
What is the gene-based cause of Tau Hyperphosphorylation in people with DS?
Tau Hyperphosphorylation is the mechanism for developent of fibrillary tangles
DYRK1A: a gene mapped to chromosome 21. The neurofibrillary tangles (tau) have been found to be immunoreactive -> self antibodies detect the DYRKA1 protein
Thus, DYRK1A gene may be a major factor influencing the progression of neurofibrillary degeneration in DS
What are the key neurobiological features of DS?
Very complex
Excessive inhibitory neuron behaviour
Multiple gene expression affected by trisomy 21
Alterations to developmental signalling pathways: e.g. sonic hedgehog, nerve growth factor
Plaque (BA) and tangle (TP) development occurs much dearlier than their onset of AD
What other health issues in DS patients may contribute to their younger age of AD onset?
Propensity for chronic inflammation
Multi medications
Propensity for Vascular Disease
Overall co-morbid life situation
