Neurodegeneration Flashcards
what is neurodegeneration?
why is this a problem?
what is the biggest risk factor for most common neurodegenerative diseases?
progressive loss of neurones beyond that of the normal ageing process
neurones cannot be replaced
age
when does neurodegeneration occur?
neurodegenerative diseases e.g. Alzheimer’s
cancer
trauma (head/spine injury)
viral diseases
vascular/circulatory disorders
developmental disorders
what are the 3 examples of neurodegeneration-associated vascular and circulatory disorders?
ischemia/infarction
transient ischemic attacks
haemorrhage
what are the various causes of stroke?
atherosclerosis
= narrowing of vessels
thrombosis
= damages vessels
embolism
= a blockage e.g. plaque/air bubble
vasospasm
= abnormal contractions cause vessel rupture
hypertensive vasculopathy
2 types of stroke
ischemic
- clot blocks blood flow to brain
= deprives neurones from nutrients + O2 etc
haemorrhagic
- bleeding occurs inside/around brain tissue
= can cause destruction of neurones
what is venous infarction?
what does it result from?
risk factors?
a haemorrhagic stroke form
venous sinus thrombosis
no. of states that result in hyper viscosity or increased coagulability
topography of focal ischemia
focus = area where neurones begin to die via necrosis
flow gradient:
densely ischemia region surrounded by areas of less severe CBF (cerebral blood flow) reduction
how can necrotic cells at a focus affect surrounding cells?
what is this called and what does it lead to?
cells break open and release contents
-> e.g. release glutamate
-> glutamate toxicity
= kills other cells
ischemia penumbra
- an area of reduced perfusion sufficient to cause reversible clinical deficits
= can be reversed by quick intervention
what is an infective disease that causes neurodegeneration?
what are the different forms?
meningitis
bacterial
tuberculous
fungal
viral
inflammation of the coating of the brain containing the meninges
- > can damage blood supply
- > damages brain
what is poliomyelitis caused by?
what can it lead to?
poliovirus (RNA virus)
3% of cases enter the CNS
1% of cases this leads to focal loss of motor neurones in the spinal cord
what neuroscience findings have been discovered from polio?
study of spinal motor neurone loss + comparison to resulting loss of muscle control
-> mapping of motor neurone foci in the spinal cord to innervated muscle
what makes neurodegenerative diseases special?
often unknown cause
no cure
progressive
sporadic +/or inherited forms
often age dependent
types of neurodegenerative diseases
dementia
- Alzheimer’s = most common
- Prion = rare
movement disorders
- Parkinson’s
= loss of dopaminergic cells
- Huntingtons
Motor neurone disease
- ALS
- MS
loss of upper + lower motor neurones
what are Amyloidogenic diseases?
examples
neurodegenerative diseases where there’s deposition of an abnormal amyloidogenic protein isoform
Alzheimer’s disease
Parkinson’s disease
Prion disease
what are amyloidogenic proteins?
those that form fibrillar aggregates with beta-sheet configurations
Alzheimer’s disease facts
most common neurodegenerative disease
most common cause of dementia
chances increase with age
- 47% if over 85yrs
Alzheimer’s potential causes
deposition of beta-amyloid
- amyloid cascade hypothesis
deposition of phosphorylated tau in the form of paired helical filaments or tangles
metal hypothesis
e.g. iron and copper become more highly concentrated in the brain in ND diseases
Amyloid cascade hypothesis
no plaque:
APP broken down by alpha-secretase into beta-amyloid
plaque formation:
APP cleavage in a different location by beta-secretase
= forms amyloid plaques
Formation of tau tangles
Tau proteins aggregate and can no longer bind to microtubules
- > deposited
- > damage neurones
Parkinson’s disease facts
2nd most common ND disease
(1 in 200 over 50yrs)
NOT a dementia
changes in movement
resting tremor
difficulty in starting movement
Parkinson’s disease cause
Due to loss of dopaminergic neurones
in the substantia nigra
loss of pathway with the striatum
-> removes inhibitory pathways
= misbalance in movement pathways
causal genes for familial forms of Parkinson’s disease
PARK1
= alpha-synuclein protein which is usually deposited as the aggregating protein in PD
PARK2
= Parkin associated with breaking down protein via UPS (ubiquitin-proteasome} pathway
PARK8
= LRRK2 associated with phosphorylation of proteins affecting the rate of protein breakdown
Prion diseases facts
v rare
transmissible (experimentally)
human and animal diseases
sporadic or inherited
e.g. Kuru from eating human brain
vCJD
Prion disease characteristics
long incubation period
(10-40yrs in humans)
deposition of large amounts of abnormal prion protein
rapid neuronal loss
gliosis = proliferation of glial cells
formation of small vacuoles
short symptomatic period before death
prion protein misfolding
normal protein has a helical structure
when misfolded:
takes on beta-sheet structure
-> can aggregate
-> initiate neurone death
once substantial amount made (during long incubation period)
-> can catalyse own misfolding
metal hypothesis
in each case (Alzheimer’s, Parkinson’s, Prion)
the normal protein is associated with binding a protein e.g. copper
suggests metals play some role
2 diseases of myelin
demyelinating diseases
- acquired disorders of myelin e.g. multiple sclerosis
dysmyelinating diseases
- genetic disorders destroying myelin during its formation
e. g. leukodystrophies
demyelinating diseases
axons are myelinated and later destroyed
via immune cell invasion theory
multiple sclerosis facts
most common disease of CNS myelin
1:1000
progressive with relapsing + remitting accumulations of focal neurologic deficits
cause thought to be autoimmune
MS symptoms
muscle weakness
ataxia (difficulty moving)
difficulty with speech + swallowing
immune cell invasion MS theory
invade spinal cord
trigger immune response against myelin
cells (e.g. microglia) become activated and either cause destruction of oligodendrocytes (which repair damaged myelin) or destroy myelin sheath directly
