Neurodegenerative Diseases - Parks Flashcards
AD, PD, HD, and ALS all show a progressive loss of (blank) in specific areas, along with loss of glial cells
neurons
What two proteins are in the inclusions in AD?
AB protein
Tau protein
Where are the inclusions located in AD?
amyloid plaques are extracellular
tau protein is intraneuronal
What is the protein in the inclusions in PD?
Alpha-synuclein
Where are the inclusions located in PD?
inside neurons
What are the two proteins involved in the inclusions in ALS?
TDP-43
SOD1
where are the inclusions located in ALS?
inside the neurons
What is the protein in the inclusion in HD?
huntingtin
where are the inclusions located in HD?
inside the neurons
what are the two fates of old or misfolded proteins?
Ubiquitinated and sent to proteosome
autophagy via lysosomes if they form aggregates
what class of proteins form aggregates?
globular proteins
Describe the formation of an inclusion body?
- wear/tear exposes hydrophobic surfaces
- small soluble oligomers form; resistant to degradation
- soluble aggregates of the oligomers form
- large aggregates become inclusion bodies
At what point in inclusion body formation is the oligomer subject to autophagy mediated degradation?
formation of soluble aggregates
T/F: individual oligomers can be the toxic substance even before inclusion formation
true
Lewy bodies are seen in which disease?
PD
What types of neurons are involved in PD?
dopaminergic
Where is the greatest neuronal loss in PD?
substantia nigra
protein aggregation and inclusion elicits a (blank) repsonse from the cell
stress response
inclusions are (directly/indirectly) toxic to neurons
directly
Some aggregates are capable of behaving like (blanks); aggregates from one neurons can be taken up by another neuron leading to more aggregates
prions
in the neurodegen dzs, misfolded proteins from what conformation?
b-sheets and amyloid fibrillar aggregates
(deep/cortical) neurons are filled with tangles and extracellular plaques
cortical
neurofibrillary tangles are outside or inside the cell?
inside
Where does AD begin in the brain?
hippocampus – temporal lobe
When are AZtherapies effective in treating AD?
only during MCI stage
an amyloid plaque as a (blank) core
beta-amyloid core
formation of amyloid plaques leads to the phsycial disruption of…
dendrites
formation of amyloid plaques elicits what “healing” response from the brain?
gliosis
What protein makes up the neurofibrillary tangles?
tau
Whence is the origin of AB protein?
amyloid precursor protein APP; a transmembrane synaptic protein
APP is cleaved by (blanks) a, b, and g, forming AB monomers
secretases
which secretase is most important in the formation of amyloid plaques?
secretase b
what is the result of the formation of AB oligomers?
formation of aggregates, amyloid fibrils, and neuronal damage
what is the function of normal tau?
a microtubular protein that is part of the cytoskeleton
Amyloid beta activates a (blank) which (blanks) tau protein
kinase; phosphorylates tau
What happens when tau becomes hyperphosphorylated?
falls off the microtubules
Tau that has fallen off the microtubules forms (blanks) which form neurofibrillary tangles
paired helical fragments
Tau is interfering with microtubules and intracellular traffic while the plaques are interfering with….
dendritic connections
do tangles form before or after plaques?
after
t/F: plaque formation is a part of normal aging
true
Radioactive imaging tracers that bind to beta amyloid can be visualized with….
PET
T/F: AD pathology overlaps with normal people
true
T/F: tangles are present in the normal aging brain
true
What are the three CSF biomarkers that help in the Dx of AD?
LOW beta-amyloid 1-42
HIGH total tau
elevated phosphorylated tau
Why is CSF beta amyloid low?
the amyloid is being deposited in the plaques and not in circulation
The CSF signature of AD has a low (specificity/sensitivity)
specificity
T/F: AD has motor components
false
PD involves what set of nuclei in the brain?
basal ganglia
the largest concentration of dopaminergic neurons in the brain are found in the…
substantia nigra
Where do the axons of the substantia nigra project?
corpus striatum
Degeneration of projections from the substantia nigra to the corpus striatum leads to what Sx?
severe tremors
muscle rigidity
Hyperactivity in substantia nigra neurons is associated with….
addictive behaviors
Cocaine causes extracellular buildup of DA in the…
limbic system
how does cocaine cause the buildup of DA in the limbic system?
inhibition of Na dependent DA reuptake
T/F: PD neurons are fucntional, its just that they lack coordination
true
what are the two components of the striatum?
caudate nucleus
putamen
What contributes the most to neuronal death in PD?
alpha synuclein oligomers
Alpha synuclein forms what type of inclusion?
lewy body
t/F: alpha synuclein can spread like a prion
true
Prion like spread of alpha synuclein in PD leads to….
dementia
dementia with lewy bodies is clinically between which two diseases?
PD and AD
What are two notable physical findings in ALS?
muscle weakness
fasciculations
What physical changes happen to the spinal column in ALS?
hardening of the lateral columns of the spinal cord
Gliosis follows the degeneration of the (blank) tracts in ALS
corticospinal
ALS involves both (blank and blank) neurons
upper and lower motor neurons!!!!
(blank) degeneration in ALS leads to demyelination and scarring
Wallerian degeneration of the axons
where do motor signals originate?
precentral gyrus – motor cortex
Signals from the precentral gyrus flow via which fibers on the way to the spinal cord?
posterior limb of internal capsule
where do the motor fibers decussate?
in the pyramids
Upper motor neurons travel down the spinal cord in which tract?
lateral corticospinal tract
Upper motor neurons synapse with lower motor neurons in the….
anterior horn of the spinal cord
Lower motor neurons then synapse directly on….
muscle fibers
on gross examination, what do you see on the anterior side of the spinal cord?
degeneration and atrophy of the roots compared to the posterior side
Stains of the spinal cord will show what changes in the posterior areas (corticospinal tracts)?
lighter in color from demyelination
Why are the corticospinal tracts ENLARGED in stains of spinal cord in ALS?
GLIOSIS
T/f: gliosis occurs in the anterior horns in ALS
true
Loss of lower motor neurons lead to…
denervation muscle atrophy aka amyotrophy
SOD1 aggregates leads to the increased release of which neurotransmitter?
glutamate
increased glutamate release from SOD1 aggregates in ALS leads to….
excitotoxicity
What are the two MOAs of Riluzole for ALS?
- inhibits glutamate release
2. blocks post-synaptic actions of NMDA receptors
Syndeham’s choreas is seen post-(blank) infx
strep
PD is (hyper/hypo)kinetic and HD is (hyper/hypo)kinetic
PD is hypokinetic
HD is hyperkinetic (chorea)
HD involves which which portion of the striatum
most notably the caudate
but also the putamen
autopsies of HD brains will show what two changes?
atrophic caudate
enlargement of the lateral ventricles
HD is a CAG trinucleotide repeat disorder that causes the formation of poly(blank) residues in the huntingtin protein
polyglutamate
Where in the cell is the huntingtin inclusion?
INTRANUCLEARA
What is the outcome in patients with less than 26 repeats?
normal; no risk to offspring
What is the outcome in patients with 27-35 HD repeats/
intermediate; will not be affected; elevated risk but less than 50% to offspring
What is the outcome in patients with 36-49 HD repeats?
reduced penetrance; may or may not be affected; 50% to offspring
What is the outcome in patients with more than 40 HD repeats?
full penetrance; will be affected; 50% to offspring
Increasing number of HD repeats affects the clinical presentation of HD how?
more repeats means presentation at younger age
