Nervous System (Block 6): Goodman Lectures On Degenerative Disorders/dementia

Front 1

what Sx's would you expect to find if neuronal populations were lost in:
- cortical neurons
- basal ganglia neurons
- cerebellar neurons
- motor neurons

Back 1

Cortical neurons: Dementia
Basal Ganglia Neurons: Movement Disorder
Cerebellar Neurons: Ataxia
Motor Neurons: Weakness

Front 2

define: fibrillogenesis

Back 2

situation in which cell is manufacturing proteins, occassionally misfold into a form prone to polymeration (formation of fibrils), forming damaging srucutres that can rip holes in membranes and mitochondria. May eventaully accumulate into aggregates in the LM.

MAIN IDEA: ABNORMAL PROTEIN IS PRODUCED, ACCUMULATES INTO FIBRILS, CAN LEAD TO CELLULAR DYSXN OR CELL DEATH & SHOWS UP IN IMMUNOHISTOCHEMISTRY

Front 3

most death in neurodegenrative dz is through APOPTOSIS/NECROSIS

Back 3

APOPTOSIS

Front 4

what are 3 pathways of neuronal death

Back 4

excitotoxicity
free radical injury (MPTP parkinsons)
fibrillogenesis

these mecahnisms work in concert with each other!

Front 5

in terms of protein fibrillogenesis, extracellular protein deposit is called _____, whereas intracellular protein deposit is called ______.

Back 5

plaque; inclusion (most inclusions found in the cytoplasm, though some nuclear)

Front 6

give examples of how neurodegeneration may start focally

Back 6

AD usually starts in hippocampal area (memory problems) or it may start in Broca's area (progressive aphasia -- speech gets worse and worse)

PD may start in one substantia nigra (hemiparkinsonism) and then progress to both sides

Front 7

for which dz are lewy bodies the major microsopic hallmark for? what is teh major protein found in it?

Back 7

parkinson's Dz (loss of DAergic neurons in substantia nigra projecting to striatum)

ALPHA-SYNUCLEIN

Front 8

what is this and what major protein is found in it? name the major disease associated with this inclusion.

Back 8

lewy body; alpha-synuclein; parkinson's dz

Front 9

what is this? what is the difference b/w left and right picture?

Back 9

left: normal substantia nigra
right: substantia nigra with in pt with PD... loss of DAergic neurons

Front 10

what are we looking at? what is the characteristic protein foudn here?

Back 10

cortical lewy body -- could be from lewy body dementia (LBD) or PD that progressed to dementia from the substantia nigra

protein: alpha-synuclein

Front 11

what pathogenesis is shown here? what specific clinical findings would you find in a patient like this? what is the fibrillogenesis protein here?

Back 11

progressive supranuclear palsy (PSP) -- "mickey mouse" midbrain

pt has atrophy of midbrain, so they'll have parkinsonism (without lewy body), vertical gaze disturbance

protein: tau

Front 12

name 2 other causes of parkinsonism. what are their proteins implicated in fibrillogenesis?

Back 12

post- encephalitc parkinsonism - tau

progressive supranuclear palsy (PSP) - tau

Front 13

what is shown here?

Back 13

neuronal tangle in PSP containt tau protein

Front 14

name the 4 tau-opathies

Back 14

-alzheimer's dz (although, technically, it's a beta-amyloid dz primarily bc of the plaques that form, then tau is found in the subsequent formation of tangles)
-progressive supranuclear palsy (PSP)
-postencephalitic parkinsonism
- pick's dz (frontotemporal dementia)

"APPP" - i hope that helps...

Front 15

name the 3 synucleinopathies

Back 15

-PD
-multiple system atrophy (MSA)
-lewy body dementia

"PML"

Front 16

what's going on with Multiple system atrophy? whats the protein invovled in fibrillogenesis?

Back 16

degenerative dz with 3 parts due to degernation of substantia nigra, putamen, olivary nuceli, pontine nuclei, and cerebellum:
- parkinsonism
- ataxia
- autonomic dysfunction

DUE TO ACCUMULATION OF ALPHA-SYNUCLEIN IN GLIAL CELLS (GLIAL CYTOPLASMIC INCLUSIONS = GCI)

Front 17

friedreich's ataxia is autosomal DOMINANT/RECESSIVE with a ____ triplet repeat expansion, causing excessive amplicfication of the ____ gene. FA is a ____ mediated neurodegenerative disorder.

Back 17

recessive; GAA; frataxin; free radical

"Friedreich's is F for Free radical!"

Front 18

what happens with less frataxin?

Back 18

loss of fxn for frataxin protein; since it's a protein invovled in mitochondrial iron handling, you don't handle iron properly and get free radicals.

Front 19

what disorder is shown here?
which tracts are involved?
what is the clinical manifestation?

Back 19

friedrich's ataxia

spinocerebellar, dorsal columsn, corticospinal tracts

ataxia, clumsiness, dysarthria, loss of tendon reflexes, impaired sensation

Front 20

fibrillogenesis protein for:
- PD
- familial ALS
- MSA
- PSP
- Alzheimer's dz/dementia (plaque vs. tangles)

Back 20

alpha-synuclein

superoxide dismutase

alpha-synuclein "MSA needs the alpha course"

tau

plaque: beta-amyloid
tangles: tau

Front 21

what dz is shown here? which parts of the spinal cord are damaged? what will this show up as clinically?

Back 21

amyotrophic lateral sclerosis (ALS)
- degeneration of corticospinal tracts (UMN) and anterior horn cells (LMN)
- dz will typically start focally/asymmetrically with both UMN findings (hyperreflexia, hypertonia) and LMN findings (atrophy, fasciculations) adn progress in 3-5 yrs with inc weakness so pt will be unable to breath (can't power diaphragm)

Front 22

familial forms of ALS contain what protein mutation?

Back 22

superoxide dismutase - these protein fibrils form damaging cells

Front 23

this dz is excllusively LMN findings - onset is in infancy and early childhool. thse pts neurons inappropriately enter apoptosis. what is the dz and what protein is found?

Back 23

spinal muscular atrophy (SMA)

neuronal apoptosis inhibitor protein

Front 24

what are the 3 dz's that can lead to dementia?

Back 24

-alzheimer's dz (most common neurodegenerative dementia)
-pick's dz (frontotemporal dementia)
-lewy body dementia

Front 25

what pathology is this showing and what dz?

Back 25

Hydrocephalus exvacuo - large ventricles that reflects loss of brain tissue, inc fluid ==> typical of alzheimer's dz

Front 26

in Alzheimers dz, atrophy usually starts where (3)? what does this mean clinically?

Back 26

amygdala, hippocampus, temporal lobe ==> MEMORY DISTURBANCES bc pt usually experiences initial inability to store new memory bc hippocampus can no longer solidify new memories into longer term memories

Front 27

in alzheimer's dz, there's typical loss of cortical _______ innervation. what is used as a therapeutic bc of this?

Back 27

cholinergic; cholinesterase inhibitors work to inhibit degerneration of ACh in central synapses -- helps slow progression of memory loss, but only symptomatic therapy.

Front 28

in regards to alzheimer's disease, what's important about its histology?

Back 28

neuritic plaques (extracellular) form first from BETA-AMYLOID deposits in the walls of cortical blood vessels.

then neurofibrillary tangles(intracellular) made of tau protein follow in formation

Front 29

what is this showing?

Back 29

plaques (the campfire) and tangles in alzheimer's dz

Front 30

what;s this?

Back 30

neurofibrillary tangles (tau protein)

Front 31

what pathology is shown here?
Name the dz.
what is the dz process?

Back 31

amyloid angiopathy in alzheimer's dz;
Normal route of handling amyloid is for it to enter the bloodstream - it has to pass through blood vessels. In AD, the pathogenic form accumulates in walls of blood vessels, giving you amyloid angioipathy. Can see that with congo red dye. This leads to tangle formation.l synapses start to disconnect. Neurites start to damage so you see this gradual disolution of the cortical circuitry. Manifested initially by memory disturbances

Front 32

if you want to see the progression of AD, what immunohistochemistry do you visualize?

Back 32

visualize using PIB how much accumulation of amyloid is in the brain

Front 33

which dz gives FRONTAL DISINHIBITION?

Back 33

Pick's disease (frontotemporal dementia) - uncommon sever dementing dz marked by temporal and frontal atrophy

Front 34

what dz process is shown here?

Back 34

Pick's dz (frontotemporal dementia) where there's atrophy of temporal and frontal lobes w/ neuronal loss and gliosis

see "knife edge" gyri

Front 35

why is there no memory loss in Pick's dz? what is an interesting positive result that could occur with Pick's dz?

Back 35

it sparees the hippocampus - only atrophy of frontal and temporal lobes

positive result = temporary disinhibition of hidden talent (artistic/musical)

Front 36

what is shown here? what dz process would this finding normally be in? what is the inclusion body named?

Back 36

pick body (Pick's dz aka. frontotemporal dementia)

- tau protein

Front 37

what is shown here? what protein?

Back 37

pick bodies in pick's dz; tau

Front 38

what is shown here? what protein is found?

Back 38

globose tangles in PSP; tau

Front 39

what is shown here?

Back 39

Neuronal loss, gliosis, rarefaction in Pick’s disease

Front 40

what cytoplasmic inclusions are shown here? where specifically are we? what dz process? what immunohistochemical protein? what clinical features?

Back 40

lewy bodies; cortical; lewy body dz; alpha-synuclein; FLUCUTATING DZ WITH GOOD/BAD MEMORY, HALLUCINATIONS,

Front 41

what do central cholinesterase inhibitors like DONEPEZIL, rivastigmine, galanthamine do? what are the side effects?

Back 41

central cholinesterase inhibitor; slows down synaptic degradation of ACh to inc ACh content of brain in Alzheimer's pts -- helps with memory improve cognitive fxn

SE: peripheral cholinergic hyperactivity

Front 42

indications and side effects of drugs that modify glutaminergic neurotransmission in Alzheimer's dz (memantine)

Back 42

non-competitive NMDA receptor antagonist (to facilitate removal of glutamate) - shown to slow progression of moderate to severe AD. can be used in combination with central cholinesterase inhibitor (donepezil)

Front 43

which is more effective for staging dementia - plaques or tangles?

Back 43

tangles