CNS 4c Flashcards
HAND (HIV-Associated neurocognitive disorders)
HIV: infection of helper T cells; immune deficiency
immune-mediated degeneration in CNS
-infected imm une cells enter CNS early in infection
cell death-> progressive cognitive decline
HAND mechanism
-HIV infected mo attracted to brain
-Neurotoxic viral proteins
-microglia-> chemokines, cytokines
-neuronal injury/death
synaptic pruning- reduced signaling(loss of branches like naked tree)
HAND manifestation
Cognitive symptoms:
progressive dementia
memory loss
disorientation
behvior changes
problems with thinking, reasoning, language
HAND tx
no tx for cognitive decline
-combined anti-retoviral treatment: supress viral load (CART)
most common neurogenerative disease
alzheimers
Alezheimers
leadin cause of demntia
incidence increases with age
biggest contributer: cerebrovascular dx
other risk factors: genetics, dm, htn
2 hallmarks of alzheimers
neuritic plaques and neurofibrillay tangles
Neuritic plaques
no (or reduced) ability to discardamyloid B protein
develop amyloid B plaques
disrupt glutamate uptake -> excitatory -> cell death
Neurofibrillary tangles
tau- structural protein, forms large intracellular tangles
axon -> instability -> cell death
alzheimers mechanism
vascular dyfxn and damage precede neuronal death
APOE gene mutation: important for vascular and neuron health
lipid metab, cholstrol transport, amyloid B protein degradation
strong correlation btwn APOE mutation and alzheimers, esp with diabetics
alzheimers cognitive sysmtoms
memory loss
mood and behavior changes
(preservation of motor /sensory fxn)
anatomical changes
neuronal loss mostly in cerebral cortex and hippocampus
brain atrophy, decrease in volume
Cholinesterase inhibitors
cholinesterase: enzyme that degrades acetylcholine (Ach)
-inhibiting breakdown of ACh increases amount of it
improves cognitive fxns, delays dementia progression
NDMA receptor antagonists
-block affects of glutamate (can block excitotoxicity)
-important with learning, memory
when liagand binds, ca channels open
in AD, excess glutamate-> excess Ca-> excitotoxicity
huntingtons dx
inherited neurodegnerative condtion with motor and cognitive symptoms
-autosomal dominant
onset not until mid-life
-atrophy of basal ganglia, enlargment of ventricles
Huntingtons dx mechanism
Huntington protein on chromsome 4
widely expressed, interacts w/ other proteins
mutation = repeat explansion -> makes protein toxic to neurons
protein tangles and collects inside cells
-may induce excitoxic pathways within cell
in huntingtons- severe degeneration of basal ganglia:
targets GABAergic neurons
-prefrontal cortex, hippocampus, hypothalamus
Motor symptoms of hunt.
involuntary jerking movements (chorea)
slow writhing movements of limbs (athetosis
cognitive symptoms
decline in thinking and reasoning abilities
memory loss
psychiatric disturbances
huntingtons tx
no cure or way to slow progression
tetrabenazine: for uncontrolled movement
antipsychotics: for uncontrolled movemnts, mood stabilizing
antidepressants: for pysch symptoms
PT/OT- to maintain funcitaion and independence
Parkinsons dx
most common caus eof parkinsonism
selective degeneration of neurions in brainstem and basal ganglia, especially dopaminergic cells of substania nigra
cytoplasmic inclusions (Lewy bodies)
Parkinsonism:
clinical syndrome of rigidity, bradykinesia, tremor, postural instability: can result from encephalitis, repeated head trauma, exposure to toxins, certain drugs
parkinsons mechanism-Genetic:
PARK1(a-synuclein)- fxn ? but hangs put in synaptic terminals
PARK2 (parkin)
PARK5 (ubiguitin hydrolase)<-degrades misfolded damages proteines normally
Glucocerebrosidase <- lysomal processing
lewy bodies
abnormal accumulation of protein inside neurons:
a-synuclein
ubiquitin
tau
a B crytallin
parkinsons mechanism: toxic exposure
agent orange: herbicide
rotenine: pesticide
polychloriinated biphenyls (PBCs_
disrupts mitchondiral fxn–> decr ATP prod and incr ROS accumulation
Parkinsins manifesrtions
Sensor: loss of smell
Motor: tremor, rigidity, bradykinesia, postural instability
cognotive: dementis (lewy body), memory loss, halluciatio, mood disorders, sleep disorder (REM behavior disorder)
dopamine precursoe
levodope: converted into dopamine by enzyhmes in the brain
most effective PD tx (can be used in dx)
dopamine agonsits
COMT/MAO-B inhibitors
prolong effect of other drugs by blocking dopamine metabolism
deep brain stimulation
electrodes implanted into brain, connected to generator (chest)
sends electrical signals - invasive
Multiple sclerosis
autoimmune demylinating and neurogenerative dx
progession varies
4 types: clinically isolated syndrome
relapsing-remitting
primary progressive
secondary progressive
MS mechanism
autoreactive Th cells activate in periphery
proinflamm cells migrate to CNS
B cells: auto-antibodies against CNS
Cytotoxic T cells attack oligodendrocytes
Mo release proinflamm cytokines
T cell reactivated by mylein fragments
loss of myelin ____
loss of neurons_____
lesions
atrophy
(both seen on MRI)
MS manifestations
sensory: numbness, pain, tingling in limbs, loss of vision
motor: weakness, tremor/spasms, slurred speech, incontinence
cognitive: depression, anxiety
MS treatments
depend on progression and frequcny of attacks
Acute attacks of MS tx
corticosteriods
plasmapheresis
AD tx-slow progession by affecting immune syestem
IFN-beta
monoclonal antibodies (natalizumab)
immunosuppressant (mitoxantrone)
Amyotrophic lateral sclerosis
degeneration of motor neurons in motor cortex and spinal cord
-neurons show cytoskeletal dysfxn- little inflamm
ALS
familial- inherited 5-10%
sparodic
theeories:
gene mutations
excess glutamate levels
disorganized immune response
protein mishandling
ALS mechanisms
-common mutations: superoxide dismutase 1 SOD1
excess ROS -> neural death
20% of familial cases
-peripherin; neurofilament
cytoskeleton proteins that maintain axon structure (motor neurons have very long axons)
mutation casues aggregation -> distruption of axonal transport-> cell death
-glutamate cytotoxicity
decr fxn of ternnaporter tht removes glutamate from synapse
excess glutamaye excess Ca (toxic)
only in motor neurons!
ALS manifestation
cognitive: depression, sleep disorders, inappropiate affect (outburts laughing/crying)
motor: extremities affected first, dx spreads
-early on weakness, clumsiness, tripping, falling, cramps, spasms
late: paralysis, breathing difficulties-> respitory failure
ALS TX
no cure, tx for symptoms
antidepressants: psych sumptoms, sleep problems
Riluzole (only FDA approved tx)
slows progression of dx, glutamine inhibitor
does not reverse damage to motoe neurons
inflammtion and neurodegeneration
`chronic NSAIDs use may dcr risk for AD
may slow progression of dx
contributors to chronic inflammtion thoiught to incr risk of neurodegen
gram-neg bacterial endotoxin (gut bacteria)
certain viral infectiooj s(EBV, HIV, Herpes simple)
toxin exposure (incr cell damage-> death) pestoscides, herbicides
endothelial cell damge
