CNS 4c Flashcards by Aisha Khan

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

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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)

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HAND manifestation

Cognitive symptoms:
progressive dementia
memory loss
disorientation
behvior changes
problems with thinking, reasoning, language

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HAND tx

no tx for cognitive decline
-combined anti-retoviral treatment: supress viral load (CART)

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most common neurogenerative disease

alzheimers

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Alezheimers

leadin cause of demntia
incidence increases with age
biggest contributer: cerebrovascular dx
other risk factors: genetics, dm, htn

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2 hallmarks of alzheimers

neuritic plaques and neurofibrillay tangles

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Neuritic plaques

no (or reduced) ability to discardamyloid B protein
develop amyloid B plaques
disrupt glutamate uptake -> excitatory -> cell death

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Neurofibrillary tangles

tau- structural protein, forms large intracellular tangles
axon -> instability -> cell death

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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

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alzheimers cognitive sysmtoms

memory loss
mood and behavior changes
(preservation of motor /sensory fxn)

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anatomical changes

neuronal loss mostly in cerebral cortex and hippocampus
brain atrophy, decrease in volume

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Cholinesterase inhibitors

cholinesterase: enzyme that degrades acetylcholine (Ach)
-inhibiting breakdown of ACh increases amount of it
improves cognitive fxns, delays dementia progression

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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

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huntingtons dx

inherited neurodegnerative condtion with motor and cognitive symptoms
-autosomal dominant
onset not until mid-life
-atrophy of basal ganglia, enlargment of ventricles

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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

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in huntingtons- severe degeneration of basal ganglia:

targets GABAergic neurons
-prefrontal cortex, hippocampus, hypothalamus

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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