Wed 10/28 NTs and MS Flashcards
The 2 types of glial cells
What is the general function of these two types?
- Macroglia – Support and maintain neuronal plasticity
- Microglia – immune cells
More detail on how microglia act as immne cells (3)
- Activation produces inflammatory cytokines within CNS
- Response of fever- increased sleep, reduced, appetite, lethargy
- Aging may provide a brain environment in which microglia activation continues, contributing to the pathogenesis of neurologic disease (meaning there is no longer a dormant phase for microglia so they keep on truckin’ and that causes problems)
Which cells are considered macroglia (3)
- astrocytes
- oligodendrocytes
- Schwann cells
Why are astrocytes important to CNS? (3)
- CNS connective tissue- provide support and structure
- Can monitor and remove extracellular glutamate and other “neuronal debris” after brain injury
- Astroglial changes are an early response in CNS injury; swelling at interface with vascular system
Why are oligodendrocytes important to CNS?
responsible for production of the myelin sheath of the axon
Why are Schwann cells important to PNS?
produce myelin sheath for PNS axons
Would a nerve conduction velocity test be appropriate for diagnosing MS?
What test may assist with diagnosis and why?
- Probably not, because it only detects abnormalities in PNS, not CNS
- EMG- records muscle activity
- A person with MS does not have normal muscle activity so abnormal EMG activity would be detected.
**NCV could be used as differential diagnosis if it was unclear about PNS vs. CNS involvement
Points to note about spinal cord glial cells and pain signals (3)
- Spinal cord glial cells amplify pain signals and are activated by certain peripheral sensory signals
- Respond by producing cytokines
- New area of research in pain control
3 large groups of neurotransmitters that we need to know
- Amines
- Amino Acids
- Neuroactive Peptides
Three types of Amines (one has two subtypes)
KNOW!
- Acetylcholine:
- Catecholamines
- Dopamine
- Norepinepherin
- Serotonin
Three types of Amino Acids
- GABA
- Glutamate
- Glycine
Two types of Peptides
- Enkaphalins and ß-endorphins
- Substance P
Acetylcholine: primary location in CNS, general effect, and associated response
KNOW!
- cerebral cortex (many areas), basal ganglia, limbic and thalamic regions, spinal interneurons
- excitation
- decreases in production associated with diseases such as Alzheimer’s disease and myastheniagravis
Dopamine: primary location in CNS, general effect, and associated response
KNOW!
- basal ganglia, limbic system
- Inhibition
- decreased levels responsible for symptoms associated with parkinsonism
Norepinephrine: primary location in CNS, general effect, and associated response
KNOW!
- Neurons originating in brainstem and hypothalamus that project through the other areas of brain
- Inhibition
- related to cocaine or amphetamine
Serotonin: primary location in CNS, general effect, and associated response
KNOW!
- neurons originating in the brainstem that project upward to hypothalmus and downward to SC
- inhibition
- involved in the control of mood and anxiety
GABA: primary location in CNS, general effect, and associated response
KNOW!
- interneurons throughout the SC, cerebellum, basal ganglia, cerebral cortex
- inhibition
- increasing GABA activity decreases incidence of seizure activity
Glycine: primary location in CNS, general effect, and associated response
KNOW!
- interneurons in SC and brainstem
- inhibition
- more active in the SC than the CNS
Glutamate: primary location in CNS, general effect, and associated response
KNOW!
- interneurons throughout brain and spinal cord
- excitation
- degenerative diseases such as Parkinson’s, ALS, or Alzheimer’s may be related to increases in glumate; increased levels contribute to the secondary damage associated with stroke and SCI
*Aspartate was listed with glutamate in Ciccone but not Goodman and Fuller chart
Enkephalins: primary location in CNS, general effect, and associated response
KNOW!
- pain suppression pathways in spinal cord and brain
- excitation
- pain control acheived by use of drugs (opiates) that bind to endorphin and enkephalin receptors
**ß-endorphins listed with Enkephalins in Goodman and Fuller chart but not Ciccone
Substance P: primary location in CNS, general effect, and associated response
KNOW!
- pathways in SC and brain that mediate painful stimuli
- excitation
- involved in pain pathways
List some clinical manifestations of CNS disorders (5)
- Coordination disorders
- Changes in higer brain/cortical function
- Movement disorders
- Brainstem dysfunction – important processing station acts as conduit for spinal cord tracts, cerebellar and vestibular functions, and Reticular formation – movement
- Sensory disturbances: Skin, muscle, joint signals, cranial nerve functions
Clinical manifestations or deficits seen more specifically in higher brain/ cortical area with CNS dysfunction (7)
- Hemispheric syndromes- (ex: stroke)– inability to orient body in space and produce appropriate motor responses
- Emotional instability, disorders of emotional adjustment
- Attention, memory, reasoning, problem-solving
- Altered states of consciousness
- Autonomic dysfunction
- Aging – loss of cells, efficiency, average loss of 15% of nerve conduction velocity in CNS
- Language
List of diagnostic tools for CNS disorder-list from Dr.T’s pp (9)
- Clinical exam – history, symptoms, signs, your assessment
- CT scan
- MRI- T1, T2, Functional MRI
- Positron Emission Tomography (PET scan)
- Single-photon emission CT (SPECT)
- Electroencephalogy (EEG)- Look at amplitude of neuronal transmission, both focal and global
- Brainstem Auditory Evoked Potentials- Useful in assessing hearing, level of function in comatose individuals, brain stem function
- Transcranial Doppler Ultrasonography- Brain hemodynamics, can also detect emboli
- Near-infrared Spectroscopy- Brain oxygen saturation
Points re: CT Scan vs. MRI
- CT uses radiation; MR uses magnets and radio waves
- CT is quicker (less than 5 minutes) than MR (30 minutes) – CT therefore used for the quick diagnosis of hemorrhagic vs. occlusive CVA for purpose of tPA
- CT generally better for bone, chest, abdomen, spine, pelvis, tumors
- MR can be better for soft tissue, joint, tendon, ligament
***Much overlap here, frequently the choice is up to the MD
Points on choosing T1 vs. T2 MRI (5)
- Goal is image contrast, and tissues show up differently as they “relax” back from the initial magnetization
- T1, longitudinal relaxation time – good for borders between brain and CSF (sulci, ventricles, cysts); not very sensitive to lesions
- T1 weighted with Gd (gadolinium) contrast used for normal vessels, vascular changes, disruption of blood-brain barrier
- T2, transverse relaxation time – good for brain anatomy, CSF spaces, most brain lesions, early hemorrhage
- Signal strength of T1 and T2 can be used to gauge age of lesions (acute vs old)
Some points on use of Functional MRI (3)
- Depends on blood oxygenation level-dependent (BOLD) image
- Looks at functional activation of brain during a given task
- Can be used in research, or to track changes in ability to do motor, visual, cognitive tasks ex: Alzheimer’s (unlikely in treatment- research only, due to cost)
Points on use of PET scan and SPECT (3)
- Cellular activity via regional blood flow; good for organ function study and figuring out the physiology of what is going on
- Regional density of some neurotransmitters
- Can also be used to look at functional brain activation
Examples of when we may use an EEG
- a person in a coma- how deep and how severa a coma is
- used for sorting out problems with people with seizures
4 Ways to control CNS damage or deficits
- Changing production and uptake of neurotransmitters
- Selective interaction with neurotransmitter receptors
- Modulation of synthesis, release, reuptake, and degradation of neurotransmitters
- Mediation of neurotransmitter release by action at presynaptic receptors
2 Examples provided by Dr. T of drugs that can inhibit neurotransmitter release
- Opiates
- Botox or Baclofen for tone inhibition
How does anesthesia act of CNS
modify neurotransmitter receptors by changing the membranes of the cells on which or within the receptors are located
Several points made in lecture about dopamine (7)
- How can activitity be increased? (4)
- major source?
- how important is it? why does this matter?
- can dopamine cross BBB?
- What are two classes of meds that work on dopamine and for what are they used?
- activity can be increased by increased synthesis, increased release, prolongation of neurotransmitter activity, director receptor stimulation
- comes from substantia nigra
- dopamine is really important- great target in CNS but a dangerous target
- does not cross BBB
- Amantadine (Parkinson’s Disease) and some tricyclic antidepressants operate on the dopaminergic system through blockade of reuptake
- MAO (monoamine oxidase) inhibitors – first antidepressants, largely replaced, but Marplan, Nardil, Emsam, Parnate still in use; may be used in Parkinson’s
- COMT (catechol-O-methyl transferase) inhibitors - used in Parkinson’s; Comtan, Tasmar
Some alternative options for treating CNS deficits/damage (4)
- Anti-oxidant therapies – may prevent CNS damage from free radicals ExL Vitamin E, estrogen
- Gene therapies, nucleic acid sequences, hold promise for new treatment
- Stem cells – using adult undifferentiated cells (also called somatic stem cells) for cell renewal
- Non-neuronal drugs can influence CNS cells (example, mannitol for cerebral edema)
4 Points on epidemiology of MS
- women affected 2-3 times more than men (that sucks)
- caucasians affected the most, though reports of increasing cases in African American women (we’re all screwed)
- typically shows up in 30s though there are some pediatric cases
- 85%-90% experiemce relapse-remitting pattern with MS
Some symptoms a person with MS can experience (7)
- fatigue
- impaired mobility
- mood and cognitive changes
- cognitive fatigue
- pain and other sensory problems
- visual disturbance
- elimination dysfunction
What allows for inflammation to predominate in MS?
Th1 and Th17 environment with T regulatory dysfunction
Dr. T “T-side gets whacked up and filters over to the B side”- in reference to the inflammation picture and info above
Do people with an immune dysfunction catch colds faster and have more difficulty getting over them?
Dr. T says anecdotally yes
7 steps of inflammatory cascade in MS in perphery
- Antigen presentation to CD4+ prompting activation and proliferation of pro-inflammatory lymphocytes (Th1 and Th17)
- Secretion of pro inflammatory cytokines
- Up-regulation of adhesion molecules
- T-cell migration across the BBB into CNS
- B cell activation, proliferation, and migration into CNS
- Migration of macrophages and monocytes into CNS
- Inadequate T regulatory function
from pg 7 of the MS thing Dr. T put on D2L
3 steps of inflammatory cascade in CNS in MS
(from pg 7 or 8 of the MS handout on D2L)
- (in the chart)- Presentation of CNS antigen to T cell with reactivation
- Recruitment of other inflammatory cells: CD8+, B cells, monocytes, macrophages, microglia
- Damage to myelin, oligodendrocytes, and axons
- cytokine damage
- antibody activity
- complement damage
- oxidative stress
- mitochondral dysfunction
MS: What are five things related to damage to myelin, oligodendrocytes, and axons?
Damage to myelin, oligodendrocytes, and axons
- cytokine damage
- antibody activity
- complement damage
- oxidative stress
- mitochondral dysfunction
What do many MS medications act on?
interferons
Side effects of the inferon focused MS drugs (3)
- flu-like symptoms
- increased hepatic transaminases (possible liver injury)
- depression, possible suicide (under the Warning heading)
5 Proposed mechanism of Action for the interferon based MS drugs
Mechanism of action in MS is not known. Subsequent research suggests:
- promotes shift from Th1-Th2
- reduces trafficking across BBB
- restores T-reg cells
- inhibits antigen presentation
- enhances apoptosis of autoreactive T-cells
True or False: There are no MS medications with a black box warning
False
There are 4 and their common warning is risk of malignancy or leukemia. These are not the interferon based meds. They have a somewhat similar mechanism of action as the interferon meds, but seem to be less specific and seem to impair or mess with WBCs, T-cells, and B-cells more generally (although I could have interpretted that last sentence wrong, so you may want to reference the handout she gave us).
From study guide: Black Box warnings, including myelosuppression and leukoencephalopathy, as this greatly tinkers with the immune system.
The non-interferon based drug that had no black box warning and was part of our in class case study
glatiramer acetate36 (Copaxone®)
Tell me a few things about glatiramer acetate36 (Copaxone®)
- indication
- mechanisms of action (3)
- side effects (6)
Indication: relapsing form of MS
Mechanism of Action:
- promotes differentiation into Th2 and T-reg cells, leading to bystander suppression in CNS
- increased release of neurotrophic factors from immune cells
- deletion of myelin-reactive T cells
Side effects: injection-site reactions, lipoatrophy, vasodilation, rash, dyspnea, chest pain
