- clinically isolated syndrome (CIS) - primary progressive (PPMS) - relapsing-remitting MS (RRMS) - secondary-progressive (SPMS)

Lecture 15: Progressive Neurodegenerative Disorders Flashcards by Avery H

innate immune system

1st line of defense, non-specific immune response that responds to all pathogens the same way

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adaptive immune system

specifically targets the type of pathogen causing infection
- slower, more accurate, can remember pathogens via antibodies

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macrophages

engulf & destroy pathogens; antigen presenting capability

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T cells

directly attack cells w/ specific antigen
- killer, helper, or regulatoryB

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B cells

major function to produce antibodies; when they encounter antigens they mature into plasma cells or memory cells

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major histocompatibility complex

encodes cell surface proteins that are responsible for presenting antigens to T cells (HLA system)

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antibody

protein produced by immune system (B cells) in response to specific infection

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two processes in MS

focal inflammation –> lesions & injury to BBB; damage to axons, neurons, synapses

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genes involved in MS

HLA-DRB1 gene, HLA-DRB115:01

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HLA-DRB1 gene

part of MHC that is crucial in presenting peptides to T cells

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DRB115:01 gene in MS

strongest genetic risk factor for MS
- mechanism of action may have to do w/ presentation of self-antigens to T cells, triggering autoimmune response

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risk factors for MS

Epstein-Barr virus
genes

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Types of MS

clinically isolated syndrome (CIS)
primary progressive (PPMS)
relapsing-remitting MS (RRMS)
secondary-progressive (SPMS)

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clinically-isolated syndrome (CIS)

1st & single episode of inflammation or demyelination in the CNS lasting > 24 hours

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primary-progressive (PPMS)

progression of neurological dysfunction/disability present from onset of MS, without relapses or remissions

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relapsing-remitting MS

most common form; attacks last days-weeks w/ periods of stability & absence of disease

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secondary-progressive

consistently progressive & includes more frequent relapses w/ minor remission; loss of physical & mental functio

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what contributes to the late stages of MS

neurodegeneration, astrocyte & oligodendrocyte damage by oxidative stress, hypoxia, altered glutamate homeostasis, pro-inflammatory environment

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what supports a diagnosis of MS

evidence of 1+ relapses (confirmed through clinical evidence of 1+ lesions or objective clinical evidence of 1 lesion w/ reliable historical evidence of a prior relapse)

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disease-modifying drugs for RRMS

IFNbeta or glatiramer acetate

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medications for MS

Natalizumab, Ocrelizumab

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what is Natlizumab

monoclonal antibody against molecule alpha4-integrin (found on white blood cells)

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method of admin for Natalizumab

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Natalizumab function

reduces inflammatory & immune cells to pass through BBB

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what does Natalizumab increase risk for

multifocal leukoencephalopathy

what is Ocrelizumab

monoclonal antibody targeting CD20 on B cells - immunosuppressant drug

what is ALS

amyotrophic lateral schlerosis - brain loses connection w/ muscles

what does ALS affect

descending corticospinal motor neurons

pathological ALS features

- SOD1 aggregates - superoxide dismutase - loss of TDP-43 from nucleus

main mechanism of ALS disease progression

excitotoxicity from reduced glutamate uptake

what causes excitotoxicity by excessive stimulation of glutamate receptors

EAAT2 (reuptake transporters) downregulation --> overactivation of NMDARs

how is TDP43 a part

upregulated a lot in ALS; may affect EEAT2 transcription

SOD1 importance to ALS

familial mutation; results in a mutant protein that aggregates & harms cells

what is SOD1 normal function

- superoxide dismutase 1 - protects cells from reactive oxygen species

how is C9orf72 implicated in ALS

- familial factor - most common ALS mutation - repeat sequence expanded 100s of times

why did Hawking live so long

his ALS did not affect either motor neurons controlling diaphragm and had no deterioration of muscles responsible for swallowing

FDA approved meds for ALS

- Riluzole - Edaravone - Relyvrio - Tofersen - Nuedexta

Riluzole function

inhibits glutamate release from presynaptic terminals by inactivating NaV channels

Edaravone function

free radical scavenger anti-oxidant

Relyvrio function

blocks apoptotic pathways in mitochondria & ER, improves mitochondrial energy production

Tofersen function

antisense oligonucleotide that targets SOD1 mutation, reduces SOD1 protein production

Nuedexta function

treat uncontrollable episodes of crying or laughing; combo of dextromethorphan (alpha1 receptor agonist, SNRI, NMDA antagonist) & quinidine (CYP2D6 inhibitor to block dextromethorphan metabolism)

mechanism of ALS progression

disruptions in protein quality, RNA metabolism, hyperactivation of microglia, & excitotoxicity via glutamate buildup

supportive therapies for ALS

palliative care, mobility, speech & swallowing, ventilation

what protects younger brains from AD

- higher levels of growth factors - better energy metabolism - better mechanisms for clearing misfolded proteins - better mechanisms for repairing cells - less neuroinflammation

canonical hallmarks of Ad

- intracellular tau-containing neurofibrillary tangles - extracellular amyloid beta deposition

what is amyloid beta formed from

amyloid precursor protein

what is amyloid precursor protein important for

synaptic formation & repair - expressed in cell membrane

why are amyloid beta plaques bad

prevent neural communication

amyloid beta function

destabilizes tau proteins by activating intracellular kinase that phosphorylates tau

tau protein importance

stabilizes microtubule tracts crucial for transport

what is acetylcholine synthesized from

acetyl CoA + choline via choline acetyltransferase (ChAT)

what is the vesicular transporter for acetylcholine

VAChT (vesicular acetylcholine transporter)

what degrades acetylcholine in the synaptic cleft

cholinesterase

what reuptakes choline

choline transporters in plasma membrane

acetylcholine receptors

nicotinic (ion channels), muscarinic (GPCRs)

acetylcholine function in AD

- reduced choline uptake - reduced Ach release - reduced ChAT - reduced nAChRs

what are the two main cholinergic projections

to the cortex, & to the thalamus & basal ganglia

AD diagnostic criteria

- family history - cognitive & neuropsychological tests - CSF taps for amyloid beta peptides & tau protein - PET or MRI scans to examine brain shrinkage & glucose metabolism

approved drugs for AD

Namzaric (combination of memantine & donepezil), Aducanumab (monoclonal antibody against amyloid beta)

four categories of AD drugs

- acetylcholinesterase inhibitors - Abeta fiber removal - NMDAR antagonists (prevents excitotoxicity) - others for AD side effects)

Lecture 15: Progressive Neurodegenerative Disorders Flashcards

(61 cards)