Neurodegenerative diseases Flashcards
What are the major areas affected in AD?
Hippocampal and cortical neurons
Are neurodegenerative disorders genetic or environmental?
Both
What is the major pathological mechanism associated with neurodegenerative disorders?
Aggregation of misfolded proteins
What is the pathological basis for ALS?
Degeneration of cortical and spinal motor neurons
What is the pathological basis for Parkinson’s and Huntington’s disease?
Loss of dopaminergic neurons in basal ganglia
How fast does death come with AD?
6-12
What is the protein that accumulates in AD? How do these aggregate?
beta-amyloid plaques
Neurofibrillary tangles
What is the protein that accumulates in PD? How do these aggregate?
alpha synuclein
Forms Parkinson Lewy bodies
What is the protein that accumulates in Huntington’s disease? How do these aggregate?
Huntingtin protein (intranuclear)
What is the protein that accumulates in creutzfeldt-jakob disease?
Prion amyloid proteins
When in life do the neurodegenerative disorders usually present?
65+
What is the gene that is implicated in early onset AD? Late?
Early = APP gene (gene for precursor amyloid protein), and PSEN1/2 Late = epsilon4 APOE allele
What are the ssx of Alzheimers?
- Loss of short term memory
- Aphasia
- Agnosia
- Disorientation
What are the neurocognitive ssx of Alzheimer’s?
Depression
Psychotic symptoms
What is aphasia?
Difficulty remembering words
What is apraxia?
Inability to carry out motor activities
What is agnosia?
Inability to recognize object, people, etc
How do you diagnose AD?
Progressive cognitive impairment
What are the elements of the neurofibrillary tangles in AD?
Hyperphosphorylation of tau proteins
What are the elements of amyloid plaques in AD?
Insoluble amyloid B proteins
What is the neurotransmitter that is lacking in AD? Which area of the brain is involved?
Deficiency in cortical ACh
What is the pre-AD state called? What are the symptoms of this? Does this always lead to AD?
Mild cognitive impairment
Cognitive impairment NOT reducing function
Does not guarantee AD
What are the ssx of mild AD?
Memory loss
Confusion
Impaired judgement
Decreased congition
What are the ssx of moderate AD? (4)
- Language impairment
- Decreased comprehension
- Disorientation
- Sleep disorders
What are the ssx of severe AD? (4)
- Dependence
- Delusions
- Agitation
- Incapacitation
What is the cholinergic hypothesis in AD?
Degeneration of ACh in subcortical cholinergic neurons
True or false: there is a strong correlation between the accumulation of beta-amyloid proteins and neuronal loss in AD
False –poor correlation
Why is it that pts with Down syndrome are predisposed to AD?
APP gene for beta-amyloid is located on chromosome 21. These pts get an extra copy of the chromosome
What is the role of APP? PSEN1-(2)?
APP = encodes amyloid beta precursor peptide
PEN1/2 = Membrane proteins involved in cleaving APP
What is the role of epsilon3 allele of APOE?
Encodes apolipoprotein E, which enhances the breakdown and clearance of A-beta within and between cells
What is the Tau hypothesis?
Hyperphosphorylation of Tau causes microtubular instability, and subsequent collapse of the neuronal transport system. This leads to cell death
What is the function of Tau normally?
Provides support for microtubule structures
What are the histological characteristics of AD?
Plaques and tangles surrounded by halo of nerve endings, with microglia
What is the primary intervention for AD?
nonpharmacologic therapy
What are the two goals of pharmacological therapy with AD?
- Symptomatically treat cognitive difficulties
- Treat behavioral and psychiatric symptoms
What are the three current focuses of R&D toward AD?
Drugs targeting Beta amyloid, Tau, and ApoE
What is the role of AChE (BChE) inhibitors in AD?
Slow down the degradation of ACh
What is the effect of AChE inhibitors on Tau function?
Rebalance the overly phosphorylated Tau protein state back to normal
What is the effect of AChE inhibitors on APP?
Increase in soluble APP and decreased production of Abeta
What are the 5 AChE inhibitors used to treat AD?
Tacrine
Donepezil
Rivastigmine
Galantamine
What is the MOA of tacrine?
AChE inhibitor
What is the MOA of Donepezil?
AChE inhibitor
What is the MOA of Rivastigmine? How is it administered?
AChE and BChE inhibitor
Transdermally
What is the MOA of Galantamine?
AChE inhibitor
What are the side effects of the AChE inhibitors?
Diarrhea
N/v
Insomnia
Weight loss
Why did Tacrine have such a low compliance rate?
Short half life meaning need for frequent dosing, which is hard for those with memory impairment
What is the half-life of Donepezil?
70-80 hours
What are the general side effects of cholinesterase inhibitors?
Salivation Lacrimation Urinary incontinence Diarrhea Intestinal cramps Emesis
What is the MOA of Memantine? Halflife?
Non-competitive antagonist of NMDA receptors
60-80 hour half life
How does Memantine provide neuroprotection?
Reducing intracellular Ca influx and glutamate induced excitotoxicity
Is estrogen effective in preventing or treating AD?
No
What is the role of vitamin E and AD?
Not valid, mixed results
What is the role of Ginkgo in AD?
Not valid, mixed results
What is the role of NSAIDs in AD treatment?
Decrease the inflammatory process of microglia, but not evidence for influencing existing A
What are the drugs used to treat the psychosis/agitated behavior associated with AD?
Atypical antipsychotics
What are the two SSRIs that are used to treat depression associated with AD?
Sertraline
Citalopram
Why should you avoid TCAs in AD?
Anticholinergic effect and the orthostatic hypotension
What is the mood stabilizers for AD pts?
Carbamazepine
