Unit 3 Neurodegenerative Flashcards
Neurodegenerative Disorders main characteristics
progressive & irreversible loss of neurons from brain regions, injury of specific type of neurons & locations, due to both genetic & environmental factors, pathology includes cellular aggregation of misfolded proteins
Alzheimer’s Disease
loss of hippocampal & cortical neurons results in impaired memory formation & cognitive deficits
Parkinson’s disease & Huntington’s disease
loss of dopaminergic neurons in basal ganglia leads to altered movement control
Amyotrophic Lateral Sclerosis (ALS)
Degeneration of control & spinal motor neurons results in muscular weakness
Alzheimer’s protein accumulation
extracellular beta-amyloid plaques & intracytoplasmic neurofibrillary tangles (tau protein)
ALS & Parkinson’s protein accumulation
Intracytoplasmic aggregates
Parkinson’s = alpha synuclein
Huntington’s protein accumulation
Intranuclear inclusions of huntingtin protein
Prion disease protein accumulation
extracellular prion amyloid plaques in different brain regions
Neurodegenerative disorders occur at what stage in life
later - over age of 65
Alzheimer’s cognitive symptoms
Loss of short-term memory, Aphasia, Apraxia, Agnosia, Disorientation
Alzheimer’s noncognitive symptoms
Depression, psychotic symptoms, behavioral disturbances
Alzheimer’s diagnosis
Based on clinical assessment - requires dementia (cognitive impairments beyond normal for their age)
Neuroimaging (CT & MRI)
Mild cognitive impairment (MCI) - initial diagnosis/manifestation of disease
MCI (mild cognitive impairment)
Can progress to Alzheimer’s but doesn’t always
Initial manifestation of progressive degeneration dementia
Cognitive impairment not reducing function (prefrontal cortex may be effected)
Most common cause of dementia in people 65 yrs or older
Alzheimer’s disease
Patients usually die within _____ of AD onset
6-12 years
Mild stage AD
First 3 years
Progressive loss of memory, impaired judgement, confusion, decreased concentration
Areas of brain effected are increasing
Moderate stage AD
2-10 years
Language impairments, decreased comprehension, sleep disorders, disorientation
Requires increase level of care
Severe stage AD
8-12 years
Most of brain affected, large amount of atrophy
Dependence, delusions, agitation, incapacitation (noncognitive disorders as well)
Needs to be in a care facility
Pathology of AD
Massive tissue damage & decreased brain volume from neuronal degeneration & atrophy, neuritic plaques, & neurofibrillary tangles
Cholinergic hypothesis of AD
Deficiency of ACh in certain brain areas due to degeneration of subcortical cholinergic neurons in hippocampus
Amyloid hypothesis of AD
Extracellular accumulations of beta-amyloid peptides that are toxic to neurons
Cleaved from APP & produced faster than cleared
Early-onset AD
Rare, related to mutations in APP & PSEN1/2 (cleave APP)
Overproduction of beta-amyloid
Late-onset AD
Common, epsilon4 allele of APOE - not as effective at clearing beta-amyloid
increases risk of AD 3x
Tau hypothesis of AD
Hyperphosphorylation of tau causes aggregates & forms neurofibrillary tangles
Causes microtubular instability, collapse of transport system, altered NT release & synaptic function, and cell death
AD treatment goals
Slow down progression, treat cognitive difficulties & preserve function, treat behavioral & psychiatric symptoms
Cholinesterase inhibitors used for
First line for symptomatic treatment of cognitive impairments in mild to moderate AD
Slows decline of cognitive & behavioral function
Cholinesterase inhibitors MOA
block AChE &/or BChE-mdiated breakdown of ACh to choline & acetate
Increase activation of postsynaptic ACh receptor
Cholinesterase inhibitors include
Tacrine, Donepezil, Rivastigmine, Galantamine
Tacrine
Cholinesterase inhibitor
No longer used - had extensive side effects & needed to be taken 4x per day (short 1/2 life) = bad compliance
Donepezil
Cholinesterase inhibitor
Primarily inhibits AChE
Long 1/2 life - once day dose
Improve cognition & clinical function, delay symptomatic progression
Rivastigmine
Cholinesterase inhibitor
Inhibits both AChE & BChE
2x per day dose
Transdermal patch can be used - has improved GI effects
Galantamine
Cholinesterase inhibitor
similar to Donepezil & Rivastigmine
2x per day dose
Main side-effects GI
Cholinesterase inhibitors side effects
GI effects main problem (nausea, vomiting, diarrhea)
Other side effects related to ACh: salivation, sweating, urinary incontinence, dizziness, muscle weakness, bradycardia
SLUDGE
Memantine
Glutamate antagonist
Non-competitive antagonist of NMDA glutamate receptor
Neuroprotection by reducing intracellular Ca influx & glutamate induced excitotoxicity
long 1/2 life
Commonly used in moderate-severe AD
Often used with other drug
Main side-effects are dizziness, headaches, depression
Preferred treatment of non-cognitive symptoms of AD are
non-pharmacologic approaches
Treatment options for Psychosis/agitated behavior in AD
Atypical antipsychotics
Treatment options for depression & anxiety in AD
SSRI - safe for elderly, better side effects (sertraline & citalopram)
Avoid tricyclics = confusion & falls
Treatment options for sleep disturbances
Antidepressants, atypical neuroleptics Avoid benzodiazepines (long acting) & antihistamines (anti-cholinergic)
