Exam 3: Alzheimer's and Dementia Flashcards
Ratio female:male for AD
2:1
AD symptoms
memory loss
impaired ability to learn/reason
impaired ability to carry out daily activities; confusion, untidiness
anxiety, suspicion, hallucinations
motor dysfunction can also occur in late-stage disease
Environmental risk factors AD
age
low educational level
reduced mental activity in late life
reduced physical activity in late life
risk for vascular disease
head injury
Amyloid Plaques
extracellular
consists of amyloid b peptide
Neurofibrillary Tangles
intracellular
consist of hyper-phosphorylated tau
Progression of neuropathology
plaques and tangles spreads through the cortex as the disease progresses
Effect of Neuropathology: Entorhinal Cortex
memory formation/consolidation
Effect of Neuropathology: hippocampus
memory formation/consolidation
Effect of Neuropathology: basal forebrain cholinergic systems
learning
Effect of Neuropathology: neocortex
memory, learning, cognition
Synapse Loss in AD
neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques see the destruction of synapse
synapse loss results in reduced levels of neurotransmitters, especially acetylcholine
dysregulated glutamate –> excess excitotoxicity and neurotoxicity
Which is the key pathogenic molecule: AB or tau?
AB
mutations in the gene encoding the AB precursor protein (APP) are linked to early onset AD
Trisomy 21 is associated wit hAD like phenotype and the APP gene is located on chromosome 21
Production of AB from APP
cleavage of APP by a-secretase in the middle of the AB segment releases a non-amyloidoogenic (non-toxic) fragment
mutations in the APP gene favor cleavage by beta or gamma secretase, resulting in the production of more AB42 relative to AB40
mutations in the gene encoding PSEN1 or 2 alter APP cleavage by gamma secretase, resulting in the production of more AB42 to AB40
Effects of AB aggregation on tau pathology
AB aggregation is thought to promote tau hyper-phosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking
Neurofibrillary Tangle Formation results in cytoskeletal defects
in unhealthy areas where tangles have accumulated, the cytoskeletal tracts are disrupted and disorganized, resulting in defects in axonal transport that leads to synaptic dysfunction (tau falls off)
Effects of AB aggregation on microglial activation
activated microglia release pro-inflammatory cytokines that cause neuroinflammation
activated microglia also release reactive nitrogen species and reactive oxygen species that cause oxidative stress
Impact of ApoE genetics on AD risk
individuals with one or two Apo4 alleles have an increased risk of AD whereas inheritance of hte ApoE2 allele decreases AD risk
Donepezil
specific reversible inhibitor of acetylcholinesterase
Rivastigmine
inhibits acetylcholinesterase and butyrylcholinesterase (patch or orally)
galantamine
selective, reversible inhibitor of acetylcholinesterase AND enhances the action of acetylcholine on nicotinic receptors
Cholinesterase Inhibitor MoA
block the degradation of acetylcholine thereby compensating for the loss of acetylcholine that results from the degeneration of cholinergic nerve terminals in AD
Memantine
NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism, reduces excitotoxicity
Strategies for Disease Modifying Therapy (AD)
AB generation (beta and gamma secretase inhibitors)
AB aggregation (inositol, polyphenols, peptides)
AB clearance (vaccine, AB antibodies (aducanumab, lecanemab, donanemab)
tau kinase inhibitors (lithium, valproate)
glutamate mediated excitotoxcity (induces expression of GLT-1 transporter)
inflammation or oxidative stress (NSAIDS, dietary antioxidants)
Florbetapir
radiolabeled agent that binds beta-amyloid, visualized by PET scanning
radiolabeled agent specific for tau: 18F-Flortaucipir
Vascular Dementia
impaired judgment or executive function
occurs as a result of brain injury associated with vascular disease or stroke
Dementia with Lewy Bodies
combination of cognitive decline and parkinsonian symptoms
visual hallucinations
cortical lewy bodies
Frontotemporal Dementia
disinhibited behavior
tau accumulations (pick’s bodies)
NCD: complex attention
sustained/divided attention, processing speed
NCD: learning and memory
immediate/recent memory, very long term memory
NCD: perceptual/motor
visual perception/praxis
NCD: executive function
planning, decision making, working memory, flexibility
NCD: language
expressive and receptive language (naming and word finding)
NCD: social cognition
recognition of emotions, range of behavior
Mild NCDs
modest cognitive decline from a previous level of performance in one or more cognitive domains
does not interfere with independence
not attributed to a delirium epsidoe
Major NCDs
evidence of significant decline from a previous level of performance in one or more domains
cognitive deficits interfere with independence
not attributed to a delirium episodes
Differential diagnosis
CV disease/vascular dementia
lewy body dementia
PD
normal pressure hydrocephalus
mixed dementia
pick’s disease
huntington’s disease
reversible causes
reversible cognitive decline
B12 or folate deficiency
hypothyroidism
CBC
liver function tests
infection (UTI)
depression
RPR/VDRL (syphilis) f
Drug Induced NCDs
skeletal muscle relaxants
tricyclic antidipreseants
bladder antispasmodics
antihistamines (anti-emetics, allergy/cough cold)
Treatment goals
slow the symptoms of cognitive decline and preserve functioning for as long as possible
Cholinesterase Inhibitors place in therapy
first line with no preference as to agent
donepezil fda approved for severe demential and is chosen first due to ease of dose titration and once-daily dosing
donepezil, rivastigmine, galantamine
NMDA receptor antagonist place in therapy
FDA approved in moderate to severe dementia only
not useful in mild cognitive impairments
marginal benefit usually realized in alzheimers
does not slow or prevent neurodegeneration
memantine, donepezil/memantine
Donepezil Dosing
initiate 5 mg once daily at bedtime, increase to 10 mg once daily at bedtime for 4-6 weeks
Donepezil AEs
GI bleeding (caution if used with NSAIDs)
N/V/D
Bradycardia
syncope
insomnia
weight loss
P450 2D6 and 3A4 substrate
Galantamine Dosing
4 mg twice daily for 4 weeks with breakfast and dinner
doses > 16 mg/day are not recommended for moderate renal/hepatic impairment
Galantamine AEs
GI bleeding (caution if used with NSAIDs)
N/V/D
Bradycardia
syncope
insomnia
weight loss
P450 2D6 and 3A4 substrate
Rivastigmine
initiate 1.5 BID for at least 2 weeks and titrate by 1.5 mg BID every 2 weeks
max dose: 6 mg
take with meals to minimize GI effects
Rivastigmine AEs
toxicity due to not removing previous patch every day
NVD
esophageal rupture in one case (restart lower dose if therapy interrupted
no P450 interactiosn
Memantine Dosing
dose adjustment required in severe renal impairment
CrCl: 5-29 mL/min, initiate 5 mg once daily x 1 week if tolerated, target dose 5 mg bid
Memantine AEs
use with caution in patients with seizure disorder
hallucinations
insomnia
confusion
Caution with CA inhibitors and Sodium bicarb
no P450 interactiosn
Memantine/Donepezil dosing
On donepezil 10 mg only: start Namzaric 7/10 daily and increase by 7 mg increments as tolerated t o28/10 mg target dosing once daily
if on memantine 10 mg bid or ER 28 mg once daily, switch to namzaric 28/10 with evening meal once daily
Memantine/Donepezil AEs
warning for vagotonic effects like bradycardia and heart block
increased risk of GI ulceration, diarrhea, NV, bladder outflow obstruction
Combo Treatment
Cholinesterase+NMDA
initial treatment is usually cholinesterase
if declien noted despite treatment at maximum tolerated dose, consider use of NMDA receptor antagonist in combo if pt is in moderate to severe stage
Key Concept of Oral Agents
sudden start/stop of therapies should be avoided
Memantine only works if initiated early on
false! can see benefit later on
Aducanumab Side Effects
ARIA: reiques MRI of brain within one year of starting treatment, then before 7th and 12th dose
Lecanemab Side Effects
ARIA: up to 30% requires MRI of brain within one year of starting treatment, then before 5th, 7th, and 14th doses
Pharmacotherapy of Dementia: mABs
requires presence of amyloid beta pathology prior to initiating treatment
