Therapeutics - Dementia Flashcards
What is the aetiology of Dementia?
Degeneration of ACh neurons in neurocortex (involved in higher brain fns: cognition, decision making, learning impairment)
Degeneration in Nucleus Basalis of Mainard (NBM) - cholinergic pathways
UNCONFIRMED: too much glutamate –> neuronal death (NMDA rece med excitotoxicity)
What is the pathophysiology of dementia?
Senile plaque formation = aggreg of beta-amyloid peptide
- Derived from cleavage of larger amyloid precuror protein (APP) via action of beta and gamma secretases (5%)
- Amyloid plaques accum & spread throughout brain in hippocampus, amygdala, cerebrocortex –> neurotoxicity, impaired neurofn
- Plaques can stim astrocytes & microglia (meant to clear debris)
- Trigger processes e.g. inflamm cytokine release that damage axons, dendrites –> loss of synapses by phagocytosis
- Synapses malfn, neurons die, abnormal patterns of activity emerge –> brain unable to process & store info properly
Neurofibrillary tangles=hyperphosphorylated tau protein aggreg forming paired helical filaments (PHF)
- tau: tubulin assoc protein in axons needed for microtubule stabilisation and intracellular transport
- Microtubule usually stabilised by tau protein
- Modified tau proteins dissoc from microtubules, adopt abnormal shape, move from apexes to cellbody, may aggreg –> tangles
- Misfolded tau proteins may spread across synapses to healthy neurons whr they make healthy neurons whr they make healthy tau proteins misfold
What are the risk factors associated w BPSD?
Medical:
Depression, anxiety
Delirium
Untreated pain
Infection
Dehydration or hyponatremia
Fatigue
Hearing/visual impairment
Drug:
Anticholinergics, ASM coricosteroids, meds w sedative action, anti-Parkinsonian
Env or social:
Unfamiliar env
Isolation, loneliness
Lack of privacy
What are the risk factors of dementia?
Age
- Affects 5-10% of ppl >65y.o.
- 50% of those >85y.o.
Female
Ethnicity: Black, Hispanic
Genetics
- Apolipoprotein E (APOE4) gene [Alzhiemer’s disease] - homozygous
HTN, DM
Binge drinking
Smoking
Limited physical activities
Obesity
Depression
Hearing loss
Conditions that cause constriction to blood vessels in brain
Head injuries
Describe the epidemiology of dementia
Most common neurodegenerative disease
One of major causes of disability and dependency among older ppl
SG
- 1 in 10 seniors >60y.o. has dementia
- ~28 000 ppl >60y.o. live w dementia
- By 2030, there will be >150 000 persons w dementia
What is the diagnostic criteria for alzheimer’s disease?
- A/w the region of brain where neurodegeneration occurs
- Affects at least 2 domains of cognition
- Memory, lang, attention, problem solving, ability to manipulate in a spatial manner, executive fn etc.
- Need to occur at least 6mo (otherwise “delirium”)
DSM-5 Criteria for MAJOR Neurocognitive Disoder (Dementia)
A. Evi of sig cognitive decline from prior level of performance in one or more cognitive domains (complex attention, executive fn, learning & memory, lang, perceptual-motor or social cognition)
1. Concern of indi, a knowledgeable informant or the clinician there has been sig decline in cognitive fn
2. Substantial impairment in cognitive performance preferable documented by standardised neuropsychological testing or in its absence other quantified clinical assessment
B. The cognitive defecits interfere w independence in everyday activities
C. The cognitive defecits do not occur exclusively in cxt of delirium
* Often acute, suddenly confused over weeks, RULE OUT
D. The cognitive defecits are not better explained by another mental disorder
What are the signs and symptoms of alzheimer’s disease
Signs
- Abnormal protein aggregates (senile plaques, neurofibrillary tangles)
- Brain atrophy: grey matter becomes thinner, wedges wider, in areas critical to cognition
- Neuronal death: neurons of multiple neurotransm sys, results in neurochem defecits & alt –> cognitive decline and neuropsychiatric behaviours
Symptoms
- Slow onset & gradual progression over months or years
- Short term memory loss, word finding difficulties
- Psychiatric symptoms esp in early stages e.g. depression, psychosis, aggression
- Progressive loss of cognitive fn, personality and self
- Progressive worsening of ADLs
- ADL, Behaviour, Cognition, Disorientation
BPSD (at least 80% of pts w dementia hv BPSD)
- Agitation, aggression, psychosis, depression and apathy
- Symptoms are often an attempt by pt to comm
- Depression and anxiety can be among 1st symptoms
- Aggression, agitation more common later
What are the principles of pharmacological management of dementia?
How do we diagnose dementia?
Hx
Cognitive exam
- Mini MSE
Neuropsychological testing
Physical exam
Fnal defecits (ADL)
Laboratory testing (TFT, vit B12, others as indicated)
Neuroimaging (CT, MRI)
If Dx uncertain and Alzheimer’s disease is suspected, consider either
- FDG-PET (fluorodeoxyglucose-positron emission tomogrophy CT) or perdusion SPECT (single photon emission CT) if FDG-PET unavail OR
- Exam CSF
a. For total tau and phosphorylated tau 181 + b. amyloid beta 1-42 or amyloid beta 1-42 and amyloid beta 1-40
What are the principles of non-pharmacological management?
Activity (physical)
- Reg exercise
- Tai Chi, music and dance, swimming, walking, gardening
Brain activities
- Mental stim
- Reading, puzzles, word games, memory trg
Connectivity (social)
- Active social life
Diet (Mediterranean, high veg, olive oil, moderate consumption of protein)
- More whole grains, nuts, poultry, fish
- Foods high in omega-3FA
Adequate sleep
Proper personal hygiene
Safety
Medical and advanced care directives
Financial planning - allocation of assets
Long term health care planning
Describe the disease progression of dementia.
Early stage manifestations:
Cognitive - episodic memory loss/impairment, word finding difficulties (anomia), loss of word meaning (semantic defecits)
Psychological - apathy, depressive symptoms
Behavioural - withdrawal from social engagement, disinhibition
Sleep - REM behaviour disorder, acting out dreams
Physical - gait impairment –> falls
Later stage manifestations
Cognitive - memory loss in working memory (ability to process and store info), more marked expressive difficulties and eventual loss of language (e.g. global aphasia)
Psychological - delusions, anosognosia - lack of insight into cognitive problems, w attempt to cont to drive or manage money
Behavioural - aggression, hallucinations, wondering
Sleep - altered sleep cycle
Physical - repetitive purposeless movements, Parkinsonism, seizures
What are the goals of management in alzheimer’s disease?
Slow progression (reducing cognitive decline & preserving fn)
Delay need to institutionalisation
- Managing behavioural problems of AD
- Support & edu for family & caregiver
Improve QoL for both pts and caregivers
- Reduce suffering caused by cognitive and accompanying symptoms e.g. mood, behaviour
What are the principles of pharmacological management wrt the cognitive presentations of alzheimer’s disease?
Mild-moderate alzheimer’s disease: Acetylcholinesterase inhib - donepezil, galantamine, rivastigmine
- Monothera
- Modestly improves cognition, ADL, behaviour
Mod-severe alzheimer’s disease:
Acetylcholinesterase inhib - donepezil, galantamine, rivastigmine
- Monothera
- If severe add on
NMDA rece antagonist - memantine
- Also used in pts intolerant to AI
What are the principles of pharmacological management wrt BPSD?
Pharm interventions limited role in management of BPSD
Only consider if
- BPSD severe
- Excluded potentially reversible causes, med problems
- Non-pharm hv been trialled
- Evi of effectiveness
- UNLESS immediate risk to pt or others or pt severely distressed
Ini as trial
- Routinely withdraw slowly after 3mo of improved symptoms unless underlying comorbid psych disorder
- Review resp to treatment, dose, ADR at least Q3mo
- Restart at lowest effective dose if symptoms return following withdrawal
- Schedule further trial withdrawal in 3-6mo
SSRI
- Effective for management of depression and anxiety in pt w dementia that cannot be managed by non-pharm alone
- Escitalopram, citalopram, setraline: reduce agitation in pts w AD, may improve other BPSD e.g. delusions
- Consider dose-dep risk of increased QTc prolongation & worsening cognition (balance risk vs benefit)
TCA
- NOT to be prescribed in pts w dementia (anticholinergic S/E)
Antipsychotics
- Only appropriate if aggression, agitation or psychotic symptoms causing severe distress OR immediate risk of harm to pt or others
(unless pre-existing comorbid mental illness whr antipsychotic are indicated
- Only modestly effective in managing BPSD
Unlikely beneficial for wandering, calling out, social withdrawal or inappropriate sexualised behaviours in pts w dementia
- Less likely for intermittent but challenging behaviours that are closely related to clear env triggers e.g. aggression that only occurs durg personal cares
- A/w increased risk of strokes, CV events & death for some older ppl, particularly those w dementia
How do we monitor alzheimer’s disease?
MMSE
* Mild: 20-24/30
o Cognitive: short term memory loss, word finding difficulties
o Fnal: loss of ADLs e.g. laundry, housekeeping and managing meds, may get lost in familiar places
* Mod: 10-19/30
o Cognitive: disorientation to time & place, inability to engage in activities and conversation
o Fnal: needs assistance w ADLs e.g. bathing, dressing, toileting
* Severe: < 10/30
o Cognitive: loss of speech and ambulation, incontinence of bowel and bladder
o Fnal: dependency in basic ADLs e.g. feeding oneself, often needs round the clock care
MoCA
* Mild cognitive impairment: 18-25 pts
* Mod cognitive impairment: 10-17 pts
* Severe cognitive impairment: <10pts
