Dementia Part 1 Flashcards
DSM-5 Clinical Definition of Dementia
CCELL
- Evidence of significant cognitive decline, from prior level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor or social cognition)
- Concern of the individual/informant/clinician that there has been significant decline in cognitive function
- Substantial impairment in cognitive performance preferably documented by standardized neuropsychological testing or in its absence other quantified clinical assessment
- Cognitive deficit interferes with independence in everyday activities (IADLs, ADLs)
- Cognitive deficits do not occur exclusively in the context of delirium
- Cognitive deficits are not better explained by another mental disorder
DSM-5 Clinical Definition of Minor Neurocognitive Disorder (MCI)
- Evidence of modest cognitive decline, from prior level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor or social cognition)
- Concern of the individual/informant/clinician that there has been mild decline in cognitive function
- Modest impairment in cognitive performance preferably documented by standardized neuropsychological testing or in its absence other quantified clinical assessment
- Cognitive deficit interferes with independence in everyday activities (IADLs, ADLs)
- Cognitive deficits do not occur exclusively in the context of delirium
- Cognitive deficits are not better explained by another mental disorder
What is Minor Neurocognitive Disorder (MCI)?
People with MCI can live for decades without developing dementia
How to differentiate diagnosis of delirium?
Diagnosis of delirium by Confusion Assessment Method (CAM)
Presence of features 1, 2 and either 3 or 4
- Acute onset and fluctuating course
- compare mental status with baseline
- symptoms of delirium come and go
- Inattention
- Disorganized thinking
- disorganized, rambling, illogical flow of ideas
- Altered level of consciousness
- as long as not alert; may be hyperalert/vigilant, lethargic/drowsy, stupor, coma
Factors that contribute to /may present with delirium
Drugs - e.g., antihistamines
Electrolyte and endocrine imbalance - e.g., dehydration, hyponatremia, hypothyroidism; blood works required
Lack of drugs - e.g., BZD withdrawal, increased pain levels
Infections - physical exam, diagnostic tests
Reduced sensory input - e.g., lack of hearing and vision aid
Intracranial disorders - e.g., stroke, bleed
Urinary and fecal disorders - e.g., urinary retention, constipation
Myocardial and pulmonary disorders - e.g., MI, arrhythmias, hypoxia, hypercapnia
(similar to factors contributing to BPSD)
Hallmark presentations of dementia
CPBSP
Canberra plaza behind sunshine plaza
- Cognitive (most prevalent symptoms)
- Early stage: short-term memory loss, anosmia, semantic deficits
- Late stage: long-term memory loss, more marked expressive difficulties and loss of language
- Psychological
- Early stage: apathy, depressive symptoms
- Late stage: delusions, lack of insights
- Behavioural
- Early stage: withdrawal from social engagement, disinhibition
- Late stage: aggression, hallucinations, wandering
- Sleep
- Early stage: rapid eye movement behavior disorder - a/w dreaming, memory consolidation (dream-enactment)
- Late stage: altered sleep-wake cycle
- Physical
- Early stage: gait impairment, falls
- Late stage: repetitive purposeless movements, parkinsonism, seizures
Types of Dementia
- Alzheimer’s disease (progressive neurodegenerative disease)
- Vascular dementia (contributed by vascular events such as stroke, that precedes dementia)
- Lewy body dementia
- Frontotemporal dementia
- Mixed type (commonly AD + VD)
Alzheimer’s disease onset and course
- Slow onset and gradual progressive over months or years
Alzheimer’s disease history, examination, and cognitive features in early stage
History:
- Presenting symptom is typically short-term memory loss
Examination/Cognitive testing:
- Episodic memory impairment accompanied by other subtle cognitive deficits, such as visuospatial problems and anomia
Alzheimer’s disease pathologic characteristics
Brain atrophy
- Esp of the mesial temporal lobe (hippocampus, involved in learning and memory), may also involve neocortex involved in cognition
- Atrophy is due to degeneration of cholinergic neurons
Histologic hallmarks
- Senile plaques (if pt has AD, high chance to see senile plaques)
- Neurofibrillary tangles (not characteristics of AD, may find in other neurodegenerative diseases as well)
How to observe senile plaques and neurofibrillary tangles?
Can only be seen in brain biopsy with is invasive, not routinely done
However, levels of amyloid and tau protein in CSF can be measured via lumbar puncture (not routinely done)
What are senile plaques?
Neuritic plaques containing aggregates of B-amyloid peptides, to form B-amyloid plaques (OUTSIDE CELL)
Derived from cleavage of larger amyloid precursor protein (APP) via action of B-secretases into insoluble peptides that create a monomer called B-amyloid
What happens?
- In normal circumstances, APP helps with neuron growth and repair
- Overtime, gets broken down by enzymes (B-secretases into insoluble peptides, a- secretases into soluble peptide that is excreted)
- B-amyloid are sticky and aggregate to form a plaque
- Plaque can potentially get between the neurons, which can interfere with neuron-to-neuron signaling, causing neurotoxicity and affecting neurofunction
What else?
- B-amyloids also start up immune response and cause inflammation which may disrupt surrounding neurons
- B-amyloids also deposit around blood vessels in the brain, may lead to amyloid angiopathy, weakened the walls of blood vessels, increase risk of hemorrhage and rupture
What are neurofibrillary tangles?
Hyperphosphorylated tau protein aggregates forming paired helical filaments (PHF) (INSIDE CELL IN CYTOPLASM/AXONS/DENDRITES)
- Tau: tubulin associated protein needed for microtubule (cytoskeleton) stabilization and intracellular transport
What happens?
- Activation of kinase, an enzyme that transfers phosphate groups to the tau protein
- tau protein changes shape and stops supporting microtubules, tau proteins clumps up/gets tangled leading to neurofibrillary tangles + loss of skeletal microtubules
- Neurons with tangles and non-functioning microtubules cannot send signals, may undergo apoptosis
Non-modifiable risk factors for AD
- Age (affects 5-10% of people >65y; 50% of people >85y)
- Female
- Ethnicity (black, hispanic)
- Genetics (APOE4 gene - regulator of lipid metabolism, affinity for B-amyloid protein)
Is routine testing for APOE4 gene done? Why or why not?
No, but may be done in cases where there is clear family history of genetic predisposition
*One allele => 50% incr risk
*Two alleles => substantial incr in risk
Modifiable risk factors for AD
- Hypertension
- Diabetes
- Binge drinking
- Smoking
- Limited physical activities
- Obesity
- Hearing loss
- Depression
Stages of AD
- Cognitive screening tools
- Mini mental state examination (MMSE) - out of 30
- Mild: 20-24
- Mod: 10-19
- Severe: <10
- Montreal cognitive assessment (MOCA)
- Mild: 18-25
- Mod: 10-17
- Severe: <10
Clinical Evaluation of Suspected Dementia
- Medical history (focusing on cognition and function)
- Cognitive examination
- Neuropsychological testing (if needed)
- Etiology of dementia determined based on:
- Medical history (neurologic/general medical/family)
- Physical examination (neurological signs - cognitive impairment, focal signs, parkinsonism; pertinent systemic signs - vascular and metabolic diseases)
- Neuropsychological testing
- Laboratory testing (thyroid function, vit b12 levels, metabolic/infectious/autoimmune etc.)
- Structural brain imaging with CT or MRI (neuroimaging is adjunct, more to exclude other brain pathologies)
- CSF and blood biomarkers of AB and pTAU not routine
Describe what will appear on structural brain imaging with CT or MRI for the diff types of dementia
AD: generalized or focal cortical atrophy, often asymmetrical, hippocampal atrophy (in mesial temporal lobe)
Vascular: brain infarcts or white matter lesions
Frontotemporal dementia: frontal lobe or anterior temporal lobe atrophy
Other abnormalities such as brain mass (Tumor) and hydrocephalus
Describe the appearance of an AD brain (only can be observed via brain biopsy after autopsy)
- Shrinkage of cerebral cortex
- Shrinkage of hippocampus
- Enlarged ventricles
What neurotransmitter is implicated in AD?
Degeneration of neurons of multiple neurotransmitter system is implicated, however, pharmacologic focus on treating the degeneration of cholinergic neurons
Cholinergic system in AD:
- Central cholinergic neurons project to widespread areas of the cortex and lay impt roles in learning and attentional processes => lead to cognitive decline and neuropsychiatric behaviors
Cholinergic pathways:
- Nucleus basalis: projects to all parts of the brain, esp at neocortex
- Dorsal tegmental: secondary pathway
Goals of AD management
- Slowing progression (reduce cognitive decline, preserve function)
- Delay need for institutionalization (manage behavioral problems, support and educate caregivers)
NOTE: there is no cure, only symptomatic treatment
Name the drugs used in AD
Acetylcholinesterase inhibitors (AChEIs)
- Donepezil
- Galantamine
- Rivastigmine
Non-competitive NMDA receptor antagonist
- Memantine
[Acetylcholinesterase inhibitors (AChEIs)]
MOA
Inhibit acetylcholinesterase enzyme, thereby promoting relative increases in acetylcholine abundance at the synaptic cleft for cholinergic neurotransmission
[Acetylcholinesterase inhibitors (AChEIs)]
Efficacy
Not very efficacious
- Slower decline for cognition outcome
- Modest improvement in ADL and behaviors
- Similar efficacy among the three drugs
Given the modest benefit and known risks, clinicians should engage in shared decision-making regarding the initiation of an AChEI for the symptomatic treatment of AD dementia
[Acetylcholinesterase inhibitors (AChEIs)]
Indication
- Mild to mod disease
- Exception: Donepezil also indicated for severe AD
[Acetylcholinesterase inhibitors (AChEIs)]
Dosing, initiation and titration
What to do if adverse effects encountered?
Slow-titration dosing regimen over 4-8 weeks to reach target dose and minimize adverse effects
If adverse effects encountered,
- Lower dosage temporarily (e.g., days to weeks) before reescalating more slowly and monitoring for recurrence of adverse effects
- Alternatively, drug can be discontinued and a different AChEI tried
[Acetylcholinesterase inhibitors (AChEIs)]
Efficacy monitoring
- Caregiver noticing a slight improvement in day-to-day life
- Routine cognitive tests (MoCA, MMSE)
[Acetylcholinesterase inhibitors (AChEIs)]
Compare the dosage form of Donepezil, Rivastigmine, and Galantamine
Donepezil: oral tablet (most start at 10mg OD, up 25mg OD if tolerated)
Rivastigmine: oral capsule and transdermal
Galantamine: oral tablet, oral solution
[Acetylcholinesterase inhibitors (AChEIs)]
Compare the use of Donepezil, Rivastigmine, and Galantamine
Donepezil - most commonly used due to familiarity + better tolerability and less SEs + more evidence of efficacy + cheaper + many generics available
Rivastigmine - patch formulation good for pt who refuse to take medication, also indicated for mild-mod dementia a/w Parkinson’s disease
Galantamine - less used as newest, higher cost, less familiarity
[Acetylcholinesterase inhibitors (AChEIs)]
Compare half-life of Rivastigmine and Galantamine
Rivastigmine has shorter half-life, hence require more frequent dosing compared to Galantamine
[Acetylcholinesterase inhibitors (AChEIs)]
Mechanism of action (Rivastigmine VS Galantamine)
Note that acetylcholine does not discriminate between muscarinic and nicotinic receptors
Galantamine may also act allosterically on nicotinic receptors in the brain, which contributes to its therapeutic effects
U2D Galantamine:
- Centrally-acting cholinesterase inhibitor (competitive and reversible). It elevates acetylcholine in cerebral cortex by slowing the degradation of acetylcholine. Modulates nicotinic acetylcholine receptor to increase acetylcholine from surviving presynaptic nerve terminals. May increase glutamate and serotonin levels.
U2D Rivastigmine:
- A deficiency of cortical acetylcholine is thought to account for some of the symptoms of Alzheimer disease and Parkinson disease dementia; rivastigmine increases acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by cholinesterase
U2D Donepezil:
- Alzheimer’s disease is characterized by cholinergic deficiency in the cortex and basal forebrain, which contributes to cognitive deficits. Donepezil reversibly and noncompetitively inhibits centrally active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine. This appears to result in increased concentrations of acetylcholine available for synaptic transmission in the CNS.
[Acetylcholinesterase inhibitors (AChEIs)]
Compare metabolism of Rivastigmine and Galantamine
Rivastigmine - primarily metabolized by kidneys
Galantamine - metabolized by liver (CYP450)
[Acetylcholinesterase inhibitors (AChEIs)]
Side effects
Cholinergic hyperactivation (too much parasympathetic):
- Nausea
- Vomiting
- Diarrhea
Less common:
- Muscle cramp
- Bradycardia
- Loss of appetite (take with food to alleviate)
- Increased gastric juice secretion (digest)
- Increased frequency of bowel movements
- Vivid dreams, insomnia (do recall that nocturnal disturbances may be manifestation of AD itself)
Patch formulation of Rivastigmine:
- Local skin irritation/reactions
Note that the bolded ones are the more common SEs, Donepezil which is better tolerated typically only have these SEs; whereas Rivastigmine/Galantamine may have some vivid dreams, insomnia)
[Acetylcholinesterase inhibitors (AChEIs)]
Contraindications
Patients with bradycardia
[Acetylcholinesterase inhibitors (AChEIs)]
Caution in patients with:
- Peptic ulcer disease (due to incr gastric acid secretion)
- Respiratory disease
- Seizure disorder
- Urinary tract obstruction (due to incr bowel movement)
[Memantine]
MOA
Non-competitive NMDA receptor antagonist (anti-glutamate)
- Putative MOA: block NMDA receptor-mediated excitotoxicity (excessive glutamate => neurons overexcited => excitotoxicity)
[Memantine]
Indication
- Moderate-severe AD (switch to memantine, or initiate with memantine if mod-severe at diagnosis)
- Patients who cannot tolerate AChEIs (switch to memantine, or add on memantine)
[Memantine]
Efficacy monitoring
- Caregiver noticing a improvement in day-to-day life
- Routine cognitive tests (MoCA, MMSE)
[Memantine]
Dosage form
Oral capsule, tablet, solution
[Memantine]
Side effects
Common:
- Headache
- Constipation
Others:
- Hallucinations
- Confusion
- Dizziness
- Light-headedness
[Memantine]
Caution in patients with:
- Cardiovascular disease
- Seizure disorder
- Severe hepatic impairment
- Severe renal impairment
Combination product in the market for AD:
Memantine + Donepezil
- capsule form
- for mod-severe dementia
What are some other considerations wrt pharmacological management?
- Reduce polypharmacy (reduce pill burden)
- Review medications that may contribute to cognitive impairment (e.g., antihistamine, anticholinergics)
- Assist caregiver on med mgmt issues (e.g., simplify regimen, consolidate doses to OD where possible, arrange med refill)
- Evaluate risk vs benefits of existing medications (consider if pt can rmb to take meds, does he/she have caregiver support? if no, then we should not start on other medications even if needed)
[Non-pharmacologic approaches in AD]
What non-pharmacologic should be part of routine advice?
- Cognitively stimulating activities (e.g., reading, games)
- Physical exercise (e.g., aerobic, anaerobic)
- Social interactions with others (e.g., family events)
- Healthy diet such as Mediterranean diet (high in green, leafy vegetable)
- Adequate sleep (e.g., uninterrupted sleep and with sufficient number of hours)
- Proper personal hygiene (e.g., regular bathing)
- Safety - e.g., kitchen appliances, driving
- Effective communication (e.g., visual aids)
- Psychological health (e.g., music)
[Non-pharmacologic approaches in AD]
Should psychotherapy be used in AD patients?
No, psychotherapy is NOT effective because AD patients have cognitive deficits, making it difficult to engage in CBT
Instead, behavioral intervention would be better (e.g., toileting abilities)
[Non-pharmacologic approaches in AD]
Discussion and planning with patient + family members:
- Medical and advanced care directives (power of attorney)
- Long-term healthcare planning (living arrangement)
- Financial planning (allocation of assets)
What are some care coordination community resources?
Dementia Singapore Care Services
- Centre-based care (dementia daycare, provide cognitive stimulating activities - e.g., art session, music session, yoga)
- Home-based intervention (home support, post-diagnostic support)
- Community support programme (helpline, caregiver support - educate, training courses for foreign domestic workers, eldersit service)
5 fundamental psychological needs for dementia patients
Attachment - bonds, relationships
Comfort - physical touch, comforting words and gestures
Occupation - involved in activity that is meaningful
Inclusion - within the community
Identity - sense of continuity with the past
