Alzheimer's and Dementia

Question 1

Amnesia

Answer 1

impairment of ability to store new memories (anterograde) or recall previously stored memories (retrograde)

Question 2

Aphasia

Answer 2

loss of ability to comprehend and/or produce language

Question 3

Apraxia

Answer 3

impaired performance despite being physically able to do so

Question 4

Agnosia

Answer 4

inability to recognize or identify objects despite intact sensory function

Question 5

Executive dysfunction

Answer 5

abnormalities in one or more capacities including planning, organizing, decision-making, strategizing, cognitive flexibility, impulse control, sequencing, abstract reasoning, and social appropriate behavior

Question 6

Describe the different types of memory

Answer 6

1) Short-term memory
2) Long-term memory:

Declarative
• Conscious, recollective, explicit
• Medial temporal lobe dependent
• Involves: event/fact learning; recall, recognition; episodic and semantic memory

Non-declarative 
•	Implicit memory 
•	Medial temporal lobe Independent 
Involves:
•	Repetition priming (perceptual and conceptual)
•	Sensorimotor adaptation
•	Classical conditioning 
•	Skill learning

Question 7

Describe the neuroanatomic substrates of memory

Answer 7

Neuroanatomical substrates:
Hippocampus
• Critical for consolidation of info into LTM
• Also for immediate coding of memory
Medial temporal lobe
PFC (lesions → less efficiently encoding and retrieval, impaired recall; problems with STM)

Cellular substrates
• Long-term potentiation = activity-dependent strengthening of synaptic connectivity = underlies formation and retention of memory
• Result from cascade of events → consolidation at cellular level

Question 8

Correlate the neuropathological changes found in Alzheimer’s disease with its clinical manifestations, in particular, amnesia.

Answer 8

Cortical atrophy
o Widened sulci, narrowed gyri
o Most severe in frontal and temporal lobes

Hydrocephalus ex vacuo
o No increase in pressure, but increased size of ventricles & shrinkage of brain structures

Senile plaques
o Networks of fibrillary material in loose, disorganized arrangement
o From swollen, degenerated neuronal processes around a central amyloid deposit

Neurofibrillary tangles
o Accumulations of large numbers of paired helical filaments in neuron cytoplasm
o Birefringent under polarized light
o Seen with silver stains

Microglial activation
o Non-specific reaction to injury = low-grade inflammation

Amyloid angiopathy

Question 9

Dementia Definition

Answer 9

Syndrome of acquired persistent decline in several areas of intellectual ability:
o	Impaired memory
o	Disturbed language
o	Visuospatial abnormalities
o	Decreased problem-solving, abstraction and other executive functions
o	Reduced attention
o	Apraxia
o	Agnosia 

50% of dementia = caused by Alzheimer’s

Question 10

Alzheimer’s: clinical features

Answer 10

Cognitive impairment:
Impaired encoding & recall of memory
o Memory loss occurs 2-3 years prior to onset
o Early: STM affected
o Eventually: LTM affected
o Progressive decline
Language: word-finding difficulties, reduced verbal fluency
Visuospatial: abnormal clock-drawing test

Functional impairment:
• Decreased ability to perform instrumental, then basic, activities of daily living (ADLs)
• Increased reliance on caregivers

Behavioral & psychological symptoms (BPSD)
• Depression, anxiety, irritability, apthay, insomnia, paranoid delusions, visual hallucinations, restlessness, yelling, swearing, physical aggression

Question 11

Alzheimer’s: risk factors

Answer 11

• Age (most between 75-85)

• Genetics:
• Apolipoprotein e4 allele
• Down syndrome (trisomy 21)
• Family history
• TBI history
• Late-life depression
• Cardiovascular risk factors (HT, dyslipidemia, atrial fibrillation, obesity, smoking)

Alcohol use:
• Abstinence = slightly higher risk
• Mild-moderate use = lowest risk
• Excessive use: higher risk

Question 12

Alzheimer’s: protective factors

Answer 12

• Genetics = Apo-e2
• Medication exposure: NSAIDs, statin
• Mild/moderate alcohol use
• Omega-3 fatty acids
• Physical exercise
• Cognitive stimulation

Question 13

Vascular dementia

Answer 13

o Causes 8% of dementia
o Dementia due to cerebrovascular disease
• Symptoms depend on location of disease

Present with abnormal neurological exam
o Course = “step-wise”
• Sudden changes in cognition and functioning
• Separated by periods of stability
o Often coexists with Alzheimer’s
o Age range: 65-75 years
o Vascular risk factors (high cholesterol, HT) = higher risk of cardiac disease, death

Question 14

Lewy Body Disease

Answer 14

o Causes 5% of dementia

Types:
Parkinson’s disease dementia = onset of cognitive symptoms at least 1 year after onset of motor symptoms
• Impairment due to Lewy bodies throughout subcortical regions

Dementia with Lewy Bodies (DLB):
• Fluctuating symptoms
• Visual hallucinations
• Cognitive impairment
• Less severe parkinsonian symptoms than in Parkinson’s Disease
• Lewy bodies are found in cerebral cortex

Question 15

Frontotermporal Dementia

Answer 15

o Causes 8% of dementia

Collection of syndromes:
• Presence of tau inclusion bodies
• Lobar degeneration of frontal and/or temporal lobe
• Behavioral disturbance and/or aphasia

o Onset: 50-65
o May be a family history of early onset dementia

Symptoms may be:
• Like MDD: apathy, amotivation, anergia
• Like mania: disinhibition, impulsivity, irritability

o Cognitive enhancing medications NOT helpful
o Course = more rapid; death occurring within average 5 years

Question 16

List the treatments available for dementia, including psychotropic medications, psychosocial interventions and caregiver interventions.

Answer 16

Medications
o Cognitive enhancing medications: donepezil, galantamine, rivastigmine, memantine
o Delay cognitive decline
o Treat: alzheimer’s, vascular dementia, and dementia with Lewy bodies
o NOT effective for Frontaltemporal dementia

Behavioral interventions
o Treat depression, anxiety, psychosis, agitation
o Includes: redirection, distraction techniques, soothing music, etc.

If interventions fail or patient behavior is dangerous:
o SSRIs
o Atypical antipsychotics (caution because increase mortality in elders with dementia)

Caregiver interventions
o High risk of depression (33%) = support and education

Question 17

Parkinson’s Disease

Answer 17

Symptoms:
o	Bradykinesia
o	Muscular rigidity
o	Resting tremor
o	Impaired balance
o	Some patients may have cognitive decline (Parkinson’s disease dementia)

5-10 year progression to rigid, akinetic state

Cause:
o Decrease in striatal dopamine levels (normally inhibitory)
o Result: unopposed striatal GABAergic neurons → excessive excitatory ACh release

Question 18

Explain why certain antipsychotic drugs cause Parkinsonism and what drugs can be used to treat this iatrogenic condition.

Answer 18

• Effects = usually reversible

Includes:
Antipsychotics: Butyrophenone, phenothiazine
• Block brain dopamine receptors

Reserpine (at high doses)
• Depletes brain dopamine

MPTP (byproduct from synthesis of illegal designer drug MPPP)
• Irreversible
• Destroys dopaminergic neurons in nigrostriatal tract
• Treating with MOAIs = protective in animals

Question 19

Describe the main antiparkinsonism mechanisms of action of levodopa, dopamine receptor agonists, selegiline, amantadine, and muscarinic blocking drugs.

Answer 19

Increase DA by stimulating DA synthesis
o Levodopa = enters brain, converted to dopamine

Increase DA by inhibiting DA metabolism
o Carbidopa = inhibits DOPA decarboxylase in periphery
o Entacapone = inhibits COMT → enhances L-DOPA accumulation
o Selegiline = inhibits MAO type B

Directly stimulate DA receptors with DA agonists
o Pramipexole = D2 and D3 full agonist
o Ropinirole = D2 and D3 full agonist
o Bromocriptine = D2 full agonist; D1 partial agonist

Block CNS ACh receptors with muscarinic antagonists
o Trihexyphenidyl
o Benztropine
o Diphenhydramine = H1 blocker (significant antimuscarinic effect)
o Amantadine = unknown mechanism

Question 20

List the drugs that inhibit DOPA decarboxylase and COMT and describe their uses in Parkinsonism.

Answer 20

• Carbidopa = inhibits DOPA decarboxylase in periphery
• Entacapone = inhibits COMT → enhances L-DOPA accumulation
• Both: function to enhance amount of DA reaching brain (less metabolized in periphery)

Question 21

Describe the two major pharmacological approaches used to treat Alzheimer’s disease: inhibition of acetylcholinesterase and antagonism of the NMDA receptor.

Answer 21

AChE inhibitor
o Alzheimer’s = decrease in ACh and nicotinic receptors → goal is to increase ACh
o Also = AChE acts as molecular chaperone → forms stable complexes with Aβ → accelerates amyloid fibril formation
Includes:
• Donepezil
• Rivastigmine
• Galantamine

NMDA receptor antagonist
o Chronic glutamatergic activity may have role in Alzheimer’s pathogenesis
o Glutamate stimulates NMDA receptors → increased neuronal [Ca2+]
o Excessive Ca2+ can damage neurons
o Ex: Memantine

Question 22

List methods used to assess cognition in patients suspected of having a neurocognitive disorder.

Answer 22

Mini-mental status exam (MMSE)
o Assess orientation to place and time
o Registration and recall of 3 small objects
o Attention, calculation, naming, repetition
o Reading comprehension, writing a sentence, copying a figure, following a 3-step command

St. Louis University Mental Status Exam (SLUMS)
o	Assess orientation to place and time
o	Registration and recall of 5 objects
o	Attention, calculation
o	Naming animals
o	Drawing a clock
o	Identifying a shape
o	Recalling a story 

Animal naming test
o Name as many animals as possible in 1 minute
o Normal score is ≥15
o Tests executive function

Clock-drawing test
o Draw a clock and set hands to specific time
o Tests visuospatial and executive function

Min-Cog
o Combines clock-drawing test with 3-object recall
o A quick cognitive screen in primary care settings

Confusion Assessment Method (CAM)
o	94% sensitive
o	90% specific 
o	91% PPV
Diagnoses deliria if met all criteria: 
•	Acute change in mental status and fluctuating course
•	Impaired attention 
•	Either disorganized thinking or altered level of consciousness

Question 23

Delirium: Epidemiology

Answer 23

o	Varies depending on setting:
o	Older adults in a community: 0.8%
o	Hospitalized with cancer: 25%
o	Nursing home residents >75 years: 60%
o	Terminally ill: 80%

Question 24

Delirium: pathophysiology

Answer 24

o Multi-factorial
o Contributors: pain, constipation, dehydration, nutrition, sensory deprivation, changes in environment

Toxic causes:

• sedative-hypnotics
• anticholinergic drugs
• opiates
• steroids
• antibiotics (quinolones)

Metabolic causes:

• hyponatremia, hypernatremia, hypocalcemia, hypercalcemia
• hypoxemia, hypercapnia
• hypoglycemia, hyperglycemia
• renal failure (uremia), hepatic failure (hepatic encephalopathy)

Infectious causes:
-UTI (in older adults), pneumonia, meningitis, encephalitis, sepsis, CNS abscess

Other causes:

• traumatic brain injury
• stroke
• epilepsy
• cardiac ischemia or arrhythmia

Final common pathway = reticular activating system (RAS)
• Associated with arousal and attention
• Facilitates sensory input to cortex via cholinergic projections from brainstem to thalamus
• Projects to cerebral cortex

Question 25

Delirium: risk factors

Answer 25

o	Age
o	Cerebrovascular disease
o	Neurodegenerative disease
o	Chronic medical conditions
o	Recent surgery
o	Being in unfamiliar environment
o	Psychotropic medications (especially sedative-hypnotics or drugs with anticholinergic properties) 
o	Malnutrition

Question 26

Delirium: clinical presentation

Answer 26

o Delirium = acute change in mental status due to underlying medical condition
o Arise over short time (hours-days)

Features:
•	Waxing and waning symptoms
•	Impairment of attention 
•	Altered level of consciousness 
o	Associated symptoms: disorientation, disturbance of sleep-wake cycle, perceptual disturbances, paranoia, memory loss, emotional disturbances

Question 27

Delirium: prognosis

Answer 27

o High mortality rate (May be marker for underlying disease)
o 15% elderly die within 1 month; 25% die within 6 months

Associated with:
•	Worse surgical outcomes
•	Increased surgical complications
•	Increased disability 
•	Longer length hospital stay
o	Many do not return to premorbid cognitive and functional level

Question 28

Describe the management of delirium.

Answer 28

• Treat underlying condition:
o Discontinue contributing medications
o Usually resolves within hours/days later

• May need to be hospitalized
• Antipsychotic if patient agitated
• Avoid benzodiazepines (except to treat delirium tremors in alcohol withdrawal)