Dementia Flashcards
what are normal, age-associated cognitive changes?
- difficulty retrieving words and names
- slower processing speed
- difficulty sustaining attention when faced with competing environmental stimuli
- learning something takes bigger effort
- no functional impairment
what is the definition of mild cognitive impairment (MCI)?
- memory complaint corroborated by an informant
- objective memory impairment for age and education
- preserved general cognition
- normal activities of daily living
- not demented
what is amnestic MCI?
memory loss not meeting criteria for dementia
- progresses to AD at risk of 10-15% per year VS 1-3% incidence in general population
- may be earliest phase of AD
- it’s a clinical diagnosis, as there’s no test for MCI
what is the DSM-IV diagnostic criteria for dementia (DSM-5 is neurocognitive disorder, mild/major)
- memory decline/impairment and at least one of the following:
- aphasia
- apraxia
- impaired executive function
- agnosia
- DSM5: decline in memory, complex attention, executive function, learning/memory, language, perceptual/motor, social cognition - cognitive deficits must impact social and occupational function
- major: patient incapable of independent living - diagnosis must be made in presence of clear sensorium
early onset AD
occurs between 30-60 yo
- rare, and familial in most cases
- single gene mutation:
- -1: abnormal presenilin 2
- -14: abnormal presenelin 1
- -21: abnormal amyloid precursor protein
late onset AD
most common form
- develops after age 60
- combination of factors is responsible (vascular, diabetic, etc)
- Xm 19: apolipoprotein E4 is implicated
what does AD look like grossly?
cerebral atrophy, especially affecting temporal, parietal, and frontal areas, with ventricular enlargement
- flat gyri, wide sulci
- hippocampus shrinks
what does AD look like microscopically?
- amyloid plaques (extracellular deposits of beta-amyloid peptide) associated with dystrophic neurites (neuritic plaques)
- A-beta deposits in cortical and leptomeningeal arteries and arterioles (amyloid angiopathy)
- neurofibrillary tangles and neuropil threads (filamentous intracellular inclusions of tau protein)
- granulovacuolar degeneration (GVD)
- Hirano bodies
what are the steps to forming the APP molecule?
pathologic cleavage by beta and gamma secretases
- creates 40 or 42 (seed, worse)
- creates neural network dysfunction, tau abnormalities, neurodegeneration, nt deficits, and memory impairment
what is the difference between neuritic plaques and diffuse plaques?
neuritic: larger, with dark brown center (represents 42 APP seed)
diffuse: smaller, don’t have brown center (40 APP)
what does cerebral amyloid angiopathy look like?
smooth muscle of vessels has been replaced by amyloid
-may cause hemorrhage and more vascular dementia
what is the major component of neurofibrillary tangles?
hyperphosphorylated tau (microtubule-associated protein) -dissociates from microtubules and assembles to form paired helical filaments, which are bundled together to form NFTs and neuropil threads (periphery of plaques)
describe what granulovascular degeneration and Hirano bodies are
nonspecific features of AD observed in hippocampi
-also in regular brains, so not important diagnostically
what is the difference between FTLD-Tau and FTLD-TDP?
- FTLD-Tau is Pick’s disease, and more common
- FTLD-TDP has no tau protein
both have profound anterior frontal and superior temporal knife-edge atrophy (parietal and occipital are spared)
-eccentric asymmetrical nuclei
what are vulnerable neurons in AD? the cytopathology?
hippocampus, entorhinal cortex, neocortex, basal forebrain cholinergic system
-NFT, neurites, A-beta deposition, and other cellular abnormalities
which are more diagnostic and which come sooner between A-beta plaques and tau proteins?
A-beta come sooner, but tau proteins are more diagnostic
what are AD risk factors?
- increasing age
- female
- FH of dementia, apolipoprotein E4 allele
- fewer years of education
- lower income and occupational status
- depression or other emotional illness
- head injury, post-operative delirium, alcohol abuse
- low folate, B12
- high plasma homocysteine
what are the 3 key features of AD?
- impaired cognition
- impaired function
- behavioral disturbances
what are early cognitive symptoms of AD?
- trouble keeping appointments
- difficulty finding words
- misplacing objects (unable to retrace steps)
what are early functional symptoms of AD?
- difficulty driving
- difficulty selecting appropriate clothes, or wearing same thing every day
- missing appointments
- problems at work
what are early behavioral symptoms of AD?
- subtle changes in personality
- social withdrawal
- depression
how does primary depression differ from dementia?
- less motivation during cognitive testing (dementia patients try very hard)
- express cognitive complaints that exceed measured deficits
- maintain language and motor skills
why is it important to diagnose AD early?
- rule out reversible causes
- initiate appropriate therapy
- enrollment for clinical trials
- advance directives and planning
brain imaging in regards to AD?
not routinely indicated, but consider if:
- focal findings on exam
- rapid onset/decline
- falls, head trauma by history
nonspecific findings are common in AD, vascular dementia:
-lacunar infarcts, small vessel changes, white matter disease
how is Pick’s disease different from Alzheimer’s?
frontotemporal dementia
- insidious onset, gradual progression
- early decline in social interpersonal conduct (losing their “filter”)
- early impairment in regulation of personal conduct with loss of insight
- early emotional blunting
- behavioral abnormalities
- memory loss occurs later
what are Rx for Pick’s disease?
- no role for cholinesterase inhibitors
- careful use of atypical antipsychotics (quetiapine, risperdol)
- divalproex (anti-seizure) for behavior control
- SSRIs for irritability, depression, impulsive behavior
what are Rx for Alzheimer’s disease?
nothing is disease-modifying; can only manage symptoms
- cholinergic therapy (cholinesterase inhibitors) are only symptom modifying
- NMDA receptor antagonists
- investigational agents
- treatment of neuropsychiatric symtpoms
why was the AD vaccine pulled?
it caused other neurological problems
why do anticholinesterases “work”?
degeneration of basal nucleus of Meynert causes wide-spread ACh deficiency
- contributes to memory deficits that characterize the disorder
- anticholinesterases block degradation of ACh, hopefully leaving enough in synapses to slow progression
what is the mechanism, dose, metabolism, and ASE of tacrine?
(now obsolete) AChE and BuChE inhibitors
- 4x a day
- metabolized by cyt P450
- ASE: nausea, vomiting, diarrhea, cramps, serum transaminase elevation
what is the mechanism, dose, metabolism, and ASE of donepezil?
AChE inhibitor
- 1x a day (start at low dose)
- metabolized by cyt P450
- ASE: N/V, sleep disturbance, syncope, hypotension
what is the mechanism, dose, metabolism, and ASE of rivastigmine?
AChE and BuChE inhibitor
- 2x a day, and can use transdermal patch
- metabolized by hydrolysis via cholinesterases
- ASE: N/V, sleep disturbance
what is the mechanism, dose, metabolism, and ASE of galantamine?
AChE inhibitor, allosteric modulator of nicotinic receptors
- 1-2x a day (can use ER version)
- metabolized by cyt P450
- ASE: N/V, sleep disturbance
what is the mechanism, dose, metabolism, and ASE of memantine?
partial antagonist of NMDA (receptor blocker as excitotoxicity by glutamate may cause neuronal damage)
- 2x a day
- most is excreted unchanged in urine
- ASE: dizziness, confusion, headache, constipation
what do you use to treat neuropsychiatric disturbances in AD patients?
- antipsychotics: risperidone, haloperidol
- antidepressants: sertraline, venlafaxine
- anxiolytics: buspirone, lorazepam
explain what vascular dementia is
multi-infarct dementia (depends on region and volume of tissue affected)
-may be due to and/or cerebral ammyloid angiopathy or HTN-related small vessel disease
explain how hypertensive small vessel disease can lead to progressive cognitive impairment
arteriosclerosis of small vessel arteries and arterioles supplying deep gray and white matter
- lacunar infarcts
- subcortical leukoencephalopathy
- subcortical dementia
- -cognitive slowing
- -impaired problem solving
- -visuospatial abnormalities
- -disturbances in mood and affect
- can result in diffuse, confluent demyelination and axon loss affecting deep white matter, especially periventricular
what are the main targets for vascular dementia?
small vessels (lenticulostriate branches off MCA), which supply the basal ganglia and internal capsule
vascular dementia clinically?
most common dementia after Alzheimer’s
- “step-wise” progression that can be abrupt after CVA
- -after each accident, lose more abilities, then level off
- usually seen with cardiovascular risk factors
- “mixed” dementia with AD or Lewy body is not unusual
- emotional liability
what is treatment for vascular dementia?
focus on controlling CV risk factors -maximize blood pressure control -statins -stop smoking -control blood sugar -diet (no simple carbs) -exercise Rx: cholinesterase inhibitors
what are Lewy bodies?
intracellular, fibrillar deposits of alpha-synuclein (presynaptic terminal protein)
-primarily in sporadic disorders, and most commonly Parkinson’s disease or Lewy body dementia
describe Parkinson’s disease clinically
most common cause of parkinsonism (resting tremor, postural instability, impaired voluntary movement)
- most cases are sporadic, affecting 1-2% of people >65 yo
- bradykinesia, shuffling gait, and parkinsonism due to dopaminergic deficit
- responsive to L-dopa therapy
where is the marked pathology in Parkinson’s disease?
pars compacta, locus ceruleus, substantia nigra
what does PD look like grossly?
pallor of substantia nigra
what does PD look like microscopically?
degeneration and loss of pigmented, dopaminergic neurons of SN pars compacta and other pigmented neurons of brainstem, like locus ceruleus
- contain 1+ eosinophilic Lewy body inclusions
- striatum, thalamus, and some cortical regions are functionally affected by loss of dopaminergic input
what happens to pigment after neuron dies?
“neuromelanin” is phagocytosed by macrophages
explain the pathogenesis of PD
- mutations in alpha-synuclein gene that are AD
- presynaptic protein that regulate synaptic vesicle trafficking
- if misfolded, may act as a prion and spread between cells - LB are made of fibrillar aggregates of a-synuclein (also make Lewy neurites)
- some of these are toxic - impaired protein degradation, inhibition of oxidative phosphorylation, impaired axonal transport, oxidative stress
- pesticide exposure may be risk factor
explain what dementia with Lewy bodies is clinically
sporadic, primarily late onset, with less-affected memory (may be short term and gradual)
- frontal and subcortical features (deficits in attention and alertness are prominent)
- pronounced fluctuations and variations in symptoms (may seem like delirium)
- neuropsychiatric symptoms: vivid visual hallucinations, delusions, REM sleep disorder, autonomic dysfunction
- motor symptoms of PD are variably present (frequent falls)
what are gross features of dementia with Lewy bodies (DLB)?
nigral pallor
- cortical atrophy is less severe than in AD
- atrophy of limbic areas is often significant
what are microscopic features of dementia with Lewy bodies (DLB)?
- “cortical”-type LBs in frontal, temporal, and insular cortex, and in limbic areas (amygdala, cingulate gyrus)
- nigral LBs
- LNs, especially in hippocampus and striatum
- DLB patients usually have plaques and tangles, and a dual diagnosis of DLB and AD applies in most cases
treatments for lewy body dementia?
- cholinesterase inhibitors may provide symptomatic support
- trial of carbidopa/levodopa for esvere movement symptoms
- avoid antipsychotic drugs due to increased sensitivity
- REM sleep disorder can be treated with clonazepam
how can you tell the difference between Lewy body dementia and Parkinson’s?
LBD: onset of dementia within 12 months of parkinsonism (dementia precedes movement disorder)
PD: onset of dementia more than 12 months after diagnosis of PD (movement problems precede dementia)
explain what the MMSE is and scoring
mini mental status examination
- standard 30 point rating scale that is screening, not diagnosing, and not specific for dementia type
- scoring can be impacted by age, education, and ethnicity
- -normal: 27-30
- -mild: 20-30
- -moderate: 10-20
- -severe: <10
explain what the MoCA is and scoring
Montreal cognitive assessment
- standardized 30 point rating scale that is screening, not diagnosing, and not specific for dementia type
- scoring can be impacted by age, education, and ethnicity
- -normal: >26
- -mild: 18-26
- -moderate: 10-17
- -severe: <10
what are the basic activities of daily living?
BADLs:
- Dressing
- Eating
- Ambulating
- Toileting
- Hygiene
need nursing home
what are the instrumental activities of daily living?
IADLs:
- Shopping
- Housekeeping
- Accounting
- Food preparation
- Transportation
need helper or assisted living
what are adult homes?
provide a room and meals
- can add on assistance with daily activities
- no complex medical problems
- not always licensed or monitored by local authorities
- cash only
what are assisted living facilities?
- assistance with IADLs
- can add on some BADLs for extra fee
- no medical or nursing care on-site
- cash only, and NOT covered by Medicaid or Medicare
what are skilled nursing facilities?
most widely recognized option
- daily skilled nursing care and onsite medical care
- dependent in all BADLs
- most patients have advanced dementia
- cash until money is depleted
- -most residents on Medicaid
