Term
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Definition
| an acquired, persistent decline of intellectual function causing impaired performance of daily activities, WITHOUT impairment of consciousness |
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Term
| diagnostic approach to patients with suspected dementia |
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Definition
1. truly abnormal?
2. more than just memory?
3. progressive?
4. potentially reversible?
5. consistent with a specific disease? |
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Term
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Definition
are the patient's symptoms truly abnormal?
everyone forgets names and facts, misplaces things
most people don't: get lost in familiar places, get confused with routine changes, pay bills incorrectly, inspire coworkers to comment on their mistakes
important to ask lots of historical questions of family and friends |
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Term
| patient's acknowledgement of their "impairment" |
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Definition
when patients can provide a DETAILED description of the circumstances on which they had memory problems, they probably do NOT have dementia
however, it is NOT TRUE that patients with dementia are always oblivious to it |
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Term
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Definition
dementia must be differentiated from:
-mild cognitive impairment
-isolated memory impairment
-Korsakoff's syndrome (and other anmestic conditions)
-delirium
-depression |
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Term
mild cognitive impairment
MCI |
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Definition
an acquired, persistent impairment on one or more cognitive domains(usually including memory), more severe than expected with normal aging, but NOT severe enough to interfere with social and occupational function
"a little worse than expected" from normal aging
a convenient term, more so useful as a definition for research purposes |
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Term
isolated memory impairment
IMI |
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Definition
| an acquired, persistent impairment in memory, more severe than expected with normal aging, without a decline in general intellectual function or performance of daily activities |
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Term
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Definition
an acute, transient, fluctuating confusional state characterized by impairment in maintaining and shifting attention
often associated with sensory misperception or disorganized thinking
can not assess a patient for dementia while they are delirious |
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Term
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Definition
depression can cause impaired cognitive function
impaired cognitive function can cause depression
sometimes, empiric treatment is the only option |
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Term
| how to distinguish dementia from cognitive impairment states |
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Definition
ask about non-memory problems to look for any other cognitive deficits
finances, chores, driving, comprehension
pin them down of how exactly it's impairing their life |
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Term
| how to distinguish dementia from delirium |
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Definition
| see if the patient can maintain attention |
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Term
| how to distinguish dementia from depression |
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Definition
ask about vegetative states
more vegetation states -- more likely depression is the primary problem |
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Term
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Definition
don't confuse progressive dementia with static (or improving conditions) such as:
post-anoxic, post-encephalitis, post-traumatic, after a single stroke, after a prolonged seizure |
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Term
| 4. is there a potentially reversible cause? |
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Definition
work up to look for additional causes
heat CT/MRI, serum testing, urinalysis |
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Term
| potential reversible causes of dementia that head scan can detect |
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Definition
mass lesion (tumor, subdural hematoma), normal pressure hydrochepalus, vascular disease
likelihood is low, but still worth checking |
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Term
| potential reversible causes of dementia that serum testing/urinalysis can detect |
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Definition
look for systemic illnesses
electrolytes, BUN, creatinine, glucose, calcium, liver enzymes, CBC, differential, platelets, ESR, vitamin B12, folate, TSH, FTA |
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Term
| 5. is the condition consistent with a specific disease? |
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Definition
Alzheimer's disease (AD)
dementia with Lewy bodies (DLB)
frontotemporal dementia (FTD)
vascular dementia (VaD)
Creutzfeldt-Jacob disease (CJD) |
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Term
Alzheimer's disease (AD)
clinical features |
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Definition
memory PLUS other cognitive deficits (i.e. dementia) but memory may be most prominent at first
gradual onset and progression
gait, bladder/bowel control not affected in early stages
normal primary sensory and motor function
personality change may occur (in either direction) |
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Term
Alzheimer's disease
risk factors |
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Definition
age (prevalence doubles every 5 years after 65)
APOE status
sex: F>M
lower education level
head trauma
~10% of patients have an autosomal dominant, early-onset condition |
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Term
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Definition
APOE = apolipoprotein E; the gene for it exists in 3 alleles (E2, E3, E4)
E4 allele higher in patient's with late-onset sporadic AD
E4>E3>E2 |
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Term
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Definition
general atrophy of the brain
-enlarged sulci, shrunked gyri
-enlarged ventricles
most prominent in medial temporal region around the hippocampus (also in parietal and frontal regions)
occipital pole and pre/post-central gyri relatively spared |
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Term
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Definition
loss or neurons and synapses
shrinkage of large cortical neurons and the dendritic arbors
*neuritic plaques and neurofibrillary tangles*
cholinergic projections are particularly affected |
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Term
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Definition
extracellular protein deposit, often separated into a dense core and peripheral halo
may be diffuse of compact
compose mainly of A-beta peptide, surrounded by degenerating or dystrophic nerve endings (neuritis) |
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Term
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Definition
A-beta peptide is a fragment of amyloid precursor protein (APP)
APP is a transmembrane protein expressed in neural and nonneural tissue, normally cleaved by alpha-secretase, at a site just above the surface of the membrane
alternate APP processing involves cleavage further from the membrane (beta-secretase) and at an intra-membran site (gamma-secretase), creating an A-beta fragment
in AD, increased A-beta fragments are produced
increased production of A-beta peptide aggregates as insoluble beta-pleated sheets that form the basis of neuritic plaques |
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Term
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Definition
intracellular cytoplasmic inclusions in axon hillock of neuron
composed of paired helical filaments
filaments consist of hyperphosporylated TAU protein |
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Term
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Definition
tau is a microtubule-associated protein
normal brain: phosphate groups rapidly removed from tau protein by phosphatases
AD tau: tau protein in the paired helical filaments is relatively resistant to dephosphorylation; excess phosphorylation may interfere with the function of the microtubule-binding regions, destabilization of MTs and abnormal cellular transport mechanisms |
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Term
AD pathophysiology
potential roles for amyloid |
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Definition
just a marker (waste product) -- unlikely
abnormal amyloid can't carry out its usual (presumably important) function
abnormal amyloid is toxic to cells
cells dispose of abnormal amyloid in plaques and the plaques are toxic |
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Term
AD pathophysiology
mouse models to help determine role(s) of tau and amyloid |
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Definition
maybe it's not the plaques or tangles
tau-depleted amyloid mutants show NORMAL behavior, despite presence of plaques (plaque itself not the problem)
other model show that suppression of over-expressed tau caused behavior improvements, despite ongoing tangle accumulation
suggestive of an interaction between amyloid and tau |
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Term
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Definition
definite - only with histo confirmation on autopsy following a typical course
probable - typical course with no atypical features in living patient
possible - atypical features (such as gait problems early on) or other disease that could explain the dementia |
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Term
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Definition
diagnosis is based on clinical features
blood tests and imaging to rule out confounding diagnosis
ApoE and other biomarker testing not sensitive or specific enough
PET with amyloid labeling seems promising |
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Term
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Definition
cholinesterase inhibitors
memantine (glutamate receptor antagonist)
vitamin E (helps scavenge free radicals) - shown helpful in one (flawed) study |
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Term
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Definition
cholinesterase inhibitors: donepesil, rivastigmine, galantamine
not curative, doesn't stop or slow progression, just DELAYS progression
shift curve ~6 months |
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Term
AD
other aspects of management |
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Definition
agitation
depression
sleep disturbance
incontinence
advance directives |
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Term
AD
future directions of treatment |
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Definition
inhibition of beta- and gamma-secretase
however, these enzymes work on a lot of other proteins in the body
amyloid antibodies
shown to help clear amyloid plaques from the brain, but carries a risk of encephalitis |
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Term
dementia with Lewy bodies (DLB)
clinical presentation |
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Definition
dementia + at least 2 core features:
-parkinsonian features (especially rigidity and bradykinesia) early in course
-recurrent visual hallucinations early in course
-marked fluctuations in cognition or awareness |
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Term
DLB
suggestive clinical features |
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Definition
REM sleep behavior disorder
extreme sensitivity to antipsychotic medications
low dopamine transported uptake in basal ganglia (on PET or SPECT) |
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Term
DLB
other common, but nonspecific features |
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Definition
episodes of falling or loss of consciousness
systematized delusions, or tactile or olfactory hallucinations
prominent depression
severe autonomic dysfunction
certain imaging or EEG findings |
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Term
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Definition
resembles AD
atrophy in the temporal, parietal, and frontal lobes; the atrophy is usually not severe
limbin structures mod-severely atrophic |
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Term
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Definition
Lewy bodies in limbic, paralimbic, and neocortical regions
2/3 of patients have AD changes (mostly plaques)
Lewy bodies and AD features overlap, but Lewy bodies more prevalent in anterior cingulate and other paralimbin regions (vs. hippocampal for AD path) |
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Term
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Definition
roughly spherical neuronal inclusions with an eosinophilic core surrounded by a paler halo
composed of alpha-synuclein and ubiquitin, which function to eliminate mis-folded proteins |
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Term
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Definition
pathophys is unclear - likely to resemble AD, Parkinson's, or both
severe cortical cholinergic deficit related to loss of neurons in the nucleus basalis of Meynert |
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Term
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Definition
diagnosis made purely on clinical grounds
consensus criteria:
-dementia and at least 2: fluctuating cognition or alertness, recurrent visual hallucinations, spontaneous features of parkinsonism |
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Term
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Definition
cholinesterase inhibitors - may produce some cognitive improvement
memantine may be beneficial too
dopaminergic agents - can be tried for parkinsonian symtopms
other symptoms managed as AD (though take caution with antipsychotics) |
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Term
frontotemporal dementia
FTD |
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Definition
| group of degenerative disorders with a predilection for the frontal and temporal lobes |
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Term
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Definition
age of onset tends to be younger than AD
hereditary (autosomal dominant) in 10% of cases, often with associated parkinsonian features |
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Term
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Definition
2 general categories of clinical presentation
-progressive behavioral disturbance
-progressive language disturbance |
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Term
FTD
clinical features of behavioral subtype |
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Definition
typical have involvement of both frontal lobes; prominent changes in personality and behavior
manifestations: apathy/blunted affect, difficulty sustaining and directing attention, poor planning, impaired reasoning, disinhibited conduct, changes in eating habits, inappropriate sexual behavior, neglect of personal hygiene |
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Term
FTD
clinical features of language subtypes |
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Definition
typically manifest as
-progressive nonfluent aphasia
-semantic dementia |
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Term
FTD
progressive nonfluent aphasia |
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Definition
language subtype syndrome of FTD characterized by non-fluent output, with relatively spared comprehension
associated with degeneration of the frontal and temporal lobes in the region bordering the Sylvian fissure (dominant hemisphere) |
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Term
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Definition
language subtype syndrome of FTD characterized by fluent by empty spontaneous speech and early loss of comprehension, usually with profound anomia (problem with recalling words or names) and difficult understanding the meaning of individual words
associated with degeneration in the anterior temporal lobe (dominant hemisphere) |
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Term
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Definition
frontal and temporal atrophy to varying degrees
symmetric or aymmetric |
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Term
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Definition
Pick's disease
tau inclusions
ubiquitin inclusions |
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Term
FTD pathoology
Pick's disease |
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Definition
Pick's bodies = spherical, slightly basophilic neuronal inclusions containing tau protein (3-repeat isoform)
neuronal loss and swollen neurons in the atrophic regions of brain
(most patients with FTD no NOT have Pick's) |
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Term
FTD pathology
tau inclusions |
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Definition
inclusions in neuronal and glial cells
accumulation of phosphorylated tau, no Pick bodies
4-repeat isoform of tau |
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Term
FTD pathology
ubiquitin inclusions |
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Definition
inclusions within neuronal and glial cells
ubiquitn = component of the principal cellular mechanism for degrading and eliminating un-/mis-folded proteins
in FTD pts, these inclusions primarily are TDP-43 (Transactivation response region - Dna binding Protein 43)
TDP-43 inclusion also in ALS patients |
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Term
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Definition
| patients with neither tau nor TDP-43 containing inclusions may have accumulation of FUS - "fused in sarcoma" protein |
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Term
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Definition
most patients with FTD (sporadic or familial) have either TDP-43 or tau inclusions
most of the rest have FUS inclusions
ALS manifestations only in TDP-43 and FUS patients (NOT tau) |
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Term
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Definition
based primarily on clinical presentation and the exclusion of other diseases that could produce a similar pattern (herpes simplex encephalitis, brain tumors, chronic subdural hematoma)
frontotemporal predominance of atrophy and hypometabolism on imaging |
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Term
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Definition
purely symptomatic
no indication that cholinesterase inhibitors are benficial
behavioral management is often the most prominent practical issue |
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Term
final thoughts
role of proteins in degenerative dementia |
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Definition
all (AD, DLB, FTD) invloved accumulations of abnormal proteins to some extent
abnormal protein can do bad things
these proteins accumulate over years (before symptoms!)
fairly subtle differences between proteins can have a big difference in clinical manifestations
we still don't know exactly how it all works: loss of normal protein function? gain of toxic protein function? toxicity of protein deposits? |
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Term
vascular dementia
clinical features |
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Definition
a series of strokes can add up to the deficits of dementia
often an abrupt, stepwise decline, but may be a bit hazy |
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Term
vascular dementia
pathology |
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Definition
| pathologic features are those of stroke |
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Term
vascular dementia
pathophysiology |
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Definition
stroke
accumulation of small, "silent", strokes may affect cerebral reserve and render the brain more susceptible to damage (such as from A-beta peptide) |
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Term
vascular dementia
diagnosis |
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Definition
"amorphous diagnosis"
there is no consensus on diagnostic criteria
Hachinski scale may be useful in identifying features that make vascular dementia more likely than just AD |
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Term
vascular dementia
management |
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Definition
cholinesterase inhibitors may be beneficial
primary and secondary prevention of stroke
same symptom management as for other dementias |
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Term
Creutzfeldt-Jakob Disease (CJD)
clinical features |
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Definition
rapidly progressive dementia (death in months to a year); typically younger pts, present in 40-50's
myoclonic jerks
ataxia, dysarthria
behavioral disturbances or psychosis
variants: cerebellar first; mainly visual; early muscle wasting and fasiculations (look like ALS) |
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Term
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Definition
non-specifc atrophy
microscopic spongiform change
-loss of neurons, axons, synapses; vacuolation
-activation & proliferation of astrocytes
-very little inflammatory response |
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Term
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Definition
PRIONS! a proteinaceous infectious particle; contains no nuclei acid
normal prion protein (PrP-c) in on the surface of cells; abnormal protein (PrP-Sc) is same AA sequence, but different conformation
PrP-Sc's can bind PrP-c and induce it to change to pathologic -Sc form (Vampire proteins!) |
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Term
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Definition
most cases sporadicm, though 5-15% are familial through a PrP mutation causing abnormal proteins
iatrogenic from implant of brain tissue (pituitary extracts, corneal implants)
ingestion |
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Term
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Definition
periodic complexed on EEG
MRI abnormalities
CSF has elevated 14-3-3 and tau protein
specifc dx from brain biopsy |
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Term
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Definition
no treatment known
if the diagnosis can be established, important prognostic information can be delivered to the family |
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