Alzheimers Disease And Dimentia Flashcards
What is the clinical challenge of diagnosing mental status
Mental status changes and complaints often present without accompanying focal neurological signs
What can cognitive, emotional, motivational, behavioral signs stem from
Dysfunction from pathology; prefrontal cortex, thalamus, basal nuclei, limbic regions, hypothalamus, brainstem NT systems, etc
Common mental status changes and complaints
- difficulty concentrating
- shortened attention span
- memory deficits
- confusion, impaired orientation to person, place, time
- impaired alertness/consciousness
A generic preliminary label meaning a diffuse brain pathology, a sense of localizing (focal) signs, various causes–infectious, metabolic, toxic, etc
Encephalopathy
A confusional state-impaired orientation, alertness, concentration-with or without additional common complaints including emotional/physical agitation and hallucinations typically an cute, subacute scenario
Delirium
What is the key question to ask to narrow the DDX when there’s delirium
Acute, subacute, or chronic onset?
What are some acute/subacute onset examples of delirium
Trauma, seizures, metabolic or toxic, infectious/inflammatory
Typically refers to a decline in cognitive and executive function, especially memory and behavioral control, with a chronic/insidious onset, usually progressive.
Dementia
What has Alzheimer’s previously been referred to
Senile dementia
When does Alzheimer’s start
Older than 65
Described as memory loss progressing to wide range of other cognitive impairments, then emotional/personality changes, and finally dementia
Alzheimer’s
What is the neuropathology of Alzheimer’s
“Senile” or “neuritic” plaques and tangles, now known as amyloid plaques and neurofibrillary tangles
-extracellular deposits distributed widely in brain at end-stage of disease
Neurotoxic-induce oxidative stress (free radical formation), disrupts neuronal membrane proteins functions, leads to excitotoxicity and neuronal cell death
Amyloid plaques-aggregates of beat-amyloid (AB) peptide
Symptomatic of neuronal cell death, degrades environment for live cells. Alzheimers
Tangles
What is the diagnosis of alzheimers
Post mortem neuropathology examination
- amyloid plaques and neurofibrillary tangles being in hippocampus/entorhinal
- then progression to other brain regions, affecting mroe functions
- new neuroimaging techniques in development to assess neuropathology
What does the cognitive decline in Alzheimer’s patients begin with
Memory impairment
What is the first stage of memory impairment in alzheimers
Memory impairment for recent events, then loss of remote memories
Late stage dementia in alzheimers
Generalized impairment in cognition and behavioral regulation- remote retrograde amnesia, disorientation, gradual loss of independence
Function of amyloid precursor protein (APP) in healthy cells
Unknown in healthy cells, cleaved to yield neurotoxic amyloid proteins
What is the normal APP enzymatically cleaved by
B-secretary
After APP is enymatically cleaved by B-secret as ever, what happens
The y-secretase further cleaves the transmembrane fragment at various amino acid sites, from 38th to 43rd amino acids
-small percent of cleavage product is a 42 amino acid product AB42 or AB
What is AB42
A small percentage of cleavage product from the y-secretase is this.
-it is neurotoxic although mechanisms still debated, possibly by disrupting function of many proteins, including cell membrane Na/K pump
How is AB42 neurotoxic
Possibly by disruptin function of many proteins, including cell membrane Na/K pumps
What does the original hypothesis say about AB42’s neurotoxicity
Must aggregate into plaques to become neurotoxic
Recent research about AB42 neurotoxicity
Suggests that all forms of AB42 are neurotoxic, but that plaques may minimize damage by isolating it
APP intracellular domain that acts as a transcription factor or regulator of transcription factors. Function remains debated but may act to promote apoptosis during brain development phase when excess neurogenesis happens and some neurons must undergo programmed cells death
AICD
Role of APP in pre-synaptic terminal
Transmembrane receptor, but ligand and transduction effects are unknown
-transported down axon, animal model evidence for involvement in synsaoe strucure, function, and plasticity
AB in pre-synaptic terminals
- like APP, AB transported down the axon
- AB intracelllar function and any secretory and extracellular roes is poorly understood
- controversy is whether AB aggregation in amyloid plaques is more toxic or minimizes damage
Accumulation of the cleaved AB protein
Accumulates in the EXTRACELLULAR matrix, these proteins bind together to form oligomers, which tend to have a toxic effect on the neurons disrupting their function
Tau protein
- hyper-phosphorylation of Tau protein de-stabilizes microtubules in dendrites and axons
- simultaneously disrupts neuronal cytoskeleton, results in cell death, and debris from destroyed axons from extracellular neurofibrillary tangles
- pathogenic cause for hyper-phosphorylation is still debated
Earliest and highest density of histopathology in alzheimers
In hippocampus and parahippocampal gyrus (especially entorhinal cortex-sends projections to dentate gyrus)
Is there a high density of neuropathology for alzheimers in the frontal lobe?
No
Braak and Braak stages of alzheimers
Based on anatomical localization pattern of neurofibrillary tangles
Cumulative effect of cellular level neuropathology in alzheimers
Gross cortical atrophy
When do amyloid deposition and neurofibrillary tangles
Before symptoms start
-present in normal aging and in mild cognitive impairment (MCI)
MCI
Statistically significant cognitive impairment but fails to meet life-disruptive criterion for alzheimers
Mild cognitive impairment: search for alzheimers biomarkers during MCI
- confirmation of alzheimers is still the post-mortem neuropathological analysis
- current status of research on in vivo dx markers
- PET/MRI of amyloid deposition, or AB load/burden
- CSF sampling for AB and tau protein
- peripheral marker candidates include inflammatory cytokines
Mechanisms driving AB and tau protein formation in alzheimers
Not known.
Current pharmacological approaches to alzheimers
- acetylcholinesterase inhibitors-block acetylcholine metabolism (degradation) in synapse
- memantine
What does acetylcholinesterase inhibitors do
- boosts cholinergic NT in sept-hippocampal system (medial septal nuclei to hippocampus)
- boosts cholinergic NT in cholinergic projections to cerebral cortex from basal nucleus if meynert and sub innominata
- enchanters attention/memory but does not stop neurodegeneration
What does memantine
NMDA glutamate receptor antagonist
-block/reduce glutamate excitotoxicity
Familial genetic factors for Alzheimer’s disease
Most AD cases are “sporadic” and not geneticall based or familial
Protein subunits of y-secretase. Mutation thought to contribute to AB42 formation
Presinilins
ApoE-Apolipoprotein E
- major risk factor, 3-12 fold, depending on the polymorphism/isoform
- in brain, produce by astrocytes
- lipoprotein that helps cells internalize cholesterol and triglycerides
- may have interactions with AB and presenilins
- not specific to alzheimers
Why is ApoE not specific to alzheimers
1/3 of AD cases do not have apoE mutations
-ApoE mutations are also seen in elderly without alzheimers
Dementia with levy bodies
Dementia combined with Parkinson’s-like movement disorder
Fronto-temporal dementia
- originally called Pick’s disease
- degeneration in frontal lobes and temporal lobes
- primary signs are behavioral disinhibition, memory loss
- degenerating neurons show tauopathy and intracellular inclusions
