J.Neuropathol.Exp.Neurol.2012Review Flashcards
Although the severity AB plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with what?
The burden of neocortical neurofibrillary tangles (NFTs)
What is required for a definitive diagnosis of AD?
Autopsy
Neurofibrillary pathology comprises what? (5)
-Aberrant
-Partly Soluble
-Protease-Resistant
-Hyperphosphorylated
TAU AGGREGATES
Neurofibrillary pathology by Electron Microscopy shows what?
Paired helical filaments
- Inside various cellular components OR
- Extracellular after death of the parent cell
Neurofibrillary tangles (NFTs) describes what?
Neurofibrillary pathology found in cell bodies
What is a pretangle?
Contains abnormal hyperphosphorylated TAU in nonfibrillar (partially soluble) and non argyrophilic forms.
T/F: Pretangles are capable of developing into NFTs.
True
What are amyloid plaques that contain the Amyloid Beta peptide (ABPs)?
- Extracellular
- Spherical (roughly) structures
- Contain AB peptide and other material
ABPs can be detected histologically with what special stains? (3)
- Congo Red
- Silver Stains
- Thioflavin-like Molecules
Diffuse ABPs may be visualized using what?
Silver stains and anti-AB immunostains
What are Neuritic AB plaques (NPs)?
-ABPs that are invested by swollen, degenerating neurites and glial cell processes
In NPs, what do the swollen neurites contain?
Filamentous TAU protein aggregates
-Structurally identical to the inclusions with the NFT
The density of NPs is graded according to what?
Consortium to Establish A Registry for Alzheimer’s Disease (CERAD) criteria
By definition, what do diffuse plaques lack?
Dystrophic tau-immunoreactive neurites
Braak stages refer to what?
Hypothetically predictable progression of NFT-type pathologic features in the brain during the course of Alzheimer disease.
Braak stages:
-(I-III)
Early stages
-Medial Temporal lobe structures ONLY
Braak stages:
-(IV-VI)
Later stages
-Progressively affect the neocortex
Medial Temporal Lobe Structures (MTLs) comprise what structures? (4)
- Amygdala
- Entorhinal Cortex*
- Cornu Ammonis (CA) fields*
- Subiculum of the Hippocampus*
*Allocortical structures
MTLs play important role in what?
Consolidating short-term memory
Hippocampal pathology is ubiquitous in AD patients but is not relevant for clinicopathologic correlation due to what?
Strong “floor-and-ceiling” effects
What is the areas of cerebral cortex outside of allocortical areas refered to as?
Isocortex/Neocortex
What is the function of the neocortical areas?
Higher order function
- Judgement
- Executive function
T/F: The distinction between the MTL areas and neocortical areas is important in comprehending the predictable, but nonlinear, progression of pathology in AD.
True
What are the neuropathologic hallmarks of AD?
- Neurofibrillary tangles (NFTs; including pretangles)
- Amyloid Beta plaques (ABPs; including diffuse and neuritic plaques*)
*also referred to as “senile plaques”
What are some additional (not pathognomic) changes seen in brains of AD patients? (8)
- Amyloid angiopathy
- Age-related brain atrophy
- Synaptic pathology
- White matter rarefaction
- Granulovaculolar degeneration
- Neuron loss
- TDP-43 proteinopathy
- Neuroinflammation
T/F: Neurofibrillary tangles are not specific for AD.
True
“NFTs are found in both controls and dements in the hippocampus, but elsewhere in the cortex was only severe or widespread in the dements…” -Tomlinson et.al (1970)
What are some other conditions were NFTs are found? (9)
*What does this suggest?
- Frontotemporal Lobar Degeneration with Tauopathy (FTLD-MAPT)
- Focal Cortical Dysplasia
- Myotonic Dystrophy
- Prion Diseases
- Metabolic/Storage Diseases
- Brain Tumors (some)
- Chronic Traumatic Encephalopathy
- Viral Encephalitis
- Other Brain diseases
*NFTs are, at least under some conditions, a secondary response to injury.
Neurofibrillary degeneration restricted to what anatomical locations are typically subclinical?
Subcortical sites
Where are Amyloid Beta plaques located?
Extracellular
T/F: ABPs are found in a high proportion of ALL elderly persons but are not universal.
True
What ABP subtype is more likely to be associated with cognitive impairment?
-What is the other subtype?
Neuritic plaques (NPs) -"diffuse plaques"
What are Neuritic Plaques?
ABPs surrounded by degenerating axons and dendrites
-Contain hyperphosphorylated TAU aggregates
*Hallmark of the current diagnostic criteria for AD
What are the High-Penetrance AD genetic risk alleles? (4)
- APOE e4 allele
- Trisomy 21
- APP mutations/duplications
- PSEN1/PSEN2 mutations
What are the high-penetrance AD genetic risk alleles associated with?
Increased AB deposition and increased formation of putative toxic AB peptide species
Genetic factors confer approximately __% of an individuals risk for AD.
70%
Dense and extensive neocortical ___ are very consistently associated with dementia and thus, according to new diagnostic criteria, are required to constitue high burden of AD neuropathologic change.
NFTs
What are the effects of anti-AB immunotherapy in patients with mid- to late-stage AD?
- Partially cleared ABPs
- No effect on NFT formation
- Little effect on disease course
In most community-based autopsy series, non-AD tauopathies constitute approximately ___% of dementia cases.
1%
What are the Non-AD Tauopathies? (6)
- FTLD-MAPT
- Progressive Supranuclear Palsy
- Corticobasal Degeneration
- Pick Disease
- Argyrophilic Grain Disease
- “Tangle-Only Dementia”
