J.Neuropathol.Exp.Neurol.2012Review

Question 1

Although the severity AB plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with what?

Answer 1

The burden of neocortical neurofibrillary tangles (NFTs)

Question 2

What is required for a definitive diagnosis of AD?

Answer 2

Autopsy

Question 3

Neurofibrillary pathology comprises what? (5)

Answer 3

-Aberrant
-Partly Soluble
-Protease-Resistant
-Hyperphosphorylated
TAU AGGREGATES

Question 4

Neurofibrillary pathology by Electron Microscopy shows what?

Answer 4

Paired helical filaments

• Inside various cellular components OR
• Extracellular after death of the parent cell

Question 5

Neurofibrillary tangles (NFTs) describes what?

Answer 5

Neurofibrillary pathology found in cell bodies

Question 6

What is a pretangle?

Answer 6

Contains abnormal hyperphosphorylated TAU in nonfibrillar (partially soluble) and non argyrophilic forms.

Question 7

T/F: Pretangles are capable of developing into NFTs.

Answer 7

True

Question 8

What are amyloid plaques that contain the Amyloid Beta peptide (ABPs)?

Answer 8

• Extracellular
• Spherical (roughly) structures
• Contain AB peptide and other material

Question 9

ABPs can be detected histologically with what special stains? (3)

Answer 9

• Congo Red
• Silver Stains
• Thioflavin-like Molecules

Question 10

Diffuse ABPs may be visualized using what?

Answer 10

Silver stains and anti-AB immunostains

Question 11

What are Neuritic AB plaques (NPs)?

Answer 11

-ABPs that are invested by swollen, degenerating neurites and glial cell processes

Question 12

In NPs, what do the swollen neurites contain?

Answer 12

Filamentous TAU protein aggregates

-Structurally identical to the inclusions with the NFT

Question 13

The density of NPs is graded according to what?

Answer 13

Consortium to Establish A Registry for Alzheimer’s Disease (CERAD) criteria

Question 14

By definition, what do diffuse plaques lack?

Answer 14

Dystrophic tau-immunoreactive neurites

Question 15

Braak stages refer to what?

Answer 15

Hypothetically predictable progression of NFT-type pathologic features in the brain during the course of Alzheimer disease.

Question 16

Braak stages:

-(I-III)

Answer 16

Early stages

-Medial Temporal lobe structures ONLY

Question 17

Braak stages:

-(IV-VI)

Answer 17

Later stages

-Progressively affect the neocortex

Question 18

Medial Temporal Lobe Structures (MTLs) comprise what structures? (4)

Answer 18

• Amygdala
• Entorhinal Cortex*
• Cornu Ammonis (CA) fields*
• Subiculum of the Hippocampus*

*Allocortical structures

Question 19

MTLs play important role in what?

Answer 19

Consolidating short-term memory

Question 20

Hippocampal pathology is ubiquitous in AD patients but is not relevant for clinicopathologic correlation due to what?

Answer 20

Strong “floor-and-ceiling” effects

Question 21

What is the areas of cerebral cortex outside of allocortical areas refered to as?

Answer 21

Isocortex/Neocortex

Question 22

What is the function of the neocortical areas?

Answer 22

Higher order function

• Judgement
• Executive function

Question 23

T/F: The distinction between the MTL areas and neocortical areas is important in comprehending the predictable, but nonlinear, progression of pathology in AD.

Answer 23

True

Question 24

What are the neuropathologic hallmarks of AD?

Answer 24

• Neurofibrillary tangles (NFTs; including pretangles)
• Amyloid Beta plaques (ABPs; including diffuse and neuritic plaques*)

*also referred to as “senile plaques”

Question 25

What are some additional (not pathognomic) changes seen in brains of AD patients? (8)

Answer 25

- Amyloid angiopathy - Age-related brain atrophy - Synaptic pathology - White matter rarefaction - Granulovaculolar degeneration - Neuron loss - TDP-43 proteinopathy - Neuroinflammation

Question 26

T/F: Neurofibrillary tangles are not specific for AD.

Answer 26

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)

Question 27

What are some other conditions were NFTs are found? (9) | *What does this suggest?

Answer 27

- 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.

Question 28

Neurofibrillary degeneration restricted to what anatomical locations are typically subclinical?

Answer 28

Subcortical sites

Question 29

Where are Amyloid Beta plaques located?

Answer 29

Extracellular

Question 30

T/F: ABPs are found in a high proportion of ALL elderly persons but are not universal.

Answer 30

True

Question 31

What ABP subtype is more likely to be associated with cognitive impairment? -What is the other subtype?

Answer 31

``` Neuritic plaques (NPs) -"diffuse plaques" ```

Question 32

What are Neuritic Plaques?

Answer 32

ABPs surrounded by degenerating axons and dendrites -Contain hyperphosphorylated TAU aggregates *Hallmark of the current diagnostic criteria for AD

Question 33

What are the High-Penetrance AD genetic risk alleles? (4)

Answer 33

- APOE e4 allele - Trisomy 21 - APP mutations/duplications - PSEN1/PSEN2 mutations

Question 34

What are the high-penetrance AD genetic risk alleles associated with?

Answer 34

Increased AB deposition and increased formation of putative toxic AB peptide species

Question 35

Genetic factors confer approximately __% of an individuals risk for AD.

Answer 35

70%

Question 36

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.

Answer 36

NFTs

Question 37

What are the effects of anti-AB immunotherapy in patients with mid- to late-stage AD?

Answer 37

- Partially cleared ABPs - No effect on NFT formation - Little effect on disease course

Question 38

In most community-based autopsy series, non-AD tauopathies constitute approximately ___% of dementia cases.

Answer 38

1%

Question 39

What are the Non-AD Tauopathies? (6)

Answer 39

- FTLD-MAPT - Progressive Supranuclear Palsy - Corticobasal Degeneration - Pick Disease - Argyrophilic Grain Disease - "Tangle-Only Dementia"