6/3- Neuropathology of Dementia

Question 1

Key feature (anatomical) of dementia?

Answer 1

Cortical degeneration

Question 2

Causes of cortical degeneration?

Answer 2

• Alzheimer’s dz
• Pick’s dz (frontotemporal dementia)
• Lewy body dementia

These are the 3 MCCs of neurodegenerative dementia (each have varied initial symptoms)

Question 3

What does this show?

Answer 3

Cortical atrophy

(Left side shows caudate atrophy and hydrocephalus ex vacuo of Alzheimer’s dz?)

(Right side shows frontotemporal degeneration/Pick’s disease; selective in frontal and temporal regions)

Question 4

2 categories of dz within Alzheimer’s?

Answer 4

Classical

Variant

Question 5

2 categories of disease within Non-Alzheimer’s neurodegenerative diseases with dementia?

Answer 5

Tauopathies (PSP):

• FTD complex/Pick’s dz

Synucleinopathies (PD, LBD):

• Lewy Body Complex

Question 6

What is seen microbiologically in Alzheimer’s dz?

Answer 6

• Beta-amyloid (extracellular) + Tau (intracellular)

Question 7

What is seen microbiologically in Pick’s dz/FTLD?

Answer 7

• Tauopathy (pure)

Question 8

seen microbiologically in Lewy Body Dementia (LBD)?

Answer 8

• Alpha synuclein

Question 9

Where does atrophy start in Alzheimer’s?

Answer 9

Starts in amygdala, hippocampus, and temporal lobe

Question 10

Neuronal changes in Alzheimer’s?

Answer 10

• Loss of cortical cholinergic innervation

(Central) cholinesterase inhibitors now in clinical use in mild-moderate cases

Question 11

Characteristics of Alzheimer’s dz (symptoms)?

Answer 11

• MEMORY DISTURBANCES
• Starts with short-term memory
• Onset may be subtle
• Early onset cases are typically genetic

Question 12

What anatomical features are seen grossly with Alzheimer’s?

Answer 12

Cortical atrophy and hydrocephalus ex vacuo

Question 13

Histological features of Alzheimer’s dz?

Answer 13

• Neuritic plaques- EXTRAcellular
• Neurofibrillary trangles- INTRAcellular
• Amyloid deposition in mature neuritic plaques and in the walls of cortical and leptomeningeal blood vessels
• Many people believe that the plaques (beta-amyloid) are the initiating event and the tangles (hyperphosphorylated tau) are 2ndary
• AD therefore is a beta-amyloidopathy

Question 14

What is this?

Answer 14

Plaques and tangle seen in Alzheimer’s dz

• Silver stain binding proteins rich in B-sheets and fibrillogenesis Seen center left is a plaque (extracellular)
• Black structures are axons adjacent to deposition of B-amyloid; stuff like tau begins to accumulate within the processes
• Most of the plaque is comprised of B-amyloid with neuroprocesses with accumulations of tau

Seen center right is a process with accumulation of tau (tangle?)

Question 15

CERAD plaque estimation in Alzheimer’s dz (picture)

Answer 15

Few, moderate, or many

Question 16

What is this?

Answer 16

Neurofibrillary tangles in Alzheimer’s dz (deposition of tau)

• When tau is deposited in this way, it becomes hyperphosphorylated

Question 17

Plaque staging or counting has a ____ (good/poor) correlation with dementia. Tangle staging has a ___ (good/poor) correlation with dementia.

Answer 17

Plaque staging or counting has a poor correlation with dementia (HOW MANY PLAQUES)

Tangle staging has a good correlation with dementia (WHERE ARE THE TANGLES)

Question 18

Progression of Alzheimer dz (main steps)?

Answer 18

• Pre-symptomatic
• Mild cognitive impairment (MCI)
• Alzheimer’s dz

Question 19

Progression of Alzheimer’s: Pre-symptomatic?

Answer 19

The pt has no cognitive impairment.

There is growing evidence that EC beta-amyloid is accumulating and tangles are beginning to form, esp in the hippocampus and adjacent temporal cortex

Question 20

Progression of Alzheimer’s: Mild cognitive impairment (MCI)?

Answer 20

The pt has mild deterioration of memory and cognitive function that worries the patient but which does not interfere with daily living

Question 21

Progression of Alzheimer’s: Alzheimer’s dz?

Answer 21

These individuals are frankly demented on clinical examination, neuropsychological evaluation and there is impairment of activities of daily living

Question 22

T/F: Alzheimer’s plaques can grow overnight

Answer 22

True

Study with mice has shown that they can grow significantly overnight

Question 23

Timeline of plaque development/growth in Alzheimer’s?

Answer 23

Plaques form in a day; macrophages/microglia react within a couple days; neurotic processes form within days

- Day 1: microplaque

- Day 2: distended neurites, amyloid-B-oligomer, astroglia and microglia first appear

- Day 3: dystrophic neurites

- Day 7: mature plaque

Question 24

How many people with MCI will go on to develop Alzheimer’s?

Answer 24

Roughly 1/2

Question 25

What is this?

Answer 25

**Amyloid angiopathy** in Alzheimer's dz - Beta amyloid in vascular walls (typically cleared in blood, but if excessive accumulation in EC space, can build up in vessel wall -\> fragility and IC hemorrhaging)

Question 26

What is Pick's disease? Key clinical features?

Answer 26

Frontotemporal dementia - Uncommon severe dementing dz Symptoms - FRONTAL DISINHIBITION - (rare cases of new artistic/musical abilities)

Question 27

Micro anatomical features of Pick's disease?

Answer 27

Micro: - Neuronal loss and gliosis - Ballooned neurons - NO plaques, tangles, or granulovacuolar - Faintly basophilic intraneuronal cytoplasmic inclusions (Pick bodies) immunoreactive for tau Pick's is a pure TAUOPATHY

Question 28

Gross anatomical features of Pick's disease?

Answer 28

Gross: - Marked temporal and frontal atrophy - "Knife edge" gyri - Sparing of post 2/3 of superior temporal gyrus, parietal lobes, and precentral (motor) gyrus

Question 29

What is this?

Answer 29

Cortical atrophy seen in Pick's disease (Frontotemporal Atrophy ) - so thin gyri that they look like "knife edge"

Question 30

What is this?

Answer 30

Pick bodies in Pick's dz

Question 31

What is this?

Answer 31

Tau inclusions: Globose tangles in PSP - Silver stain

Question 32

What is this?

Answer 32

Tau inclusions: Pick bodies in Pick's dz - Silver stain; Pick bodies are the larger blots while nuclei are smaller

Question 33

What is this?

Answer 33

Neuronal loss, gliosis, rarefaction in Pick's dz - Rarefied = not many neurons; a lot of open space - Notice: no plaques (unlike AD)

Question 34

What is seen micro in Lewy Body Dz?

Answer 34

- Subtle eosinophilic cytoplasmic inclusions in cortical neurons (Lewy bodies) - Difficult to identify on H&E; immunopositive with alpha-synuclein

Question 35

What is the most common cause of dementia? 2nd most common cause?

Answer 35

1st: Alzheimer's disease 2nd: Lewy Body disease

Question 36

Clincical features of Lewy Body disease?

Answer 36

- **Fluctuating** cognitive features (starkly different from day to day!) - **Visual hallucinations** (often well-formed, cartoon-like; pt is aware that they are hallucinating) - **Extrapyramidal features** may occur (e.g. some features of Parkinsonism)

Question 37

What is this?

Answer 37

**UL:** Parkinson's disease (loss of SN) **UR**: Lewy bodies in pigmented neurons with central core and halo **LL**: Lewy body **LR**: Cortical Lewy Bodies (PD and LBD are synucleinopathies)

Question 38

What is this?

Answer 38

Cortical Lewy Bodies - a-synuclein (Parkinson's dz and Lewy body dementia are synucleinopathies)

Question 39

Pharmacological approaches?

Answer 39

**Central cholinesterase drugs** - Donepezil - Rivastigmine - Galanthamine **Glutaminergic neurotransmission modulators** (use any place there' degeneration and a lot of glutamate buildup) - Riluzole (for ALS) - Memantine (for Alzheimer's) Parkinsonism Sx (in LBD) may be treatable with DA, but cost may exceed therapeutic benefit