Dementia Diseases

Question 1

Etiology of Alzeihmers

Answer 1

AD is the most common form of dementia

In 2013, 5.2 million people in US suffered from AD

The incidence of AD is age related, doubling every 5 y after age of 65

The prevalence increases with age and affects up to 50% of people 85 years of age and older

Disease duration varies from 2 to 20 years

Question 2

Clinical definition of AD

Answer 2

Gradual and progressive decline in cognitive function with impairments in recent memory and one additional cognitive domain that is not due to other medical or psychiatric illness, and results in a functional impairment socially or occupationally

Question 3

Cognitive domains affected by AD

Answer 3

Memory
Language
Abstract thinking and judgment

Visuo-spatial or perceptual skills

Praxis
Executive function

Question 4

Diagnostic Criteria for Alzeihemers disease

Answer 4

• Definite DAT (DAT = dementia of Alzheimer type)

-Clinical criteria for Probable DAT -Histopathologic evidence of DAT (autopsy or biopsy) (Accurate clinical dx in 80-90%)

Question 5

• Atypical onset, presentation, or progression of dementia syndrome without known etiology
• Systemic or other brain disease capable of producing dementia
• Gradually progressive decline in a single intellectual function in the absence of any other identifiable cause

Answer 5

Picture for • Possible DAT

Question 6

• Memory- new learning defective, remote recall mildly impaired
• Visuospatial skills-topographic disorientation poor complex construction
• Language- poor wordlist generation, anomia
• Psychiatric features- depression, delusions

Answer 6

Stage I ( duration 1-3 years) of AD

Question 7

• Memory- recent and remote recall more severely impaired
• Visuospatial skills-poor construction spatial disorientation
• Calculation- acalculia
• Psychiatric features- delusions

Answer 7

• Stage II ( duration 2-10 years) of AD

Question 8

• Intellectual functions-severely impaired
• Sphincter control-urinary and fecal incontinence
• Motor- limb rigidity and flexion posture

Answer 8

• Stage III ( duration 8-12 years)

Question 9

What gross pathology is seen in AD

Answer 9

Decreased brain weight and atrophy of gyri with widening of sulci

see increased size in lateral ventricles = hyrocephalus ex vacuo

Question 10

Describe diffuse plaque seen in AD

Answer 10

– Extracellular accumulation of Aß protein

– Normal protein whose function is not yet completely known

– Comes from Amyloid precursor protein

Question 11

Extracellular accumulation of Aß protein

– Normal protein whose function is not yet completely known

– Comes from Amyloid precursor protein

Answer 11

DiffusePlaque

Question 12

extracellular accumulation of Aß protein and tau containing neurites

– More closely associated with cognitive decline than the diffuse plaque

– Neurites are axons or dendrites coursing through brain tissue

Answer 12

Neuritic plaque

Question 13

What makes up a neuritic plaque

Answer 13

accumulation of AB protein and Tau protine containing neurites

Question 14

Whats this garbage?

Answer 14

Bielschowsky : these are senile plaques in the neocortex; make dx based on density of plqs

Question 15

• Almost always found in AD
• Occurs in absence of AD also

– Associated with lobar hemorrhages in elderly

Answer 15

Cerebral amyloid angiopathy

Question 16

Intraneuronal accumulation of an abnormally phosphorylated form of tau, a normal microtubule associated protein: not unique to AD; also found in other degenerative diseases

**No evidence of mutations of tau gene in AD

Answer 16

Neurofibrillary tangles

Question 17

Pathological diagnosis of AD, the current criteria utilize

Answer 17

– Density of neuritic plaques
– Staging scheme for neurofibrillary tangles

Question 18

Relationship bwn NP and NFT not understood,

Relationship between aging and AD still under investigation

–____ is (so far) biggest risk factor for AD

Answer 18

Age

( Are AD like changes in brain a sign of age or an early manifestation of AD? )

Question 19

Inheritance of AD

There are three patterns

Answer 19

– 75% - sporadic

– 20-25% - history of affected relatives who develop disease randomly

– 1-5% - prominent family history, usually consistent with autosomal dominant inheritance pattern (FAD=familial AD)

Question 20

Pts with early onset AD present with the same symtpoms and the same pathology as late set but there is a genetic difference

Answer 20

See autosomal dominant mutation that is highly penetrant

(get memory impairment followed by conginitive decline and NPs with NFTs)

pts present UNDER 60-65 are early onset

Question 21

APP is a transmembrane glycoprotein

– Gene on ______

– Normal functions not fully understood

– ßamyloidprotein,Aß,(insenileplaques)derived from ____

Answer 21

chromosome 21

APP

Question 22

Older individuals with ________ develop AD in late 30s

First mutation in APP gene described in 1991 in affected members of a British FAD kindred

– Fewer than 20 kindreds have since been described – Approx. 11 AD-associated missense mutations described
• No linkage to late-onset FAD

Answer 22

Down’s syndrome (trisomy 21)

Question 23

Describe APP processing: two ways

Answer 23

alpha secretase cleaves w/in AB sequence; no AB produced

Cleavage at B and gamal sites of APP: AB made, then B secretase enZ identified, gamma secretase enZ unknown

Question 24

Most common genetic issues in AD

Answer 24

Presenilin 1 (PSEN1 gene) on chromosome 14

– Most commonly occurring genetic mutation at this time: explains 50% of familial AD

– Transmembrane protein (endoplasmic reticulum and Golgi)

– Normal function not definitively known

Question 25

– Most commonly occurring genetic mutation at this time: explains 50% of familial AD

– Transmembrane protein (endoplasmic reticulum and Golgi)

– Normal function not definitively known

Answer 25

Presenilin 1 (PSEN1 gene) on chromosome 14

Question 26

less common genetic causes of AD

Answer 26

Amyloid precursor protein (APP gene) on chromosome 14 – Rare

Presenilin 2(PSEN2 gene) on chromsome 1 – Very rare

Question 27

What is the pattern of inheritance in AD

Answer 27

– ** Autosomal dominant** inheritance

– Result in increased deposition of Aß amyloid protein

– Result in early-onset AD (< 65 yrs age)

Question 28

Established genetic risk factor for late-onset AD

Answer 28

Apolipoprotein E protein and APOE gene

Question 29

What is ApoE4 normal role and what proteins are implicated in AD

Answer 29

Three alleles at gene locus on chr 19: ε2, ε3, and ε4 is implicated in risk!!!!

– Code three protein isoforms, E2, E3, and E4

– Apo E protein involved in cholesterol transport, metabolism, and storage

– No associated mutations in gene

Question 30

Presence of ____ modifies genetic risk is a ________ fashion

Answer 30

ε4

– Dose-dependent : people with one ε4 allele have approx 3x increased risk of

AD, people with two ε4 alleles have approx 15x increased risk of AD

– Association robust but not specific

– Presence of ε4 not necessary nor sufficient

Question 31

Increased apo E4 expression results in increased

Answer 31

AB deposition

Question 32

Cholinergic signaling deficiency seen in what diseases?

Answer 32

– Alzheimer’s Disease
– Dementia with Lewy bodies

– Vascular Dementia

Question 33

Donepezil

Rivastigmine

Galantamine

Tacrine

What type of drugs are these, what are they used for, which is the worst?

Answer 33

Centrally acting cholinesterase inhibitors

To tx AD

Worst is Tacrine

Question 34

Side effects of centrally-acting cholinesterase inhibitors

Answer 34

Modest improvement, many side effects (1/3 have GI problems), muscle cramping and abnormal dreams

Question 35

AD, like all neurodegenerative disorders, includes

Answer 35

excitotoxicity, oxidative stress and neuroinflammation

Question 36

NMDA channel blocker used to slow progression of Alzeihmers

Answer 36

Memantine

*side effects include headache and dizziness

Question 37

Second most common form of early dementia (onset younger than 65 yrs) after AD

Causes focal degeneration in the **frontal and anterior temporal lobes **

Answer 37

Frontotemporal Degeneration (FTD) : FTD refers to the clinical frontotemporal dementia syndrome

Question 38

Frontotemporal Degeneration Etiology

Answer 38

Sporadic: approximately 50% the other 50% Familial cases

(lot of times we see TDP-43 accumulation= a DNA binding protein )

Question 39

What are the two clincal subtypes of FTD

Answer 39

Behavioral variant FTD (50%)

Primary progressive aphasia

Question 40

Primary progressive aphasia is a subtype of FTD
– Progressive nonfluent aphasia (PNFA): 25% we see what on the scan?

– Semantic variant (SV): 20-25% we see what on the scan?

Answer 40

• Left peri-Sylvian atrophy on scan
• Bilateral anterior temporal lobe atrophy

Question 41

Socially inappropriate behavior, loss of manners or impulsive or careless actions

Early apathy or inertia

Early loss of sympathy or empathy

Early perseverative, stereotyped, or compulsive/ritualistic behavior

Hyperorality and dietary changes

Answer 41

Behavioral Variant FTD (bifrontal lobe atrophy)

Question 42

Symptoms are:

• Fluency • Comprehension • Repetition

• Fluency worst in nonfluent aphasia
• Comprehension worst in semantic variant

Answer 42

Primary Progressive Aphasia Subtypes of FTD

Question 43

What do we see grossly in this image?

Answer 43

Frontal and temporal lobe atrophy seen in pts with FTD

Question 44

Microscopic findings of FTD depend on subtype

Answer 44

– Tauopathies – accumulation of tau protein: Classic example :

Pick’s disease: – Atrophy of frontal & temporal lobes and Severe neuronal loss in frontal & temp cortex with Pick bodies – round cytoplasmic inclusion in neurons, contain abnormal tau filaments

– FTLD-TDP-43 – accumulation of TDP-43 = Cytoplasmic protein accumulations in frontal/temporal lobes

Question 45

When would we see accumulation of TDP-43 in the frontal and temporal lobes?

Answer 45

in FTD

Question 47

– Atrophy of frontal & temporal lobes

– Severe neuronal loss in frontal & temp cortex with round cytoplasmic inclusion in neurons, contain abnormal tau filaments

Answer 47

Picks diseae (tauopathie)

Question 48

Describe gross pathology of Picks disease

Answer 48

Distinctive atrophy- severe frontal & temporal atrophy (“Knife-edge”), sparing of parietal & occipital lobes

Question 49

What do we see here?

Answer 49

Picks disease with pink round cytoplasmic inclusion

paired helical filament/tau Ab: brown is positive