neurodegenerative dementia

Question 1

what is dementia

Answer 1

a global impairment of higher cortical function wihch is usually progressive and irreversible

Question 2

main symptoms of dementia

Answer 2

short term memory loss, day to day problem solving skills, perceptuomotor skills, social skills and emotional reactions

Question 3

Common types of dementia

Answer 3

AD - progressive starting with memory
Vascular dementia - caused by impaired blood supply, sudden or step wise symptoms, variable cognition problems
FTD/PICKS - younger diagnosis. Progressive symptoms but not memory just higher cognitive function
Dementia with lewy bodies - rapid fluctuations in cognitive ability, hallucinations, motor defects occasionally

Question 4

Protein inclusion as markers of neurodegeneration

Answer 4

AD - amyloid plaques, NFT
FTD - somtimes tangles
D with lewy bodies - lewy bodies
PICKS - pick bodies and cells

Question 5

AD symptoms

Answer 5

deficits in memory function
disruption of normal daily living/social skills intact
LT memory failure
deficits in higher cognitive functions
spatial and temporal disorientation
dyspraxia
apathy, depression, agitation, anxiety, paranoia, delusions

Question 6

how is brain affected pathalogically in AD

Answer 6

Apathy, narrowed gyri, increased sylvian fissure, global shrinkage, widened sulcal margins.

Question 7

what areas of brain are affected by AD

Answer 7

Frontal lobe, parietal lobe and temporal lobe including hippocampus

Question 8

What are markers for AD

Answer 8

Amyloid plaques and NFTs. often activated glia

Question 9

What are NFTs composition

Answer 9

teardrop shaped tangles due to hyperphosphorylated tau filling pyramidal cells

Question 10

What are Amyloid plaques composition

Answer 10

Contained in neuropil and made of 7-10nm thick protein fibres with amyloid Beta peptides and degenerative nerve endings

Question 11

Causes of AD

Answer 11

94-99 idiopathic.

1-6% mendelian genetic inheritance

Question 12

Key markers for diagnosis of AD

Answer 12

pupil dilation test with tropicamide unusually fast
altered CSF tau (high) and low AB proteins
the mini mental state exam
post mortem is definitive

Question 13

AD therapies

Answer 13

Cholinesterase inhibitors - donepezil, galantamine, rivastigmine
Partial NMDAr antagonist - memantine

Question 14

Cholinesterase inhibitor mechanism

Answer 14

inhibits AchE in cleft so Ach present for longer and not degraded as quickly. acts in septum pellucidum –> hippocampus, and nucleus of meynert –> widespread cortical connections

Question 15

partial NMDAr antagonist mechanism

Answer 15

low affinity uncompetitive NMDA antagonist, binding to open conformation. limits excitotoxicity and alters aberrant synaptic plasticity

Question 16

Hypothesis causes of AD

Answer 16

cholinergic dysfunction, glutamatergic dysfunction, amyloid, tau

Question 17

What is normal mechanism of APP processing and how is it altered in AD

Answer 17

a secretase to release APP, y secretase to release beneficial p3.
b secretase instead of a in AD. AB then released instead of p3

Question 18

where does a secretase cut

Answer 18

amino acid 17

Question 19

where does b secretase cut

Answer 19

1/11

Question 20

where does y secretase cue

Answer 20

40/42

Question 21

what is the gene for a secretase

Answer 21

ADAM 10/17

Question 22

What is the gene for b secretase

Answer 22

BACE - 1

Question 23

What are the proteins that make up y secretase

Answer 23

presenelin 1/2, nicastrin, aph1 and pen2

Question 24

What do APP mutations cause

Answer 24

increase b secretase cleavage - EOAD

Question 25

what do PSEN1/2 mutations cause

Answer 25

increase y secretase activity - EOAD

Question 26

what is the old hypothesis for AD and who came up with it

Answer 26

Hardy and HIggins, 1992. Amyloid cascade hypothesis --> amyloid leads to NFT and cell death

Question 27

Genetic evidence for amyloid hypothesis

Answer 27

Familial Mendelian AD is linked to mutations in APP, PSEN1 and 2 ApoE isoform 4 is predisposing to EOAD

Question 28

What is ApoE4 and what does it do

Answer 28

lipid transporting protein that can assist in clearance of AB. isoform 4 not as effective

Question 29

How is familial mendelian AD linked to mutations in APP, PSEN1 and 2

Answer 29

EOAD. increase in AB1-42 and AB1-40 | includes trisomy of chromosome 21 where APP gene is located

Question 30

what is most toxic form of AB

Answer 30

AB-1

Question 31

what does APP do

Answer 31

alters neuronal excitability | protective functino recently found

Question 32

what is APPswe

Answer 32

EOAD mutation

Question 33

what does APPswe do

Answer 33

not active - no calcium measure shown. increases l type ca currents. APPswe mouse has defects in neuronal structure. Spine number decreased close to plaques

Question 34

what is tau

Answer 34

microtubule associated protein which stabilises

Question 35

What does tau do in disease

Answer 35

hyperphosphorylate dissociate from microtubules misfolding and aggregation into NFTs

Question 36

how is tau hyperphosphorylated

Answer 36

upregulation if kinases or down regulation of phosphatases

Question 37

Tauopathy pathology

Answer 37

no plaques but cell death

Question 38

in rTg4510 model of tauopathy, what is mutated?

Answer 38

P301L mutation in MAPT gene found in FTDP-17

Question 39

does AB in brains always cause cognitive impairments?

Answer 39

no

Question 40

soluble or plaques as better indicator?

Answer 40

soluble as better correlation to decline in cognition

Question 41

what does soluble AB on cultured neurons cause

Answer 41

EPSC reduction

Question 42

what is first thing that AB affects?

Answer 42

synaptic transmission

Question 43

what does APP mutation not do?

Answer 43

produce amyloid

Question 44

Mutated APP with GFP experiment results and problems

Answer 44

APP mutation doesnt produce amyloid. overexpression so may not be related to disease AB is usually extracellular whereas intra in experimenty

Question 45

do AB transgenic mice studies influence tau formation?

Answer 45

yes

Question 46

what is the relationship between microglia and AB?

Answer 46

microglia found near plaques and directly activated by AB

Question 47

what is TREM2

Answer 47

genetic factor for AD which may lead to activated microglia

Question 48

what is the structure of AB fibirls

Answer 48

s shaped stack formed by AB1-42 but not AB1-40. conformation of monomers different

Question 49

main issues of b secretase inhibitors?

Answer 49

pharmacokinetics

Question 50

y secretase inhibitor problems

Answer 50

accelerated cognitive decline as no p3. also targets notch

Question 51

potential mechanism of y secretase modulators

Answer 51

preferential AB38>42 without notch 1 cleavage

Question 52

what is solanezumab

Answer 52

monoclonal antibody directed to mid section of AB. failed phase 3