neurodegenerative disease

Question 1

What are the consequences of failure of FAT?

Answer 1

accumulation of waste in axonal terminals
loss of replenishing substrates
= loss of synaptic connections = apoptosis

Question 2

What are two contributing factors in the mechanism of Alzheimer’s disease?

Answer 2

1. Protein misfolding/buildup (infection, diabetes, genes)
2. Diminished cerebral arteriolar compliance (DM, HTN, Age)

=iminished interstitial clearance of ppt’d misfolded protein + (AB amyloid clogged ISF pathways)

= Accumulation of hyperphosphorylated TAU and AB Amyloid

Question 3

How do Tau and B amyloid spread through the brain?

Answer 3

Tau - Neurofibrillary tangle, spreads up the brainstem to the cortex

B amyloid plaque - starts from frontal lobe and spreads backwards

Question 4

What are the two pathologic precipitated proteins in Alzheimer disease? what does this combination cause?

Answer 4

B-amyloid plaques in interstitial fluid channels
hyperphosphorylated Tau (tangles)

causes LOSS of NMDA receptors + disrupt FAT mechanism

Question 5

How does Alzheimers cause memory loss

Answer 5

Soluble B amyloid binds to PrPc (Prion protein) mediated by Fyn kinase (Toxic to AMPA receptors) = requiried for short and long term memory formation)

Question 6

What are 3 inherited Alzheimer Factors?

Answer 6

1. APOE 4 - disrupted lipid/cholesterol trafficking
2. Presenilin protein (PS1 and PS2) = MOST COMMON
3. Missense mutations of APP (chromosome 21)

Question 7

What is the initial cerebral geographic presentation of Alzheimers?

Answer 7

Basal frontal, basal temporal - spreads to remaining cortex

Question 8

What is the clinical presentation of Alzheimers?

Answer 8

loss of short term memory

loss of judgement

Question 9

What aberrant protein is a/w parkinson disease?

Answer 9

alpha-synuclein

Question 10

What gene encodes TAU?

Answer 10

MAPT

Question 11

What are 3 types of Tauopathies? Where in the brain do each affect?

Answer 11

1. Frontal Temporal Dementia (FTP) - Picks
   - -frontal cortex, ant temp cortex, basal ganglia
   - -young people
2. Progressive supranuclear palsy (PSP)
   - -subcortical gray matter, brainstem, cerebral cortex
   - -difficult fine motor control, probs looking down, balance
3. Chronic traumatic encephalopathy (CTE) - diffuse cortical and subcortical involvement

Question 12

What two genes are present in half of FTD’s?

Answer 12

Tau

TDP43

Question 13

behavioral change (apathy, disinhibition, agitation), lack of insight, blunted emotions > cognitive deficits, alien hand, apraxia, myoclonus, limb rigidity

Answer 13

Frontal temporal dementia

Question 14

supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia, and dementia

Answer 14

Progressive supranuclear palsy

Question 15

dementia Parkinson’s like features of rigidity, tremor, bradykinesia

Answer 15

Chronic Traumatic encephalopathy

Question 16

a-synuclein disease

diffuse cortical neuron involvement

Answer 16

Lewy body dementia

Question 17

a-synuclein disease

Lewy body accumulation primarily in the oligodendrocytes

Answer 17

MSA (multisystems Atrophy)

Question 18

How are lewy bodies formed?

Answer 18

Dopamine binds to asynuclein and form protofibrils which aggregate

Question 19

What is the function of a-synuclein? what condition causes it to build up?

Answer 19

attenuates neurotransmission

Familial parkinsons - LRRK2 mutation - buildup

Question 20

1. Preceded by REM sleep behavior disorder by 1-2 decades

2. Combination of parkinsonian features, dementia and autonomic insufficiency (prominent orthostatic hypotension)

Answer 20

Multisystem atrophy (MSA)
--synuclein accumulates in Oligodendrocytes

Question 21

What are two molecular players in Huntington Disease?

Answer 21

1. Huntington protein (HTT) - fast axonal transport protein

2. Autosomal dominant disease chromosome 4p 16.3

Question 22

What regions of the brain does Huntington Disease affect?

Answer 22

Caudate, putament, cerebral cortex

HTT protein

Question 23

chorea
dementia
behavioral changes

Answer 23

Huntington Disease