PT 536 Neurodegenerative Conditions Pathophysiology

Alzheimer's Disease

Progressive dementia characterized by plaques and tangles

memory deficits

primary clinical symptom of AD

65+: 6%

80+: 20%

95+: 95%

prevalence of AD in various ages

1%

% of familial AD cases

40-50

What is the common age of onset for familial cases of AD

age, female sex, mild cognitive impairment, diabetes, apolipoprotein E4

Risk factors for AD

33% (10% annual rate)

% of mild cognitive impairments that develop into AD

diabetes ("type 3 diabetes")

AD is often named after what disease, due to its resistance to insulin in the CNS?

False (high doses of insulin will exacerbate insulin insensitivity in the CNS)

True or false? Insulin therapy decreases risk of developing AD.

vascular dementia

What kind of dementia often occurs as a result of a stroke?

Ɛ4

There is a dose dependent risk of AD with what allele of the apolipoprotein?

AD: severe brain atrophy

How will the physical appearance of a brain from a patient with AD differ from that from a control patient?

07% (0.4% general population)

atrophy rates in the cortex of the brain seen with AD

7% (1% general population)

atrophy rates in the hippocampus of the brain seen with AD

amyloid plaques, NFTs

What will imaging show in brains of those with AD?

1. extracellular

2. intracellular

Amyloid plaques are __________________ while tau tangles are ___________________

(intracellular or extracellular)

Aβ42

All familial cases of AD involve increased in what?

Amyloid Precursor Protein (APP)

a protein that, when cleaved by secretases, produces B-amyloid

21 (prevalent with DS)

APP is most abundant on what chromosome?

Aβ42 is more aggregation-prone

How is Aβ42 different than Aβ40?

impaired Aβ clearance

Main mechanism of sporadic AD

apolipoprotein E (ApoE)

protein involved in receptor-mediated Aβ clearance

across the BBB

Where does ApoE transport Aβ to?

ApoE4

What ApoE allele binds to Aβ less efficiently?

default mode network

The network of brain structures that tends to be active when the brain is in default mode (not cognitively engaged)

medial temporal lobe, other areas affected in AD

what brain regions are included in the DMN?

Aβ accumulation

consequence of chronic DMN activity

20 years prior

how soon can plaques and tangles accumulate before cognitive impairment emerges with AD?

Pittsburgh Compound B

PET ligand that detects amyloid

Aβ oligomers

soluble intermediate proteins found near Aβ plaques, causing synapse loss, impairee tau function, and impaired learning

impairing LTP (destroy synapses involved with LTP)

How do Aβ oligomers impair learning?

hyperphosphorylation

through what mechanisms do Aβ oligomers impair tau function?

in neurons

where are tau oligomers found?

slow anterograde axonal transport

phosphorylated tau creates tau oligomers. how do tau oligomers interfere with neurons?

synaptic starvation

effect of slowed anterograde transport

tau oligomer ability to spread between neurons

what can account for the progressive nature of AD?

NMDA

Aβ oligomers stimulate what type of receptors?

excitotoxicity (Ca2+)

Aβ oligomers stimulate NMDA receptors, causing:

create membrane pores

Other than stimulating NMDA receptors, how can Aβ cause calcium excitotoxicity

forms soluble tau oligomers, impairs microtubule stability, slows anterograde transport

Why would hyperphosphorylation of tau be a problem?

loss of UMN & LMN in the cortex, brainstem, and spinal cord

Cause of ALS

2-10 / 100,000 people (after age 40)

prevalence of ALS

1.8:1

ratio of ALS in men compared to women

2.25:1

ratio of ALS in white individuals compared to black individuals

10% familial, race, males, smoking, persistent exposure to pesticides

risk factors for ALS

amyotrophy, inclusion bodies, reactive gliosis, demyelination

cellular hallmarks of ALS

amyotrophy

muscle wasting that is secondary to motor neuron loss

ventral root

what area of the spinal cord is mostly affected by als?

inclusion bodies

protein aggregates in motor neurons, including neurofilament accumulation in soma and neurites

reactive gliosis

a cause AND a consequence of motor neuron loss, specifically occurring in the anterior horn of the spinal cord in ALS

corticospinal tracts (2º to UMN loss)

where is demyelination more prominent in ALS patients?

True (sensory tracts are spared)

True or False? With ALS, demyelination is spared in the posterior columns and spinothalamic tracts.

SOD-1, TDP43, C9ORF72

common gene mutations that may cause ALS

SOD-1

enzyme that scavenges free radicals and is mutated in many cases of ALS, causing the protein to aggregate and form inclusion bodies in motor neurons

gain

is a SOD-1 mutation a loss or gain of function?

TDP43

RNA binding protein associated with ALS frontotemporal lobe dementia.

TDP43

these mutations cause the protein to form inclusion bodies in the cytoplasm, rendering it unable to shuttle RNA into the cytoplasm

loss

Are TDP43 mutations in cases of ALS a loss or gain of function?

C9ORF72

the most common mutation with ALS, involving an expanded intronic repeat of "GGGGCC" in chromosome 9 (up to 16000 repeats)

SOD-1

Which ALS mutations involve neurofilament aggregation?

TDP43, C9ORF72

Which ALS mutations involve impaired gene expression?

impaired protein production, decreased anterograde axonal transport

common mechanisms of ALS

mitochondrial dysfunction, unfolded protein response, synaptic starvation/impaired NFT support

outcomes of the common mechanisms of ALS

reactive astrocytes, glutamate toxicity

in the ventral horn of the spinal cord, gliosis can occur with ALS, leading to what two things?

decrease

reactive astrocytes decrease or increase the expression of EAT2 (glutamate transporter protein)?

false

true or false? decreased EAT2 expression limits excitotoxicity