Neurodegeneration and Dementia

Question 1

name examples of diagnostic tools for dementia

Answer 1

• neuroimaging (PET, MRI-volumetry)
• CSF biomarkers
• psychometric tests

Question 2

outline the processes of the amyloid cascade (according to the amyloid hypothesis/theory)

Answer 2

APP cut by secretases → Ab-peptide → amyloid species → soluble oligomers (which are now considered to be synaptotoxic) → amyloid fibrillies → b-amyloid plaques → neuroinflammation → tau tangles

Question 3

what are the two opposing theories on amyloid and tau pathology?

Answer 3

• amyloid theory - tau is merely a result of the amyloid cascade, but is not a main cause of the disease
• tau-protein theory - disturbed axonal transport and protein metabolism leads to amyloid plaques, which are not themselves essential to the disease

Question 4

He et al., 2017 study on tau vs. amyloid development

Answer 4

• mice injected with tau vs. amyloid
• injecting amyloid led to tau tangles, but injecting tau did not lead to amyloid plaques
• Ab-protein levels drop → amyloid plaques increase → tau tangles

Question 5

describe subjective cognitive decline (SCD)

Answer 5

• stage prior to MCI
• identified with biomarkers, and patients start recognizing mild symptoms
• the symptoms cannot yet be determined using psychometric tests

Question 6

Alzheimer’s Disease genetics

Answer 6

• APOE e4e4 increases the association between amyloid depositions and subsequent development of AD (homogenous APOE-4 carriers) - 90% risk of developing AD by the age of 90
• APOE e2e4 increases the association between amyloid depositions and subsequent development of AD (heterogeneous APOE-4 carriers), but not as significantly as APOE e4e4
• Familiar cases - mutations in three different genes, which subsequently increase the risk of developing AD

Question 7

what are Amyloid-Related Imaging Abnormalities (ARIAs) and what kinds exist?

Answer 7

• Imaging findings detected on MRI, which are associated with the investigational use of monoclonal antibodies targeting amyloid-β, including aducanumab
• ARIA-H - hemosiderin deposits (small hemorrhages)
• ARIA-E - cerebral edema (fluid accumulation)

Question 8

main risk factors

Answer 8

• non-degenerative dementias - high blood pressure, diabetes, depression, other lifestyle factors
• degenerative dementias - old age is the main risk factor for neurodegenerative diseases causing dementia (+ genetics)

Question 9

clinical trial outcomes

Answer 9

• monoclonal antibody treatments
• Aducanumab
• Lecanemab - recently approved by FDA
• not ideal for all patients, but effective for many (slows down disease progression - amyloid accumulation as well as symptom development for several months, up to 1.5y so far)