Lecture #21 (Neural Aging + Alzheimers)

Senescence

Natural biological process of aging; Progressive decline in physio functioning, more prone to disease

Happens cellularly + at lvl of whole organism

Acts largely under genetic control but can be influenced by environment

Where does senescence happen?

Cellularly + at lvl of whole organism

Is senescence genetic or environmentally influenced?

Both; Mostly genetic tho

Geriatric Medicine

Focuses on unique care needs elderly adults require

Starts at 65

Cellular Senescence

Cells naturally go through a process of aging as they stop replicating or producing proteins due to DNA damage

Result → Cell doesnt function properly

Useful for dev tho (many cells removed as we mature)

DNA damage can be due to what

• Mutagens

• Replication errors

• Shortening of chromosomes at telomeres

What is organismal aging associated with?

Increased senescent cells; Immune system naturally removes them

What causes the accumulation of senescent cells?

Aging of the immune system

Organism Senescence

Gradual deterioration in dif functions at the systems/whole organism level

Loss of cellular division + destruction results in less ability to perform tasks (eg. impaired memory, loss of muscle tone, loss of pigment in hair)

How does the brain age?

• Loss of grey + white matter volume

• Decrease in neurogenesis + division of glial cells

• Axons become damaged → irreversible at old age

• Loss of synapses associated with smaller brain volume + impairments to cog function (in healthy aging)

• Accumulation of proteins + cellular debris as glial cell function declines

Do neuronal cells divide?

No

How much brain volume do we lose per year at 20’s?

.2% volume per year

How much brain volume do we lose per year at 70+

.5% volume per year

Is aging in brain associated with cog decline?

Yes

Is cog decline domain specific + if so how?

Yes; Areas associated with neuronal growth/higher order cog function often see decline (memory formation, planning, LTM) whereas others are preserved (lang + early memory)

Are all aspects of cog + behav impacted equally with aging?

No

Why dont ppl age at the same rates?

• Genetics

• Environmental factors

Can most adults take care of themselves for most of their geriatric years?

Yes

Mild Cognitive Impairment (MCI)

Accelerated decline starts with this; Can lead to dementia

More serious than ppl realize

Dementia

Hallmark of many neurodegenerative disorders; Cannot make new memories

Very high chance if MCI

Alzheimer’s Disease

Most common neurodegenerative disease (60-80% of all cases)

Typically after 65 but has been seen in 34 (incidence increases with aging)

6th leading cause of death in US

Are men or women more likely to dev Alzheimer’s?

Geriatric women 2-3x more likely to dev disease

Alzheimer’s symptoms

Characterized by sev impairments to cog, esp

• Memory consolidation + retrieval

• Decision making

• Emotional reg

Eventually impacts independence due to confusion about time + place

Social withdrawal can accelerate this

Physical aspect of Alzheimer’s

Massive shrinkage of brain volume associated with a loss of cholinergic neurons in frontal + temporal cortex

Alzheimer’s cause

Unknown, but correlated with

• Impaired cholinergic signaling

• Protein aggregation (amyloid plaques + tau tangles)

• Neuroinflammation + stress

2 Proteins that can cause aggregation that are correlated to Alzhimers’s

Amyloid Plaques + Tau Tangles

Cholinergic Deficiency Hypothesis

Loss of cholinergic neurons explains many cog impairments (alzheimer’s patients hv 60-70% less acetylcholine than normal)

So increasing the acetylcholine lvls should improve symptoms

Cholinergic Hypothesis

Increase acetylcholine by blocking enzymes that degrade it

Done with acetylcholinesterase inhibitors

Blocking enzymes that degrade acetylcholine improve cog but do not stop progression of disease (need more inhibitors as disease worsens); May slow overall time course

Acetylcholinesterase Inhibitors

Drugs used to increase acetylcholine by blocking the enzymes that degrade them

• Donepezil

• Rivastigmine

• Galantamine

What happens when enzymes are blocked that degrade acetylcholine?

Improve cog but do not stop progression of disease

More inhibitors needed as disease worsens

Amyloid Cascade Hypothesis

Higher lvls of amyloid B clumps + tau tangles are correlated with worse cog scores

Amyloid Beta

Proteins that clump together, increasing inflammation + disrupt other proteins

Tau Tangles

Occurs when the tau protein, which stabilize neuron axon begin to come off + tangle up, resulting in axon disintegration

Amyloid Cascade Treatment

Antibodies can target amyloid beta clumps

They help microglia identify amyloid beta + clear them, resulting in smaller plaques + less overall inflammation

Amyloid Monoclonal Antibodies

Decrease amyloid plaques but doesnt correlate to as strong of improvements in cog (but a bit)

Serious side effects

• Increase neuroinflammation

• Brain swelling

• Bleeding

Amyloid Monoclonal Antibodies Side Effects

• Increase neuroinflammation

• Brain swelling

• Bleeding

Controversy around amyloid monoclonal drug

FDA approved even tho unanimous rej by board of scientists with clear evidence