BIO SCI 37 Midterm 2

What is the most significant risk factor for AD?

Age

What is the leading cause of dementia?

Alzheimer’s disorder

Normal aging vs Dementia

Dementia has more frequent/extreme/long-term forgetting

Dementia has changes in mood

Trajectories of Age-Related Cognitive Change

“Superaging”

Normal aging

Mild cognitive impairment

Abnormal aging dementia

What is “middle aging”

A period of time that shapes future cognitive trajectories and brain health. D

Different types of middle aging

Turning point

Plateau

Breakpoint

Loss of cyclicity

How does brain matter change with age?

Less gray matter = less neurons

Less white matter = thinner myelin sheaths

Synaptic plasticity

The ability of synapses to strengthen or weaken in response to activity

Often associated with structural changes

Symptoms of cognitive decline in aging brains

Slower reaction times

Lower attention level

Slower processing speeds

Decreased sensory and perceptual function

Changes in sleep pattern

Factors that influence brain aging

Genetics

Environment (ie education)

8 hours of sleep per night

The gut’s microbiome (sends signals to the brain)

Inflammation

Neurogenesis

The process by which neurons are generated from neural stem cell and progenitor cells

Progenitor cell

A rudimentary cell, can specialize to become any cell (ie heart cell, liver cell, neuron)

Adult neurogenesis

Neurons generated from adult stem cells

In which areas of the adult brain does neurogenesis occur?

Hippocampus (sub-granular zone)

Sub-ventricular zone

Sub-granular zone

Lead cells to repopulate the dentate gyrus

Sub-ventricular zone

Leads cells to repopulate olfactory bulb

Factors that influence neurogenesis

Increased neurogenesis

• Environmental Enrichment

• Exercise

Decreased neurogenesis

• Neurodegenerative disease

• Depression

• Aging

Things that delay cognitive decline

Minimized stress, exercise, social life, diet, education

Parabiosis

Greek - “leaving beside”

The anatomical joining of two individuals artificially in physiological research

Parabiosis research findings

In young-old connections, the old mouse starts to show similar bodily and brain function as the younger mouse due to the shared blood, so old mice had better cognitive function. Younger mice had worse cognitive function

Types of brain disorders

Specific disorders (focal damage)

Generalized disorders (widespread damage)

Specific disorders

Focal damage

The disorder depends on the area of the brain affected (bullet wounds, strokes, Phineas Gage)

Generalized disorders

Widespread damage

The disorder affects multiple cognitive abilities (closed head injury, dementia, demyelination, toxic substances)

Mild dementing diseases

Person retains judgement and can sustain daily activities on his/her own (personal hygiene etc) but work and social activities are impaired

Moderate dementing disorders

Independent living becomes hazardous (forgets to turn off stove, etc) and requires some degree of supervision

Severe dementing diseases

Cognitive abilities are so impaired that the person requires constant supervision

Aphasia

Loss ability to understand or express speech

Apraxia

Inability to link skilled motor movements to ideas or representations

Agnosia

Deficit in recognizing objects that occurs in the absence of deficits in sensory processing

Acalculia

The inability to perform simple mathematic calculations the patient previously knew

Clinical classifications of types of dementias

Cortical

Subcortical

Mixed

Cortical dementias

Co-occurence of many cognitive deficits including aphasia, apraxia, agnosia, acalculia, visuospatial deficits and memory problems (Alzheimer’s, Frontotemporal dementias, Creutzfeldt-Jakob)

Subcortical dementias

More likely to manifest first as personality changes, attention deficits, slowness in cognitive processing, difficulties with tasks requiring strategy (e.g. Parkinson’s, Huntington’s).

Mixed dementias

Both cortical and subcortical involvement, patterns of cognitive performance midway between cortical and subcortical types (e.g. Vascular dementia, Lewy body dementia.)

What is one of the main criterion of dementia classification?

Underlying pathologies, largely defined by accumulation of abnormal protein aggregates in the brain

What are the 6 main categories of neurodegenerative proteinopathies?

1. Amyloid-β (Aβ)

2. Microtubule-associated protein tau

3. TAR DNA-binding protein 43 (TDP-43)

4. Fused in sarcoma (FUS)

5. α-synuclein

6. Prion protein

Most non-vascular dementias are within one of these 6

Major diseases of dementia

Alzheimer’s Disease

Vascular Dementia

Dementia with Lewy Bodies

Frontotemporal Dementia

Parkinson’s Disease

(Huntington’s Disease)

How are proteins involved in neurodegenerative diseases?

Abnormal protein deposits/protein misfolding leads to problems

What features are present in an Alzheimer’s brain?

Neurofibrillary tangles

Amyloid plaque

Cortical atrophy

Inflammation

Senile Plaques

Neurofibrillary

Frontotemporal dementia

No amnesia in the early stages

Clinical syndrome associated with shrinkage of the frontal and temporal lobes

Impulsive or bored and listless

Inappropriate social behaviors

Neglect of personal hygiene

Repetitive or compulsive behavior

Speech problems, semantic deficits

Types of frontotemporal dementias

Dementia with Lewy Bodies

Presence of Lewy Bodies (alpha- synuclein neuronal inclusion bodies).

Similar to AD in terms of cognitive features and can sometimes be confused with it, however it also includes other symptoms e.g.

Bradykinesia, rigidity (similar to Parkinson’s)

Recurrent and well-formed hallucinations

Memory deficits less severe than AD but visuospatial deficits are more severe than AD.

Progression of Lewy Body Dementia

Vascular Dementia

Caused by blockages in the brain’s blood supply

The second most common form of dementia (behind Alzheimer’s)

May cause or exacerbate Alzheimer’s (complicates diagnosis as vascular factors contribute to AD).

Cognitive Profile:

• More impaired than AD patients on executive function

• Less impaired on episodic memory

Risk factors for Vascular Dementia

High blood pressure (about 50% can be caused by hypertension)

Diabetes

High cholesterol

Family history of heart problems

Obesity

Smoking

Parkinson’s Disease

Progressive neurologic disease

Fourth most common neurodegenerative disease in the elderly

Neuropathology: degeneration of dopamine (DA) producing neurons in the brain (substantia nigra)

Motor Symptoms

Neuropsychiatric Symptoms

Major symptoms of Parkinson’s Disease

Motor Symptoms:

• Tremor

• Bradykinesia

• Rigidity

Neuropsychiatric Symptoms:

• Executive dysfunction

• Memory deficits

• Attention deficits

• Visuospatial deficits

• Mood disturbances

• Impulse control behaviors (e.g. food, drugs, gambling)

Clusters of behavioral symptoms in Alzheimer’s

Depression, apathy, sleep, agitation, psychosis

How is mild cognitive impairment linked with Alzheimer’s

12-16% progress to dementia, usually Alzheimer’s for those with memory problems

Up to 50% do not progress to dementia after 10 years

Up to 20% revert to normal cognition, though this group remains at elevated risk for dementia

How long does Alzheimer’s usually progress before the patient dies?

Average 8 years, can span from 2-20 years

What is the clock drawing test?

Normal elderly control group and dementia patients are asked to draw a clock to gauge cognitive ability. Not a diagnostic, but can help spot some symptoms of cognitive impairment

What functions of neuronal function does Alzheimer’s block?

Communication, metabolism, repair

Amyloid plaques

Present in Alzheimer’s,

• Insoluble extracellular deposits which accumulate in the cortex and hippocampus.

  • Composed of amyloid – beta (Aß) protein fragments: Aß40 and Aß42.

Neurofibrillary tangles

Present in Alzheimer’s

• Bundles of insoluble helical fibers within neurons.

• Composed of hyperphosphorylated tau proteins that are normally associated with microtubules

Cortical atrophy

Loss of 1/3 of brain mass, can contribute to Alzheimers

How are amyloid and senile plaques formed?

There is normal APP in a membrane, which is broken into beta-amyloids (AB42) by an enzyme (B-secretase and y-secretase).

These beta-amyloids clump together and become amyloid plaques.

Plaques form when there is not enough clearance of AB from the brain

Genetic’s role in Alzheimer’s Disease

Point mutations in the y secretase (presenilin-1 gene) and APP gene located on chromosome 21 can lead to early onset (autosomal dominant pattern)

ApoE4 is a reliably identified genetic risk factor

Risk factors for Alzheimer’s

Age, genetics, head trauma, high blood pressure, heart disease, stroke, diabetes, high cholestrol

Individuals with Down syndrome are _________ times more likely than the general population to develop Alzheimer's disease

three to five

How does chromosome 21 influence AD?

Duplications of a small part of chromosome 21 which include the APP gene can cause early onset AD.

Point mutations in APP which cause ______________________ cause ___________________

changes in the ratio of the cleavage products, autosomal dominant early onset Alzheimer’s disease.

Protective APP mutation

A673T prevents cleavage of amyloid precursor protein (APP)

A673T protects against cognitive decline in the elderly

This finding validates a therapeutic target for Alzheimer’s disease

Molecular pathways involved in the development of Alzheimer’s

Amyloid-beta pathway

Tau protein pathology

Calcium signaling

Excitotoxicity

Changes in tau in Alzheimer’s

Tau proteins stabilize microtubules (MT) in neurons, particularly in axonal processes. MT main functions are to provide structure, organize the cytoplasm of the cell, and serve as tracks for the transport of cellular elements form the cell body to the axonal terminals (synapses).

Neuroinflammation in AD

Inflammatory cytokines, chemokines and other immune mediators are increased in tissues of individuals with AD

Prodromal Alzheimer’s Disease

Prodromal: before the development of the disease

Memory complaint corroborated by the informant

Measurable, greater-than-normal memory impairment detected with standard memory assessment tests.

Imaging the AD brain

The entorhinal cortex is first affected

Then hippocampus, amygdala and parahippocampus.Then neocortex

This loss corresponds well with NFT’s

PET Scan shows less glucose metabolism in Alzheimer’s brain

Amyloid PET Imaging for AD

Plaques can be directly imaged using amyloid tracers

TAU Pet imaging in AD

Bind to the hyperphosphorylated tau aggregates found in neurofibrillary tangles

How do CSF levels predict progression from mild cognitive impairment to Alzheimer’s?

Pathological CSF:

• Aβ42: <530 ng/L

• T-tau: >350 ng/L

• (p-Tau)

AD Prevention

Exercise: aerobic and strength, longer than 30 minutes

Social and leisure activities

Anti-amyloid agents

Antibodies against amyloid: monoclonal antibodies can prevent clumping of amyloid-b proteins.

Agrammatism

Difficulty using grammar and syntax correctly in speech or writing

Phonemic paraphasia

Difficulties selecting the correct phoneme or sound during speech (using hat instead of bat)

TAU Function and Phosphorylation

Tau is very soluble, mostly found in astrocytes

Hyper-phosphorylated tau is insoluble and turns into tangles, leading to dysfunctional microtubule destabilization

What is a tauopathy?

A class of neurodegenerative disease that is associated with pathological aggregation of tau protein in the brain.

Primary tauopathy

Disease which have tau pathology as primary pathology, Chronic Traumatic Encephalopathy and Frontotemporal Lobar Degeneration

Secondary Tuaopathy

Disease which have Tau pathology as well as other major pathologies-eg Alzheimer disease is a secondary tauopathy, it is also an amyloidosis-aggregation of senile plaques

Chronic Traumatic Encephalopathy

Progressive degenerative disease occurring with those with multiple concussions, common in athletes or war veterans

Pathological features of CTE

Tau deposition as neurofibrillary tangles

Changes in white matter

Glial degeneration

Beta-amyloid deposition is uncommon

Frontotemporal degeneration

Three subtypes

• Progressive nonfluent aphasia (affects left frontal lobe 1st)

• Semantic dementia (affects left anterior temporal lobe 1st)

• Behavioral variant frontotemporal dementia (affects right frontal lobe 1st)

All share some common features

• Progressive decline in frontal and temporal lobes

Progressive nonfluent aphasia

Starts focally in the left side of the frontal lobe

Broca’s area primarily affected - speech production

As the disease develops, speech quantity decreases and many patients become mute.

Semantic dementia

A number of frontotemporal lobar degeneration cases start in the anterior temporal lobes (left more than right)

Loss of semantic knowledge (loss of word meanings)

Starts with word-finding problems

In a subgroup of patients there is a dramatic increase in visual creativity

Behavioral Variant FTD

Begins in the frontal lobes

Orbitofrontal cortex: Involved in emotional processing

Right sided damage first - social behavioral impairments

Loss of the anterior cingulate which is critical for motivational behaviors and conflict resolution

Genetics of FTD

Approximately 40% of people with FTD have a family history of FTD or another related dementia

5-10% of patients have autosomal dominant inheritence pattern

Prion’s disease are also known as…

transmissible spongiform encephalopathies (TSEs)

What is Prion Disease/TSE

A family of rare progressive neurodegenerative disorders that affect both humans and animals.

Distinguishing features of Prion’s diseases

Long incubation period, spongiform changes associated with neuronal loss, failure to induce inflammatory responses.

Caused by prions (a type of protein)

What are prions?

Proteinaceous infectious particles refers to abnormal proteins that can induce misfolding of normal cellular proteins.

PrPC is the __________ form of the prion protein, while PrPSc is the form ___________.

normal, cellular

abnormal, misfolded, and infectious

How do prions multiply?

By a nucleation and fragmentation process similar to the growth of crystals.

Mad cow disease

Prion’s disease in cows. Researchers found that if you inject protein denaturant to inactive proteins (bleach) then you will not get the disease, showed that the disease is caused by protein malfunctions.

Normal function of the prion protein

Located in pre and postsynaptic sites

Regulate NT receptor function and maintain myelin sheath

Play a role in memory, long-term potentiation and sleep

Structural changes in prion’s proteins

More pleated sheets than alpha helices in an abnormal protein

Abnormal prion protein starts interacting with normal ones and makes it pathological, kills the cell, then released from that one and propagates

Glial cells proliferate, neurons die and the brain appears spongy, which is why they are called spongiform encephalopathies

How is prion’s spread?

From eating infected brains,

Human TSE types

Creutzfeldt-Jakob disease

Kuru

Fatal Familial Insomnia

TSE subtyping

Genetic

Sporadic

Acquired

Genetic TSE subtype

Caused by a mutation in the PrPc protein (10-15% of all TSE)

• Genetic Creutzfeldt–Jakob disease (gCJD)

• Fatal familial insomnia (FFI)

• Gerstmann–Straeussler–Scheinker syndrome (GSS)

Sporadic TSE subtype

80-95% of all TSEs

• Sporadic CJD

• Sporadic FFI

Acquired TSE subtype

Variant CJD

Kuru

Creutzfeldt-Jakob Disease (CJD)

Very rare, 1 in a million

Can be sproadic, acquired, familial

Very rapid progression and deterioration of cognitive function