Alzheimers

How does CERAD rank the level of impairment?

(A) - sparse (B) - intermediate (C) - frequent

Mini cog scoring

3 recalled words: negative 1-2 recalled words + normal drawing of clock: negative 1-2 recalled words + abnormal clock: positive for cog. impairment 0 recalled words: positive

How many drugs are available for AD?

5, and they have limited functionality

What generates the Beta-Amyloid fragment?

Beta and gamma secretases Beta-Amyloid is a protein snipped from APP

What are the four modifiable risk factors for Alzheimer's?

Cardiovascular Disease Risk Factors Less Education Decreased Social and Cognitive Engagement Severe Traumatic Brain Injury, Mild Repetitive TBI (concussions)

What causes dementia?

Damage to nerve cells in the brain (neurons). They no longer function and may die.

What are the 3 stages of Alzheimer's Disease?

Early (Mild cognitive impairment) Mild to moderate (possible Alzheimer's) Severe (Probable Alzheimer's)

T/F: the medications used address plaques and tangles

False, they are Cholinesterase inhibitors, which increase the amount of time that acetylcholine is in the synapse, and NMDA receptor agonist

What are some tau therapeutics?

Kinase inhibitors Phosphatase activators O-GlcNAcase inhibitors Tau immunotherapy Aggregation inhibitors Microtubule stabilizers Reduction of oxidative stress

How does NIA-Reagan Institute criteria relate to Braak and Cerad

Low probability= 1 or 2 and A Intermediate Probability= 3 or 4 and B High Probability= 5 or 6 and C

What are the 7 tests performed by physicians?

Medical History Physical Exam Neurological Exam Mental Status Tests Brain Imaging Biomarkers Genetic Testing

What disease is DLB associated with typically?

Parkinson's Disease

Creutzfeldt-Jakob disease

Rare and rapidly fatal mad cow disease

What are the four targets for future drugs?

Reducing β amyloid: Inhibiting proteases Antibody clearance Tau protein: Kinase inhibitors Anti-aggregation Antibody clearance Inflammation: Reducing inflammation Reducing oxidation Metabolism: Reducing insulin resistance Improving mitochondrial function

When tau is modified, what functions does it gain?

Tau modification results in oligomerization, fibrillization

Braak stage 6

Tau tangles have formed extensively throughout the brain and have caused extensive neuronal death. The outer layers of the brain that integrate activities and the deep areas of the brain that control movement are filled with tau tangles. All patients with this many tau tangles in the brain will be diagnosed as suffering from severe dementia. They will be completely unable to care for themselves and will have difficulty recognizing family members

What is CERAD?

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is an association funded to develop standardized, validated measures for the assessment of Alzheimer's disease (AD)

T/F: Alzheimer's disease is the most common cause of dementia

True

What is mixed dementia?

When there is clinical evidence of two or more causes of dementia

Ratio of people age 65 an older with alzheimer's

1 in 10

How many potential phosphorylation sites are there on tau? How many are abnormally phosphorylated in AD?

85 30

If there is so little we can do about Alzheimer's disease, why even diagnose?

A better chance to benefit from treatment More time to plan for the future Lessened anxieties about unknown problems Increased chance to participate in clinical trials Develop a relationship with doctors and care givers Benefit from care and support services

What are the three non-modifiable risk factors for Alzheimer's?

Advancing Age Family History Apolipoprotein E ε4 gene :A gene on chromosome 19 involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream.

What happens to the beta-amyloid peptides, what do they form, and what do they lead to while forming Alzheimer's disease?

Aggregate together to form oligomers, fibrils and eventually lead to Senile Plaques

What are two tests used during biomarker exams?

Cerebrospinal fluid: In general, Aβ levels are lower and total tau or phospho-tau levels are higher Blood tests: An active area of research is to identify and verify markers in blood

What is the function of Beta-secretase (BACE1)?

Cleaves APP at the beta site

T/F: There is a single test that can diagnose Alzheimer's

False, but a skilled physician can diagnose AD with more than 90% accuracy using a battery of tests

T/F: AD is the only disease in the 10 leading causes of death in the US that can be prevented, slowed, or cured

False, it cannot be prevented

T/F: Tau is not soluble

False, it is very soluble

FTLD

Fronto-temporal lobar degeneration progressive supranuclear palsy (Colleen Quick)

Disease tau function

In disease, tau is modified by unknown mechanisms that could include phosphorylation, truncation or other changes The modified tau releases from microtubules, destabilizing them

What is the function of Gamma-secretase?

It is a complex of several proteins including presenillin 1 or 2, nicastrin, Aph1 and Pen2 Cuts within the transmembrane domain Releases the amyloid intracellular domain (AICD) Can generate either Aβ 1-40 or Aβ 1-42

What is the function of alpha secretase?

It is in the non-amyloidogenic pathway and cleaves the amyloid precursor protein (APP) within the sequence of beta-amyloid-peptides and precludes their formation

What are abnormal aggregations of the protein alpha-synuclein in neurons?

Lewy bodies Dementia with Lewy Bodies (DLB)

Fill in the blanks with two possible answers: There is a strong correlation between the _____________ of tau pathology and the ____________ of cognitive impairment

Location, Type Amount, Severity

What are some features of the moderate (middle) stage of Alzheimer's?

Longest stage (years) Need greater level of care Confuse words Get angry Difficulty expressing thoughts At this point, symptoms will be noticeable to others and may include: Forgetfulness of events or about one's own personal history Feeling moody or withdrawn, especially in socially or mentally challenging situations Being unable to recall their own address or telephone number or the high school or college from which they graduated Confusion about where they are or what day it is The need for help choosing proper clothing for the season or the occasion Trouble controlling bladder and bowels in some individuals Changes in sleep patterns, such as sleeping during the day and becoming restless at night An increased risk of wandering and becoming lost Personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like hand-wringing or tissue shredding

What are some features of the Medical History exam and physical exam?

Looking at symptoms, and how they progressed Diet Overall health Test for other conditions that may affect memory

What are two commonly used tests for mental status?

Mini-mental state exam (MMSE) Mini-Cog test

What are some tests ran during a neurological exam?

Reflexes Coordination, muscle tone and strength Eye movement Speech Sensation

What are the four different staining methods to view the abnormal aggregation of tau?

Silver Tau antibodies Tau phospho-antibodies Stains (congo red, thioflavin)

When tau is modified, what functions does it lose?

Tau modification results in microtubule disruption, loss of axonal transport and neuronal dysfunction and death

Normal tau function

Tau normally binds to and stabilizes microtubules in neurons creating a stable cytoskeleton that can be used for transport

What is dementia?

Term for diseases characterized by decline in memory or other thinking skills that affects a person's ability to perform everyday activities.

What is the AICD?

The Amyloid Intracellular Domain (AICD) generated by γ-secretase (presenilin) has been shown to play a role in transcriptional regulation.

What dementia is commonly mixed with Alzheimer's?

Vascular dementia predominately also DLB

Are levels of Beta-amyloid low or high under normal physiological conditions?

low Greatly increased Aβ levels in AD Can interfere with cholinergic signaling and result in increased Aβ production

How many Braak stages are there?

six

What is believed to be the toxic form of beta-amyloid protein?

soluble oligomers Aβ oligomers may induce toxic events through interactions with receptors or by increasing membrane permeabilization for by forming channels

Location of Tau Neurofibrillary tangles

specific regions of brain inside neurons

What happens in Braak stage 1?

tau protein starts to clump into tau tangles. No external symptoms Nearly everyone will reach Braak stage 1 between 40 and 90 years of age.

What is histopathology?

the study of changes in tissue caused by disease

What are the two types of genetic tests?

1. Early Onset (Familial) AD: Amyloid Precursor Protein: Chromosome 21 Presenilin-1 (part of γ-secretase): Chromosome 14 Presenilin-2 (part of γ-secretase): Chromosome 1 2. Late Onset (sporadic) AD (LOAD): Apolipoprotein E (ApoE) allele (3 polymorphic alleles): ApoE ε2 may protect against AD ApoE ε3 seems to be neutral ApoE ε4 increases risk of AD, 2 copies of ApoE ε4 have even higher risk

What is the Amyloid Precursor Protein (APP)?

A transmembrane protein that is cleaved by proteases to release a peptide in the extracellular spaces.

Mutations in which two proteins can result in increased AB levels?

APP and presenilins

Describe the abnormal aggregation of tau

Abnormal aggregation of hyperphosphorylated microtubule-associated protein tau into filaments that accumulate in pathological structures: Neurofibrillary Tangles (NFTs) Neuropil Threads Neuritic Plaques

What are some features of mental status tests?

Evaluates memory, ability to solve simple problems and other thinking systems: Aware of symptoms? Knows the date, time and where they are Can remember a short list of words Can follow simple instructions Can do simple calculations

Location of Beta-amyloid plaques

Everywhere in brain surrounding neurons

What is the Amyloid Cascade Hypothesis?

Excessive accumulation of a peptide called beta-amyloid is the key event in Alzheimer's disease: This accumulation sets off a series of events that results in the death of brain cells, and eventually, Alzheimer's disease

What is the tau hypothesis?

Excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs

T/F: The initial result is AB production and aggregation

False

What are some features of Early stage of Alzheimer's?

May function independently. He or she may still drive, work and be part of social activities. Memory lapses, such as forgetting familiar words or the location of everyday objects. Friends, family or others close to the individual begin to notice difficulties. During a detailed medical interview, doctors may be able to detect problems in memory or concentration. Common difficulties include: Problems coming up with the right word or name Trouble remembering names when introduced to new people Challenges performing tasks in social or work settings. Forgetting material that one has just read Losing or misplacing a valuable object Increasing trouble with planning or organizing

10 Warning Signs of Alzheimer's

Memory loss that disrupts daily life Challenges in planning or solving problems Difficulty completing familiar tasks at home, at work or at leisure Confusion with time or place Trouble understanding visual images and spatial relationships New problems with words in speaking or writing Misplacing things and not being able to retrace steps Decreased or poor judgment Withdrawal from work or social activities Changes in mood and personality

Tau was the first protein to be classified as what, relating to structure?

Natively unfolded has very little secondary or tertiary structure potentially making its transition to the misfolded molten globule state easier

What are some features of the severe (late) stage of Alzheimer's?

No ability to respond to environment in any way Personality change At this stage, individuals may: Need round-the-clock assistance with daily activities and personal care Lose awareness of recent experiences as well as of their surroundings Experience changes in physical abilities, including the ability to walk, sit and, eventually, swallow Have increasing difficulty communicating Become vulnerable to infections, especially pneumonia

What are the two hallmark pathologies of Alzheimer's disease?

Progressive accumulation of the protein fragment beta-amyloid (plaques) outside of neurons in the brain. Twisted strands of the protein tau (tangles) inside neurons.

What are the three steps in processing beta-amyloid protein?

STEP1 - Newly synthesized APP traverses the trans-Golgi network (TGN) and moves to the cell membrane where it is cleaved by α-secretase to generate soluble sAPPα (non-amyloidogenic) STEP2 - Non-processed APP internalizes from the cell surface and traffics from early to late endosomes STEP3 - Processed by BACE to generate soluble amyloid precursor protein-beta (sAPPβ) and beta-amyloid protein(Aβ)

What is the function of Tau in neurons?

Stabilizes microtubule structure for transport from cell body to distal processes and back

What are the three types of brain imaging used for Alzheimer's and what do they reveal?

Structural Imaging: Provides information about the shape, position or volume of brain tissue (e.g. Magnetic Resonance Imaging (MRI) and Computed Tomography (CT)) Functional Imaging: Reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen. (e.g. Positron emission tomography (PET)and Functional MRI (fMRI)) Molecular Imaging: Uses highly targeted radiotracers to detect cellular or chemical changes linked to specific diseases (e.g. PET)

Braak stage 3

Tau tangles and neuronal death have likely caused some memory impairment, but only about 10 percent of patients will be diagnosed as suffering from dementia. About 45 percent of 80-year-olds have reached this stage.

Braak stage 4

Tau tangles are beginning to form in the outer layers of the cerebral cortex. The patient is experiencing significant impairments in memory and other aspects of cognitive function. 70 percent of patients with this level of tau tangles in the brain will be diagnosed with dementia.

Braak stage 2

Tau tangles have accumulated further and have caused some neurons to burst apart and die. Mental testing reveals minimal impairment. Tau tangles at this are found in the brains of about 60 percent of people over age 65.

Braak stage 5

Tau tangles have caused extensive neuronal death, giving rise to severe memory and cognitive impairment. They are beginning to involve deep areas of the brain that control the initiation of movement. About 80 percent of patients with this level of tangles will be diagnosed with moderate to severe dementia.

Does tau pathology spread like a prion?

Yes, events suggests that tau pathology follows synaptic circuits and can pass from one cell to another Also suggests that tau can become extracellular at some point

What are some therapeutic approaches?

γ-secretase inhibitors β-secretase inhibitors α-secretase enhancers Aggregation inhibitors Gene Therapy Stem cells