Alzheimer's disease (Pathophysiology and Treatment)

Question 1

What is Dementia? What functions are affected?

Answer 1

Dementia: loss of mental functions severe enough to affect daily life:
-Memory
-Language skills
-Visual perception
-Problem solving
-Ability to focus and pay attention
**NOT everyone with dementia has Alzheimer’s Disease
-an intra-individual pattern of decline in memory and thinking impairing at least two domains of cognition : NOT a normal part of the aging process

Question 2

What are the Neurocognitive domains?

Answer 2

Neurocognitive domains
-Perceptual-motor function: Visual perception, Visuoconstructional reasoning
Perceptual-motor coordination
-Language: object naming, Word finding
Fluency
Grammar and syntax
receptive language
-Learning and Memory: Free recall
Cued recall, recognition memory
Semantic and autobiographical long term-memory, implicit learning
-Social cognition:
recognition of emotions, theory of mind, insight
-Executive function: planning, decision-making, working memory, responding to feedback, inhibition, flexibility
-Complex attention: sustained attention, divided attention, selective attention, processing speed
-The decline in memory and thinking impairing for at least 2 domains of cognition (not a normal part of aging process)

Question 3

What is the impact of aging on brain?

Answer 3

Aging can cause changes in the brain
-Healthy, older people may notice a modest decline in their ability to learn new things and retrieve information, such as remembering names. They may perform worse on complex tasks of attention, learning and memory.
However, if given enough time to perform the task, they scores of healthy people in their 70s and 80s are often the same as those of younger adults.
As they age, adults often improve their vocabulary and other forms of verbal knowledge.

Question 4

What are changes in brain seen in people with Alzheimer’s disease?

Answer 4

a mri (magnetic resonsnce image) shows cortical atrophy and Enlarged Ventricles in brain of patient with Alzheimer’s disease
-also a PET (positron-emission tomographic ) scan shows REDUCED glucose metabolism in PARIETAL lobes (as compared with normal metabolism in other cortical areas)

Question 5

Explain how brain cells are able to stay alive? Also discuss how cells can prevent their own death

Answer 5

Repair; Staying Alive
-brain cells can live up to 100 years or longer, but in an adult, when neurons die because of disease or injury, are NOT usually replaced
-To prevent their own death, living neurons constantly maintain and remodel themselves. how?
-Growth factors like BDNF (brain-derived Neurotrophic factor) and help many neurons survive.
Exercise is most natural way of increasing BDNF.
(elevated levels of BDNF can be seen in trauma)

Question 6

What is Alzheimer’s disease? What is the greatest risk factor for the disease? What clinical spectrum is it apart of?

Answer 6

Alzheimer’s disease: most common form of Dementia: Loss of Cognitive Functioning
-Part of a Clinical Spectrum that includes:
-Vascular Dementia: impaired blood flow to the brain
-Frontotemporal Dementia: progressive loss of cell function in frontal and temporal lobes
-Lewy body Dementia: abnormal deposits of alpha-synuclein
Age is the GREATEST risk factors (65 years plus) . An estimated 5-million-plus individuals are affected by Alzheimer’s disease in the U.S. alone. With this Estimate expected to DOUBLE within the next 40-50 years.

Question 7

Discuss what the prevalence of Alzheimer’s disease will be over the Next 50 years?

Answer 7

Alzheimers Disease prevalence expected to increase by 3 to 4 times over the Next 50 years.
(greatly affecting those 85+ years)

Question 8

What are kind of onset is seen in Alzheimer’s disease?

Answer 8

Alzheimer’s disease
-Familial:
Less than 5% early onset , single gene inheritance
-15-25% Late onset, complex inheritance
-Sporadic: 75% (caused by new mutations )
-majority late onset
-Same symptoms as familial

Question 9

What are Atypical features that suggest a Diagnosis other than Alzheimer’s disease?

Answer 9

Atypical Features that suggest a Diagnosis other than Alzheimer’s disease
Feature—–> Diagnostic consideration
1. Abrupt Onset—->Vascular dementia 2. Stepwise Disorientation–> Vascular dementia
3. Prominent behavior changes–> Frontotemporal dementia
4. Profound apathy–> frontotemporal dementia
5. Prominent aphasia—>frontotemporal dementia, vascular dementia
6. Progressive gait disorder–> vascular dementia, hydrocephalus
7. Prominent fluctuations in levels of consciousness or cognitive abilities —> delirium due to infection, medications or other causes; dementia with Lewy bodies; seizures
8. Hallucinations or delusions–> Delirium due to infection, medications, or there causes; dementia with Lewy bodies
9. Extrapyramidal signs or gait—> Parkinsonian syndromes, vascular dementia
10. Eye-movemnt abnormalities–> progressive supra nuclear palsy, Wernicke’s encephalopathy

Question 10

What are Treatable causes of cognitive decline

Answer 10

Treatable causes of cognitive decline
-Depression
-chronic Drug intoxication
-Chronic CNS infection
-Thyroid disease
-Vitamin Deficiencies (ex: B12 and thiamine)
-CNS angitis (inflammation of the walls of small blood vessels)
-Hydrocephalus (can be reversible)
(hydrocephalus; build up of fluid in ventricles deep within brain)

Question 11

What are the risk factors for Alzheimer’s disease?

Answer 11

Alzheimer’s Disease Risk Factors
-Age
-Family history
-Down syndrome
-Cognitive impairment
-Low education
-Head injury
-Physical inactivity
-Lifestyle (diet, alcohol, caffeine), co-existing cardiovascular disease, environmental toxins (ex: fertilizers, pesticides)

Question 12

Describe the genetics of Familial Elary onset Alzheimer Disease? Which chromosomes are affected and what is age of onset, gene affected?

Answer 12

Genetics of Familial Early-Onset Alzheimer’s disease
-Chromosome: 21 Gene: APP (variant in gene) Age of Onset: early 50’s Proportion of Affected families : 5%

-Chromosome 14 Gene: presenilin 1
Age of Onset: 40’s (28-65)
Proportion of affected families: 50%
-Chromosome 1 Gene: presenilin2 Age of onset: 40’s (40-85)
proportion of families affected: RARE

Question 13

Which genes are involved in early onset of Alzheimer’s disease?

Answer 13

APP (amyloid precursor protein), Presenilin (PSEN) 1 and PSEN 2 genes are involved in early onset of AD (Alzheimer’s disease)
-APP, PSEN1, PSEN2 will causes altered Abeta production, leading to AD (Alzheimer’s Disease)

Question 14

What are the Genetic Risk Factors for LOAD (Late onset of Alzheimer’s disease) ? What are the risk factors for each APOE gene and how does this affect someone ?

Answer 14

Genetic Risk Factors for LOAD (Late onset Alzheimer’s disease)
*Apoliporotein E (APOE) is the STRONGEST genetic risk factor for LOAD
(more copies of APOE, increasing risk for LOAD)
- APOE: Lipid binding protein that transports lipids to cells to support cholesterol metabolism, which is an essential membrane component.
-In the brain, APOE is expressed predominantly in ASTROCYTES
-Three alleles of APOE exist (APOE2, 3 and 4) Each with differing risk factors.
- a single copy of APOE4 confers a 3-4 fold increased risk of developing LOAD, while inheritance of 2 copies increases risky by 12 fold
-Inheritance of the APOE2 allele appears to be protective
-Longitudinal clinical imaging studies have established that APOE4 carriers develop ENHANCED AMYLOID DEPOSITION with age and accumulate amyloid at more rapid rate than do Non-carriers.

Question 15

Discuss the major genetic risk factors for LOAD and how it leads to Alzheimer’s disease

Answer 15

Genetic Risk factors for LOAD,
APOE E4, other genetic factors and non-genetic factors will lead to Less Abeta clearance, Abeta aggregation, inflammation and altered Abeta production that will all contribute to Alzheimer’s disease

Question 16

Discuss the neuropathology of Alzheimer’s disease including when it is diagnosed, and types of symptoms that occur

Answer 16

Alzherimer’s Disease is a PROGRESSIVE Neuropathology
-Complex, unknown etiology, with age the Greatest risk factor
-The time from diagnosis to death varies- as little as 3 years if the patient is over 80 when diagnosed, as long as 10 or more years if the patient is younger.
-Although, the course of AD is NOT the same in every patient, symptoms seem to develop the same general stages: preclinical AD, Moderate AD and Severe AD

Question 17

What occurs during the preclinical phase of Alzheimer’s disease? What is produced?

Answer 17

The preclinical phase of Alzheimer’s disease can involve decades of Amyloid deposition and progressive synaptic abnormalities prior to the presentation of cognitive impairment

(can have increases in NFT, increased microglia and astrocyte activation, increase neuritic plaques (AlphaBeta deposition and decrease in synaptic/neuronal function)

Question 18

Describe the Alzheimer’s disease progression and what occurs in each stage. What clinical features can be seen in each stage of AD? What is the range for Alzheimer’s disease?

Answer 18

Alzheimer’s disease progression
-Mild cognitive impairment will eventually lead to Death from pneumonia or other comorbidities
- Mild—>
-Loss of recent memory
-Faulty judgement
-Personality changes
Moderate—>
- Verbal and physical aggression
-Agitation
-Wandering
-Sleep disturbances
-Delusions
Severe—>
-Loss of ALL reasoning
-Bedridden
-Incontinence (inability to
(major brain atrophy occurs in this stage)

The Alzheimer’s disease progression 8 years average, however range is 2-20 years.

Question 19

What are Amyloid Plaques and why are they significant ? What are these plaques composed of?

Answer 19

Amyloid Plaques
-The Most Characteristic molecular MARKER for AD
-Extracellular deposits originally observed by Alois Alzheimer in 1907 were found to be composed of small fragments of a peptide called amyloid-Beta (Abeta) nearly eight decades later (Glenner and Wong, 1984)

(amyloid plaques: accumulations of small protein fragments between neurons)

(AD brain contains diffuse plaques and neurofibrillary tangles)

Question 20

What is the “Amyloid Cascade? What does it mention?

Answer 20

The Amyloid Cascade:
describe a number of lines of evidence which suggest that after the Deposition of ABeta (AB) in the brain is the INITIATING step of AD (Alzheimer’s disease) , and the Amyloid hypothesis has been leading model of AD pathogenesis since it was first proposed in 1992.
Major support for hypothesis has come from genetic forms of AD (ADAD) that result in an increased amyloidosis burden

Question 21

What is progressive Amyloid burden linked to? explain how this linkage occurs ? What is being found in imaging studies?

Answer 21

progressive Amlyoid burden is LINKED to progression from Preclinical AD to Mild AD
-Diagnosis has traditionally relied on the post mortem identification of amyloid plaques in the brain
-Recent advances in imaging have enabled antemortem quantification of amyloid burden: Radio-labeled Pittsburg compound, a THIOFLAVIN Analogue that binds to amyloid fibrils in the brain
-Imaging studies have shown that Early deposition of Amyloid preceded Cortical Hypermetabolism (Glucose use) that occurs with onset of cognitive impairment

Question 22

What occurs in the Preclinical stage of Alzheimer’s disease. What areas of the brain are affected, and what are the clinical features seen during stage? what is the first sign of AD?

Answer 22

Preclinical Alzheimer’s Disease
-AD beings in the Entorhinal cortex, which has direct connections to the hippocampus, a structure essential to formation of Short-term and long-term memories. Pathology then spreads to hippocampus, and affected regions being to atrophy.
-This process is thought to start 10 to 20 years before any visible signs and symptoms appear.
- MEMORY LOSS, the first sign of disease, manifest as mild cognitive impairment (MCI). MCI is thought to be an initial, transitional phase between normal brain aging and AD.

Question 23

What occurs in the stage of Moderate Alzheimer’s disease? What areas of the brain are affected and what symptoms can bee seen? What behavioral abnormalities can be seen?

Answer 23

Moderate Alzheimer’s disease
-By this stage, AD damage has Spread to areas of CERERBAL CORTEX, that control language, reasoning, sensory processing, and conscious thought.
-Affected regions continue to atrophy and signs snd symptoms become MORE Pronounced and Widespread.
-Behavioral abnormalities such as wandering and agitation can occur
The symptoms of this stage can include
-Increasing memory loss and confusion
-shortened attention span
-problems recognizing friends and family members
-Difficulty with language; problems with reading, writing, working with. numbers
-Difficulty organizing thoughts and thinking logically
-inability to learn new things or cope with new or unexpected situations
-restlessness, agitation, anxiety, tearfulness, wandering- especially in late afternoon or at night
-repetitive statements or movement, occasional muscle twitches
-Hallucinations, delusions, suspiciousness or paranoia, irritability, loss of impulse control (Shown through sloppy table manners, undressing at inappropriate times or places, vulgar language)
OR perceptual motor-problems (such as trouble getting out of a chair or setting the table)
-

Question 24

Compare and contrast how behavior is formed in normal brain vs brain of patient with Alzheimer’s disease

Answer 24

Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. in AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors

Question 25

What occurs in the stage of Severe Alzheimer’s Disease? Discuss symptoms that may occur and how brain is affected. What occurs in Terminal phase? What kind of illnesses will most AD patients have?

Answer 25

Severe Alzheimer’s Disease
-In the last stage of AD, plaques and tangles are widespread, and the brain has atrophied further.
-Patients cannot recognize familiar faces or communicate in any way.
-They are completely DEPENDENT on others for care
-All sense of self seems to vanish. Other symptoms can include:
-Weight loss,
-Seizures, skin infections, difficulty swallowing
-Groaning, moaning or grunting
-increased sleeping
-Lack of bladder and bowel control
At the Terminal phase, patients may be in bed much or all of the time. Most people with AD will succumb to opportunistic illnesses, frequent Aspiration pneumonia

(hence you will see extreme shrinkage of cerebral cortex and hippocampus and severely enlarged ventricles in this stage)

Question 26

Compare and contrast structure of normal brain and AD brain

Answer 26

Alzheimer’s Pathology:
Normal brain: structures are normal
AD Brain: ATROPHY in many parts of brain

Question 27

What is the current understanding of Alzheimer’s Pathology? At what age do majority of cases occur. What are most cases caused by? Rare cases? What is ADAD

Answer 27

Understanding Alzheimer’s Pathology
-Pathogenesis is complex and Unresolved, but invariably presents with amyloid plaques and NFT (hyperphosphorylated Tau protein)
-The majority of cases occur > 65 years of age: Late Onset of Alzheimer’s disease (LOAD)
-In rare instances (less than 5%), cases can occur younger than 65 years: Early onset Alzheimer’s disease (EOAD)
-Most cases are SPORADIC in nature (although family history is a risk factor) But some 1-2% of of all cases are inherited in an AUTOSOMAL fashion:
Autosomal Dominant Alzheimer’s disease (ADAD)
-ADAD is characterized by very early onset and rapid progression
Much of what is known about AD pathology has arisen from study of heritable elements in Rare familial cases

Question 28

What kind of genes do ADAD mutations occur in and how does this impact the brain?

Answer 28

ADAD mutations occur in genes known to be involved in APP (amyloid precursor protein) and ABeta (amyloid-beta) production, and all result in Increased Amyloid Burden

(FAD mutations in APP or PSEN1/PSEN2 can will activate APP, and cause Abeta aggregation leading to stress to eventually dementia)

Question 29

Discuss the genetic risk factors for ADAD (autosomal dominant Alzheimer’s disease) and include genes that are affected. What accounts for majority vs small count of of EOAD cases ?

Answer 29

Genetic risk factors for ADAD (autosomal dominant Alzheimer’s disease)
-Pathogenic mutations have been identified clinically in three genes: APP, Presenilin, 1 and Presenilin 2 (gamma-secretases)
PSEN1: accounts for 30-70% of EOAD cases (early onset of AD)
Amyloid precursor protein (APP): accounts for 10-15% of EAOD
PSEN2: accounts for 5% of EOAD

Question 30

What is the diagnostic criteria for Alzheimer’s Disease?

Answer 30

Diagnostic Criteria
-Cognitive impairment severe enough to cause social or occupational disability in at least two domains:
-Memory
-Language
-Calculations
-Orientation
-Judgement

Question 31

What is the Typical syndrome of AD (Alzheimer’s Disease) ? describe the deficits in function

Answer 31

Typical clinical syndrome of AD;
1. Amnestic type of memory defect
-difficulty learning and recalling new information
2. Progressive language disorder
-beginning with anomia and progressing to fluent aphasia (loss of ability to understand or express speech)
3. Disturbances of visuospatial skills
-manifested by environmental disorientation
-difficulty copying figures in course of mental status examination
4. There are usually deficits in executive function
-Planning
-Insight
-Judgement
5. The patient is typically unaware of memory or cognitive compromise
6. All cognitive deficits progressively worsen

Question 32

What are treatments used for AD? What characteristics do they share?

Answer 32

Treatments for AD:
-Cholinesterase inhibitors will INHIBIT Acetylcholinesterase and prevent the breakdown down of Acetylcholine (Ach) (this will help maintain Ach levels in brain)
-Also NMDA receptor antagonists will bind to NMDA receptors and prevent glutamate from binding (to reduce glutamate in patients with AD)
examples
-Donepezil (Aricept): is a cholinesterase inhibitor (treats mild to moderate AD; and mod to severe AD)
-Rivastigmine (Exelon): a cholinesterase inhibitor (treats mild to mod AD)
-Galantamine (Reminyl): cholinesterase inhibitor (treats mild to moderate AD)
**Memantine (Namenda): NMDA: receptor Antagonist ** (treats moderate to severe AD)

Question 33

What were some findings seen in the Pharmacoeconomic review of Rivastigmine?

Answer 33

Rivatigmine: pharmacoeconomic Review
-Review of clinical trials and economic anaylses of rivastigmine in patients with AD
-Based on renewed data, Rivastigmine completed or partially offsets the costs of treatment by delaying cognitive decline and time to institutionalization
-Largest savings are realized in patients with Mild AD over a 2-year period

Question 34

What are the cognitive and function benefits with medical drug Galantamine?

Answer 34

Galantamine: Cognitive and Functional benefits
-Galantamine is Effective and well tolerated in the treatment of AD
-Study had 2 6-month phases
-At 6 months, galantamine (24 mg per day) produced significant benefits in cognitive and global function versus placebo
- at 12 months, AD patients who continued galantamine at 24 mg per day maintained their baseline levels of cognitive and daily function

Question 35

What findings were seen in observed case analysis of patients who used Memantine as treatment

Answer 35

Memantine
-Observed case analysis of AD patients who used Memantine had HIGHER scores for CIBIC-PLUS caregiver input (clinicians interview-based impressions of change population) and in ADCS_ADLsev (Alzheimer’s disease cooperative study activities of daily living inventory, modified for severe dementia)
-hence higher scores, and better improvement seen in AD patients who used memantine

Question 36

What is the new Medical drug that has been approved for patients with AD? Why is it beneficial?

Answer 36

AXONA is the new medical drug that has been approved for treating Alzheimer’s disease.
It has minimal side effects
-showed to help with hypometabolism that occurs in patients with AD (target nutritional needs)

Question 37

What is the Amyloid Hypothesis? What does it contain? What causes Amyloid plaques and Neuronal injury?

Answer 37

Amyloid Hypothesis (describes the build up of amyloid Beta plaques)
Pathway:
Amyloid Beta (protein)–> Aggregation–> Oligomers–> Amyloid plaques –> Neuronal injury–>Dementia

Amyloid plaques can be caused by Tau hyperphosphorylation and aggregation

-Neuronal injury and cell death can be caused by neurofibrillary triangles, oxidative stress and mitochondrial dysfunction

Question 38

Break down the word monoclonal antibodies, to discuss It meaning

Answer 38

Monoclonal antibodies
Mono= single
clonal= Clone
Single clone antibodies

Question 39

How are monoclonal antibodies made? What unique features do they have?

Answer 39

Monoclonal Antibodies (mAbs) are made by IDENTICAL Immune cells that are all clones of a unique parent cell
mAbs have HIGH Specificity and can bind to single antigen site
(have variable fragment)

Question 40

Describe the mechanism of action for aducanumab

Answer 40

proposed Mechanism of Action (MOA) for Aducanumab:
-Monoclonal antibody (adacanumab) binding to amyloid beta (aggregates of AB) promotes the REMOVAL of amyloid from brain
(hence this binding will help clear amyloid Beta plaques in brain)

Question 41

What is the future hope for treatment of Alzheimer’s Disease ?

Answer 41

Future Hope
-Reducing Amyloid production, aggregation, or enhancing its removal are promising avenues of treatment that will address the basic pathophysiology of AD

Question 42

Describe the new APOE2 gene therapy trial that has been approved and what occurred in the trial. How will patients be treated?

Answer 42

APOE2 gene therapy clinical trial approved Feb 2019:
recruiting patients with low APOE4 alleles (high risk LOAD)
-Suffereing from MCI through to severe Alzheimer’s Dementia
-Must have evidence of high amyloid burden by PET/CSF amyloid
-Recombinant virus containing the APOE2 gene to be injected into CSF of patients

Question 43

What affects on there functions in body does APOE4 impact ?

Answer 43

APOE4:
-will Decrease synaptic and neuronal function
-Increase Abeta Aggregation and Decrease AB clearance
-Decrease insulin and VEGF signaling
-Decrease Vascular function
-Increase inflammatory response
-Decrease glucose/mitochondrial metabolism
-Decrease lipid/cholesterol transport and clearance
-Increase Tau phosphorylation and Tangle formation

Question 44

Discuss the case report of resistance to autosomal dominant Alzheimer’s disease in APOE3? What was found?

Answer 44

Case report of Resistance to autosomal dominant Alzheimer’s disease in APOE3:
-identified a PSEN1 mutation carrier from the world’s largest autosomal dominant AD kindred, who was cognitively normal until her 70s
-Individual who as homozygous for a novel APOE3 allele (APOE3 R136S)
-individual had usually high amyloid levels but little to no overt neurodegeneration
-PPSEN1 carrying relatives develop MCI (mild cognitive impairment) and dementia at ages 44 and 49 respectively

(dementia usually diagnosed at in 30s)