Transcript Learning Objectives

Alzheimer’s Disease
Robert Nagele, PhD
Professor of Medicine
UMDNJ–SOM NJISA
Anita Chopra, MD, FACP
Professor, Geriatrician
and Director
UMDNJ –SOM NJISA
Alzheimer’s Disease
This medical student presentation is offered by
the New Jersey Institute for Successful Aging.
This lecture series is supported by an educational grant from the
Donald W. Reynolds Foundation Aging and Quality of Life program.
Learning Objectives
• Discuss prevalence and economic impact of
Alzheimer’s disease (AD)
• Identify core clinical criteria for diagnosis of
Alzheimer’s disease and mild cognitive impairment
(MCI)
• Discuss pathophysiology and potential biomarkers of
Alzheimer's disease
• Describe evaluation and management of patients
affected by the disease
What is AD?
Alzheimer’s disease is an
irreversible, progressive brain
disease that slowly destroys
memory and thinking skills.
Image copyright © 1997 PhotoDisc, Inc.
(http://www.hallogram.com/photodisc/lisence1.html)
• The risk of developing AD increases with age
• In most cases, symptoms first appear after age 60
• Familial AD appears early – 1 to 2% of cases are inherited and
nearly all of these are as a result of mutations in the presenilin
gene
• AD is not a part of normal aging – it is a fatal brain disease.
AD Statistics
• AD is the most common cause of
dementia among people age 65 and older.
• Estimate that around 4.5 million people
now have AD.
• For every 5-year age group beyond 65, the
percentage of people with AD doubles.
• By 2050, 13.2 to 16 million older
Americans are expected to have AD - if
the current numbers hold and if no
preventive treatments become available.
• Worldwide, 100 million are expected to be
affected by 2050
Top and middle images copyright © 1997 PhotoDisc, Inc. (http://www.hallogram.com/photodisc/lisence1.html)
Bottom image source: Microsoft Office Images #MP900185235 (http://office.microsoft.com/en-us/images/)
Care and its Costs
Where are people with AD cared for?
• Home
• Assisted living facilities
• Nursing homes (special care units)
Source: PhotoSearch Mature
Lifestyles 2 #58307
• The national cost of caring for
people with AD is about $120
billion every year.
Source: Microsoft Office Images #MP900443920 by iStockphoto
(http://office.microsoft.com/en-us/images/)
Figures from Alzheimer’s Disease International World Alzheimer Report 2010: The Global Economic Impact of
Dementia. London, UK: Alzheimer’s Disease International (ADI), 2010. Used by permission.
Alzheimer's Dementia:
Core Clinical Criteria
• Meets criteria for dementia and in addition, has the
following characteristics
– Insidious onset: symptoms have been gradual
– Clear-cut history of worsening of cognition
– The initial and most prominent cognitive deficits are evident on
history and examination in one of the following categories.
• Amnestic presentation: most common, deficits include impairment in learning and
recall of recently learned information
• Nonamnestic presentations: language problems, executive dysfunction,
visualspacial presentation
The 10 Warning Signs of AD
(from the Alzheimer’s Association)
1. Memory changes that disrupt daily life
2. Challenges in planning or solving problems
3. Difficulty performing familiar tasks at home, at work or at leisure
4. Confusion with time or place
5. Trouble understanding visual images and spacial relationships
6. New problems with words in speaking or writing
7. Misplacing things or loosing the ability to retrace steps
8. Decreased or poor judgment
9. Withdrawal from work or social activities
10. Changes in mood and personality
Preclinical AD and Mild
Cognitive Impairment
• Signs of AD are first noticed in the
entorhinal cortex, then it proceeds
to the hippocampus.
• Affected brain regions begin to
shrink as brain neurons cells die.
• Changes can begin 10-20 years
before symptoms appear.
• May notice subtle behavioral and
memory changes usually attributed
to “old age”.
• Memory loss is the first sign.
• Wide variety of symptoms – hard
to diagnose with certainty
Blue stipple indicates disease spread and extent
Images courtesy of the National Institute on Aging/National
Institutes of Health
Mild Cognitive Impairment (MCI)
Core Clinical Criteria
• Concern regarding a change in cognition
• Evidence of lower performance in one or more cognitive
domains that is greater than would be expected for the
patient’s age and educational background
• Generally maintain their independence of function in daily
life, with minimal aids or assistance
• Impairment in episodic memory (i.e., the ability to learn
and retain new information) is most commonly seen in
MCI patients who subsequently progress to a diagnosis of
AD dementia.
Mild to Moderate AD
• AD spreads through the brain. The
cerebral cortex begins to shrink as
more and more neurons stop working,
lose their synapses, and die.
• Mild AD signs can include memory
loss, confusion, trouble handling
money, poor judgment, mood changes,
and increased anxiety.
• Moderate AD signs can include
increased memory loss and confusion,
problems recognizing people, difficulty
with language and thoughts,
restlessness, agitation, wandering, and
repetitive statements.
Note preferred spread to frontotemporal
and more posterior regions
Images courtesy of the National Institute on Aging/National
Institutes of Health
Severe AD
• In severe AD, extreme brain
shrinkage occurs. Brain retracts
from cranial vault – brain ventricles
expand. Patients are completely
dependent on others for care.
• Symptoms can include weight loss,
seizures, skin infections, groaning,
moaning, or grunting, increased
sleeping, loss of bladder and bowel
control.
• Death usually occurs from
aspiration pneumonia or other
infections. Caregivers can turn to a
hospice for help and palliative care.
Note pathology is widespread – symptoms
become similar from one person to the next.
Images courtesy of the National Institute on Aging/National
Institutes of Health
Alzheimer’s Disease Progression
Mild
Cognitive
Impairment
Alzheimer’s Disease Progression
Mild
Loss of recent memory
Faulty judgment
Personality changes
Moderate
Verbal and physical aggression
Agitation
Wandering
Sleep disturbances
Delusions
Severe
Loss of all reasoning
Bedridden
Incontinence
8 years average. Range: 2-20 years
Death from
pneumonia
and/or other
comorbidities
Clinical Expression of AD
COGNITION
BEHAVIOR
Unique
Symptom
Pattern of
AD
FUNCTION
Inside the
Human Brain
To understand
Alzheimer’s disease,
it’s important to know
a bit about the
brain…
The Brain’s Vital Statistics
• Adult weight: about 3 pounds
• Adult size: a medium cauliflower
• Number of neurons:
100,000,000,000 (100 billion)
• Number of synapses (the gap
between neurons):
100,000,000,000,000 (100 trillion)
Images courtesy of the National Institute on Aging/National
Institutes of Health
Pathophysiology of AD
• Deposition of insoluble amyloid peptide both in and around neurons
– primarily involves pyramidal neurons – amyloid may or may not be
directly toxic (e.g., excessive accumulation of anything can be bad)
• Formation of millions of amyloid (neuritic) plaques – small spherical
accumulations of amyloid – each may be the end result of a single
neuron cell death event
• Formation of neurofibrillary tangles containing primarily the
hyperphosphorylated tau protein – the tau protein associates with
microtubules in axons and dendrites of neurons
• Inflammatory response
– astrocytosis (activation of astrocytes – an early event involved in clearing of
synaptic debris)
– microgliosis (activation of microglia – a later event involved in clearing of dead
cell debris and initiating a more global inflammation)
• Cholinergic deficit – loss of acetylcholine receptors in cholinergic
neurons – each neuron less able to “perform” – acetylcholinesterase
inhibitors like Aricept help resolve this
Histological Hallmarks of AD
In 1907, in the first report, Alois Alzheimer described senile plaques (SP) and
neurofibrillary tangles (NFT) SP are found in neocortex, hippocampus and in
several subcortical areas.
NFT density correlates with disease duration and severity of dementia.
• amyloid plaques, which are dense deposits of protein and cellular
material that accumulate outside and around nerve cells
• neurofibrillary tangles, which are twisted fibers that build up inside the
nerve cell
NFTs
Amyloid
Plaques
Senile (Amyloid) plaque
Neurofibrillary tangle
Vulnerable Neurons in AD
• Basal forebrain cholinergic system (nucleus
basalis)
• Monoaminergic system
• Hippocampus (CA1 and CA2 pyramidal cells)
• Amygdala
• Entorhinal cortex
• Neocortex
Amyloid (Abeta42) deposition makes neurons sick.
Sick neurons retract their axons and dendrites and lose synaptic
connections with each other  Loss of memory and cognition
Sick
neuron
Amyloid
plaque
AP
Retracted
“corkscrew”
dendrites
Amyloid plaques contain Abeta42
Images courtesy of the National Institute on Aging/National
Institutes of Health
AD and the Brain
Beta-amyloid Plaques
1.
Amyloid precursor protein (APP) is the
precursor to amyloid plaque.
1. APP sticks through the neuron
membrane.
2.
3.
2. Secretase enzymes cut the APP into
fragments of protein, including betaamyloid.
3. Beta-amyloid fragments come together
in clumps to form plaques.
In AD, many of these clumps form,
disrupting the work of neurons. This
affects the hippocampus and other areas of
the cerebral cortex.
Images courtesy of the National Institute on Aging/National
Institutes of Health
AD and the Brain
Neurofibrillary
Tangles
Neurons have an internal support structure partly made up of
microtubules. A protein called tau helps stabilize microtubules. In AD, tau
changes, causing microtubules to collapse, and tau proteins clump together
to form neurofibrillary tangles.
Image courtesy of the National Institute on Aging/National
Institutes of Health
The Continuum of Alzheimer's Disease
Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s &
Dementia 2011;7(3):280-292. Used with permission from Elsevier.
Hypothetical Model of the Alzheimer’s
Disease Pathophysiological Cascade
Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s
& Dementia 2011;7(3):280-292 with permission from Elsevier.
Biomarkers of AD
• Biomarkers of Abeta accumulation:
– abnormal tracer retention on amyloid PET imaging
– low CSFAbeta42
• Biomarkers of neuronal degeneration/injury
– elevated CSF tau (both total and phosphorylated tau)
– decreased fluorodeoxyglucose uptake on PET
involving temporoparietal cortex
– atrophy on structural magnetic resonance involving
medial, basal, and lateral temporal lobes and medial
and lateral parietal cortices
Biomarkers of Alzheimer’s Disease
Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia
2011;7(3):280-292 with permission from Elsevier.
Risk Factors for AD
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•
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Age
Gender – female has more risk
Low education and low IQ
Positive family history of AD or dementia
Apolipoprotein alleles (esp. Apo E4 genotype – ApoE4 has been
shown to be a carrier of the amyloid peptide across the blood-brain
barrier)
Mutations in Amyloid Precursor Protein (APP) – generate more
amyloid
Mutations in genes processing APP (presenilin 1 & 2) – generate more
amyloid
Down’s syndrome (chr. 21) – contains APP gene - 100% incidence of
Alzheimer’s disease
Head injury
Low serum levels of folate and vitamin B12 – evidence weak
Elevated plasma and total homocysteine levels – evidence weak
Protective Factors for AD
•
•
•
•
•
•
•
•
High education
NSAIDS
Statins
Red wine, beer?
Curcumin - curry
Blueberries – it’s the color - antioxidant
Intellectual leisure activities, socialization
Cardiovascular health
Diagnosing AD
• A detailed patient history
• Information from family and
friends
• Physical and neurological exams
and lab tests
• Neuropsychological/cognitive
tests
• Imaging tools such as CT scan or
magnetic resonance imaging
(MRI). PET scans are used
primarily for research purposes.
Source: Photodisc Health & Medicine, Volume 18 #18038
Why Diagnose AD Early?
•
•
•
•
Safety (driving, cooking, etc.)
Family stress and misunderstanding (blame, denial)
Early education of caregivers on how to handle patient
Advance planning while patient is competent (will, proxy,
power of attorney, advance directives)
• Patient’s and Family’s right to know
• Make use of specific treatments now available
– May help delay symptoms
– May delay nursing home placement
AD vs. Other Dementias
• Alzheimer’s disease (AD) 60-80%
• Vascular dementia (VaD) 10-20%
• Dementia with Lewy bodies (DLB) 10-20%
• Parkinson’s disease dementia (PDD) 1-3%
• Frontotemporal dementias (FTD) 1-2%
• Potentially reversible dementias
Atypical Features that Suggest a Diagnosis Other
than Alzheimer's Disease
Feature
Diagnostic consideration
Abrupt onset
Vascular dementia (multi-infarct)
Stepwise deterioration
Vascular dementia: involves brain quadrants fed by
major vessel that becomes blocked or has bloodbrain barrier breakdown
Prominent behavior changes
Frontotemporal dementia
Profound apathy
Frontotemporal dementia
Prominent aphasia
Frontotemporal dementia, vascular dementia
Progressive gait disorder
Vascular dementia, hydrocephalus
Prominent fluctuations in levels of
consciousness or cognitive abilities
Delirium due to infection, alcohol, medications, or
other causes; dementia with Lewy bodies; seizures
Hallucinations or delusions
Delirium due to infection, medications, or other
causes; dementia with Lewy bodies
Extrapyramidal signs or gait
Parkinsonian syndromes, vascular dementia
Assessment
• History Of The Development Of The Dementia
–
–
–
–
–
–
Ask the patient what problem has brought him to see you
Ask the family, companion about the problem
Specifically ask about Memory Problems
Ask about the First Symptoms
Inquire about Time of Onset
Ask about Any Unusual Events around the Time of Onset,
e.g., stress, trauma, surgery
– Ask about Nature and Rate of Progression
•
•
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Physical Examination
Neurological Examination
Laboratory Tests
Neuropsychological/Cognitive Assessment
Neuropsychological Testing
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•
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Memory: short-term, remote
Verbal function, fluency
Visuo-spatial function
Attention
Executive function
Abstract thinking
Clinical Tools for Cognitive
Assessment
• Folstein Mini-Mental State
Exam (MMSE)
• Clock Drawing
• Animal Naming (1 Minute)
• Short Blessed
• Mattis Dementia Rating Scale
• Alzheimer’s Disease
Assessment Scale (ADAS)
• Activities Of Daily Living
• Global Clinical Scale
• Clinical Dementia Rating
Scale
• Global Deterioration Scale/
FAST
Mini-Mental State Exam (MMSE)
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•
•
•
•
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Orientation to time
Orientation to place
Registration
Attention & calculation
Recall
Language
= 5 points
= 5 points
= 3 points
= 5 points
= 3 points
= 9 points
30 points
Specificity is good (96%) But the sensitivity is poor (63%)
Generalized Atrophy in
Alzheimer’s Disease
Brain shrinks due to widespread neuron cell death – cerebral cortex and hippocampus.
Note larger space between cerebral cortex and cranial vault.
Ventricles filled with cerebrospinal fluid (CSF) get larger to compensate for cell loss.
Image courtesy of the National Institute on Aging/National
Institutes of Health
Glucose Utilization
PET scans showing much reduced glucose utilization
in the AD brain compared to controls
Reason: Cell death means less cells capable of metabolizing glucose
Therapeutic Objectives
• Control existing symptoms by restoring cholinergic activity
- Note: Alzheimer’s disease is considered a cholinergic or cholinoceptive
disease. This means that neurons that use acetylcholine as a
neurotransmitter are primarily affected.
• Delay progression of disease after diagnosis by modifying
pathophysiology
• Delay emergence of symptoms in persons at risk (e.g., may
want to recommend frequent cardiovascular exercise because of
the important vascular contribution to this disease)
Current Drug Treatments for AD
• Acetylcholinesterase inhibitors for mild to moderate AD
-
Tacrine (Cognex)
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Reminyl)
• Neuroprotective agent for moderate to severe AD
- Memantine (Namenda)
Cholinesterase Inhibitors
Approved for Treatment of Mild to Moderate AD
• Tacrine (Cognex)
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Rezadyne)
Degree of Benefit
• Average benefit of cholinesterase inhibitors in patients with
dementia is a small improvement in cognition and activities
of daily living
• Whether these drugs significantly improve long-term
outcomes, such as the need for nursing home admission or
maintaining critical activities of daily living (ADLs), remains
in doubt, and the evidence is conflicting
• Response to cholinesterase inhibitors may be quite variable,
with as many as 30 to 50 percent of patients showing no
benefit , while a smaller proportion (up to 20 percent) may
show a greater than average response. These findings
reinforce the importance of making individualized decisions
for each patient based on clinical response and side-effects
Cholinesterase Inhibitors in
Treatment of Dementia
• Treatment trial with a cholinesterase inhibitor for
patients with mild to moderate dementia
• In patients with severe dementia, cholinesterase
inhibitors can be discontinued, but they should be
restarted if the patient worsens without the
medication.
• There is some evidence of benefit for patients with
vascular dementia (VaD), mixed dementia, dementia
with Lewy bodies (DLB), and dementia in Parkinson's
disease (PD).
Namenda (Memantine)
• NMDA receptor antagonist
• Approved for patients with moderate to severe AD
• A 2008 systemic review concluded that memantine has
been shown to improve cognition and global assessment
of dementia, but with effesmall cts that are not of clear
clinical significance; improvement in quality of life and
other domains are suggested but not proven
• As a result, treatment decisions should be individualized
and include considerations of drug tolerability and cost.
• Well tolerated with fewer side effects
Raina P, Santaguida P, Ismaila A, et al. Ann Intern Med 2008;148(5):379-397.
Glutamate Hypothesis
Abnormal glutamatergic activity leads to
sustained low-level activation of NMDA receptors
Abnormal
Intracellular
Changes
Neuronal death
following chronic insult

Excitotoxicity
Cognitive deficit due
to disruption of learning and
memory
Conclusion
• Alzheimer disease is one of the most debilitating diseases
affecting the old age.
• A clear understanding of the natural history of Alzheimer
disease will enable us to develop appropriate trial designs and
outcomes for the various stages of this condition.
• Treatment can slow disease progression, slow loss of cognitive
and functional abilities, and ameliorate behavioral symptoms
• Benefit for the treatment of symptoms in mild to severe AD
using AChEIs and Memantine is seen.
• Also, there is cautious optimism for successful disease
modification using a number of agents currently under study.