Download Clinical Trials - The Pat Summitt Foundation

Overview of Alzheimer’s Research
Roberto Fernandez MD, MPH, PhD
Medical Director
The Pat Summitt Clinic
Brain and Spine Institute
University of Tennessee Medical Center
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Overview
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Normal brain structure and function
Alzheimer’s pathology - What we know
Alzheimer’s pathology - What we don't know
The scope of research
Clinical Trials in Alzheimer’s disease
Clinical research at the Pat Summitt Clinic
Brain Function
Motor function
Spoken language
Attention
Planning
Making Choices
Suppression of
unwanted behaviors
Sensation
Visuospatial function
Integration of different
Sensory systems
Primary visual
processing
Language comprehension
Visual recognition
Auditory processing
Memory
Behavior
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Normal Brain Structure and Function
Image: http://www.nia.nih.gov
Image: www.martinos.org/neurorecovery/images/tracts.png
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Alzheimer’s Pathology. What we know…
• Not all brain
regions are
affected equally
or at the same
time
• Some areas are
more vulnerable
• Hallmark
changes are first
seen in medial
temporal lobes
Images: www.alz.org
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Beta Amyloid Plaques
Image: https://commons.wikimedia.org/
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Image: wiki.brown.edu
Amyloid is a naturally occurring protein
Formed from by cleavage of amyloid precursor protein
Beta-amyloid has tendency to aggregate forming plaques
Plaques formation is potentially toxic to neurons
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Tau and Neurofibrillary Tangles
Normal tau protein changes configuration and forms clumps, called
neurofibrillary tangles, cause cell dysfunction and eventually cell death.
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Loss of function and disease progression
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Loss of connections among brain cells and functional networks result in loss of
function (memory, language, etc) and may contribute to spread of disease and
cause further injury.
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Disease Progression
Progression of
disease leads to
inflammation,
cell injury, cell
death and brain
atrophy.
Images: www.alz.org
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Alzheimer’s Pathology: What We Don't Know
• What causes the changes in amyloid and tau
• Why individuals with amyloid burden may not develop AD
• Why are some parts of the brain more vulnerable than
others
• Why are there different variants of disease
• How does disease spread across brain regions
• What is the relationship with aging
• What’s the role of loss of connections between brain
regions
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The Scope of Biomedical Research
Basic Research
• Molecular
• Animal Models
• Human subjects
Images: http: npr.org
Images: http://www.lpzoo.org/
The Scope of Biomedical Research
Symptomatic
Drug Trials
Clinical
Research
Disease Modifying
Epidemiology
Preventive
Genetics
Imaging/EEG
Diagnostics
Labs
Other
Interventions
Cognitive
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Clinical Trials
Clinical Trials
• A clinical research study is a scientific investigation
designed to answer important questions about a specific
intervention:
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Is it safe?
Does it work?
Which dose works best?
What are the side effects?
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Clinical Trials
Progression of Clinical Trials
• Phase I: Tests new drug or treatment in a small group of
people to assess safety, safe dose range, and identify
side effects
• Phase II: Tests safety and/or efficacy
• Phase III: Studies conducted in large groups to confirm
effectiveness, monitor side effects and compare to
standard treatments
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Clinical Trials
Study Design
• Most trials are double blinded placebo-control trials
• Some may be “open label”
• Some have open label extensions after completion of
blinded portion of the study
• Most have strict inclusion criteria
• Duration, frequency of visits and procedures (e.g. tests)
varies depending on protocol
• Close monitoring for possible side effects
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Clinical Trials
When considering a clinical trial:
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Know your rights
Do not feel obligated to participate
You can decide to stop at any time
Make sure you inform yourself about research evidence backing the study
It is OK to ask for second opinion
Make sure you review and understand the informed consent. Don’t be afraid to
ask questions
• Make sure trial is conducted by a reputable institution
• All research with human subjects must be conducted by entities who have an
Institutional Review Board (IRB)
• Be aware that food supplements and natural products may not be regulated in the
same manner as therapeutic drugs, but may still have risks and possible side
effects
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Current Therapeutic Research in Alzheimer’s
• There are currently no approved medications that can cure, slow down or
revert Alzheimer’s
• Approved medications are intended to treat symptoms and may provide
temporary improvement
• Experimental drugs target know mechanism of disease through different
approaches:
• Beta-amyloid: Antibodies that help clear plaques, prevent aggregation or
block enzymes involved in amyloid formation
• Neurofibrillary tangles: Vaccine that stimulates the body’s immune
system to attack an abnormal form of tau protein that destabilizes the
structure of neurons
• Inflammatory response: Drugs that can modulate inflammation
• Neuronal network dysregulation: Anti-epileptic drugs to modulate
possible hyperexcitability of brain cells
• Neurotransmitter function
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Monoclonal Antibodies
• Selective for
aggregated betaamyloid
• Bind to amyloid plaques
• Signal to immune cells
that then recognize
plaque and remove it
Images: www.alz.org
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Clinical research at the Pat Summitt Clinic
ENGAGE Clinical Trial
• Study evaluating the efficacy and safety of an investigational drug
in people experiencing symptoms of early Alzheimer’s disease.
• It is intended for “preclinical Alzheimer’s”, also known as mild
cognitive impairment
• Study drug is aducanumab, a monoclonal antibody
• Prior studies showed statistically significant reduction in plaque
and slowing of cognitive decline
• Aim to determine whether the investigational drug can remove the
plaques and have an effect on the slowing of the progression of
the condition
• Infrequent but potentially serious adverse events have been
associated with this medication. These include brain swelling and
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brain bleeds.
ENGAGE Clinical Trial
• Approximately 1350 people with symptoms of early Alzheimer’s
disease will take part in this study around the world.
• Two phases: a placebo-controlled phase, and an optional longterm extension phase.
• Placebo-Control phase: two-in-three chance of receiving
investigational drug. This phase lasts 2 years
• Long-Term phase: All participants will receive the drug for 2
years
• Participants who meet eligible requirements will visit the clinic
once or twice per month
• During placebo- controlled phase, participants will receive either
the investigational drug or placebo every 4 weeks for
approximately 18 months (1.5 years).
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You may qualify for the study if:
• You are 50–85 years of age
• You are experiencing symptoms that might be related to
early Alzheimer’s disease, such as problems with
memory or thinking clearly
• You have someone who can be your study partner
(accompany you to certain appointments and provide
information about your health).
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Clinical Research at the Pat Summitt Clinic
Visuospatial Impairments in
Alzheimer’s Disease (AD)
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Up to 1/3 of AD begins with
visuospatial symptoms
Associated with posterior
cortical atrophy
Disabling because it
undermines independent
living
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Brain Areas for Visuospatial Orientation
and Alzheimer’s disease
Dorsal
Where?
Ventral
What?
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Optic Flow
• The visual motion seen during self movement
• Alzheimer’s can impair optic flow perception,
leading to disorientation
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Brain responses to it can be measured with EEG
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Brainwaves evoked by optic flow can differentiate early stage
Alzheimer’s from normal aging.
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Optic flow responses
are associated with
poor driving
performance and
atrophy of specific
brain regions that are
affected in
Alzheimer’s
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Current Research
• To establish the parameters of OF-ERP
components that will reliably differentiate normal
aging from Alzheimers for early diagnosis and
monitoring of disease progression
• Elucidate mechanism of Alzheimer’s disease that
are poorly understood
• Evaluate optic flow brain responses as objective
predictors of driving capacity
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Thank You