Ranjan Duara, MD, FAAN · Alzheimer’s disease Facts First described in a younger persons (50’s...
Transcript of Ranjan Duara, MD, FAAN · Alzheimer’s disease Facts First described in a younger persons (50’s...
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.Medical Director, Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach Clinical Professor of Neurology, Herbert Wertheim College of Medicine, FIU and University of Florida College of Medicine
Ranjan Duara, MD, FAAN
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Disclosure DeclarationsRanjan Duara, MD
Company
Relationship Description
(Name of drug / compound,
type of intervention /
instrument, etc)
Relationship
Stock and/or
ownership
rights > $5,000
or 5% interest
Established or
potential royalty
income
Income in the
PAST 12 months of
$5,000 or more
Income in the
NEXT 12 months
of $5,000 or more
Alzheimer’s
Therapeutic
Research Institute
AZD0530 (FYN)in Mild
Alzheimer’s Disease
Grant / Research
SupportNo NA NA NA
Avid - Eli Lilly &
Company
Amyvid™:Use of AV-45 in ADCS
Trials
Grant / Research
SupportNo NA NA NA
Avid - Eli Lilly &
CompanyTau: Tau Imaging AV 1451
Grant / Research
SupportNo NA NA NA
Eli Lilly & CompanySolanezumab: Anti-Amyloid Trial
in Asymptomatic AD (A4 Study)
Grant / Research
SupportNo NA NA NA
Janssen Research &
Development, LLC
JNJ-54861911 in Subjects who are
Asymptomatic At Risk for
Developing Alzheimer’s
Grant / Research
SupportNo NA NA NA
Medical Learning
Group
Speaker's Bureau for Eli Lilly &
Company
Consultant or
Advisor - Paid
DIRECTLY
No NA Yes Yes
Merck & CompanyMK-8931: MK-8931-019 in
Prodromal Alzheimer's Disease
Grant / Research
SupportNo NA NA NA
Toyama Chemical
Co., Ltd.
TCAD/NOBLE: Toyama Chemical
(T-817MA) in Alzheimer’s Disease
Grant / Research
SupportNo NA NA NA
vTv
THERAPEUTICS
LLC
TTP488: TTP488-301 for Mild
Alzheimer's Disease
Grant / Research
SupportNo NA NA NA
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Memories
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Auguste D & Alois Alzheimer
First patient described - 1907
51 year old woman
Memory impairment
Hallucinations, delusions, paranoia
Agitation
Disorientation
Progression over 5 years
At end - fetal position, incontinent, unresponsive
Picture of Auguste D from: Maurer K, Volk S, Gerbaldo H. Auguste D and
Alzheimer’s disease. Lancet 1997; 349: 1546-49.
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Alzheimer’s disease Facts First described in a younger persons (50’s and 60s) –
now known to be the most common cause of dementia in older persons
~ 5+ million individuals currently affected in the U.S.
Alzheimer’s affects 50% of people 85 + years of age.
By 2050 22+ million people will be affected worldwide
Medical, monetary, and human resources will be severely strained
New data suggests Alzheimer’s is the 3rd most common cause of death (Neurology, 2014)
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Genetics contribute to susceptibility
Early onset AD transmitted as a autosomal dominant trait typically <65 y/o age (esp. presenilin 1 mutation on Chromosome 14; (very rarely Chromosome 1 and Chromosome 21 mutations)
Majority of cases sporadic (not purely genetic)– but genetic factors play significant role (especially apolipoprotein e4)
Non-genetic risk factors important: age – activity, BMI, blood pressure, diabetes, diet, psychosocial factors (e.g., neuroticism, anxiety)
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Alzheimer’s Disease
AD More Likely:Age
Female sex
E4 genotype
Hypertension
Diabetes
Homocysteine
Cholesterol
Head trauma
Family history
AD Less Likely:Education
Exercise
Brain fitness
Antioxidant diet
Heart health
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PLAQUES
Amyloid beta
protein
TANGLES
abnormal
tau protein
Normal brain
Alzheimer’s disease
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Amyloid plaque
Neurofibrillary
tangle
Brain atrophy
Alzheimer’s Disease: Pathology
Images courtesy of The Brain Plaques and Tangles That Cause Alzheimer’s Disease. Available at: http://bigthink.com/ideas/the-brain-plaques-and-tangles-that-cause-alzheimers-disease . Accessed October 29, 2012.
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Amyloid Beta protein deposition considered pivotal in Alzheimer’s disease process
(Cummings JL, JAMA, May 8, 2002)
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Senile plaque distribution
(From Selkoe, DJ, Sci Am, 1991)
(Braak H, Braak E. Neuropathological
stageing of Alzheimer-related changes.
Acta Neuropathol (Berl) 82: 239-259.)
Distribution of amyloid and neurofibrillary pathology in Alzheimer’s disease
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CP1331962-17R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13 [modified]
Normal Preclinical MCI Dementia
Clinical Disease Stage
Abnormal
Amyloid- accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/MRI)
Tau-mediated neuronal injury (CSF)
Brain structure (volumetric MRI)
Cognition
Clinical function
Biomarker Changes During AD Progression
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CP1331962-18 Rowe et.al. Neurobiol. of Aging 2010;3`:1275-83
60
50
40
30
20
10
0
30 40 50 60 70 80 90 100
Age (years)
Pre
va
len
ce
(%
)
Prevalence
of PiB+ve PET
in HC
Prevalence of plaques
in HC
Prevalence
of AD
~15 yrs
(Davies, 1988, n=110)
(Braak, 1996, n=551)
(Sugihara, 1995, n=123)
(Tobias, 2008)
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Structural
Magnetic resonance imaging (MRI)
X Ray CT
Functional
Fluorodeoxyglucose positron emission tomography (FDG PET)
Functional MRI (fMRI)
Molecular and biochemical
CSF
Amyloid PET
Tau PET
PET markers of Microglial Activation
Biomarkers for Assessment of AD Pathology in the Clinic
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Medial Temporal Atrophy Rating (HP, ERC, PRC)Entorhinal Cortex
Rating = 2 Mild Atrophy
1. Mild Decrease In Thickness
Or
2. Mild Widening Of Collateral
Sulcus
Or
3. Both
Entorhinal Cortex
Rating = 3 Moderate Atrophy
1. Moderate Decrease In
Thickness (Even In The
Absence Of Widening Of
Collateral Sulcus)
Or
2. Both Moderate Decrease In
Thickness And Widening Of
Collateral Sulcus
Entorhinal Cortex
Rating = 4 Severe Atrophy
1. Severe Decrease In
Thickness (Even In The
Absence Of Widening Of
Collateral Sulcus)
Or
2. Both Severe Decrease In
Thickness And Widening Of
Collateral Sulcus
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Fennema-Notestine, Fleisher, et al. 2009. Dickerson B et al. Neurol. 2011.
MRI Biomarker and AD Progression(Reduction in Cortical Thickness Associated with Disease Stage and Future Rate of Decline)
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FDG-PET in Normal Aging, MCI, AD and FTD
fTD = frontotemporal dementia; pAD = Probable Alzheimer’s disease.
NL
MCI
pAD
fTD
• AD-Dementia
• Cog NL APOE4carriers
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[F-18] Amyloid Imaging Tracers
AD
NL
Flutemetamol1
Florbetaben3
AD
NL
Navidea NAV46944
Florbetapir2
1Vandenberghe R et al. Ann Neurol. 2010;68:319-329. 2Barthel H et al. Lancet Neurol. 2011;10:424-435. 3Wong DF et al. J Nuc Med. 2010;51:913-920. 4Chen K et al. AAIC. 2012.
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Interpreting Amyloid PET ScansPositive
A
B
C D
Negative
A
C
B
D
2012 Eli Lilly Prescribing Information, http://pi.lilly.com/us/amyvid-uspi.pdf
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1.5
1.4
1.3
1.2
1.0
0.9
1.1
20 40 60 80
All Healthy Controls
Me
an
Co
rtic
al
SU
VR
s Age 58
Age 71Age
1.5
1.4
1.3
1.2
1.0
0.9
1.1
20 40 60 80
Age 76
APOE4 Non-Carriers
Me
an
co
rtic
al
SU
VR
s
1.5
1.4
1.3
1.2
1.0
0.9
1.1
20 40 60 8030 50 70 90
Age 61
APOE4 Carriers
Me
an
co
rtic
al
SU
VR
s
Age Age
APOE4, Age and Amyloid PET
Fleisher AS et al. Neurobiol Aging. 2013;34:1-12.
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3 year Risk of Progression: Positive vs Negative Amyloid PET Scan
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
25%to MCI/AD
Neg(n=130)
Pos(n=53)
Neg(n=27)
Pos(n=60)
Odds Ratio 14Odds Ratio 4.8
MCI(n=87)
Healthy Controls(n=183)
Rowe C. AAIC 2013.
77% (47/60)to AD dementia
29% (8/27)to AD dementia
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Tau PET Imaging (11C-PBB3)
Maruyama M et al.Neuron. 2013;79:1094-1108.
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A Case Study
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History and Clinical Presentation• 54yo RHF with gradually progressive cognitive
changes
• Difficulty with judgment and decision-making
• Social/interpersonal behavior change (withdrawn)
• Some difficulty with expressive language (i.e.,
word finding problems)
• Working as psychologist but having some difficulty approximately one year after symptom onset
• General medical history unremarkable; no history of depression
• Negative family history of dementia
• MMSE 29/30; Neurological exam unremarkable;
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Case Study - Question 1
Which clinical syndrome is most compatible with this case’s history and clinical presentation?
A. Mild Cognitive Impairment (MCI)B. DementiaC. Other (e.g., Pseudodementia; Subjective Cognitive Disorder)
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Case Study - Question 2
What further tests would be considered part of a standard dementia workup? (select all that apply)
A. Detailed Neurocognitive testingB. Structural MRIC. Labs: CBC, CMP, B12, TSHD. FDG PETE. Amyloid PETF. CSF Abeta and Tau
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Case Study – Neuropsychological testing General observations
• Flat affect
• Good effort on tests
• Impairments in • Executive function• Abstract reasoning• Verbal fluency• Naming (mild)
Relatively preserved
• Other language abilities
• Visuospatial abilities
• Memory
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Case #3 – Structural MRI imaging
Possible left medial prefrontal atrophy; possible posterior parietal atrophy; radiologist was not convinced outside range of normal
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Case Study – FDG PET imaging
Mild bilateral L>R parietal hypometabolism
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Case Study - Question 3
What is the clinical diagnosis for this patient?
A. Early Alzheimer’s DiseaseB. Non Alzheimer’s
Neurodegenerative EtiologyC. Vascular Cognitive Impairment
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Case Study – Question 4
What are the possible diagnoses now?
A. MCI due to ADB. MCI due to FTDC. MCI due to Lewy body
dementiaD.Still unclear
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Amyloid PET scan: Amyloid Negative
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Amyloid PET scan: Amyloid Positive
Aβ positive
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Recommendations for Possible Prevention
Control Vascular Risk Factors, esp. HTN and DM)
Dental Hygiene
Cognitive/Social Stimulation
Physical Exercise
B complex Vit. (B12& B6)
Vitamin C
Vitamin E in food
Eat fish
Use curry (curcumin)
Antioxidants • Beans
• Berries
• Grape juice
• Pomegranate juice
• Green tea
Mediterranean diet
Quality sleep• Treat sleep apnea
Increase socialization
Control blood glucose
Treat anemia
CP1331962-41
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Neuroprotection vs. one-time improvement
Function
Time
Neuroprotection
We are still looking for our first Disease Modifying/neuroprotective agent for AD!
Symptomatic
Treatment
Natural course
of disease
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Current and Emerging Treatments and Clinical Trials in Alzheimer’s Disease
Cholinesterase Inhibitors: Donepezil, Rivastigmine & Galantamine
NMDA modulators: Memantine
New symptomatic agents: Nicotinic agonists: MK 7622
Disease-modifying agents
Anti-amyloid: Solanezumab; Bapineuzemab; Crenezumab
Anti-tau: Methylthioninium chloride (MTC); Leuko-MTC (TauRx)
Neuroprotective: Toyoma-817 MA
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Bapineuzumab Clears Plaques in AD
Placebo Bapineuzumab
* Difference between patients in the placebo group and those in the bapineuzumab group at Week 78 = -0.24
(P = 0.003).
Trial failed to show clinical benefit.About 17% of cohort found not to have amyloid in the brain.Too little or too late?
0.4
0.3
0.2
0.1
0.01
-0.11
Bapineuzumab
*
Week
Est
.ed
Me
an
Ch
an
ge
Fro
m B
ase
lin
e M
ea
n C
-PiB
Placebo
Baseline 20 45 78
Rinne JO et al. Lancet Neurol. 2010;9:363-372. Salloway S, et al. N Engl J Med. 2014;370:22-33.
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Approved Secondary Prevention Studies
A4 study: 3 year double blind, 1000 person, Solanezumab study in cognitively normal person who are florbetapir +ve
DIAN study: 40 per arm, Solanezumab and Gantenerumab vs placebo in unaffected carriers of dominantly inherited genes
ApoE 44 study: Cognitively normal, 650 person, double blind, agent to be decided
Colombian kindred study: PSEN1 Paisa mutation using Crenezumab (from Genentech) in asymptomatic carriers
CP1331962-45
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Managements of Behavioral Manifestations of Alzheimer’s
Look for, Recognize and Rx Precipitating Factors: (Infection, Pain, Constipation, Hunger/Thirst, Sensory Deprivation, Medication change, Other Medical Conditions, Change in Physical or Social Environment)
Reassure, Agree with and Comfort the Patient, “Go with the Flow” (e.g., with delusions, hallucinations) Simplify and make Environment Safe
Educate Caregiver(s) about Precipitating Factors; Encourage Support Groups
Use SSRIs (Citalopram, Sertraline) as first line Rx (treats anxiety, irritability and depression)
Use Non-D2 Antagonist Anti-psychotics (Quetiapine)
Use D2 Antagonists (e.g., Risperidone) Use very sparingly Use Anticonvulsants (esp. Lamotrigine) and Buspar as adjuvants to
antipsychotics
Treat Sleep Disorders (with Trazodone, Mirtazapine)
CP1331962-46
Do’s
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Managements of Behavioral Manifestations of Alzheimer’s
Don’ts Don’t Confront, Contradict, Offend, Alarm, Challenge
or Argue with the Patient (Don’t Say: “I already told you that” ; “Don’t you remember”)
Avoid Loud Noise and Sudden Movements Don’t Overstimulate the Patient Don’t Emphasize Patient’s Impairments Don’t Use Benzodiazepines (e.g., Lorazepam, Temazepam)
for anxiety, sleep disorder or agitation - Except for very short term use.
Don’t Use Anticholinergics (Benadryl, Unisom, Hydroxyzine Amitriptyline, Meclizine, Ditropan)
Don’t Use Haloperidol (except parentally and for short-term use (in the ER) for very aggressive and violent patients)
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CP1331962-48
In Summary• A realistic goal is to delay or prevent
AD in the Preclinical or Early Clinical Stage, and to prevent progression of established Alzheimer’s
• With a combination of clinical findings and biomarkers we are able to identify those at risk and those who have the disease
• Secondary prevention and delaying/ stopping progression may soon become a reality
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Have A Nice Day