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Mild Cognitive Impairment & Alzheimer’s Disease:From Early Diagnosis to Delirium
Trey Sunderland, M.D.Chevy Chase, Md.
APNA ConferenceReston, VA
June 28, 2009
Alzheimer’s Disease & Depression Today Symptomatic Time Course
Autopsy
MCI(12-15%/yr)
MildModerate
Severe
Nursing Home
Diagnosis of AD
3-4 years/stage
Test Results
Diagnosis
? ? AnergiaAgitated
Aggressive
Autopsy
How is MCI different from AD?
● MCI usually involves memory but can involve language, attention, reasoning, judgment, reading or writing as first & solo symptom
● Many MCI patients develop AD eventually, but some can return to normal
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What does MCI look like?
What are Diagnostic Criteria for MCI?
Evidence of Memory Impairment (amnestic)
Preservation of general cognitive and functional abilities
* Absence of diagnosed dementia
(20% population over 70 years; 10-15%/yr go on to AD)
CLOCK DRAWING TASK
Normal Control
MCI?
Early AD
Moderate AD
Moderate-Severe AD
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William Utermohlen: American Artist
74 y/o artist in London
Abstract Expressionist
1967 Self-Portrait
MCI/AD diagnosed in ‘95
Continued Painting…
1996 1997 1998
William Utermohlen: American Artist
1999 2000
William Utermohlen: American Artist
1967 2001
Stopped Painting
Recently Died
(NY Times, 10/24/06)
Works on Tour
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What does AD look like?
What is “Gold Standard” in AD?
Brief Screening tests (MMSE, Clock Drawing)
* Cognitive Testing (ADAS-Cog)
* Clinical Dementia Rating Scale (CDR)
* Clinical Global Impression of Change (CGIC)
* Brain Atrophy (CT or sMRI)
A specific laboratory test for the diagnosis of melancholia.
Standardization, validation, and clinical utility
B. J. Carroll, M. Feinberg, J. F. Greden, J. Tarika,A. A. Albala, R. F. Haskett, N. M. James, Z. Kronfol,
N. Lohr, M. Steiner, J. P. de Vigne and E. Young
Psychiatry’s Search for Biomarkers…
(Arch Gen Psychiatr38(1), January 1981)
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BIOMARKERS: Why Important in AD?
Worldwide Costs for Dementia: 2005
29.3 Million Individuals throughout world
(Wino et al., Alzheimer’s & Dementia, April 2007)
Developing ($4,827)Denmark ($70,449) vs. USA ($49,666) vs. Ethiopia ($1148)
USA (2005-2030) 3.5 to 12-14 million AD subjects
$315 Billion estimated Societal CostsAverage Base Costs: Advanced ($20,600)
Common Medical Biomarkers
Cardiac (BP, Chol, Thalium Scanning, Enzymes)
* Endocrine (TSH, Free T4, Cortisol)
* Pulmonary (CXR, Pulmonary Function tests)
* Kidney (BUN, Creatinine, Cr. Clearance)
* Liver (LFTs, Bilirubin, CT Scan, biopsy)
* Cancer (CEA, PSA, Bcl-2)
Years0
Autopsy
Clinical diagnosis
20 40 60 80 100
Test Results
Potential Biomarkers
lts
Diagnosis of MCI/AD: Today vs. Future
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Early Biomarker Missteps in AD
Pupil Dilation with Tropicamide (Scinto 1994)
* AD7C-NTP in Urine in AD (Ghanbari 1998)
* CSF Neural Thread Protein (de la Monte 1992)
* Muscarinic receptors on Skin Fibroblasts (Nadi1984)
* Serum αααα-1 antichymotrypsin (Matusubara 1989)
(Shaw et al. Nat. Rev. Drug Discov. 6:295-303, 2007)
Many Potential MCI/AD Biomarkers
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Best Candidates: 2008
--CSF ββββ-amyloid1-42
--CSF Total Tau & p-Tau231
Ideal Biomarker Characteristics:
Detects a fundamental feature of AD
Validated in autopsy-proven cases
Reliable in other laboratories
Specific for AD compared to other dementias
Non-Invasive and Simple to perform
Inexpensive
(Regan Research Institute Consensus Report Neurobiol Aging19:109-116, 1998)
Sometimes the data was hidden…
Ali-Liston FightLewiston, MEMay 25, 1965
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Years0
Gene? Autopsy
Clinical diagnosis
20 40 60 80 100
Test Results
Potential Biomarkers
lts
Diagnosis of MCI/AD: Today vs. Future
FAMILIAL ALZHEIMER’S DISEASE
(PSEN1)
GENETICS OF EARLY-ONSET ADA Brief Review
Amyloid precursor protein (APP) on chromosome 21
*Variable onset age, modified by APOE genotype
*18 reported mutations affecting 56 families
Presenilin 1(PSEN1) on chromosome 14
*Onset age 40s-50s; majority of autosomal dominant early-onset AD
*144 reported mutations affecting 289 families
Presenilin 2(PSEN2) on chromosome 1
*Variable onset age, modified by APOE genotype*10 reported mutations affecting 18 families
(Blacker et al. J. Geriatr. Psychiatr. Neurol.2006)
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AD Survival Curves for APOE Genotypes
(Roses Ann. Rev. Med. 47:387-400, 1996)
1.0
0.5
0.0
Pro
por
tion
Una
ffect
ed
20 30 40 50 60 70 80 90 100 110Age (years)
S182Mutation
APPMutation
APOE4-4 3-4
2-43-3
2-3
Years0
Gene?Amyloid
deposition Autopsy
Clinical diagnosis
20 40 60 80 100
Test Results
Potential Biomarkers
lts
Diagnosis of MCI/AD: Today vs. Future
Amyloid Plaques in AD
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Structure ofPrecursor Molecule Normal Enzymatic
ProcessingAlternative Enzymatic
Processing
Protease-RegulatingRegion
AmyloidBeta-Region Amino Terminal
MembraneTerminal
Carboxyl
Beta-regionis cut
IntactBeta-fragmentIs released
Amyloid Processing
CSF PROTEINS AS BIOMARKERS
CSF
CSF ββββ-amyloid1-42 in Older Controls and AD Subjects
(Sunderland et al. JAMA 289: 2094-2103, 2003)
1.200
0
200
400
600
800
1,000
ControlsN=72
ADN=131
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Years0
Gene?Amyloid
depositionCell
damage Autopsy
Clinical diagnosis
20 40 60 80 100
Test Results
Potential Biomarkers
lts
Diagnosis of MCI/AD: Today vs. Future
Neurofibrillary Tangles in AD
CSF Tau Levels in Older Controls and AD Subjects
1,600
1,400
1,200
1,000
800
600
400
200
0Controls
N=72AD
N=131
pg/m
l
(Sunderland et al. JAMA 289: 2094-2103, 2003)
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0
200
400
600
800
AD(108)
CSF
p-TAU
ng/ml
(Hampel et al., Arch Gen Psych 2004)
CSF p-Tau231 across Multiple Diagnoses
DLB(22)
VaD(7)
Mixed(53)
FTD(24)
OND(22)
NC(23)
Years0
Gene?Amyloid
depositionCell
damage Autopsy
Clinical diagnosis
20 40 60 80 100
Test Results
Inflammatoryresponse
Potential Biomarkers
lts
Diagnosis of MCI/AD: Today vs. Future
Inflammatory Markers in AD
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NIH Clinical Center
WEEKS
0 12
BASELINE
LOVASTATIN(40 mg/day)
IBUPROFEN(800 mg/day)
FOLLOW-UP
6
- Bloods
- Cognition- Bloods- LP
- Cognition- Bloods- LP
STATIN/NSAID Preliminary Study(DB, Randomized, No Placebo Control)
BIOCARD “NSAID” StudyCSF ββββ-amyloid1-42 Levels
beta42
ng/ml
Baseline Lovastatin40 mg/day
Ibuprofen800 mg/day
1600
10001253
15301505
3 Months Treatment
1400
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Multiple approaches may be needed…
Scatter graph of CSF TAU and ββββ-amyloid1-42in AD and Controls
1,600
1,400
1,200
1,000
800
600
400
200
0
CS
F T
AU
0 200 400 600 800 1,000 1,200
CSF β-amyloid 1-42
(Sunderland et al. JAMA 289: 2094-2103, 2003)
ββββ-amyloid1-42 + Tau92% Specificity
89% Sensitivity
CSF ββββ-Amyloid 1- 42 BY APO E GENOTYPEIn Control Subjectsand AD Patients
600
400
200
0
APOE εεεε4 0 1 2 0 1 2NCONTROLS = 39 25 7 24 25 19 = NAD
β-Amyloid 1-42
Aβ 1
_42p
g/m
l
570
420
244 223
15157
Normal Controls
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UCLA School of Medicine.UCLA School of Medicine.
100%100%
0%0%Min.Min.
Max.Max.100%100%
0%0%Min.Min.
Max.Max.
MRIMRIPET: PET: FDDNPFDDNP PET: PET: FDGFDGAD PatientAD Patient
ControlControl
DDNP: 1,1-dicyano-2-[6-(dimethylamino)-2-naphthalenyl]propene
Why Do We really Care about AD Prediction?
“BIOCARD” Study(Biomarkers in Older Controls at r isk for Dementia)
(NIMH: 1995-2005)
SUBJECTS
NGender (F:M)
Age (Yrs)Educ (Yrs)
NART-IQ
350187:143
56.4 ± 10.5
16.9 ± 2.6119 ± 10
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APOE εεεε4 Effects in BIOCARD Normals
600
400
200
0
600
400
200
0(–) (+) (+)(–)
APOE ε4
ββββ-Amyloid 1-42
TAU
**
391
589
197216
(Sunderland et al. Biol. Psych.56:670-6, 2004)
N=85 N=57 N=85 N=57
Biomarkers TODAY: CSF Aβ/β/β/β/tau
Detects a fundamental feature of AD
Validated in autopsy-proven cases
Reliable in other laboratories
Specific for AD compared to other dementias
Non-Invasive and Simple to perform
Inexpensive
(Regan Research Institute Consensus Report Neurobiol Aging19:109-116, 1998)
++ +/-+/-
No, but…Relatively…
Biomarkers will be helpful if we can quantify them…
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Years0
Gene?Amyloid
depositionCell
damage Autopsy
Clinical diagnosis
LOD?
20 40 60 80 100
Test Results
Inflammatoryresponse
Potential Biomarkers
lts
Diagnosis of MCI/AD: Today vs. Future
Psychiatric Symptoms in MCI/AD
● Depression is the most common early feature
● Anxiety & Panic can also present as early symptoms
● Paranoia and Delusional Psychosis can be early or late
● Delirium frequently accompanies concurrent infection
Alzheimer’s Disease & Depression Today Symptomatic Time Course
Autopsy
MCI(12-15%/yr)
MildModerate
Severe
Nursing Home
Diagnosis of AD
3-4 years/stage
Test Results
Diagnosis
? ? AnergiaAgitated
Aggressive
Autopsy
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APOE, Depression & Risk of AD
Case Control Study (528 AD, 524 Controls)
* N=1052, University of Miami Study (2009)
• Overall APOE association with Depression (p=0.001)
* AD/Dep have earlier Onset than AD alone (p=0.017)
(Silfer et al, Neurosci Lett May 15;455 (2) 2009)
Delirium in MCI/AD
Clinical Symptoms:
● Inattention● Disorganized Thinking● Altered Level of Consciousness
(Fick et al. J Gerontol Nurs 35:30-38, 2009)
Delirium in Nursing Home AD
● 70.3% (105/155) Subjects with Delirium● Age and Severity most associated● Other factors:
ADL Autonomy PainDepression #MedsDehydration FeverBehavioral Changes Malnutrition
(Voyer et al, Clin Nurs Res. 18:153-159 May, 2009)
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Effect of Delirium in AD Course
● Large prospective outpatient study
● 18% (72/408) developed Delirium
● Near doubling of rate of AD decline
(Fong et al. Neurology. 72(18):1570-5, May 2009)
Delirium: Nursing Home vs. Home
● N=341 patients followed prospectively
● Admissions adjusted for AD severity, hearing impairment and systemic illness
● 38% ERadmissions from NH with delirium vs. 6% for Home Care
(Han et al. J Am Geriat Soc.57(5)889-94, May 2009)
Delirium in MCI/ADClinical Symptoms:● Inattention● Disorganized Thinking● Altered Level of Consciousness
Treatment Approaches:● Prevent Infections● Alter Surroundings, inc Meds!● New Medications as last resort
(Fick et al. J Gerontol Nurs 35:30-38, 2009)
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So, where are we headed with diagnosis?
How will we diagnose MCI/AD in Future?
3. Associated Decline in sMRIhippocampal volume.
2. Subtle Change in Subsets ofCognitive Tests or Behavior.
4. Change in Known Biomarkerin Blood, CSF or Brain Image.
“Paper & Pencil”Test
Results
1. Genetic Profile Associated with increased risk of AD.
AGE & APOE
