1. Mild Cognitive Impairment and Other Early Diagnoses
Ronald C. Petersen, Ph.D., M.D.
Alzheimer’s Disease Research Center
Mayo Clinic College of Medicine
Rochester, MN
Dementia: A Comprehensive Update
Boston
June 7, 2017

2. Disclosures Roche, Inc. Merck, Inc. Genentech, Inc. Biogen, Inc.
Eli Lilly and Co.
National Institute on Aging:
U01 AG006786
P50 AG016574
U01 AG011378
R01 AG011378
R01 AG041581
GHR Foundation
Mayo Foundation for Education and Research

3. Introduction to the Recommendations from the National Institute on Aging-Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease
Clifford R. Jack, Jr, Marilyn S. Albert, David S. Knopman, Guy M. McKhann, Reisa A. Sperling, Maria C. Carrillo, Bill Thies, Creighton H. Phelps
Alz and Dementia, 2011

4. Clinical disease stage
Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade A
Tau-meditated neuronal injury and dysfunction
Brain structure
Abnormal
Memory
Clinical function
Biomarker magnitude
Normal
Cognitively normal
MCI
Dementia
Clinical disease stage
Jack et al: Lancet Neurol 2010

5. Neuroimaging in AD

6. Neuroimaging in AD Structural MRI Functional imaging FDG PET
Molecular imaging
Amyloid PET imaging
Tau PET imaging

7. Structural Imaging in AD

8. Structural MRI: Atrophy and AD Stage
Control, 70, F
MCI, 72, F
AD, 74, F

9. AD Signature Cortical Thickness

10. Functional Imaging in AD

11. 11

12. Molecular Neuroimaging

13. PIB Idealized CN AD aMCI 00-863-895 02-310-847 06-209-892 3 2.5 2 1.5
0.5

14. PIB Examples – Full SpectrumCN
aMCI 3
2.5 2
1.5 1
0.5
Low CN
aMCI AD
High

15. Tau PET

16. Brain tissue slides show the Tau imaging agent is specific for the Tau protein and not Amyloid
Stain of Tau Imaging Agent Amyloid

17. Tau PET
Clinically normal 84yo
AD dementia 71yo

18. Criteria Approach Clinical criteria Biomarkers
Molecular neuropathology
Measures of neuronal injury

19. Cognitive Continuum
Normal
MCI
Dementia

20. M C I D E M N T I A AD
FTD
DLB
VCI
MEDICAL
TRAUMA

21. M C I
DUE TO AD M C I D E M N T I A
DUE TO AD D E M N T I A

22. Old Conception of Alzheimer’s Disease
Cognitively Normal
Dementia

23. Cognitive Continuum
Normal
MCI
Dementia

24. Alzheimer’s Disease Spectrum
Preclinical AD
MCI Due to AD
Dementia Due to AD

25. Alzheimer’s Disease Spectrum
Asymptomatic
Symptomatic
Preclinical AD
MCI Due to AD
Dementia Due to AD

26. Mild Cognitive Impairment

27. Mild Cognitive Impairment Essentially normal functional activities
Cognitive complaint
Not normal for age
Not demented
Cognitive decline
Essentially normal functional activities
MCI
Memory impaired?
Amnestic MCI
Single domain
Yes
Memory
impairment only? No
Multiple domain
Non-amnestic MCI
Single domain
Yes No
Single non-memory
cognitive domain impaired?
Multiple domain
Non-amnestic MCI
Single domain
Yes No
Single non-memory
cognitive domain impaired?
Multiple domain
Petersen: J Int Med, 2004 CP

28. Mild Cognitive Impairment Essentially normal functional activities
Cognitive complaint
Not normal for age
Not demented
Cognitive decline
Essentially normal functional activities
MCI
Memory impaired?
Amnestic MCI
Single domain
Yes
Memory
impairment only? No
Multiple domain
Amnestic MCI
Single domain
Yes
Memory
impairment only? No
Multiple domain
Non-amnestic MCI
Single domain
Yes No
Single non-memory
cognitive domain impaired?
Multiple domain
Petersen: J Int Med, 2004 CP

29. Mild Cognitive Impairment Essentially normal functional activities
Cognitive complaint
Not normal for age
Not demented
Cognitive decline
Essentially normal functional activities
MCI
Memory impaired?
Yes
Amnestic MCI
Non-amnestic MCI
Single domain
Yes No
Single non-memory
cognitive domain impaired?
Multiple domain
Memory
impairment only?
Amnestic MCI
Single domain
Yes No
Amnestic MCI
Multiple domain
Petersen: J Int Med, 2004 CP

30. Clinical classification
MCI Outcomes
Etiology
Degen- erative
Vascular
Psychiatric
Med Cond
Single domain AD
Depr
Amnestic MCI
Multiple domain
VCI
Clinical classification
Single domain
FTD
Non- amnestic MCI
Multiple domain
DLB CP

31. Clinical classification
MCI Outcomes
Etiology
Degen- erative
Vascular
Psychiatric
Med Cond
Single domain AD
Depr
Amnestic MCI
Multiple domain
VCI
Clinical classification
Single domain
FTD AD
Non- amnestic MCI
DLB AD
Multiple domain CP

32. Mild Cognitive Impairment Ronald C. Petersen, MD, PhD
N Engl J Med 2011:

33. The Diagnosis of Mild Cognitive Impairment Due to Alzheimer’s Disease: Recommendations from the National Institute on Aging-Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease
Marilyn S. Albert, Steven T. DeKosky, Dennis Dickson, Bruno Dubois, Howard H. Feldman, Nick C. Fox, Anthony Gamst, David M. Holtzman, William J. Jagust, Ronald C. Petersen, Peter J. Snyder, Maria C. Carrillo, Bill Thies, Creighton H. Phelps
Alz and Dementia, 2011

34. MCI Criteria Incorporating Biomarkers
Biomarker Neuronal probability A injury (tau, Diagnostic category of AD etiology (PET or CSF) FDG, sMRI)
MCI
Uninformative
Conflicting/indeterminant
Untested
Intermediate Positive Untested
MCI due to AD – intermediate likelihood
Intermediate Untested Positive
Highest Positive Positive
MCI due to AD – high likelihood
Lowest Negative Negative
MCI – unlikely due to AD

35. CASE

36. Case Study 64-year-old right-handed man Accompanied by his wife
Has master’s degree and worked as an engineer designing computer chips
Voluntarily retired at age 62

37. History (1)
Over the past 1-2 years, patient and wife had noticed gradual change in cognition
Increasing forgetfulness and word-finding difficulties
Daily functioning normal
On recent trip, had confusion regarding instructions
Ultimately able to complete the tasks
Adult children noticed he had been behaving differently than in the past

38. History (2) Groping for words in midsentence Lost interest in reading
Reading skills preserved
Driving without difficulty
Handling family’s finances although somewhat more slowly
Preserved insight into his difficulties
Wife noted he would repeat himself, having forgotten the answer to a previous question

39. Medical History Medical Conditions
Sleep apnea for the past three years, using CPAP regularly, improved alertness
Mild hypertension
Mild hyperlipidemia
Medications
Amlodipine, 5 mg
Rosuvastatin (Crestor), 40 mg daily
Metoprolol
Supplements: Fish oil, calcium and multivitamin

40. Neuropsychiatric Mood appropriate, not depressed
Some increase in irritability particularly when aware of forgetfulness

41. Family History Father alive at 91 with moderate dementia for 6-8 years
Mother died age 83, had Parkinson’s disease for 15 years
Two maternal uncles and four maternal aunts cognitively impaired in their 80s and 90s
Maternal grandparents lived into 90s with some degree of cognitive impairment
Two brothers and one sister alive and well, but younger

42. Neurological
BP 118/62
Kokmen Short Test of Mental Status, 36/38 (MMSE = 29/30)
General neurologic exam unremarkable
With normal and symmetrical reflexes, normal strength and sensation, no extrapyramidal features or eye movement abnormalities

43. Neuropsychological Exam
Standard scores: Age and education, mean = 10, SD = 3
Dementia Rating Scale: 143/144
Premorbid Intelligence Estimate: 113 (mean 100)
Memory
Logical Memory – Immediate recall: 26; Delayed recall: 18; 69% retention
Auditory Verbal Learning Test: Trials 1-5: 4, 6, 6, 8, minute delayed recall 3
Attention/concentration
Trail Making Test Part A, SS = 6; Part B, SS = 7
Stroop: Word, SS = 9, Color, SS = 7, Color-Word, SS = 10
Language
Controlled Oral Word Association, SS = 10
Boston Naming Test, SS = 9
Visuospatial Functioning
Rey O Figure, SS = 9

44. Diagnosis?

45. Amnestic Mild Cognitive Impairment

46. MRI

47. Amyloid (PiB) PET

48. Tau (AV 1451) PET

49. Do the Criteria Work? In the General Population
Mayo Clinic Study of Aging (MCSA)

50. Mayo Olmsted County Study of Aging
(U01 AG006786) CP

51. Mayo Clinic Study of Aging
Population-based study of (2800 active) nondemented persons age years in Olmsted County, MN

52. MCSA Cycles of Recruitment and Follow-Up
70 Years Old
2004
2006
2008
2010
2012
2014
2016
October
Enrollment
F-U Cycle 2
F-U Cycle 3
F-U Cycle 4
F-U Cycle 5
F-U Cycle 6
F-U Cycle 7
50-69 Years Old
F-U Cycle 8
F-U Cycle 9, 10
2012
2013
2014
2015
2016
2017
Enrollment
F-U Cycle 2
30-49 Years Old
F-U Cycle 3
F-U Cycle 4
2015
2016
2017
2018
Enrollment
F-U Cycle 2

53. Evaluation Consent form Blood draw Clinical evaluation
Nurse/SC interview
Neurological evaluation
Cognitive assessment
Participant
Family history
Current medications
Demographic information
Memory & orientation
Medical history & risk assessment
Neuropsychiatric inventory
Study partner
Clinical dementia rating
Functional assessment (FAQ)
Neurological history
Short test of mental status
Modified Hachinski scale
Prime MD (physician form)
Neurological examination and modified UPDRS
Memory
Logical memory (delayed)
Visual reprod (delayed)
AVLT
Executive function
Trails A & B
Digit symbol substitution
Visuospatial
Picture completion
Block design
Language
Boston naming test
Category fluency
Consensus conference

54. Resources Acquired 5000+ non-demented subjects 80% Cognitively normal
18% MCI
2% Demented
5800 quantitative MRI scans
~ 5000 DNA samples
~ 5000 frozen plasma/serum samples
plus annual samples
Clinical and performance measures

55. Continuation of MCSA Add new subjects to cohort (500?)
Continue annual clinical follow-ups
Continue serial MRI/PET scans
Collect annual plasma/serum
Collected 1200 CSF’s
Performed 2800 FDG-PET scans
Performed 2800 PiB PET scans
Performed 1100 tau PET scans

56. So, How Do the Criteria Fare in the General Population?

57. Biomarker Prevalence

58. Mayo Clinic Study of Aging
Positive
Negative
Biomarker Result
Yes No
Biomarkers
SpAim 1b
SpAim 1a - 2a,b
SpAim 3 3a 3b 3c
Refuse
Participate
Olmsted County Population

59. Assessing Biomarkers in the Community
Biomarker negative (A- N-)
Amyloid neg
FDG PET/MRI neg
Amyloid positive Neurodeg neg (A+ N-)
Amyloid pos
Amyloid pos Neurodeg pos (A+ N+)
FDG PET/MRI pos
Neurodegen only (A- N+) (SNAP)

60. Preclinical AD

61. Preclinical AD Diagnostic category A (PET or CSF) Neuronal injury
Stage 1
Positive
Negative
Stage 2
Stage 3
Stage 0
Sperling et al: 2011

62. Preclinical Stage %
Preclinical AD stage

63. Clinical disease stage
NIA-AA Preclinical AD Staging in Relation to Our Hypothetical Model of Biomarkers
Preclinical Stage 1 2 3
Abnormal
43%
16%
12% 3% A
Neuronal injury
Cognitive symptoms
Biomarker magnitude
Cut points
Normal
Cognitively normal
MCI
Dementia
Clinical disease stage
Jack et al: Lancet Neuro, 2010

64. Preclinical Alzheimer’s Disease and Its Outcome: A Longitudinal Cohort Study
Stephanie J. B. Vos; Chengjie Xiong; Pieter Jelle Visser; Mateusz S. Jasielec; Jason Hassenstab; Elizabeth A. Grant; Nigel J. Cairns; John C. Morris; David M. Holtzman; Anne M. Fagan
Lancet Neurology, 12:957, Oct., 2013

65. Pre-Clinical AD Stages Neuroimaging vs CSF
MCSA, Jack et al, 2012
Vos et al, 2013 %
Petersen: Lancet Neurol, 2013

66. Progression to CDR >/= 0.5 by Preclinical Alzheimer’s Disease Stage
Normal
Stage 1
Stage 2
Stage 3
SNAP Group
St 3
Cumulative incidence probability
St 2
St 1
SNAP NL
Follow-up (years)
Vos et al: Lancet Neurol 12:957, 2013

67. Biomarker Behavior in the Population

68. Assessing Biomarkers in the Community
Biomarker negative (A- N-)
Amyloid neg
FDG PET/MRI neg
Amyloid positive Neurodeg neg (A+ N-)
Amyloid pos
Amyloid pos Neurodeg pos (A+ N+)
FDG PET/MRI pos
Neurodegen only (A- N+) (SNAP)

69. Population Frequencies of Biomarkers in Typical AD
A-N-
A+N-
A-N+
A+N+
Frequency (%)
Age (years)
Jack et al: Lancet Neurol 13:997, 2014

70. Cumulative Incidence of MCI All
1.0
A+N+
A+N–
A–N+
A–N–
0.8
0.6
Fraction progressed
0.4
0.2
0.1 70 75 80 85 90
Age

71. Rates of Progression from CN to MCI Expressed as Number of Events per 100 Person Years Overall

72. MCI Due to AD

73. Clinical disease stage
Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade A
Tau-meditated neuronal injury and dysfunction
Brain structure
Abnormal
Memory
Clinical function
Biomarker magnitude
Normal
Cognitively normal
MCI
Dementia
Clinical disease stage
Jack et al: Lancet Neurol 2010

74. MCI Due to AD Diagnostic category Biomarker probability of AD etiology
A (PET or CSF)
Neuronal injury (tau, FDG, sMRI)
MCI
Uninformative
Conflicting/ indeterminant or unavailable
MCI due to AD – intermediate likelihood
Intermediate Intermediate
Positive Untested
Untested Positive
MCI due to AD – high likelihood
Highest
Positive
MCI – unlikely due to AD
Lowest
Negative
Albert et al: 2011

75. Assessing Biomarkers in the Community
Biomarker negative (A- N-)
Amyloid neg
FDG PET/MRI neg
Amyloid positive Neurodeg neg (A+ N-)
Amyloid pos
Amyloid pos Neurodeg pos (A+ N+)
FDG PET/MRI pos
Neurodegen only (A- N+) (SNAP)

76. All MCI MCSA Population Frequencies%
Biom neg
Amyloid only
Amyloid + neurodeg
Neurodeg only
sNAP
Petersen et al: Ann Neuro , 2013

77. Practical Stuff

78. CLINICAL TRIALS IN MCI Sponsor Duration Endpoint Drugs
ADCS 3 yr AD Vitamin E Donepezil
Merck 3-4 yr AD Rofecoxib
Novartis 4 yr AD Rivastigmine
Janssen 2 yr AD Galantamine
Pfizer 6 mo Symptoms Donepezil
UCB 1 yr Symptoms Piracetam
Cortex 4 wks Symptoms Ampakine

79. MCI Clinical Trials
Subjects Duration Progression Compound (no.) (mo) rate/yr (%) Outcome
Rivastigmine 1, Neg
Galantamine Neg 1, Neg
Rofecoxib 1, Neg
ADCS Neg* Donepezil Vitamin E
ADNI –
Petersen, Ronald C MN

80. MCI Placebo Subjects in Randomized Controlled Trials

81. Practice Parameter: Early Detection of Dementia: Mild Cognitive Impairment (an Evidence-Based Review)
Report of the Quality Standards Subcommittee of the AmericanAcademy of Neurology
Ronald C. Petersen, PhD, MD; J. C. Stevens, MD; M. Ganguli, MD, MPH; E. G. Tangalos, MD; J. L. Cummings, MD; and S. T. DeKosky, MD CP

82. Publications on MCI
Articles (no.)
1990
Year
2011

83. American Acadmey of Neurology
Practice Parameter on MCI
Petersen et al., Neurology, in press

84. Coding for MCI

85. (ICD 9)331.83; (ICD 10) G31.84 Mild cognitive impairment
Coding for MCI
Nervous System (Medical) Codes
(ICD 9)331.83; (ICD 10) G31.84 Mild cognitive impairment

86. DSM 5

87. Mild Neurocognitive Disorder (MCI)
Major Neurocognitive Disorder (Dementia)
Cognition
Independence
1. Cognitive decline
2. Single cognitive domain impaired (usually)
3. Preservation of independence
1. Cognitive decline
2. Significant cognitive impairment in one or more often multiple cognitive domains
3. Loss of independence

88. NCD Etiologies Alzheimer’s Disease Frontotemporal degen
Lewy body disorders
Vascular cognitive imp
Traumatic brain injury
Substance/medications
HIV/AIDS
Prion disorders
Parkinson’s disease
Huntington disease
Other medical issues
Multiple causes

89. Prodromal AD Amnestic MCI Biomarker support Amyloid PET
CSF amyloid and tau

90. Mild Cognitive ImpairmentNo
Non-amnestic MCI
Cognitive complaint
Not normal for age
Not demented
Cognitive decline
Essentially normal functional activities
Yes
Amnestic MCI
MCI
Memory impaired?
Single domain
Multiple domain
MCI Criteria
Key Symposium
JIM, 2004
Mild Neurocognitive Disorder
DSM-5
No or conflicting Ab or MRI or FDG PET or tau
Uncertain
MCI due to AD
Plus biomarker for Ab
MRI or FDG PET or tau OR
Intermediate
Plus biomarker for Ab
MRI or FDG PET or tau
High
AND
Plus biomarker for Ab or tau/Ab
Prodromal AD
Petersen et al., J Int Med, 2013

91. But… Life is not simple

92. Tau PET
Clinically Normal 84-yo
AD Dementia 71-yo

93. Amyloid/Tau/Neurodegeneration a descriptive classification scheme for AD biomarkers Adding Tau as a Biomarker

95. AD Biomarker Combinations+ + – A T N + – – A
Amyloid T
TAU N
Neurodegeneration

96. ATN Biomarker Grouping
B-amyloid plaques (A)
CSF Ab 42 (low), or better low 42/40 ratio
Amyloid PET
Aggregated tau (T)
CSF phosphorylated tau (high)
Tau PET
Neuronal injury and neurodegeneration (N)
Structural MRI
FDG PET
CSF total tau (high)

97. TAU PET Medial Temporal
PIB-
PIB+
Dementia
2.0 CN
MCI
1.5
Tau PET SUVR
1.0

98. TAU PET Inferior Temporal
3.0
PIB-
PIB+
Dementia
2.5
MCI
2.0
Tau PET SUVR CN
1.5
1.0

99. TAU PET Lateral Temporal
3.0
PIB-
PIB+
Dementia
2.5
MCI
2.0
Tau PET SUVR
1.5 CN
1.0

100. 2.2
2.2
2.0
2.0
1.8
1.8
1.6
1.6
Tau PET, SUVR
1.4
1.4
1.2
1.2
1.0
1.0 CN
MCI
Dementia
CN A–
CN A+
MCI A–
MCI A+
Dem A+

101. Memory z-score

102. ATN Framework Summary Now can address defining features of AD in life
Plaques - amyloid
Tangles - tau
Temporal course variable
Correlation with clinical spectrum to be determined

103. Alzheimer’s Disease New Conceptualization
Alzheimer’s Disease refers to the underlying presence of plaques (amyloid) and neurofibrillary tangles (tau)
Clinical spectrum is parallel but separate from “Alzheimer’s Disease”
Cognitively normal-MCI-dementia
Alzheimer’s disease is no longer a clinical- pathological entity

104. How Early Can We Diagnose Alzheimer’s Disease?
Clinical spectrum
Sensitive tools and criteria
for Preclinical-MCI stages
Pathophysiology
Biomarkers
Imaging
CSF

105. But…

106. But, at the end of the day…

107. Aβ TDP-43 Tau Clinical Spectrum Alpha Synuclein Other Vascular Disease
Alzheimer’s Disease Aβ
TDP-43
Hippocampal
sclerosis
Tau
Clinical Spectrum
CN – MCI – Dementia
Alpha Synuclein
Other
Vascular Disease

108. Clinical Pathology Biomarker Therapy Aβ TDP-43 Tau Clinical Spectrum
Rx?
PET/CSF
Rx?
Rx?
?CSF Aβ
PET/CSF
TDP-43
Hippocampal
Sclerosis
Tau
Clinical
Pathology
Biomarker
Therapy
Clinical Spectrum
CN – MCI – Dementia
Alpha Synuclein
Other
Vascular Disease
?CSF ?
Rx?
Rx?
MRI
Rx?

109. Future Directions
Alzheimer’s disease as we know it today will only be part of the total clinical/pathological picture We will describe clinical syndrome and associate a variety of contributing etiologies Treat our patients with combination therapies depending on the biomarker/pathological profile

110. Mayo Clinic AD Research
Rochester
Brad Boeve
Dave Knopman
Cliff Jack
Val Lowe
Bob Ivnik
Glenn Smith
Michelle Mielke
Rosebud Roberts
Walter Rocca
Shane Pankratz
Jenny Whitwell
Kejal Kantarci
Joe Parisi
Eric Tangalos
Jacksonville
Neill Graff-Radford
Steve Younkin
Dennis Dickson
John Lucas
Tanis Ferman
Rosa Rademakers
Nilufer Taner-Erketin
Len Petrucelli
Gojuin Bu
Otto Pedraza
Scottsdale
Rick Caselli
Bryan Woodruff
Yonas Geda

111. Thank You