Monday, October 26, 2015
Overview of Alzheimer’s Disease and Related Dementias
Ronald C. Petersen, Ph.D., M.D.
Mayo Clinic College of Medicine
Rochester, MN
Dementia
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AD Related Dementias
- Frontotemporal lobar degeneration
- Dementia with Lewy bodies
- Vascular cognitive impairment-dementia
ALZHEIMER’S DISEASE
- Degenerative etiology
- Gradual progression
- Basic neurological exam normal early
- Clinical-pathology correlation 80-90%
Criteria for AD
- National Institute on AgingAlzheimer’s
- Association
- Alzheimers and Dementia, May, 2011
Introduction to the Recommendations from the National Institute onAging-Alzheimer’s Association Workgroups on Diagnostic Guidelinesfor 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
Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade
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Jack et al: Lancet Neurol 2010 |
Prevalence of PiB PET in Normals
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Rowe et al: 2010 |
Biomarkers for AD
- Early biomarkers
- Amyloid deposition
- PET imaging
- CSF amyloid
- Amyloid deposition
- Later biomarkers
- Neurodegeneration
- Structural MRI
- FDG PET
- Tau PET
- CSF tau
- Neurodegeneration
Neuroimaging in AD
Neuroimaging in AD
- Structural MRI
- Functional imaging
- FDG PET
- Molecular imaging
- Amyloid PET imaging
Structural Imaging in AD
Structural MRI: Atrophy and AD Stage
Control, 70, F | MCI, 72, F | AD, 74, F |
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Functional Imaging in AD
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Molecular Neuroimaging
PIB Idealized
CN | aMCI | AD | |
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PIB Examples – Full Spectrum
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Tau PET Imaging
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Alzheimer’s Disease Spectrum
- Preclinical AD
- MCI Due to AD
- Dementia Due to AD
Alzheimer’s Disease Treatments2015
Theoretical Drug Responses
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Alzheimer’s Disease
Course, Prevention, Treatment Strategies
Intervention |
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Clinical state | Normal | Pre-Clinical AD | Mild cognitive impairment | AD Dementia |
Brain pathologic state |
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Mild, moderate or severe impairment |
Strategies |
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Prevent or delay emergence of symptoms |
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Disease progression |
SYMPTOM MODIFYING AGENTS
AD TREATMENTS
- CHOLINESTERASE DRUGS
- DONEPEZIL (ARICEPT)
- RIVASTIGMINE (EXELON)
- GALANTAMINE (RAZADYNE)
- NMDA ANTAGONIST
- MEMANTINE (NAMENDA)
Immunotherapy
- Passive immunization
- Polyclonal antibodies
- IVIG
- Monoclonal antibodies
- bapineuzumab
- solanezumab
- crenezumab
- gantenerumab
- aducanumab
- Polyclonal antibodies
Secretase Inhibition
- Beta secretase inhibitors
- Promising
- Gamma secretase inhibitors
- Challenges
Clinical Trials in the Era of Prevention
API DIAN-TU |
API | A4 | SNIFF |
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Autosomal Dominant 1% of AD | E4/E4 asymptomatc 2% of population | Amyloid Positive asymptom 30% of population aged 65+ | Symptomatic MCI and Dementia 25% of population aged 65+ |
Lifestyle Modifications
Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer's Disease: A Randomized Trial
- Nicola T. Lautenschlager; Kay L. Cox; Leon Flicker; et al.
- JAMA. 2008;300(9):1027-1037 (doi:10.1001/jama.300.9.1027)
Conclusions
- Moderate exercise (150 minutes/wk) resulted in improved cognitive function at 6 months
- Some benefits maintained at 18 mos
So, where are we?
- Clinical Spectrum -- CN - MCI - Dementia
- Aß
- TAU
- Other
- Vascular Disease
- Alpha Synuclein
- TDP-43
Clinical Pathology Biomarker Therapy
- Clinical Spectrum -- CN - MCI - Dementia
- Aß
- PET/CSF
- Rx?
- PET/CSF
- TAU
- PET/CSF
- Rx?
- PET/CSF
- Other
- ?
- Rx?
- ?
- Vascular Disease
- MRI
- Rx?
- MRI
- Alpha Synuclein
- ?CSF
- Rx?
- ?CSF
- TDP-43
- ?CSF
- Rx?
- ?CSF
- Aß
Overall Conclusions
- We can diagnose cognitive impairment fairly well
- Clinical criteria
- Biomarkers
- Screening tools evolving
- Useful in practice
- Therapies being actively pursued
Thank You