jeffrey cummings, md mary s. easton center for alzheimer’s disease research deane f. johnson...
TRANSCRIPT
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Jeffrey Cummings, MDMary S. Easton Center for Alzheimer’s Disease ResearchDeane F. Johnson Center for NeurotherapeuticsDavid Geffen School of Medicine at UCLALos Angeles, California, USA
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Definition Domains of dementia Epidemiology Causes Pathology of dementias Treatment Evolving directions
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Memory impairment Impairment in one other cognitive domain
(aphasia, apraxia, agnosia, executive dysfunction)
Acquired (not presented throughout life)Disabling (occupational, social)Not present only during deliriumNot attributable to a primary psychiatric
illness (e.g., major depression, schizophrenia, etc)
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Attention (impaired in delirium) Digit span Concentration
Memory impairment Orientation (time, place) 3 word learning test with delayed recall
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Language Spontaneous speech Naming Comprehension (1,2,3 step command) Repetition
Visuospatial skills Copy figures (overlapping pentagons, cube) Draw a clock
Executive function Judgment, insight Word list generation (animals named per minute)
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Mini-Mental Status Examination (MMSE)Montreal Cognitive Assessment (MoCA)Neuropsychological assessmentDementia is under-recognized
Assumed to be normal aging No mental status examination done
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Nerve Cell Death
Cognitive ImpairmentCognitive
ImpairmentFunctional ImpairmentFunctional Impairment
Behavioral Abnormalities
Behavioral Abnormalities
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Cognitive ImpairmentCognitive
ImpairmentFunctional ImpairmentFunctional Impairment
Behavioral Abnormalities
Behavioral Abnormalities
Impairment of:Memory
LanguageJudgment
Impairment of:Memory
LanguageJudgment
Loss of:IndependencePersonal CareRelationships
Loss of:IndependencePersonal CareRelationships
AgitationDepressionIrritability
AgitationDepressionIrritability
Nerve Cell Death
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AD is a Progressive, Fatal Illness
(Year 0 – all patients were mild (blue; not shown); Comm – community mild (blue), moderate (red), severe (yellow); nh-nursing home; from Neumann PJ et al. Neurology 2001; 57: 957-964)
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% ofPopulation
WithDementia
Age
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US 5.5 million Alzheimer’s disease patients 2030 – 7.8 million AD patients $148 billion now $1 trillion annually by 2050
Global 35 million AD patients 2-30 – 65 million AD patients
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Risk factors Age ApoE-4 genotype Female gender Hypertension, elevated cholesterol Head trauma
Protective factors Education Exercise Mental activity
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Alzheimer’s disease (55-70% of late-onset dementia)
Vascular dementia Parkinson’s disease with dementia and related
disorders Dementia with Lewy bodies (DLB)
Pathology of Parkinson’s disease and Alzheimer’s disease Frontotemporal dementia (FTD) Misc: trauma, alcohol, B12 deficiency,
hypothyroidism, HIV, etc
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History Current symptoms Past history and treatments Family history
Laboratory tests B12 level Thyroid stimulating hormone (TSH) CBC, electrolytes, , blood sugar, BUN, liver
function tests Brain imaging
MRI or CT
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Dementia established by mental status examination
Dementia established by mental status examination
Laboratory TestsLaboratory Tests Hypothyroidism, B12 deficiency
Hypothyroidism, B12 deficiency
HistoryHistory Trauma, alcoholism, etcTrauma, alcoholism, etc
Focal neurol signs; + MRI
Focal neurol signs; + MRI
Vascular dementia, focal lesion
Vascular dementia, focal lesion
ParkinsonismParkinsonism Parkinson’s disease, DLB, PD+
Parkinson’s disease, DLB, PD+
None of the aboveNone of the above AD, frontotemporal dementia
AD, frontotemporal dementia
Atypical findingsAtypical findings Creutzfeldt-Jakob disease, etc
Creutzfeldt-Jakob disease, etc
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Memory impairment Impairment in one other cognitive domain
(aphasia, apraxia, agnosia, executive dysfunction)
Acquired (not presented throughout life)Disabling (occupational, social)Gradually progressiveNot present only during deliriumNot attributable to a primary psychiatric
illness or other cause of dementia
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Alzheimer’s disease Brain atrophy Neuritic plaques▪ Amyloid beta protein
Neurofibrillary tangles▪ Hyperphosphorylated tau protein
Loss of nerve cells
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NormalAlzheimer’s Disease
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Neuritic Plaque
Neurofibrillary Tangle
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ADNormal
Histopathology of Alzheimer’s Disease
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Vascular dementia Ischemic white matter lesions Small infarctions in basal ganglia, thalamus,
white matter Large infarctions
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Dementia with Lewy bodies (DLB) and PD dementia Alpha-synuclein Lewy bodies in brainstem,
cortex Limited AD-type pathology in most
Frontotemporal dementia Tau protein inclusions TDP-43 protein inclusions Other
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Protein Inclusions
Tau/TDP-43• Frontotemporal dementia• Progressive supranuclear palsy• Corticobasal degen.
Amyloid• AD• Dementia with
Lewy bodies
Alpha-synuclein• Parkinson’s disease• Dementia with
Lewy bodies• Multiple system
atrophy
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Cholinesterase inhibitors (ChE-Is) Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Razadyne)
NMDA receptor antagonist Memantine (Namenda)
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Symptomatic effectsMild improvement and delay of decline
Cognition Function (activities of daily living) Behavior Global measures
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Many patients are treated (off label) with psychotropic agents
Antidepressants Atypical antipsychotics
Care of the caregiver is an important aspect of patient management
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Side effectsCholinesterase inhibitors
Diarrhea Nausea, vomiting
Memantine Headache Dizziness Somnolence
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Dementia Treatment
Parkinson’s disease Rivastigmine (FDA approved); psychotropics
Vascular dementia ChE-Is (off label); psychotropics; control risk factors (hypertension, cholesterol)
Dementia with Lewy bodies ChE-Is (0ff label); psychotropics
Frontotemporal dementia Memantine (off label); psychotropics
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Dementias are preceded by states of mild cognitive impairment
Memory impairment without functional loss
Not all MCI progresses to dementia Some are stable in MCI state Some improve Some progress to AD (60% of MCI) Some progress to non-AD dementias
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Memory impairment Progressive Not attributable to another cause (e.g.,
hypothyrodism) Biomarker evidence of AD as the cause of the
“MCI” Medial temporal atrophy on MRI Parietal hypometabolism on FDG PET (bilateral) Positive amyloid imaging CSF with low amyloid and high tau/p-tau levels
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MCINormal
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FDG PET Shows Reduced Brain Metabolism in the Parietal Lobes
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Klunk WE, et al. Ann Neurol. 2004;55:306-319.
PIB = PittsburghCompound B; amyloidimaging
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Anti-amyloid therapies Gamma secretase inhibitors (decrease production) Aggregation inhibitors (prevent toxicity) Immunotherapies (passive; vaccination)(remove
deposits) Tau-related therapies Neuroprotective agents
Latreperdine/dimebon Anti-oxidants
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Amyloid Precursor ProteinAmyloid Precursor Protein
Aggregated AßAggregated Aß
Neurofibrillary tangles, mitochondrial dysfunction,
oxidation, synaptic dysfunction, neuronal loss
Neurofibrillary tangles, mitochondrial dysfunction,
oxidation, synaptic dysfunction, neuronal loss
New Therapies Address the Neurobiology
of AD
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Amyloid Precursor ProteinAmyloid Precursor Protein
Aggregated AßAggregated Aß
Neurofibrillary tangles, mitochondrial dysfunction,
oxidation, synaptic dysfunction, neuronal loss
Neurofibrillary tangles, mitochondrial dysfunction,
oxidation, synaptic dysfunction, neuronal loss
Aß Aggregation: Aß Removal
Aß Aggregation: Aß Removal
Mitochondrial Function; Oxidation; Inflammation;
Neuroprotection
Mitochondrial Function; Oxidation; Inflammation;
Neuroprotection
Aß ProductionAß Production
New Therapies Address the Neurobiology
of AD
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Dementia is common among the elderly and growing in frequency
Dementia requires memory loss, loss in another cognitive domain and functional impairment
Dementia has many causesAlzheimer’s disease is the most common
cause of dementiaAD is treated with cholinesterase
inhibitors and memantine