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Jeffrey Cummings, MD Mary S. Easton Center for Alzheimer’s Disease Research Deane F. Johnson Center for Neurotherapeutics David Geffen School of Medicine at UCLA Los Angeles, California, USA. Diagnosis and Management of Alzheimer’s Disease. Dementia. Definition Domains of dementia
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Jeffrey Cummings, MD Mary S. Easton Center for Alzheimer’s Disease Research Deane F. Johnson Center for Neurotherapeutics David Geffen School of Medicine at UCLA Los Angeles, California, USA Diagnosis and Management of Alzheimer’s Disease
Dementia • Definition • Domains of dementia • Epidemiology • Causes • Pathology of dementias • Treatment • Evolving directions
Dementia (DSM-IV) • 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 delirium • Not attributable to a primary psychiatric illness (e.g., major depression, schizophrenia, etc)
Dementia is Recognized by Mental Status Examination • Attention (impaired in delirium) • Digit span • Concentration • Memory impairment • Orientation (time, place) • 3 word learning test with delayed recall
Dementia is Recognized by Mental Status Examination • 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)
Dementia is Recognized by Mental Status Examination • Mini-Mental Status Examination (MMSE) • Montreal Cognitive Assessment (MoCA) • Neuropsychological assessment • Dementia is under-recognized • Assumed to be normal aging • No mental status examination done
Domains of Dementia Nerve Cell Death Cognitive Impairment Functional Impairment Behavioral Abnormalities
Domains of Dementia Nerve Cell Death Cognitive Impairment Functional Impairment Behavioral Abnormalities Impairment of: Memory Language Judgment Loss of: Independence Personal Care Relationships Agitation Depression Irritability
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)
Epidemiology of Dementia % of Population With Dementia Age
Epidemiology of Dementia • 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
Risk and Protective Factors • Risk factors • Age • ApoE-4 genotype • Female gender • Hypertension, elevated cholesterol • Head trauma • Protective factors • Education • Exercise • Mental activity
Causes of Dementia • 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
Evaluation of Dementia to Determine Its Cause • 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
Approaching the Differential Diagnosis of Dementia Dementia established by mental status examination History Trauma, alcoholism, etc Laboratory Tests Hypothyroidism, B12 deficiency Focal neurol signs; + MRI Vascular dementia, focal lesion Parkinsonism Parkinson’s disease, DLB, PD+ None of the above AD, frontotemporal dementia Atypical findings Creutzfeldt-Jakob disease, etc
Diagnosis of Alzheimer’s Disease • Memory impairment • Impairment in one other cognitive domain (aphasia, apraxia, agnosia, executive dysfunction) • Acquired (not presented throughout life) • Disabling (occupational, social) • Gradually progressive • Not present only during delirium • Not attributable to a primary psychiatric illness or other cause of dementia
Pathology of Dementias • Alzheimer’s disease • Brain atrophy • Neuritic plaques • Amyloid beta protein • Neurofibrillary tangles • Hyperphosphorylated tau protein • Loss of nerve cells
Brain Atrophy in Alzheimer’s Disease Normal Alzheimer’s Disease
Histopathology of Alzheimer’s Disease Neurofibrillary Tangle Neuritic Plaque
Histopathology of Alzheimer’s Disease Normal AD
Pathology of Dementias • Vascular dementia • Ischemic white matter lesions • Small infarctions in basal ganglia, thalamus, white matter • Large infarctions
Pathology of Dementias • 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
Pathology of Dementias Protein Inclusions • Tau/TDP-43 • Frontotemporal dementia • Progressive supranuclear palsy • Corticobasal degen. • Amyloid • AD • Dementia with Lewy bodies • Alpha-synuclein • Parkinson’s disease • Dementia withLewy bodies • Multiple system atrophy
Treatment of Alzheimer’s Disease • Cholinesterase inhibitors (ChE-Is) • Donepezil (Aricept) • Rivastigmine (Exelon) • Galantamine (Razadyne) • NMDA receptor antagonist • Memantine (Namenda)
Treatment of Alzheimer’s Disease • Symptomatic effects • Mild improvement and delay of decline • Cognition • Function (activities of daily living) • Behavior • Global measures
Treatment of Alzheimer’s Disease • Many patients are treated (off label) with psychotropic agents • Antidepressants • Atypical antipsychotics • Care of the caregiver is an important aspect of patient management
Treatment of Alzheimer’s Disease • Side effects • Cholinesterase inhibitors • Diarrhea • Nausea, vomiting • Memantine • Headache • Dizziness • Somnolence
Mild Cognitive Impairment (MCI) • 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
New Criteria Allow Diagnosis of AD before Dementia • 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
MRI Demonstrates Brain Atrophy in Early Alzheimer’s Disease Normal MCI
FDG PET Shows Reduced Brain Metabolism in the Parietal Lobes
Amyloid Imaging Shows Deposition of Amyloid in Plaques PIB = Pittsburgh Compound B; amyloid imaging Klunk WE, et al. Ann Neurol. 2004;55:306-319.
Disease-Modifying Therapies are Evolving for Alzheimer’s Disease • 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
New Therapies Address the Neurobiology of AD Amyloid Precursor Protein Aggregated Aß Neurofibrillary tangles, mitochondrial dysfunction, oxidation, synaptic dysfunction, neuronal loss
New Therapies Address the Neurobiology of AD Amyloid Precursor Protein Aß Production Aggregated Aß Aß Aggregation: Aß Removal Neurofibrillary tangles, mitochondrial dysfunction, oxidation, synaptic dysfunction, neuronal loss Mitochondrial Function; Oxidation; Inflammation; Neuroprotection
Summary • 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 causes • Alzheimer’s disease is the most common cause of dementia • AD is treated with cholinesterase inhibitors and memantine