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

Definition Domains of dementia Epidemiology Causes Pathology of dementias Treatment Evolving directions

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)

Attention (impaired in delirium) Digit span Concentration

Memory impairment Orientation (time, place) 3 word learning test with delayed recall

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)

Mini-Mental Status Examination (MMSE)Montreal Cognitive Assessment (MoCA)Neuropsychological assessmentDementia is under-recognized

Assumed to be normal aging No mental status examination done

Nerve Cell Death

Cognitive ImpairmentCognitive

ImpairmentFunctional ImpairmentFunctional Impairment

Behavioral Abnormalities

Behavioral Abnormalities

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

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)

% ofPopulation

WithDementia

Age

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 factors Age ApoE-4 genotype Female gender Hypertension, elevated cholesterol Head trauma

Protective factors Education Exercise Mental activity

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

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

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

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

Alzheimer’s disease Brain atrophy Neuritic plaques▪ Amyloid beta protein

Neurofibrillary tangles▪ Hyperphosphorylated tau protein

Loss of nerve cells

NormalAlzheimer’s Disease

Neuritic Plaque

Neurofibrillary Tangle

ADNormal

Histopathology of Alzheimer’s Disease

Vascular dementia Ischemic white matter lesions Small infarctions in basal ganglia, thalamus,

white matter Large infarctions

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

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

Cholinesterase inhibitors (ChE-Is) Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Razadyne)

NMDA receptor antagonist Memantine (Namenda)

Symptomatic effectsMild improvement and delay of decline

Cognition Function (activities of daily living) Behavior Global measures

Many patients are treated (off label) with psychotropic agents

Antidepressants Atypical antipsychotics

Care of the caregiver is an important aspect of patient management

Side effectsCholinesterase inhibitors

Diarrhea Nausea, vomiting

Memantine Headache Dizziness Somnolence

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

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

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

MCINormal

FDG PET Shows Reduced Brain Metabolism in the Parietal Lobes

Klunk WE, et al. Ann Neurol. 2004;55:306-319.

PIB = PittsburghCompound B; amyloidimaging

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

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

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

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