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What is Alzheimer’s?What is Alzheimer’s?
David Cravens, MD, MSPH, CMDDavid Cravens, MD, MSPH, CMDAssistant ProfessorAssistant Professor
U of Mo. School of MedicineU of Mo. School of MedicineMedical Director – Lenoir HealthcareMedical Director – Lenoir Healthcare
Alzheimer's DiseaseAlzheimer's Disease
A condition that damages several parts of A condition that damages several parts of the brain the brain
Accounts for the majority of dementia cases Accounts for the majority of dementia cases – Alzheimer’s Type Dementia (50-75 % of cases)Alzheimer’s Type Dementia (50-75 % of cases)– Vascular dementia (10 to 20 %)Vascular dementia (10 to 20 %)– Dementia with Lewy bodies (10 to 15 %)Dementia with Lewy bodies (10 to 15 %)– Frontotemporal dementia (5 to 15 %) Frontotemporal dementia (5 to 15 %)
from Kawas CH. Early Alzheimer's disease. N Engl J Med 2003;349:1058.
FeatureFeature Diagnostic considerationDiagnostic consideration
Abrupt onset Vascular dementia
Stepwise deterioration Vascular dementia
Prominent behavior changes Frontotemporal dementia
Profound apathy Frontotemporal dementia
Prominent aphasia Frontotemporal dementia, vascular dementia
Progressive gait disorder Vascular dementia, hydrocephalus
Prominent fluctuations in levels of consciousness or cognitive abilities
Delirium due to infection, medications, or other causes; dementia with Lewy bodies; seizures
Hallucinations or delusions Delirium due to infection, medications, or other causes; dementia with Lewy bodies
Extrapyramidal signs or gait Parkinsonian syndromes, vascular dementia
Eye-movement abnormalities Progressive supranuclear palsy, Wernicke's encephalopathy
Atypical Features that Suggest a
Diagnosis Other than Alzheimer's Disease
Figure 1. Scans of Patients with Probable Alzheimer's Disease. In Panel A, a magnetic resonance image shows cortical atrophy and ventricular enlargement. In Panel B, a positron-emission tomographic scan shows reduced glucose metabolism in the parietal lobes bilaterally (blue-green) as compared with more normal metabolism in other cortical areas (yellow).
NEJM.Volume 351:56-67 July1,2004. Number 1
Normal aging
http://www.med.harvard.edu/AANLIB/cases/caseNA/pb9.htm
Prevalence & Incidence of SDATPrevalence & Incidence of SDAT
2.3 million (range, 1.09-4.8 million).2.3 million (range, 1.09-4.8 million). Doubles every 5 years after the age of 60 Doubles every 5 years after the age of 60
– 1% among those 60- to 64-years-old1% among those 60- to 64-years-old– Up to 40% of those aged 85 years and older Up to 40% of those aged 85 years and older
More common among women than men by a ratio More common among women than men by a ratio of 1.2 to 1.5of 1.2 to 1.5
360,000 new cases per year360,000 new cases per year– 980 new cases per day or 40 new cases every hour 980 new cases per day or 40 new cases every hour
– Cummings, et.al. Alzheimer DiseaseCummings, et.al. Alzheimer Disease JAMA.JAMA. 2002;287:2335-2338 2002;287:2335-2338
Economic ImpactEconomic Impact
Direct costs for the care of patients in 1991 Direct costs for the care of patients in 1991 were calculated at US $20.6 billionwere calculated at US $20.6 billion
Total cost was calculated to be $76.3 billionTotal cost was calculated to be $76.3 billion Most direct costs of care for patients with Most direct costs of care for patients with
AD are absorbed by the expense of nursing AD are absorbed by the expense of nursing home care, approximately $47,000 per home care, approximately $47,000 per patient per year.patient per year.
Risk FactorsRisk Factors
Age, Female sexAge, Female sex Most potent risk factor - presence of the Most potent risk factor - presence of the
apolipoprotein apolipoprotein ( (APOEAPOE 4) allele.4) allele.– Lifetime risk of AD for an individual Lifetime risk of AD for an individual
without the without the 4 allele is approximately 9% 4 allele is approximately 9% carrying at least 1 carrying at least 1 4 allele is 29% 4 allele is 29%
4 genotype is not sufficiently specific or 4 genotype is not sufficiently specific or sensitive for the diagnosis of AD to allow its sensitive for the diagnosis of AD to allow its use as a diagnostic test use as a diagnostic test
Other Risk Factors Other Risk Factors
Head injuryHead injury Low serum levels of folate and vitamin B12Low serum levels of folate and vitamin B12 Elevated plasma and total homocysteine Elevated plasma and total homocysteine
levelslevels Family history of AD or dementiaFamily history of AD or dementia Fewer years of formal educationFewer years of formal education Lower incomeLower income Lower occupational status Lower occupational status
Lower Risk of ADLower Risk of AD
Higher levels of educationHigher levels of education Moderate levels of daily wine consumptionModerate levels of daily wine consumption Higher levels of fish in the diet Higher levels of fish in the diet
Differences in the prevalence of AD among Differences in the prevalence of AD among population groups worldwide suggest as yet population groups worldwide suggest as yet undisclosed genetic or environmental effects undisclosed genetic or environmental effects on the prevalence of AD on the prevalence of AD
Putative Amyloid Cascade.
•This hypothesis of the amyloid cascade, which progresses from the generation of the beta-amyloid peptide from the amyloid precursor protein, through multiple secondary steps, to cell death, forms the foundation for current and emerging options for the treatment of Alzheimer's disease. APP denotes amyloid precursor protein, and Abeta-amyloid.
Diagnostic CriteriaDiagnostic Criteria
Cognitive impairment severe enough to Cognitive impairment severe enough to cause social or occupational disability in at cause social or occupational disability in at least two domainsleast two domains– MemoryMemory– LanguageLanguage– CalculationsCalculations– OrientationOrientation– Judgment Judgment
8 years average. Range – 2-20 years
MMSEMMSE
Orientation to timeOrientation to time Orientation to placeOrientation to place RegistrationRegistration Attention & CalculationAttention & Calculation RecallRecall LanguageLanguage
5 points5 points 5 points5 points 3 points3 points 5 points5 points 3 points3 points 9 points9 points
MMSEMMSE
Specificity is good (96%) Specificity is good (96%) But the sensitivity is poor (63%)But the sensitivity is poor (63%) Using a standard cutoff score of 24 will leave a Using a standard cutoff score of 24 will leave a
substantial proportion of cases of early dementia substantial proportion of cases of early dementia undetected. undetected.
Asking patients and knowledgeable informants Asking patients and knowledgeable informants about deficits may enhance detection of early about deficits may enhance detection of early stages of AD stages of AD – abnormalities in learning and retaining new informationabnormalities in learning and retaining new information– difficulty handling complex tasksdifficulty handling complex tasks– impaired reasoning abilityimpaired reasoning ability– changes in language or behavioral alterationschanges in language or behavioral alterations
Typical Clinical Syndrome of AD Typical Clinical Syndrome of AD
1.1. Amnestic type of memory defect Amnestic type of memory defect – difficulty learning and recalling new information difficulty learning and recalling new information
2.2. Progressive language disorder Progressive language disorder – beginning with anomia and progressing to fluent beginning with anomia and progressing to fluent
aphasia aphasia
3.3. Disturbances of visuospatial skillsDisturbances of visuospatial skills– manifested by environmental disorientation andmanifested by environmental disorientation and– difficulty copying figures in the course of mental status difficulty copying figures in the course of mental status
examination examination
Typical Clinical Syndrome of ADTypical Clinical Syndrome of AD
4.4. There are usually deficits in executive There are usually deficits in executive function function – PlanningPlanning– InsightInsight– JudgmentJudgment
5.5. The patient is typically unaware of memory The patient is typically unaware of memory or cognitive compromise. or cognitive compromise.
6.6. All cognitive deficits progressively worsen.All cognitive deficits progressively worsen.
Copyright restrictions may apply. Cummings, J. L. et al. JAMA 2002;287:2335-2338.
Morphology and Distribution of Neuritic Plaques and Neurofibrillary Tangles
Pathologic diagnosis of AD require the presence of both neuritic plaques and neurofibrillary tangles in excess of the abundance anticipated for age-matched healthy controls.
Neuritic plaques consist of a central core of amyloid protein surrounded by astrocytes, microglia, and dystrophic neurites often containing paired helical filaments.
Neurofibrillary tangles are the second major histopathological feature of AD. They contain paired helical filaments of abnormally phosphorylated tau protein that occupy the cell body and extend into the dendrites
Treatments for AD Treatments for AD
(Aricept) (Exelon) (Reminyl) (Namenda)
Treatments for AD Treatments for AD
Vitamin E (2000 IU/d) and selegiline (10 mg/d) Vitamin E (2000 IU/d) and selegiline (10 mg/d) have been shown to reduce the rate of decline of have been shown to reduce the rate of decline of functions in patients with AD. functions in patients with AD. – Combined therapy was not superior to either agent Combined therapy was not superior to either agent
alone.alone. Evidence to support the use of other antioxidants, Evidence to support the use of other antioxidants,
anti-inflammatory agents, or herbal medications anti-inflammatory agents, or herbal medications such as ginkgo biloba is insufficient to recommend such as ginkgo biloba is insufficient to recommend use as standard therapies. use as standard therapies.
Estrogen in standard doses has been shown Estrogen in standard doses has been shown notnot to improve cognition in postmenopausal women to improve cognition in postmenopausal women with AD with AD
MemantineMemantine
Primary Efficacy Variables. Primary Efficacy Variables. The mean (±SE) scores at each specified time in the observed-cases analysis are shown. The boxes indicate the The mean (±SE) scores at each specified time in the observed-cases analysis are shown. The boxes indicate the
mean (±SE) at the end point in the analysis with the last observation carried forward in the intention-to-treat mean (±SE) at the end point in the analysis with the last observation carried forward in the intention-to-treat population. Panel A shows the change from base line in the Clinician's Interview-Based Impression of Change population. Panel A shows the change from base line in the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global scores. Panel B shows the change from base line in the Alzheimer's Plus Caregiver Input (CIBIC-Plus) global scores. Panel B shows the change from base line in the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, modified for severe dementia (ADCS-ADLsev). Disease Cooperative Study Activities of Daily Living Inventory, modified for severe dementia (ADCS-ADLsev).
NEJM Volume 348:1333-1341 April 3, 2003. Number 14NEJM Volume 348:1333-1341 April 3, 2003. Number 14
Future HopeFuture Hope
Reducing amyloid production, aggregation, Reducing amyloid production, aggregation, or enhancing its removal are promising or enhancing its removal are promising avenues of treatment that will address the avenues of treatment that will address the basic pathophysiology of AD. basic pathophysiology of AD.
Immunization, secretase inhibition, and Immunization, secretase inhibition, and other strategies to accomplish this are being other strategies to accomplish this are being studied. studied.
Future HopeFuture Hope
Epidemiologic data suggest that some agents may Epidemiologic data suggest that some agents may decrease the likelihood of developing AD. decrease the likelihood of developing AD. – nonsteroidal anti-inflammatory agentsnonsteroidal anti-inflammatory agents– hormonal treatmentshormonal treatments– histamine H2 blockers histamine H2 blockers – antihypertensive agentsantihypertensive agents– statins statins
Clinical trials of these compounds to test their Clinical trials of these compounds to test their roles in the treatment or prevention of AD are roles in the treatment or prevention of AD are planned or under way.planned or under way.
TreatmentTreatment
Building an alliance with family caregivers is critical to Building an alliance with family caregivers is critical to success in the management of patients with AD. success in the management of patients with AD.
Family caregivers provide most of the care received by Family caregivers provide most of the care received by patients with AD over the course of their illness and are patients with AD over the course of their illness and are responsible for ensuring adherence to treatment regimens. responsible for ensuring adherence to treatment regimens.
Caregivers are prone to depression and physical illness as Caregivers are prone to depression and physical illness as a result of the chronic stress associated with caregiving. a result of the chronic stress associated with caregiving.
Families benefit from short-term education programs and Families benefit from short-term education programs and support groups.support groups.
The Alzheimer's Association is an important ally in The Alzheimer's Association is an important ally in identifying and providing community resources for patients identifying and providing community resources for patients with AD and their caregivers. with AD and their caregivers.
Rate of Death from Alzheimer's Disease and Costs Associated with Depression in Family Caregivers, 1979 through 1998.
Age-adjusted, population-based death rates were obtained from the National Center for Health Statistics, Centers for Disease Control and Prevention. The number of caregivers of patients who had Alzheimer's disease and were in the last year of life was estimated on the basis of the death rate among patients with Alzheimer's disease, under the conservative assumption of one family caregiver for each patient who died. The prevalence of depression among caregivers of patients with end-stage Alzheimer's disease is 42.9 percent, as estimated by Schulz et al. The costs associated with depression were derived from estimates reported by Chisholm et al.,1 under the assumption that the cost per case is the same in all years after adjustment for inflation.
NEJM Volume 349:1891-1892 Nov.13, 2003.
SummarySummary
Alzheimer’s is a progressive diseaseAlzheimer’s is a progressive disease Age is the biggest risk factorAge is the biggest risk factor We don’t know what causes itWe don’t know what causes it We can temporarily slow it’s progressionWe can temporarily slow it’s progression We can’t cure itWe can’t cure it Caregivers and support groups are very Caregivers and support groups are very
importantimportant There is always hope for the futureThere is always hope for the future
Questions or Comments?Questions or Comments?
Thanks!Thanks!
