1 the dementias william s. woodfin, m.d. neurology specialists of dallas clinical assoc. prof. of...
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The Dementias William S. Woodfin, M.D.
Neurology Specialists of DallasClinical Assoc. Prof. of NeurologyUT Southwestern Medical School
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Definition
Dementia:The development of multiple cognitive deficits suffficiently severe to cause impairment in occupational or social functioning
Mild Cognitive Impairment: usually refers to a single cognitive domain
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Classification
Alzheimer’s Disease: Sporadic v. Familial
Parkinson Syndromes
Fronto-Temporal Lobar
Vascular
Infectious
Metabolic
Pseudodementia
Others
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Differential Diagnosis of Dementia
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DEMENTIA SYNDROMES
Lewy Body Parkinson’s
Disease
MultipleSystem Atrophy
FXTAS
Diffuse Lewy Body
Disease
SupranuclearPalsy
CorticobasalganglionicDegeneration
Alzheimer’sDisease
Fronto-temporalDementia
VascularParkinsonism
TAUOPATHIES α-SYNUCLEINOPATHIES
NormopressureHydrocephalus
Amyloid and Tau
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Alzheimer’sHistory: Alois Alzheimer 1906
Epidemiology: * 4 million pts.
* A disease of advancing age but not normal aging.
Loss vs. shringage of neurons
* Age 60 1%
Age 85 30-50%
* Underdiagnosed
* Women more than men
* Cost $110 billion
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DSM-IV Definition of Alzheimer’s Disease
Development of multiple cognitive deficits manifested by both memory impairment (amnesia) and 1 or more of the following cognitive disturbances: aphasia, apraxia, agnosia, or disturbance in executive functioning (abstractions)
Cognitive deficits cause significant impairment in social functioning and represent a significant decline from a previous level of functioning
Course is gradual in onset with continuingcognitive decline
Deficits are not due to any other CNS disorder, systemic illness, or substance-induced condition
Deficits do not occur exclusively during the courseof delirium
Source: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:85-86.
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Alzheimer’s Disease (AD): More Than Just Memory Loss
AD is a progressive, degenerative disease involving:
A Decline in ability to perform activities of daily living
B Changes in personality and behavior
C Loss of memory and other cognitive functions
D Eventual nursing home placement, death
$ Increases in resource utilization
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0
5
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15
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0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9
Years
MM
SE
sc
ore
Early Diagnosis Mild-Moderate Severe
Cognitive Symptoms
Loss of ADLs
Behavioral Problems
Nursing Home Placement
Death
Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer’s Disease. 1996, 239-253.
Progression of Alzheimer's Disease
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Risk Factors for Alzheimer’s Disease
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Apolipoprotein E
ε 4 allele: a “susceptibility gene” on chromosome 19
single copy→ 2-3 x risk, double copy→ 5 x risk
lowers age of onset
may be assoc. c clearing of Aβ- increased plaques,
but no increase in NFTs
ε 2 allele appears protective
“Not necessary or sufficient”- ½ of AD pts. don’t have
the allele, 10-20% of normal older adults carry one or
two
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Gross Pathology
Temporal lobes esp. hippocampus & entorhinal cortex. Olfactory bulbs and tracts
Parietal lobes
Subcortical nuclei that project to the cortex:
Nucleus Basalis of Meynert (AcH)
Locus ceruleus (NE)
Raphae nuclei (Serotonin)
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Neuropathologic ChangesNeuropathologic ChangesCharacteristic of Alzheimer’s DiseaseCharacteristic of Alzheimer’s Disease
Normal
AP = amyloid plaques.NFT = neurofibrillary tangles.Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation.
AD
AP NFT
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EXTRACELLULAREXTRACELLULAR INTRACELLULARINTRACELLULAR
NORMALNORMAL ALZHEIMER’SALZHEIMER’S
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βaptists v Tauists
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Microscopic Pathology
Amyloid (Senile) Plaques: Extraneuronal
Aβ
Dystrophic axons and dendrites
Astrocytes
Microglia
Neurofibrillary Tangles: Intraneuronal- predominantly
axonal, longer axons
Hyperphosphorylated tau protein
Neuronal loss
Vascular change: Cerebral Amyloid Angiopathy
Aβ 40
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Etiology: Amyloid Hypothesis
Cleavage of transmembranous APP by secretases
Aβ 40 & Aβ 42
Insoluble oligomers
Insoluble fibrils
Diffuse plaque
Mature plaque- due to inflammatory reaction with astrocytes and microglia
Neuronal and synaptic injury
NFTs and Neuronal death
Loss of neurotransmitters
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Evidence for the Amyloid Hypothesis
Aβ neurotoxic in vitro
Overexpression of APP in transgenic mice=disease
Mutations in APP = early onset disease
All known mutations= increased Aβ
Downs Syndrome with 3 copies of APP gene
Apolipoprotein E € 4 accelerated Amyloid deposition
Amyloid antibodies in mice and men slows disease
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Familial Alzheimer’s
Chromosome 14 c presenilin 1 gene
Chromosome 1 c presenilin 2 gene
Both code for a portion of γ-secretase
Chromosome 21 c APP mutations
Onset of sxs. In 40s & 50s
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PET Imaging of Amyloid
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Tau Association With Microtubules
Tau bound to microtubule
Microtubule
Hyperphosphorylated tau subunits
PHF composed of tau subunits
PHF = paired helical filaments.
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Prevention
Anti-Inflammatories
Hormones
Vitamins and Herbs
Diet and Antioxidants
Alcohol and Smoking
Exercise
Basic Medical Care
Blood Pressure
Lipids
Homocystine
Specific Agents
Cholinesterase Inhibitors
NMDA Receptor Blockers
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Anti-Inflammatories
Dutch study, NEJM 2001: RR 0.95 < 1 month
0.83 1-24 months
0.20 > 2 years
No benefit with trials of: Prednisone
Diclofenac
Rofecoxib
Naproxen
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Estrogens
Mechanisms: Estrogen receptors associated with NGF receptors
May enhance neurotransmitter function, esp. Ach
May diminish excitatory effect of Aβ
May alter APP resulting in less Aβ
PET shows increased blood flow and glucose metabolism in hippocampus
Early studies mixed: Prior to 1999, 4 impairment, 7 improvement
WHIMS: Estrogen & Progesterone: Mild increase in stroke and dementia
Estrogen alone: stopped this year, risk of dementia about the same
Would earlier institution of estrogens or longer duration of treatment be useful? Cache Co. Utah study
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Vitamins and Herbs
Vitamin E- No help
Potential toxicity: bleeding, HA,N,V,diarrhea, bone pain, hair loss
Vitamin C- No compelling evidence
Folic Acid- Increasing evidence for protection for AD and VaD
Would use more than 400 mcgm/day
Ginko Biloba- several studies suggest some improvement
St. Johns Wort- caution
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Diet & Antioxidants
Fats: Diets high in unsaturated, unhydrogenated fats and low in saturated/transunsaturated fats may protect against dementia and coronary disease.
Cholesterol: Mixed findings. Dietary cholesterol has less impact on serum cholesterol than does saturated fat intake.
Dietary Flavinoids: May diminish risk
Caloric Intake: Animal studies show all degenerative diseases associated with aging diminish with reduced caloric intake.
Increased oxidative stress and accumulation of free radicals.
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Alcohol & Smoking
Red Wine: 250-500 ml/day may protect
May be due to flavanoids, also found in tea,fruit, and vegetables.
Beer: May worsen odds with low intake of thiamine and other B vitamins
Dangers in the elderly: Lean body mass
Trauma
Interactions with medications
Smoking: Accelerates microvascular cerebral disease
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Exercise
Physical: Decreases glucose and LDL levels, raises HDL
Aerobic vs. anaerobic and frontal lobe function
Mental: Educational attainment
Ongoing cognitive efforts: Nun study- Top 10% were 47% less likely than bottom 10% to become demented.
Sensory support: eyeglasses, hearing aids
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Basic Medical Care
Control of blood pressure and glucose
Statins: Inhibit activity of β and γ secretase
May limit effects of APO € 4 allele
Endothelial remodeling
Increase e NOS
Decrease endothelin-1
PROSPER study (Pravastatin)
HPS study (Simvastatin)
Atorvastatin
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Specific Pharmaceutical Intervention
Cholinesterase Inhibitors: Donepezil (Aricept)
Rivistigmine (Exelon)
Galantamine (Reminyl→Razadyne))
NMDA Inhibitors: Memantine (Namenda)
Considerations in their use: Cognition
Behavior
Activities of Daily Living
Efficacy, Safety, Side Effects and Cost (~$140/mo.)
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Parkinson Syndromes
1)Idiopathic PD:
Up to 40% c dementia; 65% by age 85
3rd leading cause overall
Increases c age at dx., early hallucinosis & advanced motor signs, presence of depression
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Pathological changes are those of Alzheimer’s dis. In addition to the typical pathology of Lewy bodies and neuronal loss in the substantia nigra.
Lewy bodies- intraneuronal, eosinophilic inclusions containing misfolded α-synuclein
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2) Diffuse Lewy Body Disease
Motor sxs, dementia c often striking fluctuation and prominent haullucinosis
Lewy bodies are diffusely distributede in the cerebral cortex
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Fronto-Temporal Lobar
1)Fronto-Temporal Dementia: Characterized by behavioral & executive function changes. 40-50% is familial. 10-20% of all dementias. Earlier age of onset. Atrophy of frontal & temporal poles. Pick bodies- argyrophilic round intraneuronal inclusions composed mainly of abnormal tau proteins. Unresponsive to AChI- tret c SSRIs & ? Memantine.
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2) Primary Progressive Aphasia
Predominantly expressive
Other cognitive domains essentially intact
Focal atrophy seen on imaging
Eventual dementia
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3) Semantic Aphasia
Predominantly a receptive aphasia
Atrophy seen more in parietal and posterior temporal regions
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4) Other Tauopathies
Progressive Supranuclear Palsy (Steele-Richardson-Olsewski Syn.)
Corticobasal ganglionic degeneration
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Vascular
2nd leading cause of dementia
Subtypes: Cortical- large vessel & embolic stroke. Stepwise progression. More severe aphasia. Sensoro-motor abnormalities.
Subcortical- small vessel. Pseudobulbar palsy, gait impairment ( marche à petit pas), urinary incontinence
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Treatment of Vascular Dementia
Attempt to limit progression: Hypertension, diabetes, homocysteine, lipids, cardiac
Cognitive: possibly AChIs & memantine
Behavioral: above + SSRIs
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Alzheimer’sDisease
FTD
Dementia withLewy Bodies
Ischemicvasculardementia
NPH
+
+
+
+
+
MemoryLoss
++
±
–
±
–
ImpairedLanguage
+
–
–
±
–
VisuospatialImpairment
Typical Differential Points of Common Dementias at Initial Presentation
MotorSigns
_
AbnormalBehavior
VascularEvent
_
++
+
+
_ _
+_
+
+
_
_
++
_
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Infectious
Cruetzfeldt-Jacob Disease
Familial
Sporadic
New Variant
Fatal familial insomnia
Gerstmann-Sträussler-Scheinker
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Other Infectious
HIV
GPI
Lyme disease
Fungal
Tuberculous
PML
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Metabolic
Thyroid
B 12
Folate
Thiamine
Hepatic
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Other
Huntington’s disease: irritability, apathy, impulsive behavior, poor personal hygeine, psychosis. Etiol. unclear until chorea appears esp. c spontaneous mutation.
HD gene on chrom. 4 contains trinucleotide repeats,CAG, encoding for glutamine preventing normal turnover of protein, huntingtin, in cytoplasm and nuclei. Abn. aggregation of this protein may→ pathology, cortical 7 subcortical
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Other continued
Tumor
Subdural hematoma
Hydrocephalus
Demyelinating
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Pseudodementia
Probably the most common etiology in the 30-60 patient population
Stress
Depressive disorders
Anxiety disorders
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Clinical Evaluation
History
Neurological Exam
N-P testing
Blood work
Imaging & EEG
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Counseling for Patients & Families
Prognosis re. rate of decline & life expectancy
Patient & family goals for treatment
Review of finances & power of attorney
Medical advance directives
Driving
Home safety
Wandering (www.alz.org/Services/SafeReturn.asp)
Long term care
Resources for family and caregiver includ. Alz. Assoc. & ABA Commission on Legal problems for the Elderly
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