DELIRIUM, DEMENTIA, AND AMNESTIC and OTHER COGNITIVE DISORDERS Second Year Medical School J. Wesson Ashford, M.D., Ph.D. U...
Dementia  Definition <ul><li>Multiple Cognitive Deficits: </li></ul><ul><ul><li>Memory dysfunction </li></ul></ul><ul><ul>...
Differential Diagnosis:  Top Ten  (commonly used mnemonic device: AVDEMENTIA) <ul><li>1.   A lzheimer Disease  (pure ~40%,...
Diagnostic  Criteria  For Dementia Of The Alzheimer Type   (DSM-IV, APA, 1994) <ul><li>Multiple Cognitive Deficits </li></...
AAMI / MCI  DEMENTIA ALZHEIMER’S DISEASE
Alzheimer’s  Disease versus  Dementia <ul><ul><li>50 - 70% of dementias are AD </li></ul></ul><ul><ul><li>Probable AD - 30...
Vascular  Dementia (DSM-IV - APA, 1994) <ul><li>Multiple Cogntive Impairments </li></ul><ul><ul><li>Memory Impairment </li...
Factors Associated with Multi-infarct Dementia <ul><li>History of stroke (especially in Nursing Home) </li></ul><ul><ul><l...
 
Post-Cardiac Surgery <ul><li>53% post-surgical confusion at discharge (delirium) </li></ul><ul><li>42% impaired 5 years la...
Drug  Interactions <ul><li>Anticholinergics:  amitriptyline, atropine, benztropine, scopolamine, hyoscyamine, oxybutynin, ...
Drug Toxicity <ul><li>Anti-cholinergic </li></ul><ul><ul><li>Peripheral:  blurred vision, dry mouth, constipation, urinary...
Depression <ul><li>Onset:  rapid </li></ul><ul><li>Precipitants: psycho-social (not organic) </li></ul><ul><li>Duration: l...
Delirium Definition (more often a problem in medical in-patients) <ul><li>Disturbance of consciousness </li></ul><ul><ul><...
Delirium <ul><ul><li>Susceptibility may be symptom of early dementia, or delirium may predispose to later dementia  </li><...
Ethanol <ul><li>Possibly Neuroprotective </li></ul><ul><ul><li>May not kill neurons directly  (?Dietary recommendation?) <...
Medical / Endocrine <ul><li>Thyroid dysfunction </li></ul><ul><ul><li>Hypothyoidism – elevated TSH </li></ul></ul><ul><ul>...
Eyes, Ears, Environment <ul><li>Must consider sensory deficits might contribute to the appearance of the patient being dem...
Neurological Conditions <ul><li>Primary Neurodegenerative Disease </li></ul><ul><ul><li>Diffuse Lewy Body Dementia  (? 7 -...
Other Neurologic Conditions <ul><ul><li>Subdural hematoma </li></ul></ul><ul><ul><li>Huntington’s disease </li></ul></ul><...
<ul><li>Tumor </li></ul><ul><ul><li>Primary brain tumor </li></ul></ul><ul><ul><ul><li>M eningioma (treatable) </li></ul><...
Trauma <ul><ul><li>Concussion, Contusion </li></ul></ul><ul><ul><ul><li>Occult head trauma if recent fall </li></ul></ul><...
Infectious Conditions  Affecting the Brain <ul><ul><li>HIV </li></ul></ul><ul><ul><li>Neurosyphilis </li></ul></ul><ul><ul...
AMNESIC  DISORDER DSM-IV <ul><li>Memory impairment </li></ul><ul><ul><li>-  inability to learn new information, or </li></...
Causes of Amnesic Disorders <ul><li>Amnesia </li></ul><ul><ul><li>Dissociative: localized, selective, generalized </li></u...
Age-Associated Memory Impairment vs Mild Cognitive Impairment <ul><li>Memory declines with age </li></ul><ul><li>Age - rel...
Advances in Alzheimer’s Disease <ul><li>Incidence and prevalence </li></ul><ul><li>Search for etiology, genetics </li></ul...
Total = 281,421,906 >65  =  35,008,753 >85  =  4,256,587
www.cdc.gov
 
 
PREVALENCE  of  AD  <ul><li>Estimated 4 million cases in US (2000) </li></ul><ul><ul><ul><li>(2000  -  46 million individu...
 
 
 
Oeppen & Vaupel, 2002
Oeppen & Vaupel, 2002
 
ECONOMIC IMPACT OF AD <ul><li>2 million AD patients in nursing homes </li></ul><ul><ul><li>Projection to Kentucky – 22,000...
Etiology <ul><li>Age ( initial genesis vs response to stress) </li></ul><ul><ul><li>Bigger factor than for mortality </li>...
RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE <ul><li>Family history of dementia 3.5 (2.6 - 4.6) </li></ul><ul><li>Family ...
NEUROPATHOLOGY OF AD <ul><li>Senile plaques </li></ul><ul><ul><ul><li>beta-amyloid protein (? Primary problem) </li></ul><...
New Neuropath Mechanisms <ul><li>Amyloid PreProtein (APP - ch21) (early changes) </li></ul><ul><ul><li>metabolism occurs o...
 
 
Genes and Alzheimer’s disease (60% - 80 % of causation) (all known genes relate to   amyloid) <ul><li>Familial AD (onset ...
APO-E genotype and AD onset <ul><li>e2  --  7% of the population </li></ul><ul><li>e3  --  78% of the population  </li></u...
APO-E genotype and AD risk 46 Million in US > 60 y/o //// 4 Million have AD (data from Saunders et al., 1993; Farrer et al...
Biopsychosocial  Systems Affected  by  AD (all related to neuroplasticity) <ul><li>Social Systems </li></ul><ul><ul><li>In...
Why Diagnose AD Early? <ul><li>Safety (driving, compliance, cooking, etc.) </li></ul><ul><li>Family stress and misundersta...
Early Recognition of AD: Consensus Statement (AAGP, AGS, Alzheimer’s Association) <ul><li>AD continues to be missed as dia...
Need for Better Screening  and Early Assessment Tools <ul><li>Genetic vulnerability testing </li></ul><ul><li>Early recogn...
Alzheimer Warning Signs Top Ten Alzheimer Association <ul><li>1.  Recent memory loss affecting job </li></ul><ul><li>2.  D...
Need for a Brief Screening Test for Alzheimer’s Disease <ul><li>Recent evidence of benefits of anti-cholinesterase agents ...
Available Screening Tests <ul><li>MMSE  10 -- 15 min </li></ul><ul><ul><ul><li>Too long </li></ul></ul></ul><ul><li>7-Minu...
Ashford et al., 1995
Mini-Mental State Exam items
 
Brief Alzheimer Screening <ul><li>Repeat these three words: “apple, table, penny”. </li></ul><ul><li>So you will remember ...
 
BLT/Ashford Memory Test (to detect AD onset) <ul><li>New test to screen patients for Alzheimer’s disease using the World-W...
Assessment <ul><li>History Of The Development Of The Dementia </li></ul><ul><ul><li>Ask the Patient What Problem Has Broug...
PHYSICAL/NEUROLOGICAL EXAMINATION <ul><li>CHECK BLOOD PRESSURE </li></ul><ul><li>IDENTIFY SYSTEMIC DISORDERS </li></ul><ul...
CURRENT APPROACHES TO SEVERITY ASSESSMENT <ul><li>MINI-MENTAL STATE EXAM </li></ul><ul><li>CLOCK DRAWING </li></ul><ul><li...
NEUROPSYCHOLOGICAL TESTING  (WAIS, WECHSLER) <ul><li>MEMORY: SHORT-TERM, REMOTE </li></ul><ul><li>VERBAL FUNCTION, FLUENCY...
 
LABORATORY TESTS  (routine) <ul><li>BLOOD TESTS </li></ul><ul><ul><li>electrolytes,  liver, kidney function tests, glucose...
SPECIAL LABORATORY TESTS  <ul><li>FUNCTIONAL BRAIN IMAGING  (SPECT, PET) </li></ul><ul><li>EEG,  Evoked Potentials (P300) ...
Justification for Brain Scan in Dementia Diagnosis <ul><li>Differential Diagnosis:  Tumor, Stroke, Subdural Hematoma, Norm...
 
 
 
Ashford et al, 2000
Shoghi-Jadid et al., 2002 UCLA group, J. Amer. Ger. Psych, 2002
2-(4’-methylamino-phenyl)-6-hydroxybenzothiazole  (Pittsburgh Compound) 67-year-old control Alzheimer patient PET brain im...
Are we ready to do genetic testing to predict AD? <ul><li>The family members want it </li></ul><ul><ul><li>They consider r...
BEHAVIORAL PROBLEMS IN DEMENTIA PATIENTS <ul><li>MOOD DISORDERS – depression – early in AD </li></ul><ul><li>PSYCHOTIC DIS...
NEUROPSYCHIATRIC TREATMENTS <ul><li>First  treat  medical  problems </li></ul><ul><li>Second  environmental  interventions...
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  • Neuropsychological Testing (WAIS, WECHSLER) Memory: Short-term, Remote Verbal Function, Fluency Visuo-Spatial Function Attention Executive Function Abstract Thinking Account for Education Account for Prior Dysfunctions
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    1. 1. DELIRIUM, DEMENTIA, AND AMNESTIC and OTHER COGNITIVE DISORDERS Second Year Medical School J. Wesson Ashford, M.D., Ph.D. University of Kentucky VAMC, Lexington February 12, 2003 Slides at: www.medafile.com/demdx03a.ppt
    2. 2. Dementia Definition <ul><li>Multiple Cognitive Deficits: </li></ul><ul><ul><li>Memory dysfunction </li></ul></ul><ul><ul><ul><li>especially new learning, a prominent early symptom </li></ul></ul></ul><ul><ul><li>At least one additional cognitive deficit </li></ul></ul><ul><ul><ul><li>aphasia, apraxia, agnosia, or executive dysfunction </li></ul></ul></ul><ul><li>Cognitive Disturbances: </li></ul><ul><ul><li>Sufficiently severe to cause impairment of occupational or social functioning and </li></ul></ul><ul><ul><li>Must represent a decline from a previous level of functioning </li></ul></ul>
    3. 3. Differential Diagnosis: Top Ten (commonly used mnemonic device: AVDEMENTIA) <ul><li>1. A lzheimer Disease (pure ~40%, + mixed~70%) </li></ul><ul><li>2. V ascular Disease, MID (5-20%) </li></ul><ul><li>3. D rugs, D epression, D elirium </li></ul><ul><li>4. E thanol (5-15%) </li></ul><ul><li>5. M edical / M etabolic Systems </li></ul><ul><li>6. E ndocrine (thyroid, diabetes), E ars, E yes, E nviron. </li></ul><ul><li>7. N eurologic (other primary degenerations, etc.) </li></ul><ul><li>8. T umor, T oxin, T rauma </li></ul><ul><li>9. I nfection, I diopathic, I mmunologic </li></ul><ul><li>10. A mnesia, A utoimmune, A pnea, A AMI </li></ul>
    4. 4. Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994) <ul><li>Multiple Cognitive Deficits </li></ul><ul><li>1. Memory Impairment </li></ul><ul><li>2. Other Cognitive Impairment </li></ul><ul><li>B. Deficits Impair Social/Occupational </li></ul><ul><li>Course Shows Gradual Onset And Decline </li></ul><ul><li>Deficits Are Not Due to: </li></ul><ul><li>1. Other CNS Conditions </li></ul><ul><li>2. Substance Induced Conditions </li></ul><ul><li>E. Do Not Occur Exclusively during Delirium </li></ul><ul><li>F. Not Due to Another Psychiatric Disorder </li></ul>
    5. 5. AAMI / MCI DEMENTIA ALZHEIMER’S DISEASE
    6. 6. Alzheimer’s Disease versus Dementia <ul><ul><li>50 - 70% of dementias are AD </li></ul></ul><ul><ul><li>Probable AD - 30% of cases, 90% correct </li></ul></ul><ul><ul><ul><ul><li>20% have other contributing diagnoses </li></ul></ul></ul></ul><ul><ul><li>Possible AD - 40% of cases, 70% correct </li></ul></ul><ul><ul><ul><ul><li>40% have other contributing diagnoses </li></ul></ul></ul></ul><ul><ul><li>Unlikely AD - 30% of cases, 30% are AD </li></ul></ul><ul><ul><ul><ul><li>80% have other contributing diagnoses </li></ul></ul></ul></ul>
    7. 7. Vascular Dementia (DSM-IV - APA, 1994) <ul><li>Multiple Cogntive Impairments </li></ul><ul><ul><li>Memory Impairment </li></ul></ul><ul><ul><li>Other Cognitive Disturbances </li></ul></ul><ul><li>Deficits Impair Social/Occupational </li></ul><ul><li>Focal Neurological Signs and Symptoms or Laboratory Evidence Indicating Cerebrovascular Disease Etiologically Related to the Deficits </li></ul><ul><li>Not Due to Delirium </li></ul>
    8. 8. Factors Associated with Multi-infarct Dementia <ul><li>History of stroke (especially in Nursing Home) </li></ul><ul><ul><li>Followed by onset of dementia within 3 months </li></ul></ul><ul><li>Abrupt onset, Step-wise deterioration </li></ul><ul><li>Cardiovascular disease - HTD, ASCVD, & Atrial Fib </li></ul><ul><li>Depression (left anterior strokes), personality change </li></ul><ul><li>More gait problems than in AD </li></ul><ul><li>MRI evidence of T2 changes (?? Binswanger’s disease) </li></ul><ul><ul><li>Basal ganglia, putamen </li></ul></ul><ul><ul><li>Periventricular white matter </li></ul></ul><ul><li>SPECT / PET show focal areas of dysfunction </li></ul><ul><li>Neuropsychological dysfunctions are patchy </li></ul>
    9. 10. Post-Cardiac Surgery <ul><li>53% post-surgical confusion at discharge (delirium) </li></ul><ul><li>42% impaired 5 years later (dementia) </li></ul><ul><li>May be related to anoxic brain injury, apnea </li></ul><ul><li>May be related to narcotic/other medication </li></ul><ul><li>May occur in those patients who would have developed dementia anyway (? genetic risk) </li></ul><ul><li>Cardio-vascular disease and stress may start Alzheimer pathology </li></ul><ul><li>Any surgery may have a similar effect related to peri-op or post-op anoxia or vascular stress </li></ul>Newman et al., 2001, NEJM
    10. 11. Drug Interactions <ul><li>Anticholinergics: amitriptyline, atropine, benztropine, scopolamine, hyoscyamine, oxybutynin, diphenhydramine, chlorpheniramine, many anti-histaminics </li></ul><ul><ul><li>May aggravate Alzheimer pathology </li></ul></ul><ul><li>GABA agonists: benzodiazepines, barbiturates, ethanol, anti-convulsants </li></ul><ul><li>Beta-blockers: propranolol </li></ul><ul><li>Dopaminergics: l-dopa, alpha-methyl-dopa </li></ul><ul><li>Narcotics: may contribute to dementia </li></ul>
    11. 12. Drug Toxicity <ul><li>Anti-cholinergic </li></ul><ul><ul><li>Peripheral: blurred vision, dry mouth, constipation, urinary obstruction </li></ul></ul><ul><ul><li>Central: confusion, memory encoding block </li></ul></ul><ul><li>Gaba-agonist: </li></ul><ul><ul><li>Muscle relaxant, anti-convulsant, sedative, anti-anxiety, amnesic, confusion </li></ul></ul><ul><li>Medication induced electrolyte imbalance </li></ul><ul><ul><li>Confusion (watch for in nursing home) </li></ul></ul>
    12. 13. Depression <ul><li>Onset: rapid </li></ul><ul><li>Precipitants: psycho-social (not organic) </li></ul><ul><li>Duration: less than 3 months to presentation </li></ul><ul><li>Mood: depressed, anxious </li></ul><ul><li>Behavior: decreased activity or agitation </li></ul><ul><li>Cognition: unimpaired or poor responses </li></ul><ul><li>Somatic symptoms: fatigue, lethargy, sleep, appetite disruption </li></ul><ul><li>Course: rapid resolution with treatment, but may precede Alzheimer’s disease </li></ul>
    13. 14. Delirium Definition (more often a problem in medical in-patients) <ul><li>Disturbance of consciousness </li></ul><ul><ul><li>i.e., reduced clarity of awareness of the environment with reduced ability to focus, sustain, or shift attention </li></ul></ul><ul><li>Change in cognition (memory, orientation, language, perception) </li></ul><ul><li>Development over a short period (hours to days), tends to fluctuate </li></ul><ul><li>Evidence of medical etiology </li></ul>
    14. 15. Delirium <ul><ul><li>Susceptibility may be symptom of early dementia, or delirium may predispose to later dementia </li></ul></ul><ul><ul><li>Predisposing factors - Age, infections, dementia </li></ul></ul><ul><ul><li>Medical conditions </li></ul></ul><ul><ul><ul><li>Infections: </li></ul></ul></ul><ul><ul><ul><ul><li>G.U. - urinary </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Respiratory (URI, pneumonia) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>G.I. </li></ul></ul></ul></ul><ul><ul><ul><li>Constipation </li></ul></ul></ul><ul><ul><li>Drug toxicity </li></ul></ul><ul><ul><li>Fracture (especially related to hip fracture) </li></ul></ul>
    15. 16. Ethanol <ul><li>Possibly Neuroprotective </li></ul><ul><ul><li>May not kill neurons directly (?Dietary recommendation?) </li></ul></ul><ul><li>Accidents, Head Injury </li></ul><ul><li>Dietary Deficiency </li></ul><ul><ul><li>Thiamine – Wernicke-Korsakoff syndrome </li></ul></ul><ul><li>Hepatic Encephalopathy </li></ul><ul><li>Withdrawal Damage (seizures) Delayed Alcohol Withdrawal </li></ul><ul><ul><li>Watch for in hospitalized patients </li></ul></ul><ul><li>Chronic Neurodegeneration </li></ul><ul><ul><li>Cerebellum, gray matter nuclei </li></ul></ul>
    16. 17. Medical / Endocrine <ul><li>Thyroid dysfunction </li></ul><ul><ul><li>Hypothyoidism – elevated TSH </li></ul></ul><ul><ul><ul><li>Compensated hypothyroidism may have normal T4, FTI </li></ul></ul></ul><ul><ul><li>Hyperthyroidism </li></ul></ul><ul><ul><ul><li>Apathetic, with anorexia, fatigue, weight loss, increased T4 </li></ul></ul></ul><ul><li>Diabetes </li></ul><ul><li>Hypoglycemia (loss of recent memory since episode) </li></ul><ul><li>Hyperglycemia </li></ul><ul><li>Hypercalcemia </li></ul><ul><li>Nephropathy, Uremia </li></ul><ul><li>Hepatic dysfunction (Wilson’s disease) </li></ul><ul><li>Vitamin Deficiency (B12, thiamine, niacin) </li></ul><ul><ul><li>Pernicious anemia – B12 deficiency, ?homocysteine </li></ul></ul>
    17. 18. Eyes, Ears, Environment <ul><li>Must consider sensory deficits might contribute to the appearance of the patient being demented </li></ul><ul><li>Central Auditory Processing Deficits (CAPD) </li></ul><ul><li>Hearing problems are socially isolating </li></ul><ul><li>Visual problems are difficult to accommodate by a demented patient, ?To do cataract op? </li></ul><ul><li>Environmental stress factors can predispose to a variety of conditions </li></ul><ul><li>Nutritional deficiencies (tea & toast syndrome) </li></ul>
    18. 19. Neurological Conditions <ul><li>Primary Neurodegenerative Disease </li></ul><ul><ul><li>Diffuse Lewy Body Dementia (? 7 - 50%) </li></ul></ul><ul><ul><ul><ul><li>Note relation to Parkinson’s disease, symptoms </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hallucinations, fluctuating course, neuroleptic hypersensitivity) </li></ul></ul></ul></ul><ul><ul><li>Fronto-temporal dementia (tau gene) </li></ul></ul><ul><ul><ul><ul><li>Impaired attention, behavioral dyscontrol </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Decrease blood flow, hypometaboism on SPECT / PET </li></ul></ul></ul></ul><ul><ul><ul><ul><li>(Pick’s disease, Argyrophylic grain disease) </li></ul></ul></ul></ul><ul><li>Focal cortical atrophy </li></ul><ul><ul><li>Primary progressive aphasia (many causes) </li></ul></ul><ul><ul><li>Unilateral atrophy, hypofunction on EEG, SPECT, PET </li></ul></ul><ul><li>Normal pressure hydrocephalus </li></ul><ul><ul><li>Dementia with gait impairment, incontinence </li></ul></ul><ul><ul><li>Suggested on CT, MRI; need tap, ventriculography </li></ul></ul>
    19. 20. Other Neurologic Conditions <ul><ul><li>Subdural hematoma </li></ul></ul><ul><ul><li>Huntington’s disease </li></ul></ul><ul><ul><li>Creutzfeldt-Jakob disease </li></ul></ul><ul><ul><ul><li>Rapid progression </li></ul></ul></ul><ul><ul><ul><li>Characteristic EEG changes </li></ul></ul></ul><ul><ul><li>Multiple sclerosis </li></ul></ul><ul><ul><li>Corticobasal degeneraton </li></ul></ul><ul><ul><li>Cerebellar degeneration </li></ul></ul><ul><ul><li>Progressive supranuclear palsey </li></ul></ul>
    20. 21. <ul><li>Tumor </li></ul><ul><ul><li>Primary brain tumor </li></ul></ul><ul><ul><ul><li>M eningioma (treatable) </li></ul></ul></ul><ul><ul><ul><li>Glioma (usually not responsive to therapy) </li></ul></ul></ul><ul><ul><li>Metastatic brain tumor </li></ul></ul><ul><ul><li>Remote effects of carcinoma </li></ul></ul><ul><li>Toxins </li></ul><ul><ul><li>Heavy metal screen if considered </li></ul></ul>
    21. 22. Trauma <ul><ul><li>Concussion, Contusion </li></ul></ul><ul><ul><ul><li>Occult head trauma if recent fall </li></ul></ul></ul><ul><ul><li>Subdural hematoma </li></ul></ul><ul><ul><li>Hydrocephalus: </li></ul></ul><ul><ul><ul><li>Normal pressure (late effect of bleed) </li></ul></ul></ul><ul><ul><li>Dementia pugilistica </li></ul></ul><ul><ul><li>Possible contributor to Alzheimer’s disease initiation and progression (? 4% of cases) </li></ul></ul><ul><ul><li>Concern re: physical abuse by caretakers </li></ul></ul>
    22. 23. Infectious Conditions Affecting the Brain <ul><ul><li>HIV </li></ul></ul><ul><ul><li>Neurosyphilis </li></ul></ul><ul><ul><li>Viral encephalitis (herpes) </li></ul></ul><ul><ul><li>Bacterial meningitis </li></ul></ul><ul><ul><li>Fungal (cryptococcus) </li></ul></ul><ul><ul><li>Prion (Creutzfeldt-Jakob disease); (mad cow disease) </li></ul></ul>
    23. 24. AMNESIC DISORDER DSM-IV <ul><li>Memory impairment </li></ul><ul><ul><li>- inability to learn new information, or </li></ul></ul><ul><ul><li>- Inability to recall previously learned information </li></ul></ul><ul><li>Memory disturbance significantly impairs social, occupational function, deterioration from past </li></ul><ul><li>Memory not due to delirium, dementia </li></ul><ul><li>Physiological basis or substance induced </li></ul><ul><ul><li>- Distinguish from dissociative disorders, dissociative amnesia, dissociative identity disorders </li></ul></ul><ul><li>Specify </li></ul><ul><ul><li>- Transient – less than 1 month </li></ul></ul><ul><ul><li>- Chronic - more than 1 month </li></ul></ul>
    24. 25. Causes of Amnesic Disorders <ul><li>Amnesia </li></ul><ul><ul><li>Dissociative: localized, selective, generalized </li></ul></ul><ul><ul><li>Organic - damage to CA1 of hippocampus </li></ul></ul><ul><ul><ul><li>thiamine deficiency (WKE), hypoglycemia, hypoxia </li></ul></ul></ul><ul><li>Epileptic events </li></ul><ul><ul><li>Partial complex seizures </li></ul></ul><ul><li>Specific brain diseases </li></ul><ul><ul><li>Transient global amnesia </li></ul></ul><ul><ul><li>Multiple sclerosis </li></ul></ul>
    25. 26. Age-Associated Memory Impairment vs Mild Cognitive Impairment <ul><li>Memory declines with age </li></ul><ul><li>Age - related memory decline corresponds with atrophy of the hippocampus </li></ul><ul><li>Older individuals remember more complex items and relationships </li></ul><ul><li>Older individuals are slower to respond </li></ul><ul><li>Memory problems predispose to development of Alzheimer’s disease </li></ul>
    26. 27. Advances in Alzheimer’s Disease <ul><li>Incidence and prevalence </li></ul><ul><li>Search for etiology, genetics </li></ul><ul><li>Understanding pathophysiology </li></ul><ul><li>Better screening tools for early recognition </li></ul><ul><li>Improved diagnosis </li></ul><ul><li>Developing interventions </li></ul><ul><li>Behavioral conditions and management </li></ul>
    27. 28. Total = 281,421,906 >65 = 35,008,753 >85 = 4,256,587
    28. 29. www.cdc.gov
    29. 32. PREVALENCE of AD <ul><li>Estimated 4 million cases in US (2000) </li></ul><ul><ul><ul><li>(2000 - 46 million individuals over 60 y/o) </li></ul></ul></ul><ul><li>Estimated 500,000 new cases per year </li></ul><ul><li>Increase with age (prevalence) </li></ul><ul><ul><li>1% of 60 - 65 (10.7m) = 107,000 </li></ul></ul><ul><ul><li>2% of 65 - 70 ( 9.4m) = 188,000 </li></ul></ul><ul><ul><li>4% of 70 - 75 ( 8.7m) = 350,000 </li></ul></ul><ul><ul><li>8% of 75 - 80 ( 7.4m) = 595,000 </li></ul></ul><ul><ul><li>16% of 80 - 85 ( 5.0m) = 800,000 </li></ul></ul>
    30. 36. Oeppen & Vaupel, 2002
    31. 37. Oeppen & Vaupel, 2002
    32. 39. ECONOMIC IMPACT OF AD <ul><li>2 million AD patients in nursing homes </li></ul><ul><ul><li>Projection to Kentucky – 22,000 (6,000 in Eastern KY) </li></ul></ul><ul><li>Nursing homes cost - $120 to $160 per day </li></ul><ul><li>Annualized cost of nursing homes ranges from $40 to $70,000 per year </li></ul><ul><li>Care of AD patients costs $80 billion per year </li></ul><ul><li>With lost wages of patients and families plus costs for non-nursing home patients: </li></ul><ul><ul><li>Total costs: $ 120 billion annually ( Am J Publ Hlth ) </li></ul></ul><ul><ul><li>Projection to Kentucky – $1.5 billion annually! </li></ul></ul>
    33. 40. Etiology <ul><li>Age ( initial genesis vs response to stress) </li></ul><ul><ul><li>Bigger factor than for mortality </li></ul></ul><ul><ul><li>Design in a plastic (memory) system, energy demands </li></ul></ul><ul><ul><li>Stressor response ( adequate repair mechanisms) </li></ul></ul><ul><ul><ul><li>Trauma (head injury), vascular (stroke), surgery, loss, grief, etc. </li></ul></ul></ul><ul><li>Genetics (amyloid related) </li></ul><ul><ul><li>Familial, early onset: APP (21), PS (14, 1) (less than 5%) </li></ul></ul><ul><ul><li>Late onset: APOE e4 (ch19) (?50% of AD) </li></ul></ul><ul><ul><ul><li>relation to brain cholesterol metabolism? </li></ul></ul></ul><ul><ul><ul><li>APOE e2 may be most protective </li></ul></ul></ul><ul><ul><li>many other candidate genes </li></ul></ul><ul><li>Relation to vascular factors, cholesterol, BP </li></ul><ul><li>Education (? design vs protection) </li></ul><ul><li>Environment - diet, exercise, smoking </li></ul>
    34. 41. RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE <ul><li>Family history of dementia 3.5 (2.6 - 4.6) </li></ul><ul><li>Family history - Downs 2.7 (1.2 - 5.7) </li></ul><ul><li>Family history - Parkinson’s 2.4 (1.0 - 5.8) </li></ul><ul><li>Maternal age > 40 years 1.7 (1.0 - 2.9) </li></ul><ul><li>Head trauma (with LOC) 1.8 (1.3 - 2.7) </li></ul><ul><li>History of depression 1.8 (1.3 - 2.7) </li></ul><ul><li>History of hypothyroidism 2.3 (1.0 - 5.4) </li></ul><ul><li>History of severe headache 0.7 (0.5 - 1.0) </li></ul><ul><li>NSAID use or statin use 0.2 (0.05 – 0.83) </li></ul>Roca, 1994, t’Veldt, 2002
    35. 42. NEUROPATHOLOGY OF AD <ul><li>Senile plaques </li></ul><ul><ul><ul><li>beta-amyloid protein (? Primary problem) </li></ul></ul></ul><ul><li>Neurofibrillary tangles </li></ul><ul><ul><ul><li>hyper-phosphorylated tau (loss of synapses, dementia) </li></ul></ul></ul><ul><li>Neurotransmitter losses </li></ul><ul><ul><ul><li>Acetylcholine (Ach) – major loss of nicotinic receptors </li></ul></ul></ul><ul><ul><ul><li>Norepinephrine, serotonin, glutamate, GABAss </li></ul></ul></ul><ul><li>Inflammatory responses </li></ul>
    36. 43. New Neuropath Mechanisms <ul><li>Amyloid PreProtein (APP - ch21) (early changes) </li></ul><ul><ul><li>metabolism occurs on cholesterol “rafts” </li></ul></ul><ul><ul><ul><li>Cholesterol transport by APOE (ch 19) </li></ul></ul></ul><ul><ul><li>alpha-secretase vs beta/gamma secretase metabolism </li></ul></ul><ul><ul><li>influence toward alpha-secretase by Acetylcholine </li></ul></ul><ul><ul><li>gamma-secretase (PreSenilin genes, ch14,1) </li></ul></ul><ul><ul><li>break down - Insulin Degrading Enzyme (ch10), etc. </li></ul></ul><ul><ul><li>prevention of fibril formation by melatonin </li></ul></ul><ul><li>Tau hyperphosphorylation (relation to dementia) </li></ul><ul><ul><li>glycogen-synthase-kinase (GSK) 3-beta </li></ul></ul><ul><ul><li>inhibition by Ach, lithium, valproic acid </li></ul></ul>
    37. 46. Genes and Alzheimer’s disease (60% - 80 % of causation) (all known genes relate to  amyloid) <ul><li>Familial AD (onset < 60 y/o) (<5%) </li></ul><ul><ul><li>Presenilin I, II (ch 14, 1) </li></ul></ul><ul><ul><li>APP (ch 21) </li></ul></ul><ul><li>Non-familial (late onset) </li></ul><ul><ul><li>APOE </li></ul></ul><ul><ul><ul><li>Clinical studies suggest 40 – 50% due to  4 </li></ul></ul></ul><ul><ul><ul><li>Population studies suggest 10 – 20% cause </li></ul></ul></ul><ul><ul><ul><li>Evolution over last 300,000 to 200,000 years </li></ul></ul></ul><ul><ul><li>At least 20 other genes </li></ul></ul>
    38. 47. APO-E genotype and AD onset <ul><li>e2 -- 7% of the population </li></ul><ul><li>e3 -- 78% of the population </li></ul><ul><li>e4 -- 15% of the population </li></ul><ul><li>e3/3 - average age of onset = 74 y/o </li></ul><ul><li>e3/4 and e4/4 average age = 69 y/o </li></ul>
    39. 48. APO-E genotype and AD risk 46 Million in US > 60 y/o //// 4 Million have AD (data from Saunders et al., 1993; Farrer et al., 1997) See: Ashford & Mortimer, 2002, Journal of Alzheimer’s Disease
    40. 49. Biopsychosocial Systems Affected by AD (all related to neuroplasticity) <ul><li>Social Systems </li></ul><ul><ul><li>Instrumental ADLs - Early </li></ul></ul><ul><ul><li>Basic ADLs - Late </li></ul></ul><ul><li>Psychological Systems </li></ul><ul><ul><li>Primary Loss Of Memory </li></ul></ul><ul><ul><li>Later Loss Of Learned Skills </li></ul></ul><ul><li>Neuronal Memory Systems </li></ul><ul><ul><li>Cortical Glutamatergic Storage </li></ul></ul><ul><ul><li>Subcortical (acetylcholine, norepi, serotonin) </li></ul></ul><ul><ul><li>Cellular Plastic Processes </li></ul></ul><ul><ul><ul><li>APP metabolism – early, broad cortical distribution </li></ul></ul></ul><ul><ul><ul><li>TAU hyperphosphorylation – late, focal effect, dementia related </li></ul></ul></ul>
    41. 50. Why Diagnose AD Early? <ul><li>Safety (driving, compliance, cooking, etc.) </li></ul><ul><li>Family stress and misunderstanding (blame, denial) </li></ul><ul><li>Early education of caregivers of how to handle patient (choices, getting started) </li></ul><ul><li>Advance planning while patient is competent (will, proxy, power of attorney, advance directives) </li></ul><ul><li>Patient’s and Family’s right to know </li></ul><ul><li>Specific treatments now available, may delay nursing home placement longer if started earlier </li></ul>
    42. 51. Early Recognition of AD: Consensus Statement (AAGP, AGS, Alzheimer’s Association) <ul><li>AD continues to be missed as diagnosis </li></ul><ul><li>AD is unrecognized and under-reported </li></ul><ul><ul><li>patients do not realized </li></ul></ul><ul><ul><li>families tend to compensate </li></ul></ul><ul><li>Effective treatment and management techniques are available </li></ul>Small et al., JAMA, 1997
    43. 52. Need for Better Screening and Early Assessment Tools <ul><li>Genetic vulnerability testing </li></ul><ul><li>Early recognition (10 warning signs) </li></ul><ul><li>Screening tools (6th vital sign in elderly) </li></ul><ul><li>Positive diagnostic tests </li></ul><ul><ul><li>CSF – tau levels elevated, amyloid levels low </li></ul></ul><ul><ul><li>Brain scan – PET – DDNP, Congo-red derivatives </li></ul></ul><ul><li>Mild Dementia severity assessments </li></ul><ul><li>Detecting early change </li></ul><ul><ul><li>predicting progression, measuring rate </li></ul></ul>
    44. 53. Alzheimer Warning Signs Top Ten Alzheimer Association <ul><li>1. Recent memory loss affecting job </li></ul><ul><li>2. Difficulty performing familiar tasks </li></ul><ul><li>3. Problems with language </li></ul><ul><li>4. Disorientation to time or place </li></ul><ul><li>5. Poor or decreased judgment </li></ul><ul><li>6. Problems with abstract thinking </li></ul><ul><li>7. Misplacing things </li></ul><ul><li>8. Changes in mood or behavior </li></ul><ul><li>9. Changes in personality </li></ul><ul><li>10. Loss of initiative </li></ul>
    45. 54. Need for a Brief Screening Test for Alzheimer’s Disease <ul><li>Recent evidence of benefits of anti-cholinesterase agents in the treatment of mild Alzheimer’s disease </li></ul><ul><ul><li>Improvement of cognition </li></ul></ul><ul><ul><li>Slowing of progression </li></ul></ul>
    46. 55. Available Screening Tests <ul><li>MMSE 10 -- 15 min </li></ul><ul><ul><ul><li>Too long </li></ul></ul></ul><ul><li>7-Minute Screen 7 – 10 min </li></ul><ul><ul><ul><li>Too complex </li></ul></ul></ul><ul><li>Clock Drawing Test 2 – 4 min </li></ul><ul><ul><ul><li>Not sensitive </li></ul></ul></ul><ul><li>Mini-cog 3 – 5 min </li></ul><ul><ul><ul><li>Complex scoring, unclear adequacy </li></ul></ul></ul><ul><li>Memory Impairment Screen 4 min </li></ul><ul><ul><ul><li>Need for slightly shorter, easier test </li></ul></ul></ul><ul><li>(a suitably accurate test that takes less than 2 minutes is not available) </li></ul>
    47. 56. Ashford et al., 1995
    48. 57. Mini-Mental State Exam items
    49. 59. Brief Alzheimer Screening <ul><li>Repeat these three words: “apple, table, penny”. </li></ul><ul><li>So you will remember these words, repeat them again, twice. </li></ul><ul><li>What is today’s date? </li></ul><ul><ul><ul><li>1 point if within 2 days. </li></ul></ul></ul><ul><li>“ Name as many animals as you can in 30 seconds, GO!” </li></ul><ul><ul><ul><li>1 point for naming 10 animals </li></ul></ul></ul><ul><li>“ What were the 3 words I asked you to repeat?” (no prompts) </li></ul><ul><ul><ul><li>1 for each word, </li></ul></ul></ul><ul><li>TOTAL (max = 5) </li></ul><ul><ul><ul><li>A score of 4 or 5 indicate a very low likelihood of dementia. </li></ul></ul></ul><ul><ul><ul><li>A score of 2 or 3 suggests that more testing is needed. </li></ul></ul></ul><ul><ul><ul><li>A score of 0 or 1 indicate a very high likelihood of dementia. </li></ul></ul></ul><ul><ul><ul><li>(palm-pilot scoring under development) </li></ul></ul></ul><ul><li>If score of 2 or 3: </li></ul><ul><ul><li>Spell World Backwards </li></ul></ul><ul><ul><li>Draw a Clock (gives some impression of visuospatial problems) </li></ul></ul><ul><li>If continued difficulties, ask questions about ADLs </li></ul>
    50. 61. BLT/Ashford Memory Test (to detect AD onset) <ul><li>New test to screen patients for Alzheimer’s disease using the World-Wide Web – based testing and CD-distribution </li></ul><ul><li>Test only takes 1-minute </li></ul><ul><li>Test can be repeated often (quarterly) </li></ul><ul><li>Any change over time can be detected </li></ul><ul><li>Test is at: www.ibaglobal.com/BLT </li></ul><ul><li>For info, see: www.medafile.com </li></ul>
    51. 62. Assessment <ul><li>History Of The Development Of The Dementia </li></ul><ul><ul><li>Ask the Patient What Problem Has Brought Him to See You </li></ul></ul><ul><ul><li>Ask the Family, Companion about the Problem </li></ul></ul><ul><ul><li>Specifically Ask about Memory Problems </li></ul></ul><ul><ul><li>Ask about the First Symptoms </li></ul></ul><ul><ul><li>Enquire about Time of Onset </li></ul></ul><ul><ul><li>Ask about Any Unusual Events Around the Time of Onset, e.g., stress, trauma, surgery </li></ul></ul><ul><ul><li>Ask about Nature and Rate of Progression </li></ul></ul><ul><li>Physical Examination </li></ul><ul><li>Neurological Examination </li></ul>
    52. 63. PHYSICAL/NEUROLOGICAL EXAMINATION <ul><li>CHECK BLOOD PRESSURE </li></ul><ul><li>IDENTIFY SYSTEMIC DISORDERS </li></ul><ul><li>CRANIAL NERVES </li></ul><ul><ul><li>Olfactory dysfunction, poor eye tracking </li></ul></ul><ul><ul><li>Check for hearing, vision deficits </li></ul></ul><ul><li>SENSORY DEFICITS </li></ul><ul><ul><li>Proprioception, vibration </li></ul></ul><ul><li>DEEP TENDON REFLEXES </li></ul><ul><ul><li>Brisk, check for focal reflexes </li></ul></ul><ul><li>PATHOLOGIC REFLEXES </li></ul><ul><ul><li>Hyperactive snout reflex, Gegenhalten </li></ul></ul>
    53. 64. CURRENT APPROACHES TO SEVERITY ASSESSMENT <ul><li>MINI-MENTAL STATE EXAM </li></ul><ul><li>CLOCK DRAWING </li></ul><ul><li>ANIMAL NAMING (1 minute) </li></ul><ul><li>MATTIS DEMENTIA RATING SCALE </li></ul><ul><li>ALZHEIMER’S DISEASE ASSESSEMENT SCALE (ADAS) </li></ul><ul><li>ACTIVITIES OF DAILY LIVING </li></ul><ul><li>GLOBAL CLINICAL SCALE </li></ul><ul><li>CLINICAL DEMENTIA RATING SCALE </li></ul><ul><li>GLOBAL DETERIORATION SCALE / FAST </li></ul>
    54. 65. NEUROPSYCHOLOGICAL TESTING (WAIS, WECHSLER) <ul><li>MEMORY: SHORT-TERM, REMOTE </li></ul><ul><li>VERBAL FUNCTION, FLUENCY </li></ul><ul><li>VISUO-SPATIAL FUNCTION </li></ul><ul><li>ATTENTION </li></ul><ul><li>EXECUTIVE FUNCTION </li></ul><ul><li>ABSTRACT THINKING </li></ul><ul><li>ACCOUNT FOR EDUCATION </li></ul><ul><li>ACCOUNT FOR PRIOR DISFUNCTIONS </li></ul>
    55. 67. LABORATORY TESTS (routine) <ul><li>BLOOD TESTS </li></ul><ul><ul><li>electrolytes, liver, kidney function tests, glucose </li></ul></ul><ul><ul><li>thyroid function tests (T3, T4, FTI, TSH) </li></ul></ul><ul><ul><li>vitamin B12, folate </li></ul></ul><ul><ul><li>complete blood count, ESR </li></ul></ul><ul><ul><li>VDRL, HIV (if indicated) </li></ul></ul><ul><li>EKG (if indicated) </li></ul><ul><li>CHEST X-RAY (if indicated) </li></ul><ul><li>URINALYSIS </li></ul><ul><li>ANATOMICAL BRAIN SCAN – CT (cheapest), MRI </li></ul>
    56. 68. SPECIAL LABORATORY TESTS <ul><li>FUNCTIONAL BRAIN IMAGING (SPECT, PET) </li></ul><ul><li>EEG, Evoked Potentials (P300) </li></ul><ul><li>REACTION TIMES (slowed in the elderly, especially when complex response is required </li></ul><ul><li>CSF ANALYSIS - ROUTINE STUDIES </li></ul><ul><ul><li>ELEVATED TAU (future possible) </li></ul></ul><ul><ul><li>DECREASED AMYLOID (future possible) </li></ul></ul><ul><li>HEAVY METAL SCREEN (24 hr urine) </li></ul><ul><li>GENOTYPING </li></ul><ul><ul><li>APO-LIPOPROTEIN-E (for supporting dx) </li></ul></ul><ul><ul><li>AUTOSOMAL DOMINANT (young onset) </li></ul></ul>
    57. 69. Justification for Brain Scan in Dementia Diagnosis <ul><li>Differential Diagnosis: Tumor, Stroke, Subdural Hematoma, Normal Pressure Hydrocephalus, Encephalomalacia </li></ul><ul><li>Confirmation of atrophy pattern </li></ul><ul><li>Estimation of severity of brain atrophy </li></ul><ul><li>MRI shows T2 white matter changes </li></ul><ul><ul><li>Periventricular, basal ganglia, focal vs confluent </li></ul></ul><ul><ul><li>These may indicate vascular pathology </li></ul></ul><ul><li>SPECT, PET - estimation of regions of physiologic dysfunction, areas of infarction </li></ul><ul><li>Helps family to visualize problem </li></ul>
    58. 73. Ashford et al, 2000
    59. 74. Shoghi-Jadid et al., 2002 UCLA group, J. Amer. Ger. Psych, 2002
    60. 75. 2-(4’-methylamino-phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound) 67-year-old control Alzheimer patient PET brain images
    61. 76. Are we ready to do genetic testing to predict AD? <ul><li>The family members want it </li></ul><ul><ul><li>They consider recommendations against genetic testing to be “paternalistic” </li></ul></ul><ul><li>Family members can make more powerful financial decisions based on this knowledge than the relevance of insurance companies implementing changes in actuarial calculations </li></ul><ul><li>Those at risk can seek more frequent testing </li></ul><ul><ul><li>This is the best opportunity for early recognition </li></ul></ul><ul><li>Those at risk will be better advocates for research </li></ul><ul><li>Specific preventive treatments can be developed for each genetic factor </li></ul>
    62. 77. BEHAVIORAL PROBLEMS IN DEMENTIA PATIENTS <ul><li>MOOD DISORDERS – depression – early in AD </li></ul><ul><li>PSYCHOTIC DISORDERS </li></ul><ul><ul><li>Particularly paranoia, e.g, people stealing things </li></ul></ul><ul><li>INAPPROPRIATE BEHAVIORS (sexual </li></ul><ul><li>AGGRESSION: verbal, physical </li></ul><ul><li>PURPOSELESS ACTIVITY: verbal, motor </li></ul><ul><li>MEAL TIME BEHAVIORS </li></ul><ul><li>SLEEP DISORDERS </li></ul>
    63. 78. NEUROPSYCHIATRIC TREATMENTS <ul><li>First treat medical problems </li></ul><ul><li>Second environmental interventions </li></ul><ul><li>Third neuropsychiatric medications </li></ul><ul><ul><li>Cognitive impairment </li></ul></ul><ul><ul><li>Psychotic symptoms </li></ul></ul><ul><ul><li>Depressive symptoms </li></ul></ul><ul><ul><li>Insomnia symptoms </li></ul></ul><ul><ul><li>Anorexia symptoms </li></ul></ul><ul><ul><li>Parkinsonian symptoms </li></ul></ul>
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