1 / 71

MILD COGNITIVE IMPAIRMENT DIFFERENTIAL DIAGNOSIS

MILD COGNITIVE IMPAIRMENT DIFFERENTIAL DIAGNOSIS. J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California May 14, 2004. MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology) (Petersen et al., 2001 – Neurology 56:1133).

salena
Download Presentation

MILD COGNITIVE IMPAIRMENT DIFFERENTIAL DIAGNOSIS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. MILD COGNITIVE IMPAIRMENTDIFFERENTIAL DIAGNOSIS J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California May 14, 2004

  2. MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology)(Petersen et al., 2001 – Neurology 56:1133) • Memory complaint, preferably corroborated by an informant • Objective memory impairment • Normal general cognitive function • Intact activities of daily living • Not demented - Earlier descriptions by: Jonker, Hooyer, 1990 Flicker, Ferris, Reisberg, 1991 Zaudig, 1992

  3. MILD COGNITIVE IMPAIRMENT ISSUES IN DEFINITION(Petersen et al., 2001 – Neurology 56:1133)

  4. Yesavavage et al., 2002 Markov Chain model

  5. ALZHEIMER’S DISEASE AAMI / MCI DEMENTIA Ashford et al., 1995

  6. Age-Associated Memory ImpairmentvsMild Cognitive Impairment • Memory declines with age – need to consider relative to APOE genotype! • Age - related memory decline corresponds with atrophy of the hippocampus • Older individuals remember more complex items and relationships • Older individuals are slower to respond • Memory problems predispose to development of Alzheimer’s disease • Thus --- screening for MCI / early AD must consider age! • And should consider APOE genotype!

  7. Early Recognition of AD: Consensus Statement(AAGP, AGS, Alzheimer’s Association) • AD continues to be missed as diagnosis • AD is unrecognized and under-reported • patients do not realized • families tend to compensate • Effective treatment and management techniques are available • (AChEIs FDA approved) • Several other approaches are beneficial Small et al., JAMA, 1997

  8. DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE(DSM-IV, APA, 1994) A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS 1. MEMORY IMPAIRMENT 2, OTHER COGNITIVE IMPAIRMENT B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN IN SOCIAL OR OCCUPATIONAL ACTIVITIES C. COURSE SHOWS GRADUAL ONSET AND DECLINE D. DEFICITS ARE NOT DUE TO: 1. OTHER CNS CONDITIONS 2. SUBSTANCE INDUCED CONDITIONS F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM G. ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER

  9. Differential Diagnosis: Top Ten (commonly used mnemonic device: AVDEMENTIA) 1. Alzheimer Disease (pure ~40%, + mixed~70%) 2. Vascular Disease, MID (5-20%) 3. Drugs, Depression, Delirium 4. Ethanol (5-15%) 5. Medical / Metabolic Systems 6. Endocrine (thyroid, diabetes), Ears, Eyes, Environ. 7. Neurologic (other primary degenerations, etc.) 8. Tumor, Toxin, Trauma 9. Infection, Idiopathic, Immunologic • Amnesia, Autoimmune, Apnea, AAMI • VA – consider PTSD, Gulf War Syndrome

  10. Dementia Definition • Multiple Cognitive Deficits: • Memory dysfunction • especially new learning, a prominent early symptom • At least one additional cognitive deficit • aphasia, apraxia, agnosia, or executive dysfunction • Cognitive Disturbances: • Sufficiently severe to cause impairment of occupational or social functioning and • Must represent a decline from a previous level of functioning

  11. Alzheimer’s Disease versus Dementia • 50 - 70% of dementias are AD • Probable AD - 30% of cases, 90% correct • 20% have other contributing diagnoses • Possible AD - 40% of cases, 70% correct • 40% have other contributing diagnoses • Unlikely AD - 30% of cases, 30% are AD • 80% have other contributing diagnoses

  12. Vascular Dementia(DSM-IV - APA, 1994) • Multiple Cogntive Impairments • Memory Impairment • Other Cognitive Disturbances • Deficits Impair Social/Occupational • Focal Neurological Signs and Symptoms or Laboratory Evidence Indicating Cerebrovascular Disease Etiologically Related to the Deficits • Not Due to Delirium

  13. Factors Associated with Multi-infarct Dementia • History of stroke (especially in Nursing Home) • Followed by onset of dementia within 3 months • Abrupt onset, Step-wise deterioration • Cardiovascular disease - HTD, ASCVD, & Atrial Fib • Depression (left anterior strokes), personality change • More gait problems than in AD • MRI evidence of T2 changes (?? Binswanger’s disease) • Basal ganglia, putamen • Periventricular white matter • SPECT / PET show focal areas of dysfunction • Neuropsychological dysfunctions are patchy

  14. Post-Cardiac Surgery • 53% post-surgical confusion at discharge (delirium) • 42% impaired 5 years later (dementia) • May be related to anoxic brain injury, apnea • May be related to narcotic/other medication • May occur in those patients who would have developed dementia anyway (? genetic risk) • Cardio-vascular disease and stress may start Alzheimer pathology • Any surgery may have a similar effect related to peri-op or post-op anoxia or vascular stress Newman et al., 2001, NEJM

  15. Drug Interactions • Anticholinergics: amitriptyline, atropine, benztropine, scopolamine, hyoscyamine, oxybutynin, diphenhydramine, chlorpheniramine, many anti-histaminics • May aggravate Alzheimer pathology • GABA agonists: benzodiazepines, barbiturates, ethanol, anti-convulsants • Beta-blockers: propranolol • Dopaminergics: l-dopa, alpha-methyl-dopa • Narcotics: may contribute to dementia

  16. Drug Toxicity • Anti-cholinergic • Peripheral: blurred vision, dry mouth, constipation, urinary obstruction • Central: confusion, memory encoding block • Gaba-agonist: • Muscle relaxant, anti-convulsant, sedative, anti-anxiety, amnesic, confusion • Medication induced electrolyte imbalance • Confusion (watch for in nursing home)

  17. Depression • Onset: rapid • Precipitants: psycho-social (not organic) • Duration: less than 3 months to presentation • Mood: depressed, anxious • Behavior: decreased activity or agitation • Cognition: unimpaired or poor responses • Somatic symptoms: fatigue, lethargy, sleep, appetite disruption • Course: rapid resolution with treatment, but may precede Alzheimer’s disease

  18. Delirium Definition(more often a problem in medical in-patients) • Disturbance of consciousness • i.e., reduced clarity of awareness of the environment with reduced ability to focus, sustain, or shift attention • Change in cognition (memory, orientation, language, perception) • Development over a short period (hours to days), tends to fluctuate • Evidence of medical etiology

  19. Delirium • Susceptibility may be symptom of early dementia, or delirium may predispose to later dementia • Predisposing factors - Age, infections, dementia • Medical conditions • Infections: • G.U. - urinary • Respiratory (URI, pneumonia) • G.I. • Constipation • Drug toxicity • Fracture (especially related to hip fracture)

  20. Ethanol • Possibly Neuroprotective • May not kill neurons directly (?Dietary recommendation?) • Accidents, Head Injury • Dietary Deficiency • Thiamine – Wernicke-Korsakoff syndrome • Hepatic Encephalopathy • Withdrawal Damage (seizures) Delayed Alcohol Withdrawal • Watch for in hospitalized patients • Chronic Neurodegeneration • Cerebellum, gray matter nuclei

  21. Medical / Endocrine • Thyroid dysfunction • Hypothyoidism – elevated TSH • Compensated hypothyroidism may have normal T4, FTI • Hyperthyroidism • Apathetic, with anorexia, fatigue, weight loss, increased T4 • Diabetes • Hypoglycemia (loss of recent memory since episode) • Hyperglycemia • Hypercalcemia • Nephropathy, Uremia • Hepatic dysfunction (Wilson’s disease) • Vitamin Deficiency (B12, thiamine, niacin) • Pernicious anemia – B12 deficiency, ?homocysteine

  22. Eyes, Ears, Environment • Must consider sensory deficits might contribute to the appearance of the patient being demented • Central Auditory Processing Deficits (CAPD) • Hearing problems are socially isolating • Visual problems are difficult to accommodate by a demented patient, ?To do cataract op? • Environmental stress factors can predispose to a variety of conditions • Nutritional deficiencies (tea & toast syndrome)

  23. Neurological Conditions • Primary Neurodegenerative Disease • Diffuse Lewy Body Dementia (? 7 - 50%) • Note relation to Parkinson’s disease, symptoms • Hallucinations, fluctuating course, neuroleptic hypersensitivity) • Fronto-temporal dementia (tau gene) • Impaired attention, behavioral dyscontrol • Decrease blood flow, hypometaboism on SPECT / PET • (Pick’s disease, Argyrophylic grain disease) • Focal cortical atrophy • Primary progressive aphasia (many causes) • Unilateral atrophy, hypofunction on EEG, SPECT, PET • Normal pressure hydrocephalus • Dementia with gait impairment, incontinence • Suggested on CT, MRI; need tap, ventriculography

  24. Other Neurologic Conditions • Subdural hematoma • Huntington’s disease • Creutzfeldt-Jakob disease • Rapid progression • Characteristic EEG changes • Multiple sclerosis • Corticobasal degeneraton • Cerebellar degeneration • Progressive supranuclear palsey

  25. Tumor • Primary brain tumor • Meningioma (treatable) • Glioma (usually not responsive to therapy) • Metastatic brain tumor • Remote effects of carcinoma • Toxins • Heavy metal screen if considered

  26. Trauma • Concussion, Contusion • Occult head trauma if recent fall • Subdural hematoma • Hydrocephalus: • Normal pressure (late effect of bleed) • Dementia pugilistica • Possible contributor to Alzheimer’s disease initiation and progression (? 4% of cases) • Concern re: physical abuse by caretakers

  27. Infectious Conditions Affecting the Brain • HIV • Neurosyphilis • Viral encephalitis (herpes) • Bacterial meningitis • Fungal (cryptococcus) • Prion (Creutzfeldt-Jakob disease); (mad cow disease)

  28. AMNESIC DISORDERDSM-IV • Memory impairment - inability to learn new information, or - Inability to recall previously learned information • Memory disturbance significantly impairs social, occupational function, deterioration from past • Memory not due to delirium, dementia • Physiological basis or substance induced - Distinguish from dissociative disorders, dissociative amnesia, dissociative identity disorders • Specify - Transient – less than 1 month - Chronic - more than 1 month

  29. Causes of Amnesic Disorders • Amnesia • Dissociative: localized, selective, generalized • Organic - damage to CA1 of hippocampus • thiamine deficiency (WKE), hypoglycemia, hypoxia • Epileptic events • Partial complex seizures • Specific brain diseases • Transient global amnesia • Multiple sclerosis

  30. Etiology of Alzheimer’s Disease • Age (initial genesis vs response to stress) • Bigger factor than for mortality • Design in a plastic (memory) system, energy demands • Stressor response (inadequate repair mechanisms) • Trauma (head injury), vascular (stroke), surgery, loss, grief, immunological response, etc. • Genetics (amyloid related) • Familial, early onset: APP (21), PS (14, 1) (less than 5%) • Late onset: APOE e4 (ch19) (40% to 90% of AD) • relation to brain cholesterol metabolism? • APOE e2 may be most protective • many other candidate genes • Relation to vascular factors, cholesterol, BP • Education (? design vs protection) • Environment - diet, exercise, toxin, smoking, infectious agent

  31. Patient initially diagnosed with AD AD Is Often Misdiagnosed Patient’s first diagnosis other than AD 35% 14% 14% No 72% 9% Yes 28% 7% 21% Stroke Dementia (not AD) No diagnosis Depression Normal aging Other Source: Consumer Health Sciences, LLC. Alzheimer’s Caregiver Project. 1999.

  32. AD is Underdiagnosed • Early Alzheimer’s disease is subtle – it is easy for family members and physicians to miss the initial signs and symptoms • Less than half of AD patients are diagnosed • Estimates are that 25% to 50% of cases remain undiagnosed • Undiagnosed AD patients often face avoidable social, financial, and medical problems • Early diagnosis and appropriate intervention may lessen disease burden • No definitive laboratory test for diagnosing AD exists Evans DA. Milbank Quarterly. 1990; 68:267-289

  33. AD Can Be Readily Diagnosed McKhann G et al. Neurology. 1984;34:939-944. Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164. • A diagnosis of Alzheimer’s disease can be made with a high degree of certainty • Using NINCDS-ADRDA criteria, accuracy in autopsy-verified cases is approximately 90% • Diagnosis is a 2-step process: • Detection through screening • Confirmation through patient history and physical, caregiver interview, brain imaging, and appropriate laboratory studies

  34. Assessment History Of The Development Of The Dementia • Ask the Patient What Problem Has Brought Him to See You • Ask the Family, Companion about the Problem • Specifically Ask about Memory Problems • Ask about the First Symptoms • Enquire about Time of Onset • Ask about Any Unusual Events Around the Time of Onset, e.g., stress, trauma, surgery • Ask about Nature and Rate of Progression • Physical Examination • Neurological Examination

  35. RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE • Family history of dementia 3.5 (2.6 - 4.6) • Family history – Downs 2.7 (1.2 - 5.7) • Family history - Parkinson’s 2.4 (1.0 - 5.8) • Maternal age > 40 years 1.7 (1.0 - 2.9) • Head trauma (with LOC) 1.8 (1.3 - 2.7) • History of depression 1.8 (1.3 - 2.7) • History of hypothyroidism 2.3 (1.0 - 5.4) • History of severe headache 0.7 (0.5 - 1.0) • NSAID use or statin use 0.2 (0.05 – 0.83) Roca, 1994, t’Veldt, 2002

  36. FACTORS INFLUENCING ALZHEIMER’S DISEASE(age at onset, rate of progression) • age • sex • genotype (presenilin, APO-E) • education • environment (head injury) • surgery • psychological problems: depression, agitation, anxiety, sleep disturbance • medication

  37. PHYSICAL/NEUROLOGICAL EXAMINATION • CHECK BLOOD PRESSURE • IDENTIFY SYSTEMIC DISORDERS • CRANIAL NERVES • Olfactory dysfunction, poor eye tracking • Check for hearing, vision deficits • SENSORY DEFICITS • Proprioception, vibration • DEEP TENDON REFLEXES • Brisk, check for focal reflexes • PATHOLOGIC REFLEXES • Hyperactive snout reflex, Gegenhalten

  38. 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 DISFUNCTIONS

  39. CURRENT APPROACHES TO SEVERITY ASSESSMENT • MINI-MENTAL STATE EXAM • CLOCK DRAWING • ANIMAL NAMING (1 minute) • MATTIS DEMENTIA RATING SCALE • ALZHEIMER’S DISEASE ASSESSEMENT SCALE (ADAS) • ACTIVITIES OF DAILY LIVING • GLOBAL CLINICAL SCALE • CLINICAL DEMENTIA RATING SCALE • GLOBAL DETERIORATION SCALE / FAST

  40. LABORATORY TESTS (routine) • BLOOD TESTS • electrolytes, liver, kidney function tests, glucose • thyroid function tests (T3, T4, FTI, TSH) • vitamin B12, folate • complete blood count, ESR • VDRL, HIV (if indicated) • EKG (if indicated) • CHEST X-RAY (if indicated) • URINALYSIS • ANATOMICAL BRAIN SCAN – CT (cheapest), MRI

  41. SPECIAL LABORATORY TESTS • FUNCTIONAL BRAIN IMAGING (SPECT, PET) • EEG, Evoked Potentials (P300) • REACTION TIMES (slowed in the elderly, especially when complex response is required • CSF ANALYSIS - ROUTINE STUDIES • ELEVATED TAU (future possible) • DECREASED AMYLOID (future possible) • HEAVY METAL SCREEN (24 hr urine) • GENOTYPING • APO-LIPOPROTEIN-E (for supporting diagnosis) • AUTOSOMAL DOMINANT (young onset)

  42. Justification for Brain Scan in Dementia Diagnosis • Differential Diagnosis: Tumor, Stroke, Subdural Hematoma, Normal Pressure Hydrocephalus, Encephalomalacia • Confirmation of atrophy pattern • Estimation of severity of brain atrophy • MRI shows T2 white matter changes • Periventricular, basal ganglia, focal vs confluent • These may indicate vascular pathology • SPECT, PET - estimation of regions of physiologic dysfunction, areas of infarction • Helps family to visualize problem

  43. Shoghi-Jadid et al., 2002 UCLA compound

  44. 67-year-old control Alzheimer patient PET brain images 2-(4’-methylamino-phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound)

  45. Genes and Alzheimer’s disease(60% - 80 % of causation)(all known genes relate to bamyloid) • Familial AD (onset < 60 y/o) (<5%) • Presenilin I, II (ch 14, 1) • APP (ch 21) • Non-familial (late onset) • APOE • Clinical studies suggest 40 – 50% due to e4 • If e2 is considered, may be 95% of causation • Population studies suggest 10 – 20% cause • Evolution over last 300,000 to 200,000 years • At least 20 other genes

  46. APO-E genotype and AD risk46 Million in US > 60 y/o //// 4 Million have AD(data from Saunders et al., 1993; Farrer et al., 1997) JW Ashford, MD PhD, 2003

  47. Are we ready to do genetic testing to predict AD? • The family members want it • They consider recommendations against genetic testing to be “paternalistic” • Family members can make more powerful financial decisions based on this knowledge than the relevance of insurance companies implementing changes in actuarial calculations • Those at risk can seek more frequent testing • This is the best opportunity for early recognition • Those at risk will be better advocates for research • Specific preventive treatments can be developed for each genetic factor

  48. www.census.gov Total = 281,421,906 >60 = 45,809,291 >65 = 35,003,844 >85 = 4,251,678 >100= 62,545 JW Ashford, MD PhD, 2003

  49. www.cdc.gov JW Ashford, MD PhD, 2003

More Related