Mild and Major Cognitive Impairments in the Elderly: Diagnostic Considerations and Implications for Capacity

1. Mild and Major Cognitive Impairments in the Elderly: Diagnostic Considerations and Implications for Capacity David Loewenstein PhD, ABPP/CN Professor of Psychiatry, Miller School of Medicine, University of Miami

2. Growing Older In America The population of the United States is growing older and living longer than ever before

3. The United States population is growing older • In 2000 the number of older adults (age 65 or above) in the United States was estimated to be 35 million • In 2030 it is estimated that there will be greater than 71 million older adults • Age is the greatest risk factor for cognitive impairment and for conditions such as Alzheimer’s disease (AD)

4. Cognition and Aging • Memory and cognition change as we get older • Basic processes of change in cognitive aging: • Changes in brain structure and chemistry

5. Cognitive Abilities Preserved in Healthy Older Adults (Rubert, Loewenstein, and Eisdorfer, 2001) • Attention Span • Remote or Tertiary Memory • Everyday Communication Skills • Lexical, Phonological and Syntactic Knowledge • Discourse Comprehension • Simple Visual Perception

6. Cognitive Abilities That Decline as a Function of Aging (Rubert, Loewenstein and Eisdorfer, 2001) • Verbal Fluency • Confrontation Naming of Low Frequency Stimuli • Selective Attention • Cognitive Flexibility and Shifting Cognitive Sets • Complex Visuoconstructive Skills • Complex Logical Analysis • Perceptual Speed Tasks

7. Cognitive Decline in the Older Adult It is essential to be able to differentiate between normal aging and mild cognitive impairment since the latter may represent the earliest manifestations of early neurodegenerative disease

8. What happens?

9. Dementia: Scope of the Problem • In 2010 35.6 million older adults across the globe are living with dementia (predominantly Alzheimer’s disease) By 2030- estimated 65.7 million cases By 2059- estimated 115.4 million cases • The total estimated worldwide costs of dementia in 2010 are US $604 billion • Source: World Alzheimer’s Association (2010)

10. Earliest Manifestations of AD • One of the earliest manifestations of AD is subtle changes in cognitive function • Memory deficits are typically among the earliest deficits observed in AD but atypical presentations have been observed (i.e., dysexecutive function, language disturbance, spatial deficits)

11. GOALS OF THIS PRESENTATION • To become familiar with the definitions of dementia and mild cognitive impairment (MCI) as contrasted by the normal aging process • Know the etiological considerations (e.g. Alzheimer's disease) that may underlie cognitive impairment in the elderly • Examine types of cognitive domains that may be affected in older age (e.g. memory, executive function and problem-solving, language) • Explore how cognitive impairment may affect decision-making capacity

12. Let’s Try to Keep those Memories

13. DSM-IV Criteria for Dementia • A. The development of multiple cognitive deficits manifested by both • 1) memory impairment • 2) one or more cognitive disturbances (aphasia, apraxia, agnosia, disturbance in executive function) • B. Cognitive deficits cause significant impairment which represents decline in social and occupational function • C. Deficits do not occur exclusively during the course of a delirium

14. Alzheimer’s disease Over 5.5 million people in the United States are currently afflicted with Alzheimer’s Disease Greatest risk factor is age (Risk at 85 Years of Age as High as 35%-50%) There is presently no cure, only mild amelioration of symptoms

15. Probable ALZHEIMER’S DISEASE: CLINICAL DIAGNOSIS- NINCDS-ADRDA Criteria (McKhann et al., 1984) • Dementia • Diagnosis of exclusion (Approximately 85% accuracy)- Rule out other disorders, such as stroke, Parkinson’s, and ‘reversible’ conditions, such as drug side-effects • Clinical features: -Onset is insidious, course is gradually progressive; memory deficits early; depression often early • Behavioral symptoms such as delusions, agitation and wandering commonly occur later • Average duration is 8-10 years, with great variation (1 to 25 years)

16. NEUROPATHOLOGY OF ALZHEIMER’S Plaques Tangles

17. AD and the Brain Beta-amyloid Plaques Amyloid precursor protein (APP) is the precursor to amyloid plaque. 1.APP sticks through the neuron membrane. 2.Enzymes cut the APP into fragments of protein, including beta-amyloid. 3.Beta-amyloid fragments come together in clumps to form plaques. 1. 2. In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex. 3. Slide 17

18. AD and the Brain Neurofibrillary Tangles Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.

20. Progressive Atrophy of ERC & HPC Young Aged (control) MCI Mild AD

21. Sagittal MRI: Progressive HPC/ Amygdala Atrophy

22. [11C] PIB and PET:In Vivo Imaging of β-Amyloid Plaques Sagittal Axial PIB = Pittsburgh compound-B; PET = positron emission tomography. Image courtesy of William E. Klunk, MD, PhD, and Chet Mathis, PhD. Source: Klunk WE et al. Ann Neurol. 2004;55:306-319.

23. Prediction of Progression of MCI Based on amyloid imaging using PIB 82% of 11 C-PIB positive subjects with MCI progressed to AD in three years Okello A, Koivunen J, Brooks DJ, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: An 11C-PIB PET study Neurology 2009

24. Amyloid Plaques Are Not Seen Only in Clinical AD Significant Amyloid Plaques Are Seen Postmortem in Older Nondemented Subjects • 27% (age ≥ 75 years; Price & Morris, 1999) • 45% (age ≥ 66 years; Hulette CM et al, 1998) • 29% (age ≥ 65 years; Tomlinson BE et al, 1968) • 34% (mean age, 85 years; Katzman R et al, 1988) • ~33% (age ≥ 47 years; Braak & Braak, 1991) Sources: Price JL, Morris JC. Ann Neurol. 1999;45:358-368. Hulette CM et al. J Neruopathol Exp Neurol. 1998;57:1168-1174. Tomlinson BE et al. J Neurol Sci. 1968;7:331-356. Katzman R et al. Ann Neurol. 1988;23:138-144. Braak H, Braak E. Acta Neuropathol (Berl). 1991;82:239-259.

25. COULD THOSE WITH NORMAL COGNITION ACTUALLY HAVE EARLY AD DUE TO COGNITIVE RESERVE? • Alzheimer’s Pathology is seen on autopsy among 30% of subjects who are not cognitively impaired in their lifetime. • This raises the possibility that those with high cognitive reserve may be able to handle increased amyloid load and subsequent early neurodegeneration without exhibiting symptoms

26. FACTORS THAT INCREASE THE PROBABILITY THAT MCI REPRESENTS EARLY ALZHEIMER’S DISEASE • Atrophy of the hippocampus and particularly the entorhinal cortex • PET Scan amyloid imaging or FDG • CSF levels of AB 42 and tau • Homozygous for the ApoE allele (4/4) or Heterozygous for the ApoE allele

27. Vascular Dementia: L Frontal Infarct

28. Microvascular Disease of the Brain

29. NOT ALL MCI REPRESENTS ALZHEIMER’S DISEASE • Neuropsychologist Must Insure That Sensory Deficits (Hearing and Vision Loss) Are Not Mistaken for MCI • Anxiety/ Depression/ Stress and Cultural Factors Need To Be Accounted For With Regards To Impact On Cognitive Performance • Degenerative: Lewy Body Disease; Fronto-Temporal Dementia • Vascular: Strokes, TIAs, Vasculitis • Toxic/ Metabolic/Endocrine (Drugs, Alcohol, Thyroid) • Space Occupying Lesions (Tumors, Subdural Hematomas Hydrocephalus)

30. Therapeutic Implications of Disease Course Normal Prodromal Prevent Onset Clinical Dementia Slow Progression CognitiveFunction Treat Symptoms & Slow Decline Disease Progression

31. MILD COGNITIVE IMPAIRMENT CRITERIA (Petersen et al., 2001 – Neurology) • Memory complaint, preferably corroborated by an informant • Objective memory impairment • Normal general cognitive function • Intact activities of daily living • Not demented

32. WHEN IS MCI EARLY ALZHEIMER’S DISEASE? • Morris (2001) 100% of MCI patients in memory disorders clinic progressed to dementia over a 9.5 year period (84% met neuropathological pathological criteria for AD) • Reviewing of epidemiological studies, reversion rate of MCI to normal is as much as 30% (see Brooks and Loewenstein,2010; Ganguli et al., In Press)

33. MILD COGNITIVE IMPAIRMENTCONVERSION TO DEMENTIA

34. MCI was expanded by Petersen (2003) to include non-amnestic and multiple cognitive domains The number of persons with MCI in the US age 70 and above is estimated to be between 5 and 6 million Plassman et al Annals of Internal Medicine 2008

35. WHAT IS THE BEST WAY TO ASSESS COGNITIVE AND FUNCTIONAL CAPACITY? • Neuropsychological Testing Supervised by an Experienced Clinical Neuropsychologist • Neuropsychology is the Study of Brain Function Through Cognitive and Behavioral Testing

36. What is a Neuropsychologist? • Generally a PhD or equivalent in Clinical Psychology • One Year Clinical Internship with Primary Emphasis in Neuropsychology • One to 2 Year Post-doctoral Fellowship in Neuropsychology

37. PURPOSES OF NEUROPSYCHOLOGY • To assess whether there is a cognitive deficit • To determine the nature and extent of cognitive impairment (i.e., memory, language, executive function) • To determine how these cognitive impairments relate to diagnosis of brain disease (more sensitive than neuroimaging in many conditions) • To plan for treatment and/or remediation

38. REAL LIFE APPLICATIONS OF NEUROPSYCHOLOGICAL TESTING • Treatment plan after head injury or stroke • Determine whether there are subtle cognitive deficits ( surgeon with aneurysm clipping) • Determining capacity to return to work • Diagnosis of early neurodegenerative disease from pure affective or anxiety disorders affecting cognition

39. Ms. B • Referred for Evaluation • 3rd Grade education • Depressed • Sister is sure that she is having significant memory deficits, brother is sure that she is normal, children are not sure • Does she have early Alzheimer’s disease?

40. Advantages of Neuropsychological Testing • Objective • Compared to Age and Education Related Normative Data • Patterns of Strengths and Weaknesses can give information about diagnosis and treatment

41. Domains of Function Assessed By the Neuropsychologist • MEMORY • LANGUAGE (Expressive and Receptive) • VISUOSPATIAL SKILLS • EXECUTIVE FUNCTION • ATTENTION • PROCESSING SPEED • SENSORY MOTOR SKILLS

42. Anatomy of Memory Bilateral damage to the hippocampus results in anterograde amnesia (Patient H.M.)

43. Three Stages of Memory • Stage 1-Sensory Memory is a brief representation of a stimulus while being processed in the sensory system • Stage 2 -Short-Term Memory (STM) is working memory • Limited capacity (7 items) • Duration is about 30 seconds • Stage 3 - Long-Term Memory (LTM) is large capacity and long duration

44. TYPES OF TESTS THAT ARE GIVEN • Tests of Learning Over Multiple Trials (Serial Position effects, learning curves, immediate versus delayed recall, recognition memory) • Memory for Passages (Immediate and delayed) • Visual Reproduction (Immediate and delayed)

45. Items To Be Recalled On an Object Memory Test

46. Language • Confrontation Naming (Boston Naming Test) • Semantic Fluency (Animals, Fruits, Vegetables) • Letter Fluency • Reading, Repetition, Writing, Calculations • Receptive Language (Token Test, Simple and more complex commands)

47. Visuospatial Skills/Praxis • Block Design • Object Assembly • Copying simple and more complex geometric designs

48. Executive Function • Abstract Reasoning (Similarities) • Concept Formation and Shifting Cognitive Sets (Wisconsin Card Sorting Test, Stroop Color Word Interference, Trailmaking Test)

49. Attention • Span (Digits Forwards and Backwards) • Vigilance (Continuous Performance Test) • Divided Attention • Visual Tracking • Auditory Tracking

50. Sensory/Motor • Grooved Pegboard • Finger Tapping • Grip Strength • Finger Gnosis • Sensory Perceptual Examination