1. Cognitive Impairment and Dementia Debra Bynum, MD Associate Professor of Medicine Division of Geriatric Medicine University of North Carolina

2. Outline What is Mild Cognitive Impairment? What is Dementia? Dementia, Delirium and Depression What are the different types of Dementia? Risk Factors and Prevention Treatment Future Directions Key points

3. What is Dementia I know it when I see it…..?????

4. DSM IV Definition Memory impairment associated with(at least 1): Aphasia (disturbance in language) apraxia (impaired motor ability) agnosia (inability to identify objects) disturbance in executive functioning (ie, planning, organizing, sequencing, and abstracting) Impact social, functional, or occupational activities Decline from a previous level of functioning Does not occur solely in the setting of delirium

5. DSM 5 Definition… Two Biggest Changes Terminology: Minor and major neurocognitive disorder rather than Dementia Does NOT rely on presence of memory impairment

6. Domains of neurocognitive impairment Memory Orientation Language Perceptual

7. Minor neurocognitive disorder Evidence of modest cognitive decline (change from baseline) in at least one domain And a decline in neurocognitive performance testing (1-2 Standard Deviations below norm) Cognitive deficits do not interfere with independence (IADLs or complex activities), but require greater effort or compensatory changes or accommodation to maintain independence Cannot occur exclusively during episode of delirium Not attributable to another disorder such as schizophrenia or major depression

8. Major neurocognitive disorder Substantial cognitive decline (change) in one or more domain based on concerns of individual, informant, or clinician Decline in neurocognitive performance on testing (2 or more Standard Deviations below norm….) Interfere with independence Do not occur exclusively in presence of delirium Not attributable to another disorder (schizophrenia, depression)

9. Assessment Tools Mini Mental Status Exam, 3 item recall Clock drawing Trails B Must have memory changes with other changes (aphasia, apraxia, executive function, etc) MMSE: can be influenced by primary language and educational level!!

10. MMSE Commonly used Limitations: Educational level Language Hearing and sight Does not work as well for people at either end of the “spectrum” -- previously highly functional/well educated or poorly educated/learning problems

11. MOCA Able to more sensitively detect MCI Problem: Includes parts of many other tests we commonly used

12. MMSE Plus Memory disorders clinic Lots of information Often more time consuming

13. Mini-Cog My preferred tool for general use 3 item recall plus clock draw I like to do clock draw on all patients

14. Trails B Good for executive functioning The only test that has any predictive value for driving ability

15. Verbal Fluency Phonetics: F words – frontotemporal dementia Categories (animals, vegetables): Alzheimer’s

16. Key Points…. The score on any assessment or screening instrument (such as the Mini Mental Status Exam) is not a component of the definition of dementia You can have a low MMSE and NOT have dementia, You can have a nearly normal MMSE and HAVE dementia Memory changes MUST impact everyday activities and functional status

17. Mild Cognitive Impairment Memory changes without the significant impact on daily activities, do not meet criteria for dementia but do not have normal cognitive functioning Very mixed group of people who have this label On average, risk of progression from MCI to dementia 10% per year

18. More terms MCI Dementia Delirium Depression

19. Delirium Acute state of confusion Characteristics: Change in consciousness (more agitated or less alert) Inattention, inability to focus Confusion Waxes and wanes

20. Delirium Acute change from baseline Sign of underlying problem Infection (even urinary tract infection, pneumonia) Recent surgery or procedure Medications Pain Sleep deprivation Frequently seen in hospital, change of environment, acute illness (30-40% of hospitalized elders may develop delirium– often missed)

21. Delirium Can be seen in patients with dementia Can be seen in patients without dementia Does not diagnose with dementia Is associated with increased risk of developing dementia

22. Depression Depression in older people can be associated with memory problems and apathy, both symptoms that are also seen in dementia (previously referred to as “pseudodementia”) Depression in later life is associated with an increased risk of developing cognitive impairment and dementia

23. Common Types of Dementia Alzheimer Disease Vascular Dementia Overlap (AD/Vascular) dementia Fronto-temporal dementia Dementia with Lewy Body Dementia due to Parkinson’s Disease Parkinson “Plus” syndromes with dementia Alcohol related dementia Infections: HIV, neurosyphilis, prion disease (mad cow)

24. Alzheimer Disease Gradual short term memory loss Personality changes Visuospatial problems: difficulty with clock drawing, getting lost in previously familiar settings Apraxia : motor problems, affect ability to dress and walk Medial temporal lobe atrophy on MRI Early disease: AD pattern of inheritance Difficulty with naming categories (animals, vegetables)

25. Vascular Dementia Classic: Step wise decline May have associated vascular dementia, vascular parkinson’s May have less visuospatial dysfunction (can copy clock face, but cannot remember how to draw it )

26. Overlap Reality: Most cases of dementia in older patients are mixed AD and Vascular (largest risk factor for both is age) Observations that vascular risk factors increase risk for AD as well as vascular dementia Studies that demonstrate cholinesterase inhibitors work just as well (or poorly) in patients with vascular dementia and AD

27. Frontotemporal Dementia Behavioral symptoms (disinhibition) Executive function problems Language dysfunction (difficulty naming words that begin with certain letter….) Frontal release signs Can occur in patients with motor neuron diseases (ALS) Can have earlier onset and more often familial than AD

28. Dementia with Lewy Body 15-25% cases of dementia in patients >65 Early visual (vivid) hallucinations Prior sleep disorders (may precede dementia by years) Parkinsonian features (not overt tremor, but some stiffness, cogwheeling) More rapid decline Decline with antipsychotics (especially typical agents) Fluctuating course (can resemble delirium with good days and bad days)

29. DSM 5 criteria Core diagnostic features of Lewy body dementia include the following: fluctuating cognition with pronounced variations in attention and alertness; recurrent visual hallucinations that are typically well formed and detailed; and spontaneous features of Parkinsonism with onset at least one year later than the cognitive impairment. Suggestive diagnostic features of Lewy body dementia include the following: rapid eye movement sleep behavior disorder; severe neuroleptic sensitivity; and low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging

30. Dementia with Parkinson’s Disease 30% of patients with PD will develop cognitive decline and dementia Typically dementia comes MUCH later in the course of PD Can have vascular etiology to PD and dementia (may be more acute decline and more resistant to treatment, less response to sinemet and other medications)

31. Parkinson Plus Syndromes Multiple Systems Atrophy/Shy Drager syndrome Some parkinsonian features (stiffness, gait instability) Usually not much of a tremor if any Can be more quickly progressive Associated with significant orthostasis (drop in blood pressure with standing) and other neurological problems (urinary retention causing a bladder that does not work, erectile dysfunction, constipation)

32. Alcohol related dementia Can also have gait/balance problems due to long term effects on cerebellum Memory loss can be associated with elaborate stories and confabulation (Korsakoff’s syndrome) We often underestimate…

33. Infections HIV Neurosyphilis Prion disease (mad cow) Remembering to think about and screen for STD in older people

34. Risk Factors for cognitive decline Age HTN Diabetes, hyperlipidemia, smoking HIV ETOH abuse Prior Severe Head trauma Genetic Factors ApoE gene (variable association, less association with decline in older age) Down syndrome

35. Risk Factors/Associations Late life depression Delirium

36. Prevention No clear evidence to support preventing cognitive decline with Vitamin E, Gingko Biloba, leisure activities, fish oil, estrogen, NSAIDS….. Observational studies looking at lifestyle changes, mental activity (crosswords, puzzles), etc all challenging because of potential selection bias “Vitamin E is a drug looking for a disease….” Dr. Zell Hoole

37. Prevention Most evidence suggestive of preventing future cognitive decline by preventing vascular disease (preventing or treating HTN, hyperlipidemia, obesity, smoking cessation) Biggest impact likely by targeting vascular risk factors in midlife Tightest link between treating HTN and decreasing development of dementia Prevention of both vascular and Alzheimer type dementias

38. Prevention Take home point: exercise, lowering vascular risk factors, basically taking care of yourself in early/mid life decrease your risk for dementia Educational level reported to be protective, but likely more that this serves as a “cushion” Genetics and factors that we still do not understand

39. Treatment Unfortunately, there is NO current treatment that makes dementia better or reverses cognitive impairment Medications that are commonly marketed overall slow the progression of the decline in cognitive function -- patients still get worse over time, but the medications seem to slow the rate Overall the effect on slowing the decline is very very small

40. Treatment options Cholinesterase Inhibitors Donepezil (aricept), galantamine, rivastigmine All are similar in effect All show a small effect to slow the decline of progression and give people a few additional months before the need for nursing home placement

41. Cholinesterase Inhibitors Side effects: Nightmares and sleep problems Urinary incontinence (the opposite effect of ditropan – givs some people urge urinary symptoms) Slow heart rate/bradycardia Nausea, decreased appetite, weight loss

42. Cholinesterase Inhibitors Work just as well (or not as well, depending on your view) in vascular disease as in Alzheimer’s disease (probably because most people actually have mixed pattern of dementia) Approved for use in moderate to severe dementia Some evidence to support use in severe dementia, although benefits seem to trail off No evidence to support use in Mild Cognitive Impairment

43. Memantine NMDA receptor antagonist Small clinical benefit in patients with moderate to severe AD (studies limited) Marginal benefit in patients with mild to moderate AD Marginal benefit in patients with mild to moderate vascular dementia Patients taking memantine were slightly less likely to develop agitation/behavioral symptoms Well tolerated with no significant side effects, but costly

44. ?Combination cholinesterase inhibitors and memantine Study in NEJM 2012: Patients with moderate to severe dementia Previously on donepezil/aricept at least 3 months 4 arms: all placebo, aricept only, both aricept and memantine, only memantine

45. Study results Patients in all groups declined over the year Patients in donepezil only group declined less than other groups Patients in memantine group also declined less than combination or placebo group, but less effect than donepezil Less benefit seen in patients with more severe dementia (basically no change in those patients)

46. Take home from NEJM study Patients taking donepezil, probably ok to continue NO benefit to having patients on both drugs Could consider change to memantine if not tolerating donepezil due to side effects

47. Treatment: other drugs Stopping medications that may be making confusion worse (benadryl, ambien, benzodiazepines) ?statins: Data unclear (some data suggesting statin use prevents future decline of cognitive functioning, some case reports of increased confusion on statins in patients with dementia)

48. Treating behavioral symptoms with dementia Agitation, sundowning, aggressive behaviors can occur with dementia Reflex to treat with psychoactive drugs (antipsychotics such as risperidone/haldol): associated with slight increase risk of mortality and never proven to be of benefit: bottom line, weigh risks and benefits in individual patient

49. Treating depression in patients with dementia Difficult to assess and data unclear Some patients seem to benefit, others do not, weigh risks of antidepressants (side effects, decrease blood pressure when standing, falls, fractures increased with most agents) Dementia: hard to differentiate apathy of dementia from apathy with depression Bottom line: consider trial, but also consider discontinuing, weighing risk of side effects closely

50. Future directions More specific diagnosis with use of imaging, PET scans, CSF and blood work Working within the new criteria of the DSM 5 Treatment options other than cholinesterase inhibitors….

51. Summary Mild cognitive impairment, Dementia, delirium, and depression: separate definitions, all tied together Many different types of dementia, but most commonly people have combination of vascular and alzheimer Risk factors/prevention: primarily CV health! Treatment: still disappointing overall Future directions: more specific and earlier diagnoses, prevention?