1. Dementia: Diagnosis and Treatment Debra L. Bynum, MD Division of Geriatric Medicine University of North Carolina at Chapel Hill

2. Case Mr. Jones is a 72-year-old gentleman brought to you by his daughter for progressive memory loss. He denies any problems. Previously an accountant, he is now unable to balance his check book. He has had difficulty with getting lost while driving to the store. He was diagnosed with depression two years ago after his wife died. In addition, he has HTN and DM. His father was diagnosed with Alzheimer’s disease at the age of 85. On exam, his BP is 170/90; he is oriented, scores 26/30 on the MMSE (0/3 recall and difficulty with the intersecting pentagon); he is unable to do the clockface. A few months later, his MMSE is 24/30; on exam he has some mild cogwheel rigidity and a slight shuffling gate, but no tremor. His daughter reports that he has been having vivid visual hallucinations and paranoid thought.

3. Questions: 1.What are some limitations to the MMSE? 2.Is there any association between HTN and dementia in the elderly? 3.What are the risk factors for dementia? 4.What type of dementia might Mr. Jones have?

4. Outline Risk factors and definition of dementia Types of dementias MMSE and testing Treatment options

5. Question: What are some risk factors for the development of dementia?

6. Risk Factors for Dementia Age Family hx of AD or Parkinson’s (10-30% risk of AD in patients with first degree relative) Head trauma Depression (?early marker for dementia) Low educational attainment? ?hyperlipidemia ?diabetes HTN !!!

7. Risk Factors for AD Gender (confounding in literature – women more likely to live longer, be older….) Down’s syndrome ?estrogen (probably not) ?NSAIDS (probably not)

8. Question: What is the definition of a dementia? What is the “line” between “normal” memory loss with age and dementia…

9. Cognitive Decline with Aging Mild changes in memory and rate of information processing Not progressive Does not interfere with daily function or independence

10. Mild Cognitive Impairment 12% of people over age 70 Usually memory affected Does not significantly interfere with daily function 3 times increased risk of developing AD 10–15% /year will develop dementia

11. DSM Criteria 1. Memory impairment 2. At least one of the following: Aphasia Apraxia Agnosia Disturbance in executive functioning 3. Disturbance in 1 and 2 interferes with daily function or independence 4. Does not occur exclusively during delirium

12. Activities of Daily Living ADLs: bathing, toileting, transfer, dressing, eating IADLs (executive functioning): Maintaining household Shopping Transportation Finances

13. Diagnosis of Dementia Delirium: acute, clouding of sensorium, fluctuations in level of consciousness, difficulty with attention and concentration Depression: patient complains of memory loss Delirium and depression: markers of dementia? 5% people over age 65 and 35–50 % over 85 have dementia, therefore pretest probability of dementia in older person with memory loss at least 60%

14. Question: What are some classic features of an Alzheimer’s type dementia?

15. Alzheimer’s Disease Role of the Hippocampus Patient HM with surgery for seizures to remove bilateral medial temporal lobes resulting in severe anterograde amnesia Formation of new memories Spatial navigation Early evidence for damage in this area

16. Alzheimer’s Disease 60–80% of cases of dementia in older patients Early personality changes Loss of short term memory Functional impairment Visual spatial disturbances (early finding) Apraxia Language disturbances Delusions/hallucinations (usually later in course)

17. Alzheimer’s Disease Depression occurs in 1/3 Delusions and hallucinations in 1/3 Extracellular deposition of amyloid-beta protein, intracellular neurofibrillary tangles, and loss of neurons at autopsy Clinical diagnosis: 87% of diagnosed AD confirmed pathologically (but high pretest probability increases predictive value of clinical diagnosis!!!)

18. Alzheimer’s Disease Onset usually near age 65; older age, more likely diagnosis Absence of focal neurological signs (but significant overlap in the elderly with hx of CVAs…) Aphasia, apraxia, agnosia Family hx (especially for early types) Normal/nonspecific EEG MRI: bilateral hippocampal atrophy (suggestive)

19. Question: What features would make you think more about a vascular etiology to a dementia?

20. Vascular Dementia Onset of cognitive deficits associated with a stroke (but often no clear hx of CVA but multiple small, undiagnosed CVAs) Abrupt onset of sxs with stepwise deterioration Findings on neurological examination Infarcts on cerebral imaging (but ct/mri findings often have no clear relationship)

21. Overlap Most patients previously categorized as either Alzheimer’s type or vascular type dementias probably have BOTH Likelihood of AD and vascular disease significantly increases with age, therefore likelihood of both does as well Vascular risk factors predispose to AD -- ?does it allow the symptoms of AD to be unmasked earlier??

22. Question: What is the risk of dementia with Parkinson’s disease?

23. Dementia with Parkinson’s 30% with PD may develop dementia; Risk Factors: Age over 70 Depression Confusion/psychosis on levodopa Facial masking upon presentation Hallucinations and delusions May be exacerbated by treatment

24. Some Other Dementias

25. Dementia with Lewy Bodies Cortical Lewy Bodies on path 10–20% of dementias Compare to PD: Lewy Bodies in substantia nigra Overlap with AD and PD 40% patients with AD have LBs on path

26. Dementia with Lewy Bodies Visual hallucinations (early) Parkinsonism Cognitive fluctuations Dysautonomia Sleep disorders Neuroleptic sensitivity Memory changes later in course

27. Dementia with Lewy Bodies Visual hallucinations 2/3 of patients with DLB Rare in AD May precede other symptoms of DLB Psychosis, paranoia and other psychiatric manifestations early in course

28. Dementia with Lewy Bodies Cognitive Fluctuations 60–80% Episodic Loss of consciousness, staring spells, more confused or delirious like behavior Days of long naps Significant impact on functional status

29. Dementia with Lewy Bodies Parkinsonism 70–90% More bilateral and symmetric than with PD Tremor less common Bradykinesia, rigidity, gait changes

30. Dementia with Lewy Bodies Sleep disorders REM sleep behavior disorder/parasomnia Acting out of dreams: REM dreams without usual muscle atonia 85% of patients with DLB May precede other symptoms by years

31. DLB: Neuroleptic Hypersensitivity 30–50% of patients May induce Parkinsonian symptoms or cognitive changes that are not reversible, leading to rapid decline in overall status NOT dose related Slightly less likely with newer atypical antipsychotics, but can STILL happen

32. DLB: Treatment More progressive course than AD or Vascular dementia Possibly better response to cholinergic drugs than AD or vascular dementias ?response of psychiatric type symptoms to cholinergic agents/cholinesterase inhibitors

33. Progressive Supranuclear Palsy Uncommon Vertical supranuclear palsy with downward gaze abnormalities Postural instability Falls (especially with stairs) “Surprised look” Difficulty with spilling food/drink

34. Frontotemporal Dementia Impairment of executive function Initiation Goal setting Planning Disinhibited/inappropriate behavior (90%) Cognitive testing may be normal; memory loss NOT prominent early feature 5–10% cases of dementia Onset usually 45–65 (rare after age 75) Familial: 20–40%

35. Pick’s Disease Subtype of frontal lobe dementia Pick bodies (silver staining intracytoplasmic inclusions in neocortex and hippocampus) ?Serotonergic deficit? Language abnormalities and behavioral disturbances Logorrhea (abundant unfocused speech) Echolalia (spontaneous repetition of words/phrases) Palilalia (compulsive repetition of phrases) Fluent or non-fluent forms

36. Primary Progressive Aphasia Patients slowly develop non-fluent, anomic aphasia with hesitant, effortful speech Repetition, reading, writing also impaired; comprehension initially preserved Slow progression, initially memory preserved but 75% eventually develop non-language deficits; most patients eventually become mute Average age of onset = 60 Subset of FTD

37. “Reversible” Causes of Dementia ?10% of all patients with dementia; in reality, only 2–3% at most will truly have a reversible cause of dementia

38. “Modifiable” Causes of Dementia Medications Alcohol Metabolic (b12, thyroid, hyponatremia, hypercalcemia, hepatic and renal dysfunction) Depression? (likely marker though…) CNS neoplasms, chronic subdural NPH

39. Question: An elderly patient with ataxia, incontinence, memory loss and “large ventricles” scan should raise suspicion for …?

40. Normal Pressure Hydrocephalus Triad: Gait disturbance Urinary incontinence Cognitive dysfunction

41. NPH: Clinical Features Gait Early Feature Most responsive to shunting Magnetic/gait apraxia/frontal “ataxia” Cognitive Psychomotor slowing, apathy, decreased attention Urinary Urgency or incontinence

42. NPH Hydrocephalus in absence of papilledema, with normal CSF pressure Begins as transient/intermittent increased CSF pressure, leading to ventricular enlargement; ventricular enlargement leads to normalization of CSF pressure Thought to be due to decreased CSF absorption at arachnoid villi Causes: SAH, tumors, CVA

43. NPH Diagnosis: initially on neuroimaging Ventricular enlargement our of proportion to sulcal atrophy Miller Fisher test: objective gait assessment before and after removal of 30 cc CSF Radioisotope diffusion studies of CSF MRI: turbulent flow in posterior third ventricle and within aqueduct of sylvius MRI flow imaging SPECT (Single Photon emission CT): decreased blood flow in frontal and periventricular areas

44. NPH: ?Shunting? Limited data Gait may be most responsive Predictors of better outcome: Lack of significant dementia Known etiology (prior SAH) New (< 6 months) symptoms Prominence of gait abnormality

45. Creutzfeldt-Jacob Disease Rapid onset and deterioration Motor deficits Seizures Slowing and periodic complexes on EEG Myotonic activity

46. Other Infections and Dementia Syphilis HIV

47. Question: What are some tools available to assess for the presence and severity of cognitive impairment?

48. MMSE 24/30 suggestive of dementia (sens 87%, spec 82%) Not sensitive for MCI Spuriously low in people with low educational level, low SES, poor language skills, illiteracy, impaired vision Not sensitive in people with higher educational background

49. MMSE Tips No on serial sevens (months backwards, name backwards… assessment of attention) Assess literacy prior Assess for dominant hand prior to handing paper over Do not over lead 3-item repetition, repeat all 3 then have patients repeat; 3-stage command, repeat all 3 parts of command and then have patient do…

50. Other Evaluation Tools Trails B test Numbers 1–25 and letters scattered across page; patient must connect, 1-A, 2-B, 3-C, etc; normally able to do in <10 minutes Good for patients with high function/education Verbal Fluency Test Name all within category in 30 seconds – 1 minute Letters FAS, animals, vegetables Tests executive function and language, semantic memory Normally should name 20–30 in 60 seconds Highly associated with educational level Insight with grouping, rhyming, categories

51. Additional Evaluation Clockface Short assessments with good validity: 3-item recall and clockface Neurological exam (focality, frontal release signs such as grasp, jawjerk; apraxia, cogwheeling, eye movements) Lab testing and neuroimaging

52. Treatment of AD

53. Tacrine Cholinesterase inhibitor 1 systematic review with 5 RCTs, 1434 people, 1–39 weeks No difference in overall clinical improvement Some clinically insignificant improvement in cognition Significant risk of LFT abnormalities: NOT USED

54. Donepezil Aricept Cholinesterse inhibitor Easy titration (start 5/day, then 10) Side effects: GI (nausea, diarrhea) Can be associated with bradycardia Main effect seems to be lessening of rate of decline, delayed time to needing nursing home/more intensive care

55. Other Agents Rivastigmine Galantamine Cholinesterase inhibitors ?more side effects, more titration required Future directions: Prevention of delirium in at-risk patients (cholinergic theory of delirium) Behavioral effects in those with severe dementia? Treatment of Lewy Body dementia Treatment of mixed Vascular/AD dementia

56. Comments about Cholinesterase Inhibitor Studies Highly selected patients (mild – moderate dementia) ?QOL improvements Not known: severe dementia and mild CI

57. Memantine NEJM April 2003 Moderate to severe AD (MMSE 3–14) N-methyl D aspartate (NMDA) receptor antagonist; theory that overstimulation of NMDA receptor by glutamate leads to progressive neurodegenerative damage 28-week, double blinded, placebo controlled study; 126 in each group; 67% female, mean age 76, mean MMSE 7.9

58. Memantine Found less decline in ADL scores, less decline in MMSE (-.5 instead of –1.2) Problem: significant drop outs (overall 28% dropout rate) in both groups; data analyzed did not account for drop outs, followed those “at risk”

59. Selegiline Unclear benefit Less than 10mg day, selective MAO B inhibitor Small studies, not very conclusive

60. Vitamin E (Alpha Tocopherol) NEJM 1997: selegiline, Vit E, both, placebo for tx of AD Double blind, placebo controlled, RCT with mod AD; 341 patients Primary outcome: time to death, institutionalization, loss of ADLS, severe dementia Baseline MMSE higher in placebo group No difference in Primary outcomes; adjusted for MMSE differences at baseline and found delay in time to NH from 670 days with Vit E to 440 days with placebo

61. Ginkgo Biloba 1 systematic review of 9 double blind RCTs with AD, vascular, or mixed dementia Heterogeneity, short durations High withdrawal rates; best studies have shown no significant change in clinician’s global impression scores

62. Other Treatments NO good evidence to support estrogens or NSAIDS

63. Other Treatments Behavioral/agitation: Nonpharmacologic strategies Reasons for NH placement: Agitation Incontinence Falls Caregiver stress

64. ?Antipsychotics NO data to support any significant benefit for treating behavioral symptoms of dementia with antipsychotic agents Small group of patients with active psychoses, disturbing hallucinations, or aggressive behaviors who may have some benefit

65. Antipsychotics Side Effects: Sedation Anticholinergic effects Prolonged QT Edema Orthostasis Weight gain Confusion Warnings: FDA black box warning for increased mortality (OR 1.5–1.7), and increased ?increased stroke risk

66. Antipsychotics NO if you suspect DLB

67. Antipsychotics Risperidone (0.5 BID) Olanzepine (zyprexa): 2.5–5 mg/day Quetiapine (seroquel) Rapid titration, use in PD 12.5–200 mg/day Clozapine Use in PD (least risk of tremor) Agranulocytosis and limited use Ziprasidone (geodon) QT prolongation

68. Prevention? HTN and DM linked to ALL types dementia Studies of treating systolic hypertension in the elderly (SHEPS and others): decreased risk of development of cognitive impairment in patients in treatment group Decreased risk included vascular AND Alzheimer type dementias Cholinesterase inhibitors seem to work as well (or as poorly) for both vascular and Alzheimer type of dementias What is the link? Both common, ?unmasking?

69. ?Link with Hyperlipidemia Conflicting data Retrospective studies suggest decreased risk in those patients who are treated with statins PROSPER study 6000 patients age 70–80 with vascular risk factors given pravastatin or placebo 3 year: no effect on cognitive function ?Long enough follow up?

70. Future Treating vascular risk factors to decrease development/unmasking of dementia? Actively seeking to differentiate different types of dementia, while also Recognizing significant OVERLAP of dementia etiologies in older patients Move toward agents other than cholinesterase inhibitors? Move away from broad use of antipsychotic agents