1. Clinical Issues in Moderate - Severe Dementia Dr. William Dalziel Chief, Ottawa Regional Geriatric Assessment Program Associate Professor, University of Ottawa April, 2005

3. SITTING WORLD

4. MAN campus

5. 1.Based on evidence and/or clinical experience, a trial with a cholinesterase inhibitor should be offered to all patients who have never had a trial even if their dementia is severe (MMSE <10) if there is some “perceived quality of life.” A)Strongly disagree B)Mildly disagree C)Neutral D)Mildly agree E)Strongly agree

6. 2.All patients with dementia on cholinesterase inhibitors (CI) regardless of MMSE (even if over 10) 1 month after admission to a Nursing Home should automatically have the CI discontinued A)Strongly disagree B)Mildly disagree C)Neutral D)Mildly agree E)Strongly agree

7. The Continuum of Vascular Dementia and Alzheimer’s Disease VaD AD Mixed AD + Cerebrovasular Disease Infarcts, white matter lesions, vascular risk factors Post-stroke dementia Amyloid plaques and neurofibrillary tangles

8. From the Nun Study The presence of 1–2 lacunar infarcts in basal ganglia, thalamus or deep white matter increased odds ratio by 20.7 for those with AD lesions within neocortex Fewer neuropathological lesions of AD appear to be needed to result in “clinical dementia” in those with lacunar infarcts.. or deep white matter infarcts than those without infarcts. (Snowdon JAMA 1997; 277: 813-7)

9. It is now increasingly clear that risk factors should be treated in dementia whether the diagnosis is AD, VAD or mixed AD / VAD = 80% of dementia STROKE PREVENTION = DEMENTIA PREVENTION  Atrial fibrillation  Hypertension especially systolic  Smoking  Diabetes  Hyperlipidemia

10. Distribution of AD in Different Settings CSHA Working Group, CMAJ, 1994. CSHA Working Group, Can J Aging, 1994. AD within Institutions Severe 55% Mild 11% Moderate 34%

11. How would you differentiate mild dementia from moderate/severe dementia?

12. Severity of Dementia 1. Cognition: Memory vs executive function. 2. Function: IADLs vs PADLs 3. Interval of Need: 24 hr vs 8 hr 4. Behaviour: AD vs non Alzheimer’s dementias 5. Safety 6. Caregiver Impression/ Burden 7. Cost 8. Institutionalization

13. Gauthier S. CMAJ, 2002. MMSE ScoreStageLevel of autonomy 27-30NormalIndependent living 18-26Mild ADIndependent living 10-17Moderate ADSupervision required <10Severe ADTotal dependence Severity Diagnosing Severe AD: Mini-Mental State Examination (MMSE)

14. Reisberg B et al. Psychopharmacol Bull, 1988. Diagnosing Severe AD: Functional Assessment Staging (FAST) FAST Scale Stage Characteristics 1 Normal adultNo functional decline. 2 Normal older adultPersonal awareness of some functional decline. 3 Early ADNoticeable deficits in demanding job situations. 4 Mild ADRequires assistance in complicated tasks such as handling finances, planning parties, etc. 5 Moderate ADRequires assistance in choosing proper attire. 6 Moderately-severe ADRequires assistance dressing, bathing, and toileting. Experiences urinary and fecal incontinence. 7 Severe ADSpeech ability declines to about a half-dozen intelligible words. Progressive loss of abilities to walk, sit up, smile, and hold head up. Severity

15. AD Caregiver Time by Disease Severity Hux et al. CMAJ, 1998.

16. Mean Annual Cost of AD by Disease Severity Hux et al. CMAJ, 1998.

18. Outcome measures used in Alzheimer’s Disease Caregiver burden Function (DAD/ADCS- ADL) Cognition (ADAS-Cog) Behaviour (NPI) Global (CIBIC-plus) ADAS-Cog Alzheimer’s Disease Assessment Scale, Cognitive subscale CIBIC-plus Clinician Interview-Based Impression of Change with Caregiver Input DAD Disability Assessment in Dementia ADCS-ADL Alzheimer's Disease Co- Operative Study – Activities of Daily Living NPI * Neuropsychiatric Inventory SCGB Screen for Caregiver Burden *Contains subscale NPI-D, which measures caregiver distress

19. Benefits Seen with AChEIs in RCTs Global clinical impression Cognition Function (instrumental and personal activities of daily living: ADLs) Behaviour (both delayed emergence and treatment effects) Decreased psychotropic use in long-term care. Direct caregiver time decreased one hour per day Delay to LTC placement (approximately 21-month delay) Reduced risk for nursing home placement RR.63 (p=0.004) Cost (studies show cost neutral to slightly cost beneficial)

20. Seek and Treat Comorbid Medical Conditions 1. The dementia patient is a TERRIBLE “historian”. 2. “Irreversible” dementia improves with “tuning up” morbid conditions. 3. Dementia is a HUGE risk factor for delirium. 4. Quiet delirium is really dangerous. (Be watchful +++ in patients with dementia). 5. MEDS, MEDS, MEDS, MEDS

22. Confusion Assessment Method Acute change in mental status AND Inattention/fluctuation PLUS Disorganized thinking OR Altered level of consciousness Sensitivity 94-100% Specificity 90-95% Ann Intern Med. 1990; 113:941 Arch Intern Med. 1995; 155:301

23. Spectrum Of Delirium Spectrum of Psychomotor Activity : HYPOACTIVE delirium (lethargy, excess somnolence, sluggish) Individuals often not recognized as they may not cause a disturbance so they don’t get ATTENTION

24. Spectrum Of Delirium HYPERACTIVE delirium (agitated, hallucinating, inappropriateness) MIXED - combination of both

25. Delirium: Signs Restlessness, agitation “Picking” at the air/clothes... Myoclonus (often multifocal) Asterixis (suggests a metabolic cause) Hallucinations (usually visual, tactile)

26. Causes of Delirium: A Checklist D:Drugs anticholinergics, ETOH E:Endocrine BS, Na, Ca, Mg, cortisol, etc. M:Metabolic organ failure, hypoxia, etc. E:Epilepsy or seizures postictal status N:Neoplasm especially SIADH, CNS T:Trauma concussion, surgery I:Infection any A: “Apoplexy” any vascular event MI, PE, CVA

27. Any drug can potentially cause confusion Take a careful history of any new drug STARTED or any old drug STOPPED recently Medications Associated with Delirium

28. Sedatives - hypnotics; Benzodiazepines - toxicity or withdrawal Narcotics - especially Demerol Anticholinergics Antihistamines eg. Gravol Tricyclic antidepressants eg. Amitriptyline Antiparkinsonian agents Cardiac eg. Digitalis Miscellaneous H 2 blockers– Lithium Steroids– Anticonvulsants Metoclopramide– NSAIDs eg. Indocid

29. Miscellaneous Causes of Delirium Pain Fecal Impaction Urinary Retention Alcohol Intoxication or withdrawal

30. Delirium: Etiology Good Physical Exam Assess Hydration Status ? New localizing Neurological findings ? CHF/Pneumonia Rectal Exam to R/O Impaction ? Distended Bladder ? Infected Ulcer

31. Delirium: Search for Underlying Etiology Review medication list Measurement of serum levels of medications eg. Digoxin/phenytoin... Metabolic work up CBC lytes/BUN/creat/glucose Ca, albumin liver function tests R/O infection eg. CXR; urine C&S O 2 saturation/ABG’s to R/O  pCO 2

32. Delirium: Search for Underlying Etiology ECG to R/O silent MI CXR to R/O pneumonia as physical exam often difficult/inaccurate CNS work-up (if indicated): ie. CT Head

33. Delirium: Search for Underlying Etiology Positive urine cultures Common in the elderly Should only be used as the cause for a delirium when patient has new urinary symptoms.

34. Delirium - Conclusions A medical emergency!! Common but under-recognized Treatment: Address the underlying cause

35. Symptomatic Effect and Slowing of Disease Progression Change from baseline in functioning 2 1 0 -2 -3 -4 -5 -6 Baseline Gauthier S: Brain Aging 2002; 2(3):9-22. Farlow MR: Int J Clin Pract 2001; Suppl. 127:37-44.

36. Natural history of AD Time (years) Symptoms Diagnosis Loss of functional independence Behavioural problems Nursing home placement Death Mini-Mental State Examination (MMSE) Early diagnosis Mild-to-moderate Severe 12345678123456781234567812345678 0 5 10 15 20 25 30 Feldman & Grundman. From Clinical Diagnosis & Management of Alzheimer’s Disease (2 nd Edition); (Ed) Gauthier, 1999

37. Time to NH Placement by Treatment Duration Feldman et al. Poster presentation at the European Federation of Neurological Societies, Paris, France, 2004 n=596

38. Do not stop ACHEI because  The patient’s MMSE < 10  The patient develops behaviour problems  The patient changes address/moves to Retirement or Nursing Home Do Stop if  Quality of life is significantly diminished

39. What is the evidence of benefit for AChEIs in moderate to severe AD?  Aricept (donepezil)  Exelon (rivastigmine)  Reminyl (galantamine)

40. Donepezil in Advanced AD: MSAD Study Objectives Examine the efficacy and safety of donepezil in patients with moderate to severe AD (sMMSE 5 to 17) Assess the treatment effect of donepezil as a function of baseline dementia severity Gauthier S et al. Neurology, 2003.

41. Donepezil in Advanced AD: MSAD Study Design Design 24-week, randomized, double-blind, placebo-controlled study in Canada, France and Australia 290 patients were randomized to receive donepezil (5 mg/d for 28 days, followed by 10 mg/d, as per clinician’s judgement) or placebo, 145 of which had severe AD Subjects Patients residing in the community or in assisted living facilities, but not receiving total nursing care Outcome measures Primary: CIBIC-plus Secondary: sMMSE, SIB, DAD, IADL+, PSMS+, NPI, FRS Other: CSS, SF-36, CAUST Gauthier S et al. Neurology, 2003.

42. Clinical improvement Clinical decline No change 0Week 24 LOCF (72) (73) 4 n=69 n=70 12 68 62 18 64 8 61 24 62 63 Donepezil Placebo p=0.0004 p=0.0017 p=0.0007 p=0.0006 p=0.002 p=0.0002  = 0.7 CIBIC-plus Donepezil in Advanced AD (sMMSE 5-12): Global Function 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 Study week LS mean score ± SE Donepezil Placebo Gauthier S et al. Neurology, 2003.

43. Donepezil in Advanced AD (sMMSE 5-12): Cognition Clinical improvement Clinical decline Baseline 0 71 73 Week 24 LOCF (71) (73) 4 67 70 12 66 62 18 63 65 8 61 24 62 63 Donepeziln= Placebon= p=0.007 p=0.0091 p=0.0005 p=0.0099 p=0.0033 p=0.0017  = 7.4SIB Gauthier S et al. Neurology, 2003.

44. Donepezil in Advanced AD (sMMSE 5-12): ADLs Clinical improvement Clinical decline Baseline 0 72 69 24 63 Donepeziln= Placebon= Week 24 LOCF (72) (69) 12 68 63 p=0.0431 p=0.0251 p=0.0082  = 7.2 DAD Gauthier S et al. Neurology, 2003.

45. Donepezil in Advanced AD (sMMSE 5-12): Behaviour Clinical improvement Clinical decline Baseline 0 71 72 Week 24 LOCF (71) (72) 4 67 69 12 67 62 18 63 65 8 61 59 24 62 Donepeziln= Placebon= p=0.0252 p=0.0198 p=0.0062 p=0.0314  = 6.9 NPI 12-item total Gauthier S et al. Neurology, 2003. -8 -6 -4 -2 0 2 4 6 8 Study week LS mean change from baseline ± SE Donepezil Placebo

46. Donepezil in Advanced AD (sMMSE 5-12): Behaviour Gauthier S et al. Neurology, 2003. Delusions Hallucinations Agitation/aggression Depression Anxiety ElationApathy Disinhibition Irritability Aberrant motor behaviour Night-time behaviour Appetite/eating Clinical improvement Clinical decline p=0.0159 p=0.036 p=0.0275 NPI individual item analysis -2.0 -1.5 -0.5 0.0 0.5 1.0 1.5 LS mean change from baseline item score at Week 24 (LOCF) Donepezil (n=72) Placebo (n=73)

47. Donepezil in Advanced AD (sMMSE 5-12): Summary Donepezil-treated patients demonstrated benefits in: Global function, as shown by a clinician’s assessment of change reflected by improved CIBIC-plus scores versus placebo Cognition, as shown by improvement in scores on the MMSE and SIB scales versus placebo Activities of daily living, as shown by a slower decline on the DAD scale versus placebo Behaviour, as shown by improvement in overall NPI score, as well as on several individual NPI items, versus placebo Gauthier S et al. Neurology, 2003.

48. Rivastigmine in Advanced AD: Study Design Doraiswamy et al. Prog Neuropsychopharmacol Biol Psychiatry, 2002. Design A post hoc analysis of patients with advanced AD (GDS  5) from a 26- week, double-blind, randomized, placebo-controlled phase followed by a 26-week open-label phase Double-blind phase: Patients were randomized to receive rivastigmine 1-4 mg/d, 6-12 mg/d or placebo for 26 weeks Open-label phase: Patients all received rivastigmine 1-6 mg b.i.d. for 26 weeks Subjects 158 patients diagnosed with AD with: GDS  5 (moderately severe stage) Average MMSE score: Approx. 16 Outcome measures Primary efficacy measure: ADAS-cog

49. Rivastigmine in Advanced AD: Summary The moderately severe patient group was characterized by: GDS score  5, and MMSE scores of ~16 Rivastigmine-treated moderately severe AD patients demonstrated benefits in: Cognition, as shown by improvement in scores on the ADAS-cog scale versus placebo Early treatment with rivastigmine leads to sustained benefits over a period of 1 year Rivastigmine was safe and well tolerated in this patient cohort Doraiswamy et al. Prog Neuropsychopharmacol Biol Psychiatry, 2002.

50. Wilkinson DG et al. Int J Clin Pract, 2002. Design Post hoc analysis of pooled data from 4 randomized, double-blind, placebo-controlled, multicenter trials Subjects 502 patients diagnosed with AD with: ADAS-cog >30 Average MMSE: Approx. 15 Outcome measures Primary: ADAS-cog, DAD, ADCS-ADL, NPI Galantamine in Advanced AD: Study Design

51. Galantamine in Advanced AD: Summary Galantamine-treated patients demonstrated benefits in: Cognition, as shown by improvement in scores on the ADAS-cog scale versus placebo Activities of daily living, as shown by stabilization on the ADCS-ADL scale versus placebo Behaviour, as shown by stabilization in overall NPI score versus placebo Galantamine was safe and well tolerated in this patient cohort These data suggest that galantamine may be useful in patients with advanced AD Wilkinson DG et al. Int J Clin Pract, 2002.

53. Neurotransmitter imbalance in AD In terms of treatment strategies in AD, two neurotransmitters have been studied Acetylcholine Levels of acetylcholine are abnormally low – the basis for the use of acetylcholinesterase inhibitors Glutamate Levels of the excitatory neurotransmitter, glutamate, are elevated

54. Mechanism of action Memantine is a voltage-dependent, low to moderate affinity, uncompetitive NMDA receptor antagonist Memantine blocks the effects of tonic pathologically elevated levels of glutamate that may lead to neuronal dysfunction However, it preserves physiological activation through the receptor required for learning and memory Ebixa ® Product Monograph

55. Memantine treatment in patients with moderate to severe AD already receiving donepezil Tariot et al 2004 JAMA 2004;291:pg 317-24

56. Study objectives To compare the efficacy and safety of memantine versus placebo in patients with moderate to severe AD already receiving stable treatment with the AChEI, donepezil Primary: SIB, modified ADCS-ADL 19 Secondary: CIBIC+, NPI, BGP Tariot et al 2004

57. Study design Randomised, double-blind, placebo-controlled study 37 investigator sites in the US 24-week, double-blind treatment period Memantine 20 mg/day (10 mg b.i.d. titrated over a 4-week period) or placebo, in patients already receiving stable doses of donepezil (5–10 mg/day) Tariot et al 2004

58. Summary of key efficacy results (mean change from baseline) Tariot et al 2004 *p-values are two-way analysis of covariance LOCF analysis (last observation carried forward) Week 24 OC analysis (observed cases) Memantine # Placebo # p-value*Memantine # Placebo # p-value* SIB 0.9 (n=198) -2.5 (n=196) <0.001 1.0 (n=171) -2.4 (n=153) <0.001 ADCS- ADLsev -2.0 (n=198) -3.4 (n=197) 0.03 -1.7 (n=172) -3.3 (n=152) 0.02 CIBIC-plus 4.41 (n=198) 4.66 (n=196) 0.03 4.38 (n=172) 4.64 (n=152) 0.03 NPI -0.1 (n=193) 3.7 (n=189) 0.002 -0.5 (n=171) 2.9 (n=152) 0.01 BGP-Care 0.8 (n=185) 2.3 (n=179) 0.001 0.6 (n=172) 2.2 (n=151) 0.001

59. Cognition: SIB Mean change from baseline, OC analysis Tariot et al 2004 Memantine Placebo *p<0.05 **p<0.01 ***p<0.001 * ** *** Improvement Worsening n=198 n=197 n=194 n=190 n=180 n=185 n=169 n=181 n=164 n=171 n=153 -4 -2 0 2 4 04812162024 Week SIB score difference (± SEM)

60. Function: ADCS-ADLsev Mean change from baseline, OC analysis Tariot et al 2004 Memantine Placebo *p<0.05 * * Improvement Worsening * * n=198 n=197 n=198 n=195 n=190 n=182 n=185 n=170 n=181 n=163 n=172 n=152 * * -4 -3.5 -3 -2.5 -2 -1.5 -0.5 0 0.5 1 04812162024 Week ADCS-ADLsev score difference (± SEM)

61. Memantine treatment in patients with moderate to severe AD already receiving donepezil – summary First prospective, randomised, placebo-controlled study examining benefits of an NMDA receptor antagonist in patients with moderate to severe AD receiving stable treatment with an AChEI, donepezil Memantine treatment compared with placebo, in AD outpatients, resulted in: Significantly more patients completing the trial Significant improvements on global measures and assessments of cognition, function in ADLs, and behaviour Sustained, improved cognitive performance relative to baseline vs. progressive decline over the same duration of treatment Memantine/AChEI treatment was safe and well tolerated Tariot et al 2004

62. Efficacy in AD Reisberg et al 2003 NEJM 2003;348:1333-41

63. Study objectives and design Objectives: Efficacy and long-term tolerability of memantine in patients with moderate to severe Alzheimer’s disease Design: Placebo-controlled, 28-week, double-blind, randomised, parallel-group, fixed-dose, multicentre trial with optional 24-week, open-label extension Reisberg et al 2003

64. Patient selection Male and postmenopausal female outpatients aged  50 years Diagnosis of dementia: Alzheimer’s disease (DSM-IV) Probable Alzheimer’s disease (NINCDS-ADRDA) Severity: MMSE score 3–14 GDS stage 5 or 6 FAST stage  6a CT or MRI scan, in last 12 months, consistent with AD Reisberg et al 2003

65. Efficacy measures Efficacy measures were: Primary: Global endpoint (CIBIC-plus) Functional endpoint (ADCS-ADLsev inventory) Secondary: Cognitive assessment (SIB) Behavioural assessment (NPI) MMSE, GDS, FAST Resource Utilisation in Dementia (RUD) Reisberg et al 2003

66. Summary of key efficacy results (mean change from baseline) Reisberg et al 2003 *p-values are based on Wilcoxon rank-sum test for between treatment comparison # Numbers in parentheses represent patient numbers LOCF analysis (last observation carried forward) OC analysis (observed cases) Memantine # Placebo # p-value*Memantine # Placebo # p-value* CIBIC-plus 4.5 (n=118) 4.8 (n=118) 0.06 4.4 (n=97) 4.7 (n=84) 0.03 ADCS- ADLsev -3.1 (n=124) -5.2 (n=123) 0.02 -2.5 (n=97) -5.9 (n=84) 0.003 SIB -4.0 (n=124) -10.1 (n=123) <0.001 -4.5 (n=96) -10.2 (n=83) 0.002 FAST 0.2 (n=121) 0.6 (n=118) 0.02 0.1 (n=97) 0.5 (n=84) 0.007

67. Global change: CIBIC-plus Mean change from baseline, OC analysis Reisberg et al 2003 Placebo Memantine (20 mg/day) *p=0.03 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 0481216202428 Week CIBIC-plus global score Improvement Worsening * n=126 n=107 n=105 n=97 n=84

68. Assessment of functional improvement DCS-ADL inventory customised to severe dementia List of selected items 1. Eating 2. Walking 3. TOILETING* 4. Bathes 5. Grooms 6. Gets dressed 7. USES A TELEPHONE* 8. Watches TV 9. MAKES CONVERSATION* 10. CLEARS A TABLE* 11. FINDS BELONGINGS* 12. Obtains a beverage 13. DISPOSES OF LITTER* 14. Travels outside home 15. Can be left alone 16. Turns faucet on 17. Turns faucet off 18. Turns light on 19. Turns light off Galasko et al 1997, Galasko et al 2000; H. Lundbeck A/S, Data on file

69. Function: ADCS-ADLsev Mean change from baseline, OC analysis Reisberg et al 2003 *p=0.003 Placebo Memantine (20 mg/day) -7 -6 -5 -4 -3 -2 0 1 0481216202428 Week ADCS-ADLsev score difference Improvement Worsening * n=126 n=119 n=107 n=117 n=97 n=84 n=126 n=106

70. CAREGIVING TIME Memantine reduced caregiving time by 42 hr/month = 1.4 hr/day

71. Reisberg et al: Efficacy summary Treatment with memantine (20 mg/day) results in significant improvement in core domains: global response, function, and cognition, in patients with moderate to severe AD Memantine improves patients ’ ability to carry out ADLs, thus helping them to maintain a degree of independence and reducing the burden to their carers Memantine slows cognitive decline Behavioural improvements in agitation/aggression and delusions (NPI) Memantine provides clinically meaningful benefits to patients, carers and the community as a whole

72. Memantine in Severe Dementia Winblad et al 1999 Int. J of Ger Psych 1999; 14:pg 135-46

73. Patient selection Male and female inpatients aged 60–81 years Diagnosis of dementia: Symptoms of dementia for at least 12 months DSM-III-R criteria GDS stages 5–7 MMSE score <10 Modified HIS and, in some patients, CT scan used to identify VaD sub-group Winblad & Poritis 1999; Rosen et al 1980

74. Efficacy measures Efficacy variables: Global endpoint:CGI-C score Functional endpoint: BGP ‘care dependency’ sub-scale score Items 1 and 3 of CGI score BGP total score and sub-scale scores Modified D-test score Winblad & Poritis 1999

75. Global endpoint: CGI-C 1. ‘ very much improved ’ 2. ‘ much improved ’ 3. ‘ minimally improved ’ 4. ‘ no change ’ 5. ‘ minimally worse ’ 6. ‘ much worse ’ 7. ‘ very much worse ’ Regarded as a response to treatment Classified as a non-response Global change: CGI-C response Winblad & Poritis 1999

76. Global change: CGI-C, ITT population Winblad & Poritis 1999 Percentage of responders Memantine (10 mg/day) Placebo *p=0.006; **p<0.001, stratified Wilcoxon test (n=166) 0 10 20 30 40 50 60 70 80 Week 4Week 12 * ** 59 40 73 45

77. Function: BGP care dependency, ITT population Winblad & Poritis 1999; H. Lundbeck A/S, Data on file 10 15 20 25 30 02468101214 Mean (± SEM) BGP care dependency score * Placebo Memantine (10 mg/day) *p=0.016, stratified Wilcoxon test Week Worsening Improvement

78. Behaviour and function: D-test items Winblad & Poritis 1999 0102030405060 2 3 4 5 6 9 13 14 Frequency of improvement (%) Percentage of patients with dementia who improved in their ability to carry out D-test items, TPP dataset (n=151), p<0.05 Ability to take a shower or bath Ability to dress Ability to use the toilet Group activities Hobbies/interests Ability to stand up Ability to move Ability to wash Memantine Placebo

79. Winblad et al: Efficacy summary Patients with moderately-severe to severe dementia (AD and VaD) benefit from treatment with memantine, and statistically significant differences in core domains can be demonstrated already at 12 weeks Treatment with memantine resulted in functional, cognitive and global improvement and reduced care dependence in AD patients as measured by BGP and CGI-C scores This study provides solid evidence to support the use of memantine in patients with moderately-severe to severe dementia and clearly demonstrates that patients who receive memantine decline more slowly than they do without treatment

80. Memantine Precautions/Tolerability No cholinergic GI side effects Less CVS concern I.e. heart block/ ↓ HR Very low side effects Renally cleared Mild – no dosage change Moderate – 10 mgm/day Severe – contraindicated No hepatic clearance, cyt p450 problems

81. To The Future – Triple Therapy 1.Treat risk factors aggressively 2.Care for caregivers aggressively 3.The Dementia Cocktail: AChEI ASA Memantine Vitamin E Vitamin B6/B12/Folate Statin