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Management of Alzheimer’s Disease and Other Dementias

Management of Alzheimer’s Disease and Other Dementias. Linda A. Hershey, MD, PhD Professor of Neurology University of Oklahoma. Disclosures. I receive an honorarium to write for Medlink Neurology about Memory Disorders.

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Management of Alzheimer’s Disease and Other Dementias

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  1. Management of Alzheimer’s Disease and Other Dementias Linda A. Hershey, MD, PhD Professor of Neurology University of Oklahoma

  2. Disclosures • I receive an honorarium to write for Medlink Neurology about Memory Disorders. • Our laboratory is funded by Baxter Healthcare Corporation to perform a clinical trial of IVIg on patients with mild-moderate Alzheimer’s disease.

  3. Learning Objectives of this Talk • To classify three common dementing illnesses (Alzheimer’s disease, dementia with Lewy bodies and vascular (mixed) dementia). • To describe the use of cholinesterase inhibitors and memantine in treating patients with AD, DLB and vascular (mixed) dementia. • To report the role of antidepressants, anxiolytics and antipsychotic agents in treating patients with AD and other dementing illnesses.

  4. Question #1 • Alzheimer’s disease is an illness associated with all of the following features, EXCEPT: a) memory loss b) diffuse brain atrophy c) focal signs of weakness d) motor apraxia

  5. Question #2 • Dementia with Lewy bodies is a an illness associated with all of the following features, EXCEPT: a) memory loss b) vertical gaze palsy c) parkinsonism d) visual hallucinations

  6. Question #3 • In the recent Great Britain study of drugs in moderate-severe AD, which statement is the most accurate summary of the results? a) Those assigned to donepezil alone had the best cognitive outcome at 12 months. b) Those assigned to the combination of donepezil and memantine had the best cognitive outcome at 12 mo. c) Those assigned to placebo had the best behavioral outcome at 12 months.

  7. Question #4 • The advantages of mirtazapine for sleep in dementia patients include all of the following, EXCEPT: a) It does not cause ataxia. b) It is not an anticholinergic agent. c) It does not cause hypotension. d) It is not habit-forming.

  8. 56 year old female 711 cashier • CC: “My head is in a fog most of the time”. • May, 2010….Onset of poor conc & memory (MRI = mild atrophy; MMSE = 25/30…poor recall). • April, 2011…She lost her job as a cashier at the 711 (MMSE in Aug = 21/30)…..no hallucinations. • Jan, 2012…..Continued to have memory problems (IADL =11/16; MMSE = 18/30…exam = motor apraxia, but no signs of stroke or parkinsonism). What is this woman’s diagnosis? Treatment?

  9. Alzheimer’s Disease (AD) • Insidious onset and gradual decline in activities, behavior and cognition over time. • Dementia by DSM IV criteria: ….memory loss ….1 or more other cognitive impairments ….functional impairment in IADLs ….exclusion of delirium McKhann et al. Neurology 1984; 34: 939-944.

  10. Lawton’s IADL Scale • Using the telephone….2 (no help)….0 (unable). • Driving………………2….......1……0……… • Grocery shopping……2……..1……0……… • Preparing meals……...2……...1……0……… • Doing housework……2……..1……0……… • Doing laundry……….2……...1……0……… • Taking medications….2……...1……0……… • Managing money…….2……..1…….0……… Lawton & Brody, The Gerontologist 1969; 9:179-186.

  11. The Cholinergic Hypothesis for AD • Cholinergic cells in the nucleus basalis of Meynert die early in AD:

  12. Management of Mild Alzheimer’s • Start donepezil (Aricept) 5mg/d • Advise caregiver to attend an AD support group • Advise her wearing an ID (Medic Alert) bracelet • Advise patient to assign POA to caregiver • Obtain screening labs (B12, TSH, RPR, HbA1c) • Reduce alcohol intake to 1-2 beers/d • Begin discussion of “the driving issue”

  13. What about ginkgo biloba? • Objective: The Ginkgo Evaluation of Memory study compared 1545 older adults or MCI pts on G biloba and 1524 older adults or MCI pts on placebo…they were followed for 6.1 yrs. • Results: Annual rates of decline on cognitive tests did notdiffer between G biloba group (120mg bid) and the placebo group (attention, memory, language, executive function). Snitz, BE, et al: JAMA 2009: 302: 2663-2670.

  14. What about Mediterranean diet? • Objective: To assess the association between food combination and AD risk. • Design: Prospective cohort study. • Methods: 2148 elderly subjects without dementia in NYC were evaluated every 1.5 yrs. • Results: 253 subj developed AD within 3.9 yrs. • Lower risk of AD with oils, nuts, fish, tomatoes, poultry, fruits, vegetables. Gu Y, et al. Arch Neurol 2010; 67: 699-706.

  15. 47 year old retired supervisor • CC: memory loss, parkinsonism, visual hallucinations • 2007: He first noted REM sleep behavior disorder. • 2008: Memory loss began to impair his work. • 2010: Tremors began & he c/o visual hallucinations. • 2011: He began to c/o excessive daytime sleepiness. • 2011: MMSE=17/30; IADL=12/16. • Exam: Motor apraxia + BL rigidity, bradykinesia. • Shuffling gait with postural instability (eyes closed). What is this man’s diagnosis? Treatment?

  16. Dementia with Lewy Bodies • DLB is 2nd most common dementia after AD. • REM sleep disorder improves Dx accuracy (50% of all DLB pts have RBD). • Two or three core features are needed for Dx: a) fluctuations in alertness during the day b) parkinsonism (bradykinesia, rigidity>tremor) c) visual hallucinations Ferman TJ et al: Neurology 2011; 77:875-882.

  17. The Cholinergic Hypothesis for DLB • Cholinergic cells in the nucleus basalis of Meynert die early in DLB:

  18. Dementia with Lewy Bodies • SPECT changes in DLB can look like AD.

  19. Management of DLB • Start donepezil (Aricept) 5mg/d for dementia. • Start Sinemet 25/100 tid for parkinsonism. • Start clonazepam 0.5mg qhs for RBD. • Advise caregiver to attend AD/DLB support group. • Neuropsychology testing (Dr. Scott/Dr. Adams). • P.T. x 2/wk for gait & balance training. • Advise wearing a MedicAlert ID bracelet. • Recommend that the pt STOP DRIVING (pt meets criteria for moderate dementia).

  20. 63 year old bench jeweller • CC: Adm in Oct, 2010 with an acute HTN emergency (he was acutely confused and disoriented). He had forgotten to take pills. • Gait disorder and falls had been present x 2 yrs.

  21. Vascular Dementia • Acute or subacute onset of gait disorder and/or memory loss. • Cerebrovascular disease by history, exam, or brain imaging (and a temporal relationship between the CVD and dementia). • Dementia according to DSM-IV criteria: ….memory disorder ….other cognitive deficits (loss of exec func) ….functional impairment (IADLs) ….absence of delirium Roman et al. Neurology 1993; 43: 250-260.

  22. Management of VaD • Start donepezil (Aricept) at 5mg/d. • Start ECASA 325mg/d. • Start lisinopril 10mg/d (keep BP < 140/90). • Start simvostatin 40mg/d (keep LDL <70). Advise caregiver to attend caregiver classes. • P.T. x 2 days/wk for gait & balance training. • Recommend that the pt STOP DRIVING (he has homonymous hemianopsia).

  23. Does Donepezil Improve Symptoms in Mod-Severe Alzheimer’s?

  24. Donepezil vs Memantine for Mod-Severe Alzheimer’s Disease • Who? 295 community-dwelling AD patients in Great Britain, who scored 5-13 on the MMSE and were taking donepezil (Aricept). • What? Randomized to continue donepezil, d/c donepezil, d/c donepezil and start memantine, or continue donepezil and start memantine. • Outcomes? Clinically important outcomes= 1.4 pts on the MMSE; 3.5 pts on the BADLs. Howard, Robert et al: NEJM 2012;366:893-903.

  25. Kaplan–Meier Actuarial Plot of the Cumulative Probability of Withdrawal from the Assigned Study Drug. Howard R et al. N Engl J Med 2012;366:893-903.

  26. Donepezil vs Memantine for Mod-Severe Alzheimer’s Disease • In pts with moderate-severe AD, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference over 12 months: • Those assigned to donepezil (vs placebo) had MMSE scores that were 1.9 pts higher. • Those assigned to memantine (vs placebo) had MMSE scores that were 1.2 pts higher.

  27. Other Pearls from the NEJM Study • D/C of donepezil did not produce a withdrawal phenomenon. • Memantine was beneficial in moderate-severe AD, but it was not as dramatic an effect as donepezil’s benefit. • There was no significant benefit from adding memantine to donepezil in mod-severe AD.

  28. Does Donepezil Delay NH Placement in AD? • Objective: To assess relationship between donepezil treatment and NH placement in AD. • Design: F/U of 1115 pts enrolled in 3 trials. • Results: Use of donepezil at a dose of at least 5mg/d was associated with significant delays in NH placement (time gained was 17-21 months). Geldmacher et al. J Am Geriatr Soc 2003;51: 937-944.

  29. Memantine for Mild-Mod AD

  30. Memantine for Moderate-Severe AD

  31. Do Cholinesterase Inhibitors help DLB patients? • Objective: To determine whether galantamine would improve global function, behavior, or cognition in patients with DLB. • Design: A 24-wk open-label, multi-center study of 50 DLB patients at 4 centers (VT, WNY, IN, TX). • Results: At 24 wks, improvements were seen in visual hallucinations (p=0.01), night-time behaviors (p=0.004) and global cognitive impression of change (p=0.01). Edwards et al. Dementia 2007; 23: 401-405.

  32. Does memantine help DLB ? • Objective: To determine whether memantine would help pts with PDD and DLB. • Design: Double-blind, placebo-controlled clinical trial in Norway, Sweden and UK (n=72). • Results: At 24 wks, the pts on memantine had better clinical global impression of change scores, compared to the placebo pts (p=0.03). Aarsland et al. Lancet Neurology 2009; 8: 613-618.

  33. Does donepezil delay onset of AD in patients who have MCI? • No. At three yrs, donepezil pts = placebo pts. Petersen RC, et al. NEJM 2005; 352: 2379-2388.

  34. What is the Exception to the MCI “Rule”? • Donepezil delays progression to AD in MCI subjects who have depressive symptoms. • Design: n=756 participants in the 3-yr study of donepezil vs placebo in MCI patients. • Results: n=208 pts were found to be depressed using the Beck Depression Inventory. These depressed MCI pts progressed to AD more slowly if they were treated with donepezil (p=0.025 at 2 yrs). Lu PH, et al. Neurology 2009; 72: 2115-2121.

  35. Donepezil for MCI + depression Lu PH, et al. Neurology 2009; 72:2115-2121.

  36. Antidepressants for Dementia Patients who Cannot Sleep • Mirtazapine (Remeron)…....7.5mg qhs.

  37. Advantages of mirtazapine for sleep • It does not cause gait & falling problems like benzodiazepines (important for DLB & PSP). • It does not have anticholinergic activity like diphenhydramine, amitriptyline, trazodone, or hydroxyzine. • It is not habit-forming like zolpidem (Ambien).

  38. Antipsychotic Agents for Dementia • ID = 68 year old man with a 3 yr Hx of memory loss, geographic disorientation and excessive daytime sedation & agitation (“He starts sundowning at noon”, according to his wife). • HPI = For the last 2 yrs, this pt has had visual hallucinations, paranoid ideas, agitation, tremors, motor restlessness and acting out his dreams at night (REM sleep behavior disorder).

  39. Antipsychotic Agents for Dementia Pts who have Paranoia & Insomnia • Quetiapine (Seroquel)……..25mg qhs.

  40. Clinical Outcome Measures • Clinical Dementia Rating (CDR) • Instrumental Activities of Daily Living (IADL) • Neuropsychiatric Inventory (NPI) • Mini-Mental State Examination (MMSE)

  41. Clinical Dementia Rating (CDR) • 0.5 = Questionable dementia …..no impairment of IADLs or BADLs. • 1.0 = Mild dementia…….some impairment of IADLs, but no impairment of BADLs. • 2.0 = Moderate dementia…pt is dependent on others for most IADLs and some BADLs. • 3.0 = Severe dementia…...pt is dependent on others for all IADLs and BADLs. Morris JC Neurology 1993; 43: 2412-2414

  42. Lawton’s IADL Scale • Using the telephone….2 (no help)….0 (unable). • Driving………………2….......1……0……… • Grocery shopping……2……..1……0……… • Preparing meals……...2……...1……0……… • Doing housework……2……..1……0……… • Doing laundry……….2……...1……0……… • Taking medications….2……...1……0……… • Managing money…….2……..1…….0……… Lawton & Brody, The Gerontologist 1969; 9:179-186.

  43. Neuropsychiatric Inventory (NPI) • Delusional ideas • Hallucinations • Agitation • Depression • Anxiety • Elation/euphoria • Apathy/loss of interests • Disinhibition • Irritability/lability • Motor disturbance/pacing • Nighttime behaviors • Appetite/weight change Cummings J L, et al. Neurology 1994;44:2308-2314.

  44. Question #1 • Alzheimer’s disease is an illness associated with all of the following features, EXCEPT: a) memory loss b) diffuse brain atrophy c) *** focal signs of weakness d) motor apraxia

  45. Question #2 • Dementia with Lewy bodies is an illness associated with all of the following features, EXCEPT: a) memory loss b) *** vertical gaze palsy c) parkinsonism d) visual hallucinations

  46. Question #3 • In the recent Great Britain moderate-severe AD study, which statement was the most accurate? a) ** Those assigned to donepezil alone had the best cognitive outcomes at 12 mo. b) Those assigned to the combination of donepezil and memantine had the best cognitive outcomes at the end of 12 months. c) Those assigned to placebo had better behavioral outcomes at the end of 12 months.

  47. Question #4 • The advantages of mirtazapine for sleep in dementia patients include all of the following, EXCEPT: a) It does not cause ataxia. b) It is not an anticholinergic agent. c) ** It does not cause hypotension. d) It is not habit-forming.

  48. Summary • Cholinesterase inhibitors and memantine “buy time” for AD and DLB pts, but they do not change the underlying disease processes. • The depression and psychosis associated with dementing illnesses are treatable conditions. • CDR, IADL, NPI and MMSE are useful outcome measures to use in a clinical setting to monitor the effectiveness of drug therapy.

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