1. Alzheimer’s Disease Update ALOMA February 2016 CME Conference Jennifer L. DeWolfe, DO Associate Professor of Neurology UAB Epilepsy Division Director, BVAMC Sleep Center

2. Special Acknowledgment: Marissa C. Natelson Love, MD David Geldmacher, MD UAB Division of Memory Disorders & Behavioral Neurology

3. Disclosures  I have not received any support from industry in the development of this talk  I receive Research support from Marinus Pharmaceuticals and NINDS  The slides in this presentation were donated by Marissa Natelson Love, MD and David Geldmacher, MD

4. Learning objectives:  Identify the typical symptoms of neurodegenerative dementia syndromes.  Outline the standard of care in evaluation and treatment of dementia.  Discuss resources for managing the care of patients with cognitive impairment.

5. Neurological Definitions  Mild cognitive impairment-  ↓ cognitive function from baseline  preserved function of IADLs & ADLs  Dementia-  ↓ cognitive function from baseline  ≥ 2 domains  loss of functional abilities

6. Definitions  Amnestic Mild Cognitive Impairment  Mild Dementia- needs help with IADLs (finances, driving, medications, cooking, shopping)  Moderate Dementia- needs help with ADLs (feeding, bathing, dressing, toileting)  Severe Dementia- bedridden, communication limited

7. Symptoms

8. Amnesia- poor episodic memory  Poor recall of recent events  e.g., if you went to the store yesterday, would you remember that you went? Anomia  Spontaneous  e.g., “word-finding difficulty”  Confrontational  e.g., “what is this called?” watch, ring, pen, shoe, jacket

9. Symptoms Visuospatial deficits e.g., copying figures Poor orientation This requires attention and memory! Poor abstraction e.g., “What is the similarity between these two items?” Semantic deficits – (General Knowledge)  Disorganized semantic word lists Social behavior better than cognition

10. Early v. Late Onset  Early Onset Alzheimer’s Disease  < age 65  ~5% of the 5 million Americans with AD  Associated with the following three autosomal dominant mutations: PSEN1, PSEN2 or APP  Late Onset Alzheimer’s Disease  Associated with the APOE4 gene allelic variant

11. Epidemiology http://www.alz.org/alzheimers_disease_facts_and_figures.asp#quickFacts

12. Prevalence by Age http://www.alz.org/downloads/Facts_Figures_2014.pdf

13. Diagnosis Made with: patient history, collateral history from relatives, and clinical observations AND Imaging with computed tomography (CT) or magnetic resonance imaging (MRI) AND/OR histological examination post-mortem.

14. Diagnosis Probable AD* Dementia Insidious Onset Worsening of cognition over time Amnestic vs. non-amnestic presentation Not due to another dementia diagnosis Includes Evidence of AD pathophysiology Aβ (CSF or amyloid PET) Neuronal injury (CSF tau, FDG-PET, structural MRI) http://www.alz.org/research/diagnostic_criteria* 2011 NIA-AA Classification

15. Dementia due to Alzheimer’s disease  Insidious onset  Clear-cut history of worsening of cognition  Amnestic: most common, impaired learning and recall of recently learned information AND ≥ 1 other cognitive domain  Nonamnestic:  Language presentation: most prominent  Visuospatial presentation: spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia.  Executive dysfunction: impaired reasoning, judgment, and problem solving. NIA-AA 2011 Criteria

16. DSM-V Criteria for Major Neurocognitive Disorder Due to Alzheimer’s Disease  insidious onset & gradual progression ≥ 2 cognitive domains  Probable- either:  genetic mutation (fmh or test)  1) decline in memory & ≥ 1 other cognitive domain,  AND 2) steady progression,  AND 3) no evidence of mixed etiology Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, American Psychiatric Association, 2013

17. Evidence for Neurologic Injury Structural MRI Normal HippocampiMild Cognitive ImpairmentAlzheimer’s Disease

18. Preclinical AD  Research Diagnosis:  Evidence of  CSF Abeta decreases with increased tau  Deposition of Amyloid by Amyloid PET  Autosomal Dominant AD mutation

19. Amyloid Imaging  Sensitivity and specificity of new Aβ agents remain unclear for clinical diagnosis Alzheimer’s brains “Normal” brain

20. Evaluation

21. Who to Screen?

23. Score ≤ 4 impaired

24. Mini-Cog ● 3 items ● clock drawing ● free recall of 3 items

25. Cognitive Assessment Toolkit  Informant assessment:  AD8- 8 yes or no questions (2 positive answers = impaired)

26. Alabama Brief Cognitive Screener (ABCs)

27. They’re impaired, what now?  Screening labs for reversible causes:  CBC  Electrolytes, glucose, kidney function, liver function  thyroid function  vitamin B12 level  Notably absent: syphilis screening unless they have a specific risk factor

28. Neuroimaging  “Structural Neuroimaging is appropriate to detect lesions that may result in cognitive impairment” *  Rule out cerebrovascular disease  detect segmental atrophy of neurodegenerative syndromes * “Practice Parameter: Diagnosis of Dementia” (Knopman et al, Neurology 2001:56:1143-53)

29. Dementia due to Alzheimer’s disease-  Insidious onset  Clear-cut history of worsening of cognition  Amnestic: most common, impaired learning and recall of recently learned information AND ≥ 1 other cognitive domain  Nonamnestic:  Language presentation: most prominent  Visuospatial presentation: spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia.  Executive dysfunction: impaired reasoning, judgment, and problem solving. NIA-AA 2011 Criteria

30. DSM-V Criteria for Major Neurocognitive Disorder Due to Alzheimer’s Disease  insidious onset & gradual progression ≥ 2 cognitive domains  Probable- either:  genetic mutation (fmh or test)  1) decline in memory & ≥ 1 other cognitive domain,  AND 2) steady progression,  AND 3) no evidence of mixed etiology Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, American Psychiatric Association, 2013.

31. Treatment Disclaimer  Although there is currently no way to cure Alzheimer's disease or stop its progression, we are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.

32. Cognition Enhancing Drugs Cholinergic Agents (AChEI) - Donepezil/Aricept -Rivastigmine/Exelon -Galantamine/Razadyne NMDA Antagonist -Memantine/Namenda http://www.thefix.com/content/performan ce-enhancing-smart-drugs-olympics8838

33. Acetylcholinesterase Inhibitors Mechanism of Action:  Inhibits centrally-acting acetylcholinesterase, making more acetylcholine available  This compensates in part for degenerating cholinergic neurons that regulate memory

34. FDA Approved Use of AChEI #1 Mild/Moderate AD

35. FDA Approved Use of AChEI #2  Moderate AD  Severe AD- for rivastigmine and donepezil only

36. FDA Approved Use of AChEI #3  Parkinson’s disease-related dementia- rivastigmine only

37. AChEI side effects  Diarrhea  Urination  Miosis/muscle weakness  Bronchorrhea  Bradycardia  Emesis  Lacrimation  Salivation/sweating Muscle Cramps Insomnia/ incontinence Nausea Diarrhea

38. What about Namenda and Namenda XR (memantine)? ● regulates glutamate in the brain ● key role in processing information ● may delay the worsening of symptoms ● may allow patients to maintain daily functions  FDA approved as an addition to AChEI in mod/sev AD only

39. Generics!  Memantine immediate release  Rivastigmine patch  So everything except Namenda XR- no starter packs

40. Behavioral Therapy  Nonpharmacologic intervention  Antidepressants  Antipsychotics if necessary

41. Exercise! Image from bodbot.com

42. Benefits of Exercise Image from bodbot.com

43. Nonpharmacological Strategies Advise caregiver(s) to: 1) Use scheduled toileting and prompted toileting for incontinence. 2) Offer graded assistance (as little help as possible to perform ADLs), role modeling, cueing, and positive reinforcement to increase independence. 3) Avoid adversarial debates; try to redirect conversation instead. 4) Maintain a calm demeanor. 5) Use services of caregiver support groups.

44. Depression in dementia  Seen in up to 40% of AD patients; may precede onset of AD  Signs include sadness, loss of interest in usual activities, anxiety, and irritability  Suspect if patient stops eating or withdraws  May cause acceleration of decline if untreated  Recreational programs and activity therapies have shown positive results

45. Apathy v. depression in dementia  High prevalence and persistence throughout course of AD  Causes more impairment in Activities of Daily Living than expected for cognitive status  High overlap with depressive symptoms but lacks depressive mood, guilt, and hopelessness

46. Agitation or aggression- What is it?  Seen in up to 80% of patients with Alzheimer’s disease  A leading cause of nursing-home admission

47. Agitation- What do you do?  Identify context of behavior (is it harmful to patient or others?)  Identify environmental triggers (eg, overstimulation, unfamiliar surroundings, frustrating interactions)  Exclude underlying physical discomfort (eg, pain or hunger)

48. Psychosis in dementia  Seen in about 20% of Alzheimer’s disease (AD) patients  Delusions may be paranoid (eg, people stealing things, spouse unfaithful)  Hallucinations (~11% of patients) are more commonly visual

49. Psychosis- what do you do?  Determine whether delusions or hallucinations are interfering with function

50. Black box warning on antipsychotics in dementia  [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo.  cardiovascular or infectious (eg, pneumonia)  quetiapine has a lower propensity to cause extrapyramidal side effects *  risperidone not as sedating for daytime use * APA, [Rabins 2007]

51. Resources for managing dementia Attorney for will, conservatorship, estate planning Community: neighbors & friends, aging & mental health networks, adult day care, respite care, home- health agency Organizations: Alzheimer’s Association, Alzheimer’s of Central Alabama Services: Meals-on-Wheels, senior citizen centers

52. Educational Websites  Alzheimer’s of Central Alabama- support groups and daycare programs- http://alzca.org/http://alzca.org/  Alzheimer’s Association- advocacy and research info- http://www.alz.org/ http://www.alz.org/  AlzOnline- patient and caregiver education- http://alzonline.phhp.ufl.edu/ http://alzonline.phhp.ufl.edu/  Association for Frontotemporal Degeneration- theaftd.org  Lewy Body Dementia Association- http://www.lbda.org/http://www.lbda.org/  The MSA Coalition- https://www.multiplesystematrophy.org/ https://www.multiplesystematrophy.org/  www.uab.edu/alzheimers www.uab.edu/alzheimers