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1 #CHAIR2015 September 24 26, 2015 JW Marriott Miami Miami, Florida Sponsored by

2 Case Challenge Workshop Alzheimer s Disease Anand Kumar, MD University of Illinois at Chicago, College of Medicine Chicago, IL

3 Anand Kumar, MD Disclosures Other Financial Interest: Associate Editor, The American Journal of Geriatric Psychiatry

4 Learning 1 Objective Implement routine cognitive screening to facilitate early identification and early intervention of Alzheimer s disease.

5 Learning 2 Objective Partner with patients and caretakers to openly and compassionately discuss the diagnosis of AD.

6 Learning 3 Objective Discuss the role and clinical utility of biomarkers and imaging for current use in the diagnosis and early intervention in AD..

7 Clair Rosemont Clair R is a 62 year old Caucasian woman who presents with a chief complaint of occasional forgetfulness; her husband insisted that she speak with a doctor about it. She works as an office temp and states that she sometimes looses her place in a paper that she may be typing, misplaces her desk items in the office, just feels not as sharp as she used to.

8 Differential Diagnosis It is important to differentiate normal agerelated cognitive changes from MCI or dementia. Depression is an important consideration in the differential diagnosis of Alzheimer s disease (AD). Depression is a common presentation or comorbidity in AD Teng E, et al. Am J Geriatr Psychiatry (6):

9 Clair Rosemont: History Her past medical history includes osteoarthritis since age 45 She is overweight but otherwise relatively healthy, walks to work every day Standard laboratory blood workup is negative except for mild hypercholesterolemia Neurologic exam unremarkable Family history includes a maternal uncle with dementia who is in his 90 s

10 Risk Factors 1 Increasing age Family history Female gender Past head trauma APOE-4 allele Cardiovascular dysfunction Type 2 Diabetes Down Syndrome MCI Low levels of education Removal of ovaries 2 Depression 1. National Institute on Aging. Preventing Alzheimer s Disease: What Do We Know? Risk Factors for Alzheimer s Disease. NIH Website Updated March 21, Parker WH, et al. Womens Health (Lond Engl). 2009;5(5): PMID:

11 The Projected Effect of Risk Factor Reduction on Alzheimer s Disease Prevalence Estimated number of Alzheimer s patients 5 million in US 34 million worldwide Modifiable risk factors: Low education, smoking, physical inactivity, depression, hypertension, diabetes, obesity Projected effect of a 25% risk factor reduction: US: 3 million fewer cases Worldwide: 17 million fewer cases Barnes DE, et al. Lancet Neurol. 2011;10(9): PMID:

12 Protective Factors of AD Protective genes Intellectual activity Higher levels of education Good overall health/vascular health Merril DA, et al. Psychiatr Clin North Am. 2011;34(1): PMID:

13 Warning Signs Suggestive of (Early) AD The Alzheimer's Association has compiled a list of warning signs suggestive of (early) AD. Memory loss that disrupts daily life Difficulty completing familiar tasks at home, work or leisure Global changes in mood or personality, such as becoming confused or anxious Poor judgment when dealing with money or making decisions Misplacing belongings (and finding them in unusual places) Difficulties in planning or solving problems (such as difficulty following a familiar recipe or taking much longer to accomplish familiar activities) Alzheimer s Association. Updated 2015

14 Next Steps Mini-Mental Status Exam (MMSE) score is 24/30 an her clock drawing is good. PHQ-9 no evidence of depression

15 The Continuum of Alzheimer s Disease Cognitive Function Years Sperling RA, et al. Alzheimers Dement. 2011;7(3): PMID:

16 Preclinical Phase Conceptual Phase Early evidence of AD pathophysiology APOE4 allele Autosomal dominant mutations PS1, PS2 ADP biomarkers Do not meet criteria for MCI/AD Sperling RA, et al. Alzheimers Dement. 2011;7(3): PMID:

17 Alzheimer s Disease (AD) Probable AD Amnestic Presentation Non-Amnestic Presentation Language Visuospatial Executive dysfunction Decline from previous level of functioning Insidious onset Prominent cognitive deficits Interfere with ability to function McKhann GM, et al. Alzheimers Dement. 2011;7(3): PMID:

18 Possible AD Atypical course Etiologically mixed presentation a) Vascular b) Lewy Body c) Other McKhann GM, et al. Alzheimers Dement. 2011;7(3): PMID:

19 Probable/Possible AD With evidence of AD pathophysiology Clinical presentation PLUS a) Increased PiB binding b) CSF increase in total/phosphorylated tau c) CSF decrease in Aβ42 d) Decrease FDG metabolism e) Hippocampal atrophy PiB = Pittsburgh Compound B; Aβ42 = Abeta42; FDG = fluorodeoxyglucose McKhann GM, et al. Alzheimers Dement. 2011;7(3): PMID:

20 Mild Cognitive Impairment (MCI) Concern about change in cognition Impairment in 1 or more cognitive domains Memory, learning, executive function, visuospatial 1.5 standard deviations from the norm Preservation of independent functioning No dementia no social, occupational, functional impairment Albert MS, et al. Alzheimers Dement. 2011;7(3): PMID:

21 Mrs. Rosemont Makes A Request Mrs. Rosemont and her husband, after some Internet research, are requesting a PET scan to assess volume of amyloid plaques They also request assessment for CSF biomarkers Their insurance company declined coverage, so they agreed to pay themselves. They want to know what is in store for them

22 Biomarkers of Alzheimer s Disease Markers of amyloid-β accumulation Amyloid- β in cerebrospinal fluid PET amyloid imaging using 11C-Pittsburgh compound B or 18F radiotracers to bind to fibrillar amyloid-β Markers of neurodegeneration Tau and phospho-tau in cerebrospinal fluid Markers of neuronal activity Functional MRI measures of task-based neuronal activation, and resting neuronal connectivity Markers of neuronal loss MRI measures of cortical thinning, hippocampal volume, and whole-brain volume Markers of synaptic dysfunction 18F-fluorodeoxyglucose PET Langbaum JB, et al. Nat Rev Neurol. 2013;9(7): PMID:

23 PET Amyloid Ligands [ 18 F]FDDNP (2-(1-{6-[(2-[ 18 F]fluorethyl) (methyl)amino]-2-naphthyl}-ethylidene) malononitrile) FDDNP 1,2 [ 11 C]PIB (2-(4 -[ 11 C]methylamino)phenyl-6- hydroxybenzothiazole) - PIB 1,2 [F-18]3 -F-PiB (flutemetamol) 3 [F-18]AV-45 (florbetapir) 3 [F-18]-BAY (florbetaben) 3 1. Shoghi-Jadid K, et al. AmJ of Geriatr Psychiatry. 2002;10(1): PMID: Klunk WE, et al. Ann Neuro. 2004;55(3): PMID: Johnson KA, et al. Alzheimers Dement. 2013;9(1):e-1-e16. PMID:

24 Biomarkers in AD Biomarkers of Aß deposition Spinal fluid Aß levels (low) PET amyloid imaging (high) Biomarkers of neuronal injury Spinal fluid tau levels (high) MRI looking at hippocampus, temporal lobe or whole brain (smaller) FDG-PET (areas of reduced metabolism) SPECT (areas of reduced blood flow) McKhann GM, et al. Alzheimers Dement. 2011;7(3): PMID:

25 Amyloid Imaging in AD and MCI Florbetapir PET Amyloid Positivity by Diagnosis Doraiswamy PM, et al. Mol Psychiatry Sep;19(9): PMID:

26 Clinical Significance Higher binding in AD vs. controls Tracks progression from MCI to AD 1. Small GW, et al. N Eng J Med. 2006;355(25): PMID: Morris JC, et al. Arch Neurol. 2009;66(12): PMID:

27 DSM-5 & Diagnostic Markers DSM-5 language includes a description of biomarkers to aid in diagnosis Computed tomography (CT) or structural magnetic resonance imaging (MRI) may show distinct patterns of atrophy Emerging biomarkers for Alzheimer s disease (e.g., cerebrospinal fluid amyloid-beta and tau levels, and amyloid imaging) may help in the differential diagnosis Biomarkers need to be validated American Psychiatric Association. Diagnostic and Statistical Manual. American Psychiatric Press 2013.

28 Mrs. Rosemont s Results Mrs. Rosemont s PET scan was amyloid positive comparable with an individual with MCI. Her CSF analysis showed: spinal fluid Aß levels (low) spinal fluid tau levels (high)

29 Analysis of Results Biomarkers and PET suggest early AD Now what do we do?

30 Alzheimer s Disease Medication Facts Drug Name Memantine Galantamine Rivastigmine Donepezil Combination Memantine/ Donepezil Manufacturer s Recommended Dosage Tablet: initial dose of 5 mg 1/day May increase dose to 10 mg/day, 15 mg/day, 20 mg/day at minimum 1- week intervals if well tolerated Tablet: initial dose of 8mg/day May increase dose to 16 mg/day and 24 mg/day at minimum 4-week intervals if well tolerated Capsule: initial dose of 3 mg/day May increase dose to 6 mg/day, 9 mg/day, and 12 mg/day at minimum 2-week intervals if well tolerated Tablet: initial dose of 5 mg 1/day May increase dose to 10 mg/day after 4-6 weeks if well tolerated, then to 23 mg/day after at least 3 months Capsule: 28 mg memantine ER+ 10 mg donepezil QD 14 mg memantine extended-release + 10 mg donepezil once a day (for patients with severe renal impairment) National Institute on Aging. Alzheimer's Disease Genetics Fact Sheet. NIH Updated: July 16, Accessed August 20, 2014.

31 Various Therapeutic Drug Targets in AD Targeting Ab protein (anti-amyloid approach) Targeting tau protein Modulating levels of neurotransmitter Other pharmacotherapeutic strategies Targeting amyloid transport Inhibition of tau phosphorylation Acetylcholinesterase inhibitors (AChEIs) Cholesterol lowering drugs Modulation of secretase enzymes Targeting microtubule stabilization Modulation of GABAergic neurons Neuroprotective gonadotropin hormones Targeting amyloid aggregation Blocking tau oligomerization NMDA receptor antagonism Neurogenesis Targeting amyloid clearance Enhancing tau degradation Modulation of serotonin receptor Epigenesis Amyloid based vaccination therapy Tau based vaccination therapy Histaminergic modulators Kumar A, et al. Pharmacol Rep Apr;67(2): PMID:

32 Mrs. Rosement Has Questions for You Am I going to develop dementia? If so when? What can you do to prevent this from happening?

33 Sharing Results of Diagnosis with Patients and Families When discussing results, include family members or others providing care Find a private/quiet location and schedule ample time for the visit Find out about their concerns and understanding of the disease and meaning of tests Explain findings, implications and limitations of results Address concerns about prognosis, expectations, and treatment options Grossberg ET, et al. Prim Care Companion J Clin Psychiatry. 2010;12:PCC.09cs PMID:

34 Clinical Connections Early screening for neurocognitive disorders can improve recognition and clinical management It is important to educate patients about the modifiable and non-modifiable risk factors for AD Biomarkers such as CSF and PET have the potential to improve early detection of AD

35 Questions & Answers

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