Alzheimer s Disease Dementia and Memory Concerns. November 17, 2018 Fresno Dharma Temple

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1 Alzheimer s Disease Dementia and Memory Concerns November 17, 2018 Fresno Dharma Temple Helena Chui, MD Director, USC Alzheimer Disease Research Center University of Southern California Los Angeles Memory Concerns How bad is it? What s causing it? What can I do about it? 1

2 Cognitive domains Executive Visual Spatial Language Episodic Memory Attention Executive Language Visual spatial Memory Attention Motivation Alertness 3 R s to Remember 3. Retrieve Frontal cortex 2. Record Hippocampus 1. Register Brainstem 2

3 Varieties of Forgetfulness Impair Registration Impair Record Button Attention deficit disorder Side effects of medications Depression Sleep deprivation Alzheimer disease Anoxic encephalopathy Herpes simplex encephalitis Hippocampal sclerosis When should I be concerned about my memory? Problems remembering things that are normally important or meaningful to you, even after paying attention, 120 Slowly progressive loss of cognitive ability: Normal aging, Mild cognitive impairment (MCI), Dementia 100 Normal aging Cognitive Capacity Presenile Dementia MCI, CDR 0.5 Dementia Senile Dementia Age 3

4 Stages of Dementia Clinical Dementia Rating Scale (CDR) 0 Normal Aging 0.5 Mild cognitive Impairment Can Compensate 1 Mild Dementia Needs help with complex activities 2 Moderate Dementia Needs help dressing 3 Severe Dementia Needs help toileting 4 Profound Dementia Needs help eating 5 Terminal Dementia Needs help with everything Ischemic Vascular Dementia IVD Study (n=612): White Japanese American Total Sample N=612 N Mean (sd) N Mean (sd) p value Age (yrs) (8.2) (6.1) 0.49 Education (yrs) (3.2) (2.2) Clinical Dementia Rating (CDR) (0.6) (0.6) 0.74 Mini Mental State Exam (MMSE) (4.9) (5.3)

5 ----- Japanese Americans Caucasian Americans Memory Concerns How bad is it? What s causing it? What can I do about it? 5

6 Hisayama Study, Japan 828 participants > 65 yrs followed for 17 years 275 persons developed dementia (32%) Alzheimer Mixed Vascular Parkinson Matsui Y et al. JNNP 2008; 80: Life-time risk of Alzheimer Disease (AD) or Stroke after age 65 years Women 15-20% Men 8-16% AD AD Age in Years Framingham Study: Stroke 2006;37:345. 6

7 Alzheimer s Disease 1907: Plaques and Tangles 1980: Misfolded Amyloid and Tau proteins Tangle (Tau) Amyloid-β Plaque Plaque (Amyloid-β) Tau The two hallmarks of Alzheimer disease are plaques (beta amyloid) and tangles (p tau). P-tau Neurofibrillary Tangles Beta Amyloid Senile Plaques Arnold et al. Cerebral Cortex. 1991;1:

8 Brain Imaging in the Diagnosis of AD Clinical Diagnosis FDA-approved Research Misfolded Proteins and Amyloid Fibrils in Neurodegenerative Disorders Fronto Temporal Dementia (FTLD) (tau or TDP 43) Alzheimer Disease (AD) (Amyloid ß; tau) Parkinson Disease (PD, DLB) (α synuclein Lewy bodies) Prion Disease (CJD) (Prion deposits) Huntington Disease (HD) (Huntingtin deposits)) 8

9 Self-propagation of pathogenic protein aggregates β-amyloid P-tau α-synuclein TDP-43 Jucker M & Walker LC. Nature 2013; 501:45-51 Observational Findings: Increased and Decreased Risk for AD Risk Factor HR > 1 Protective? HR < 1 Age Mutations in 3 genes ApoE4 (HR 2 to 10X ) Other genetic variants ApoE2 Education High cognitive activity (HR 0.6) Physical Exercise 9

10 Different Forms of Genetic Risk for AD Karch CM & Goate AM. Biol Psych 2015; 77: 93. ApoE4 gene increases risk of AD ApoE4/- Age Specific Incidence rates ApoE ApoE4 ApoE3 ApoE2 ApoE4/4 Population baseline ApoE3/3 ApoE2/- Desikan RS. PLOS 2017:

11 ApoE shuttles lipids and amyloid in the brain ApoE apoe carries lipids to repair cell membranes Toxic apoe clears amyloid from brain to blood Holtzman DM. Perspect Med and Me: Health & Ancestry My Genetic Risk 4.3 out of 100 My Name My ApoE genotype ApoE ε3/ε3 11

12 Clinical Evaluation Clinical assessment Medical history (Risk factors, Medications) Family History Daily function and behavior Mental status testing Neurologic examination Neuropsychological examination Laboratory testing Blood count, chemistry panel TSH, B12, methylmalonic acid Neuro imaging Structural brain scan: CT or MRI Molecular imaging: FDG PET, β Amyloid PET Cerebrospinal fluid (CSF): β amyloid, tau Knopman et al. Practice parameter: Diagnosis of dementia. Neurology 2001; 56: MRI Findings in AD McEvoy LK, et al, Expert Review Neurotherapy Frisconi GB, et al, Neurology, 2013 Visual Read: Sensitivity =70-60% Specificity = 75-79% 12

13 Level I: Current FDA approved Symptomatic Treatment for AD: Cholinesterase Inhibitor (CI) and NMDA receptor antagonist Drug (Brand) Generic Target (Action) Dosing Aricept (tablets and orally disintegrating tablets) FDA Approval Donepezil AChE (inhibition) 5, 10 mg q.d. Mild AD Moderate AD Severe AD Exelon Rivastigmine AChE (inhibition) BuChE (inhibition) Exelon Patch Rivastigmine AChE (inhibition) BuChE (inhibition) Razadyne ER Galantamine AChE (inhibition) nachr (modulation) 1.5, 3, 4.5, 6 mg b.i.d. (with food) 4.6 (5 cm 2 ), 9.5 (10 cm 2 ) mg/d 8, 16, 24 mg q.d. (with food) Mild AD Moderate AD Mild/Mod PDD Mild AD Moderate AD Mild/Mod PDD Mild AD Moderate AD Namenda (tablets and oral solution) Memantine NMDA Receptor (antagonism) 5, 10 mg b.i.d. Moderate AD Severe AD Patient and Family Education and Support Integrate medical care and support Alzheimer s Association (800) Alzheimer s Los Angeles (844) ALZ Direct Connect Referral Program (free case management Discuss diagnosis and treatment Report dementia diagnosis to local health office (CA law) Involve early stage patients Discuss progression Discuss end of life decisions Guideline for Alzheimer s Disease Management. California Work Group CA.pdf 13

14 ALZ Direct Connect Referral Program Blood Vessels of the Human Brain In the adult human brain, the total surface area of microvasculature is 12 m 2, the total length of capillaries is 390 miles (= distance from Los Angeles to San Francisco) Zlokovic BV; Apuzzo ML Neurosurgery. 1998; 43(4):

15 Cerebrovascular Tree From Pial Arteries to Capillaries Iadecola, C. Neuron 2017;96:

16 Risk Factors for Coronary Heart Disease and Stroke Age Male > 45 yr; Female > 55 yr Female with premature menopause without estrogen replacement High LDL Cholesterol Low HDL cholesterol (< 35 mg/dl) Note: HDL > 65 mg/dl is protective Hypertension Diabetes mellitus Current cigarette smoking Atherosclerosis Large Vessel Disease Hyperlipidemia Smoking 16

17 Arteriolosclerosis Small Vessel Disease Hypertension, Diabetes Retinal photography Progressive loss of vision results from damage to capillaries in the retina 17

18 Stroke results from sudden blockage or breakage of arteries and loss of blood flow to the brain (Brain Attack) 35 Vascular disease leads to stroke and other forms of brain Injury Major artery infarcts Small artery infarcts White matter hyperintensities Microbleeds 18

19 Discontinue smoking Treatment of VCID Manage vascular risk factors (hypertension, hyperlipidemia, diabetes mellitus) Antiplatelet medications for secondary stroke prevention Anti coagulation for atrial fibrillation Healthy diet Aerobic exercise Part II: What can we do? November 17, 2018 Fresno Buddhist Temple Helena Chui, MD Director, USC Alzheimer Disease Research Center University of Southern California 19

20 What can I do? Join a Research Study Lifestyle Resolutions Research at USC ADRC Neuroimaging Informatics Stevens Institute Basic Science Zilkha Neurogenetics Institute (ZNI) Clinical Trials Alzheimer s Therapeutic Research Institute (ATRI) Clinical Research Alzheimer s Disease Research Center (ADRC) 20

21 Observational Study: No study medications Annual Evaluation (history and physical exam) Annual Memory Tests (neuropsychology) Laboratory studies (blood) Brain imaging every 1-2 years (MRI) Molecular brain imaging (PET scan) Cerebrospinal fluid (CSF) evaluation Ischemic Vascular Dementia IVD Study (n=612): White Japanese American Total Sample N=612 N Mean (sd) N Mean (sd) p value Age (yrs) (8.2) (6.1) 0.49 Education (yrs) (3.2) (2.2) Clinical Dementia Rating (CDR) (0.6) (0.6) 0.74 Mini Mental State Exam (MMSE) (4.9) (5.3) /75 = 44% of Japanese Americans were from Fresno! 21

22 Continuous MRI measures (% intracranial volume) T 2 -Weighted Lacune Proton Density T 1 -Weighted Cortical Gray Matter Hippocampus WML Cortical GM WML or WMSH Segmented Image Lacune Percentage of IVD participants with vascular factors White Japanese Hypertension Hyperlipidemia Diabetes mellitus Coronary artery disease Stroke 22

23 ----- Japanese Americans Caucasian Americans Model Derived Cognitive Trajectories for Hypothetical Cases: Normal Controls Mungas et al., Neurology 2005; 65:

24 AD: Defined by HIP and CGM Mungas et al., Neurology 2005; 65: 565. AD + SIVD: Addition of LAC event at years 2 and 4 Affects EXEC rather than MEM Mungas et al., Neurology 2005; 65:

25 Rush Memory & Aging Project and Rush Religious Orders Studies Combined (N=856 autopsies) Boyle, PA 2013 MRI and PiB PET in pure VBI and mixed AD/VBI Rho JH. Journal of Stroke 2014;16(1):

26 Aging Brain Program Project: PiB+ versus PiB PIB + (n=22) PIB (n=44) p values Age ± ± Sex (M/F) 19/3 29/ Education ± ± MMSE ± ± CDR (64%) 17 (39 %).055 PIB uptake 1.46 ± ± ** FCRP score ± ± ApoE4 7 (35%) 7 (18%).145 Reed BR et al. JAMA Neurology 2014;71: The Aging Brain Study (n=61) Docosahexanoic acid (DHA) An essential fatty acid Lower DHA quartile level was associated with greater brain amyloid retention DHA (% total fatty acids) was inversely correlated with PiB Index, in both E4 and non-e4 carriers Yassine H. et al. JAMA Neurology 2016; 73:

27 LDL Cholesterol is associated with increased; while HDL cholesterol is associated with decreased brain amyloid Correlation between LDL- C(left) and LDL-C (right) and PIB index, controlling for HDL-D (left ) o r LDL-C (right panel), age, sex apoe4 status Reed BR et al. JAMA Neurology,in press. HDL Cholesterol may be protective? associated with less brain atrophy in amyloid positive subjects (n=22) A HDL cholesterol A G P=.0001 P=.05 P=.0001 Aβ = -.14 (p=.o7); HDL = +.45 (p<.00); Interaction =.36 (p=-01) Villeneuve S, et al. Neurology 2014; 83:

28 Clinical Trial: Comparison of Study Medication vs. Placebo Baseline Evaluation to determine Eligibility (Inclusion/exclusion criteria) History, physical exam, neuropsychological tests Laboratory studies (blood, CSF, urine, EKG) Brain imaging (MRI/PET) Random and blind assignment to receive study medication versus placebo for 1-2 years. Scheduled follow-up visits measure outcomes (memory and everyday function, brain imaging) monitor safety. Randomized Clinical Trials (RCT) Earlier the better Prevention MCI AD Dementia

29 15 years + 2 billion dollars for 1 FDA approved drug Drug Development Pipeline Drug Research in Alzheimer s disease Mangialasche F, Lancet Neurology 2009; 9:

30 Aducanumab removes amyloid from brain Sevigny J. et al Nature 217; 537: The Problem: Enrollment Bottle Neck in Preclinical Asymptomatic AD Trials Screening evaluation very time consuming Screen fail rate may be 80 90% Need a pool of well characterized patients for trials 30

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32 What can I do to improve my brain health? Personalized Risk Assessment Personal Lifestyle Resolutions Mid-life Risk Factors for Dementia after 25 years: Atherosclerosis Risk in Communities (ARIC: n=15,744) Risk Factor Increase in Risk Age 2x every 5 years ApoE4 gene 1.98 Diabetes 1.77 Hypertension 1.39 Gottesman RF et al., JAMA Neurology

33 23 and Me: Health & Ancestry My Genetic Risk 4.3 out of 100 My Name My ApoE genotype ApoE ε3/ε3 What is my risk of heart or brain attack? 33

34 8 Sleep Well Physical Exercise: 150 min/week 1. Maintains cerebrovascular integrity 2. Reduces vascular risk factors 3. Stimulates release of neurotrophins 4. Reduces cortisol and levels of stress Health Cumulative 30 min/day 5 7 times per week Gardening, walking 50 85% max heart rate Fitness > 30 minutes 3 5 times per week Running, swimming 60 90% max heart rate 34

35 Daily Goal: 1-2 grams of omega-3 fatty acids Fish sources (4 oz serving) High content = 3 gram Chinook salmon, Tuna, Lake Trout, Sardines, Herring, Mackerel Medium content = 2 gram Pink/red/coho Salmon Fair content = 1 gram Bass, Catfish, Cod, Grouper, Hake, Halibut, Kingfish, Perch, Pollock, Shark, Rainbow Trout, Skipjack Tuna, Crab, Oysters, Blue Mussel, Shrimp, Squid Plant sources Flaxseed oil, 1Tbsp = 8 g Canola oil, 1 Tbsp = 1.5 g Soybean oil, 1 Tbsp =1.2 g Peanut Oil Soybeans, cooked, ½ cup, 4 oz = 0.5 g Walnuts, ½ oz = 0.5 g Thank you to Los Angeles and Orange County Aging Brain Research Study Participants February 24, 2014 Thank you Fresno! November 17,