Preventing Cognitive Decline and Dementia: The Glenn Biggs Institute for Alzheimer s and Neurodegenerative Diseases

Transcription

1 Preventing Cognitive Decline and Dementia: The Glenn Biggs Institute for Alzheimer s and Neurodegenerative Diseases Sudha Seshadri, MD Founding Director, Glenn Biggs Institute for Alzheimer s and Neurodegenerative Diseases Robert R. Barker Distinguished University Chair Professor of Neurology, Psychiatry and Cellular and Integrative Physiology San Antonio Geriatric and Palliative Education (SAGE) Symposium: September 27th, 2018 NIA: U01 AG049505, R01 AG033040, R01 AG R01 AG049607, U01 AG052409, R01 AG NINDS: R01 AG017950, UH2 NS NIDDK, NHLBI, Alzheimer Association

2 Disclosure No conflicts of interest

3 Learning Objectives- 1 Various lifestyle factors that could change the rate of cognitive decline and risk of dementia Life course impact of lifestyle factors; need to start early to have a public health impact Need for further clinical trials to understand How and why a lifestyle intervention may or not benefit cognitive aging Effect of genetics, environment, dose and timing of intervention 3

4 Outline What are Normal and Abnormal Cognitive Decline? What Are Dementia and Alzheimer Disease? How Can We Prevent Dementia? How Can We Help Patients and Care Partner s Today? 4

5 Prevention Cognitive Decline is a Continuum Early life Risk/Reserve Factors Subjective Cognitive Impairment Mild Cognitive Impairment (MCI) Dementia Cognitive Continuum Success of Intervention Prevention Needs to Start Early!

6 Memory Loss: Amnesia, Agnosia Losing or Misplacing things Repeating questions Difficulty learning new things Rapidly forgetting recent events Not remembering even with clues Making things up Orientation to time, place and person Knowing Objects by Sight, Navigating Spaces

7 Language: Aphasia Speaking Less Trouble Finding Right Words Difficulty with Names Speech is Garbled or Strange (neologisms) Simplification of Communication Difficulty Understanding Losing More Recently Learnt Language

8 Attention, Initiative and Executive Function: Loses Interest Less Insight Less Initiative or disinhibited Judgment impaired; falls for scams Behavior Problems Sleep & Eating disturbances Depression & Anxiety Incontinence Hallucinations, Delusions, Paranoia Agitation, Wandering Reasoning diminished Problem Solving Harder; less safe in emergencies, challenges Organizational Skills impacted Apraxia

9 9 What determines Cognitive Reserve? What Determines Rate of Decline? Cognitive Reserve Pathologies causing decline Aging-related decline Cognitive Function Clinical Dementia Threshold Is it Dementia? Or Drugs Depression Deficiency (B12) 0 Age Diseases of body

10 Outline What is Normal and Abnormal Cognitive Decline? What Are Dementia and Alzheimer Disease? How Can We Prevent Cognitive Decline? How Can We Help Patients and Care Partner s Today? 10

11 Brain has Neurons, Glia, Vessels Genes in Developmental Pathways also important in aging, response to injury: GBA in Gaucher s and Parkinson s TREM2 in Nasu-Hakola and Alzheimer s

12 Persons with Dementia Emerging concept: Whether clinical dementia develops depends on Cognitive Reserve and Number and Severity of Pathologies Normals

13 AD is a subtype of dementia Dementia is a syndrome Mostly Due to Alzheimer Disease and Vascular Disease AD is a neurodegenerative disease 2 hallmark features Frontotemporal dementia Neurofibrillary tangles Neuritic plaques Dementia with lewy bodies Parkinson s Dementia Mixed (VD+AD) Accumulation of an abnormal form of the protein tau inside neurons Progressive accumulation of the protein beta-amyloid Aβ outside neurons Vascular Contributions (VCID) Alzheimer s disease (AD) Most prevalent subtype of dementia Exam, Blood Tests, Brain Imaging 13

14 EOAD, Autosomal Dominant, Randall Bateman, MD Phd WUSTL ~5% of all AD is early-onset PSEN1: Chr 14, 219 mutations, 77% PSEN2: Chr 1, 16 mutations, 5% APP: Chr 21, 51 mutations, 17% Down s PSEN1, PSEN2 APP APOE + other genes Age in yrs ε ε2 20 yrs 40 yrs yrs 4 80 yrs Early Late Modified from Elliott, Love 2004

15 IGAP AD Mega-meta Manhattan plot 30+ Alzheimer genes identified to date Expressed in neurons, but also in astrocytes and microglia Some drugs seem to work only with certain genetic variants

16 Big Ideas in Treatment Alzheimer is not all one disease Understanding, leveraging these differences Collaborative Many Biological Patient Pathways Registry = Many Drug Targets Longevity = Cognitive Resilience? Analyze trial datasets Genetic and Phenotypic details Design targeted trials Design easy-to-use markers For each a unique cocktail!

17 Tau and amyloid Alzheimer Dementia Synuclein and amyloid Lewy Body Dementia Tau and ubiquitin/tdp-43/ FUS Frontotemporal Dementia

18 Memory and Orientation: Alzheimer Dementia Visuospatial and executive functions: (Parkinsonism, REM sleep disorder, visual hallucinations) Lewy Body Dementia Language, Behavior Frontotemporal Dementia

19 Genetics of FTD Each gene is known to cause diverse types of Many genes Complex gene to phenotype relations Interesting and novel biology

20 Figure 1. (A) Quan Yin, watercolor on paper FTD may release artistic abilties Mell, J. C. et al. Neurology 2003;60:

21 Figure 2. (A) Chinese Horoscope Figure, lithograph Mell, J. C. et al. Neurology 2003;60:

22 Figure 3. (A) Early Cafe Drawing, ink on paper Mell, J. C. et al. Neurology 2003;60:

23 NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease Clifford R. Jack, David A. Bennett, Kaj Blennow, Maria C. Carrillo, Billy Dunn, Samantha Budd Haeberlein, David M. Holtzman, William Jagust, Frank Jessen, Jason Karlawish, Enchi Liu, Jose Luis Molinuevo, Thomas Montine, Creighton Phelps, Katherine P. Rankin, Christopher C. Rowe, Philip Scheltens, Eric Siemers, Heather M. Snyder, Reisa Sperling Cerise Elliott, Eliezer Masliah, Laurie Ryan, Nina Silverberg Clifford R. Jack, David A. Bennett, Kaj Blennow, Maria C. Carrillo, Billy Dunn, Samantha Budd Haeberlein, David M. Holtzman, William Jagust, Frank Jessen, Jason Karlawish, Enchi Liu, Jose Luis Molinuevo, Thomas Montine, Creighton Phelps, Katherine P. Rankin, Christopher C. Rowe, Philip Scheltens, Eric Siemers, Heather M. Snyder, Reisa Sperling Cerise Elliott, Eliezer Masliah, Laurie Ryan, Nina Silverberg Alzheimer's & Dementia: The Journal of the Alzheimer's Association Volume 14, Issue 4, Pages (April 2018) DOI: /j.jalz Copyright 2018 The Authors Terms and Conditions

24 Alzheimer's & Dementia: The Journal of the Alzheimer's Association , DOI: ( /j.jalz ) Copyright 2018 The Authors Terms and Conditions

25 67 y/o cognitively normal man A+/T-/N- (Preclinical Alzheimer Disease) Should we just call it cerebral amyloidosis? Cost! Ethical Concerns Blind to other pathways?? Avoid a PSA type danger? Alzheimer's & Dementia: The Journal of the Alzheimer's Association , DOI: ( /j.jalz ) Copyright 2018 The Authors Terms and Conditions

26 Woman with Clinical Dementia of the Alzheimer Type, no amyloid A-/T-/N+ (Suspected non-ad pathology) or SNAP Alzheimer's & Dementia: The Journal of the Alzheimer's Association , DOI: ( /j.jalz ) Copyright 2018 The Authors Terms and Conditions

27 Outline What is Normal and Abnormal Cognitive Decline? What Are Dementia and Alzheimer Disease? How Can We Prevent Dementia? How Can We Help Patients and Care Partner s Today? 27

28 The Crisis in Texas Texas has 3 rd largest number of persons with AD 2 nd in deaths due to AD Less well studied Harder to reach: 1% of trial subjects 2 of every 5 Texans is Hispanic Hispanics have 30-50% higher risk Higher care burden Among HISPANICS, expect 6X increase in Numbers by 2050! 28

29 The Problem / Challenge 5.7 Million with Alzheimer s Disease in the US 1 in 3 die with AD or another dementia Only Leading Cause of Death Trending UP, not down 16.1 Million Care Partners are affected Costs the US, $277 Billion/Year 1 in 6 caregivers is under % of household wealth dissipated in care If UNCHECKED, Expect TRIPLING (3X) of THESE NUMBERS by 2050!

30 Is there a Solution? Vision: Alzheimer In 10 years Third: Preventable Third: Slow Progression Reverse some Symptoms Third: Non-progressive How? Understand Biology Prevention Personalized Rx

31 FRAMINGHAM HEALTH STUDY 3 generational, life course, community-based study

32 Big Ideas in AD Prevention: Ref. The Monster Can Be Beat!! -22% -38% -44% 5-year epochs Mean age when symptoms began, in years What are we doing right? Control of BP, Stroke, Atrial fibrillation NO DATA exist on trends In Hispanics and Native Americans

33 Cause for Favorable Dementia Trends: Societal/Lifestyle Factors? Prenatal Care, Education & Nutrition: Reserve Unknown factors: Infections, Lead, Pollution Cognitive engagement, hearing Physical activity/fitness/sedentary time Diet Sleep Social interactions Stress

34 Mediterranean MIND Wine (little) Fish (Omega-3) Ketogenic

35 Neurology Less REM, higher dementia risk Xie et al., Science 2013

36 Exercise, Caloric Restriction Social Networks BDNF Greater emotional support = 30% more BDNF and 30% lower 10-year risk of dementia

37 Life Course Impact of VRF Pre-natal factors (smoking, diet) Childhood, young adult (education, diet, fitness) Midlife (fitness, obesity, BP, diabetes, toxins) Late-life (BP, Rapid weight loss, Social Networks, Physical activity, Cognitive Engagement, Mood) Need to understand: dose, duration, interactions including with age, race, genes causal pathways: inflammation, oxidative stress etc.

38 AGE Figure 5 Number of patients with white-matter hyperintensities at a voxel location Pauline Maillard, Sudha Seshadri, Alexa Beiser, Jayandra J Himali, Rhoda Au, Evan Fletcher, Owen Carmichael... Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study The Lancet Neurology Volume 11, Issue Among 579 young middle-aged (45+9) healthy individuals, elevated SBP has a subtle, negative effect on WM microstructural integrity, especially in the corpus callosum. This reinforces the view that vascular brain injury may develop insidiously over several decades.

39 Figure 3 Cerebral regions in which decreasing grey-matter volumes were significantly associated with increasing systolic blood pressure (A) and age (B) The voxel-based regression included grey-matter probability as the dependent variable and age and systo... Pauline Maillard, Sudha Seshadri, Alexa Beiser, Jayandra J Himali, Rhoda Au, Evan Fletcher, Owen Carmichael... Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study The Lancet Neurology Volume 11, Issue

40 Figure 4 Regression curves relating brain integrity as expressed by the first principal component as a function of the hypertension category and age of the individual (A) and the difference in brain ageing increase between hypertension categories according... Pauline Maillard, Sudha Seshadri, Alexa Beiser, Jayandra J Himali, Rhoda Au, Evan Fletcher, Owen Carmichael... Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study The Lancet Neurology Volume 11, Issue Hypertensive 40 year old had loss of brain integrity equivalent to normotensive person aged 47 years

41 Individualized Prevention in AD Risk Stratification: clinical, genetics, markers Interventions: Need to Specify Exercise, Diet, Cognition, Multimodal interventions FINGER, MAPT, PreDIVA trials; POINTER trial A4 trial and A3 trials Based on amyloid PET Alzheimer Prevention Initiative Trials Based on E4 status

42 Dementia Risk Prediction Congress has passed an act requiring cognitive screening at Medicare Annual Wellness visit But there is concern about high % of false +ves Dementia Risk Assessment Framingham Study - Cardiovascular Health Study Sacramento Area Latino Study of Aging -Health & Retirement Study Age, Education, BMI, DM, Stroke, Money/Meds, Depression

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44 Trials to Prevent/Postpone Clinical AD Multidimensional interventions: Finnish FINGER imported here FINGER Pre-DIVA MAPT etc. Need Single Domain Interventions to understand details Add standard cognitive assessments to trials on VRF (ACCORD-MIND, SPRINT-MIND, VITAL etc. to study effects of Diabetes, Hypertension, Vitamin D)

45 Accelerometry suggests: Any Steps are Better than None; Do not need Moderate to Vigorous Activity Steps/day in persons not meeting MVPA guidelines Associated with larger MRI brain volumes Nicole L. Spartano, PhD Current T32 fellow AHA Grant DOSE Zaldy. Tan, MD, MPH Former FHS Fellow, Assoc Prof., Geriatrics, UCLA

46 Intervene at What Stage? Age? 46

47 Genes Determine Rate pf Cognitive Decline in All Cognitive test score declines for 3,673 non-carriers of A673T and 41 carriers of A673T (average of 6.5 determinations of cognition /person)

48 Gene-Environment Interaction Lifestyle, risk factor data and gene-environment interactions Having an APOE e4 allele increases extent of brain injury in persons with vascular risk factors Val66Met mutation in BDNF moderates benefit of physical activity on memory Exercise improves memory performance more in BDNF Val66Met Met carriers

49 Prevention: Public Health Messaging Despite Variations that will require Precision Medicine Approaches There remains a major role for public health approaches that will benefit most, albeit to varying extents

50 Big Ideas In AD Prevention Preclinical phase of 20+ years: Opportunity! Biomarkers can help identify persons at higher risk Blood, genetics, eye, walking Healthy Lifestyle Helps 1 point more on American Heart Associations Simple 7 = 3.5 years less cognitive decline, brain shrinkage Pase et al., Stroke 2016 Never Too Early to Start Prevention Impact of being diabetic is 6 years of brain aging at 65 ~20 years at age 42! Weinstein et al., Neurology 2015 BP Control Physical Activity Cognitive Enrichment

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52 Outline What is Normal and Abnormal Cognitive Decline? What Are Dementia and Alzheimer Disease? How Can We Prevent Dementia? How Can We Help Patients and Care Partner s Today? 52

53 Mission: The Care Family Goal: Superb Care & Research at one stop Comprehensive Neurologists, Psychiatrists, Neuropsychologists, Mid-level Providers, Counselors, Social Worker, Nurse, Dietician, Occupational-, Physical-, Speech- therapists, Cognitive Rehab Healthy Brain Clinic: Preventing Dementia Familial Dementia, FTD/ALS, Parkinson s/dementia with Lewy Bodies Geriatric Medicine, Palliative, and End-of-Life Care (CCPD Clinic) Sleep, CTE, PTSD, Cancer Caring for the Caregiver Preventing Elder Neglect and Abuse Resources for Caregivers Clinical Trials 53

54 Drugs Entering Trials Are Now More Diverse 54

55 Why Do We Need More Trials? Dementia is not all one disease Understand and use the differences Precision Medicine Approach Study each patient carefully, throughout their course Link up with other centers world-wide Design targeted trials 55

56 The Scientist, Community and Patient Partnership Sharing Your Story Some details of diet, exercise, sleep, lifestyle Your medical records here and outside Your response if you enroll in a clinical trial Sharing Your Biological Markers Leftover Blood Sample Genetic Information Sharing Worldwide Deidentified information Ethical, Legal Concerns Precision Medicine Needs You - Registry, lifestyle, imaging data - Medical records linkage - Biobank, brain bank 56

57 Genetics and Biomarkers: How Could These Help? Prediction of Risk Planning the Future Targeted Prevention Trials e.g. The Right Diet The Right Drug Trial Finding Your Biological Counterparts Worldwide Precision Trials Safer Prescribing Understanding differences in side-effects, response 57

58 Big Ideas in Care Partner with the Experts Persons with Dementia Their Care Partners Everyone else- the worried Understand and Educate Synthesize, implement, verify, advocate Dementia Friendly Cities: Oct 4 th, UTHSA

59 Thanks!! To All of You Supporters, Advisors, and a Growing, Dedicated Biggs Team 59