Standard Deviations from Mean Memory Matters: Preventing and Treating Late-Life, Cognitive Decline Daniel L. Murman, MD, MS Director, Behavioral and Geriatric Neurology Program Professor & Vice Chair, Clinical and Translational Research Department of Neurological Sciences University of Nebraska Medical Center DISCLOSURE DECLARATION Dr. Murman has the following financial relationships: Grants/Research Support in the area of Alzheimer s disease clinical trial research: Eli Lilly & Co, Novartis, Roche, Genetech, and National Institutes of Health Learning Objectives: Understand the effects of aging on cognition and factors that can slow or accelerate decline Describe mild cognitive impairment and the most common causes of dementia List tools that can be used in evaluating cognitive decline in older adults Discuss the pathophysiology of Alzheimer s disease and experimental treatment approaches Know the important role of primary care providers in managing symptoms of dementia 1.5 1 0.5 0-0.5-1 -1.5 Cognition and Normal Aging Crystallized Abilities (Vocabulary) Fluid Abilities (Processing Speed) 20 30 40 50 60 70 80 Age (years) Murman, Semin Hear 2015; 36:111-21. Neuronal Synapses Synapses, Age, and Health Healthy Aging Disease 1
Synaptic Density (% of maximal) Synaptic and Cognitive Reserve Synapses are created and strengthen with learning and mentally stimulating activities Having more synapses builds redundancy in neuronal connections and systems and creates cognitive reserve Synapses are gradually lost with normal aging and much more rapidly with disease Greater cognitive reserve delays symptoms onset in the face of neurodegenerative diseases such as Alzheimer s disease Cognitive Decline with Age and Disease 100 90 80 70 60 50 40 30 20 10 0 25 50 75 100 125 150 Age (years) Normal Reserve/Normal Aging Normal Reserve/Normal Aging + AD Normal Reserve/Slower Aging Decreased Reserve/Normal Aging Dementia Threshold Murman, Semin Hear 2015; 36:111-21. Factors that Increase or Decrease Risk of Cognitive Decline Factors that Increase or Decrease Risk of Dementia Baumgart et al. 2016 Alzheimer s & Dementia Baumgart et al. 2016 Alzheimer s & Dementia Lifestyle for Brain Health Aging, MCI, and Dementia oexercise Regularly omentally Engaged ohealthy Diet osocially Connected ocontrol HTN, Lipids, DM ogood Sleep oavoid Toxins/Head Trauma Alzheimer s Association 2
Types of Dementia Dementia is the loss of memory due to changes in the brain Alzheimer s is the most common form Many mixed cases Many memory disorders are reversible and not truly dementia 3 Alzheimer s Disease Most common cause of dementia Gradual onset, gradual progression Memory loss first and most prominent symptom No focal findings or gait disorder early Genetic causes and genetic risk factors Becomes exponentially more common with age 3-5% of population at age 65 30-50% of population at age 85 AD Diagnostic Red Flags Abrupt onset, stroke symptoms Rapid progression Early gait changes, tremor, parkinsonism Early visual hallucinations, disinhibition, Early loss of expressive language Early myoclonus, seizures Clinical Features of AD vs VaD Feature Alzheimer s Disease Vascular Dementia Onset Gradual, insidious Sudden or gradual Progression Constant Slow, stepwise Focal Signs Usually absent Present Memory Deficits Early and severe Milder, Subcortical Executive Dysfunction Late Early and severe Neuroimaging Normal, atrophy Vascular abnormalities Lewy Body Dementia Importance of Non-AD Dementias Cerebrovascular disease is preventable Dementia with Lewy Body (DLB) patients are at increased risk of adverse medication reactions, delirium, falls, and institutionalization. DLB patients do respond to cholinesterase inhibitors Normal Pressure Hydrocephalus is treatable Rapidly progressive dementia may represent a treatable autoimmune condition or prion disease 3
Evaluation of Memory Loss History Time course, change in function, medications, depression, alcohol, sleep Physical Exam Test cognition, signs of stroke, stroke risk, parkinsonism, gait abnormalities Basic Labs CMP, TSH, vitamin B12 (B1, B6) Brain Imaging Head CT or Brain MRI Assessment Tools: Cognition Ascertain Dementia 8 (AD8) Questionnaire Mini-Cog Mini-Mental State Examination (MMSE) Montreal Cognitive Assessment (MoCA) Formal Neuropsychological Evaluation Assessment Tools: Function Functional Activities Questionnaire (FAQ) Functional Assessment Staging Tool (FAST) Assessment Tools: Psychiatric Neuropsychiatric Inventory Questionnaire (NPI-Q) * Structural Imaging Small Vessel, Vascular Dementia Mild Moderate Severe *Contains Copies of a Variety of Assessment Tools White Matter Lesions Large Vessel Infart CSF Biomarkers in AD Micro- Hemorrhage Small Vessel Infarct Lancet 2015; 386:1698-06 4
Functional Imaging FDG-PET Alzheimer s Disease Amyloid Plaques Auguste D. Alois Alzheimer Neurofibrillary Tangles What Alois Alzheimer s saw and described in 1906 Completely Independent Reminders Assistance with IADLs Supervision Assistance With Basic ADLs Completely Dependent AD: Facts and Figures In 2014, there are an estimated 5.2 million people living with AD in the US 5 million >65 years old; 200,000 < 65 years AD is very common in Midwest 33,000 cases in NE; 62,000 cases in IA In 2014, the direct cost of dementia of care in the US was estimated at $214 billion annually AD is the 6 th leading cause of death in US, and one third of elderly adults die with dementia From 2014 AD Facts and Figures, Alzheimer s Association (www.alz.org) Costs of Dementia Care Projected Increase in AD $214 Billion Per Year in US in 2014 15 11.3 14.3 $36 $37 $28 $113 Medicare Medicaid Out of Pocket Other From 2014 AD Facts and Figures, Alzheimer s Association (www.alz.org) 10 Millions 5 0 8.7 5.8 6.8 4 2000 2010 2020 2030 2040 2050 Year Evans DA, et al. Milbank Q 1990; 68:267-89. 5
Amyloid Tau Genes and Amyloid b Amyloid Cascade Hypothesis APP Soluble p3 APP, PS1, PS2 mutations Ab 1-42 apoe e4 Plaque formation Neurofibrillary tangles Loss of synapses Inflammatory response Oxidative injury Neuronal death Toxic Effects of Amyloid b 1-42 PET Biomarkers in AD Biomarkers and Stages of AD Evolution of Amyloid and Tau Accumulation in AD Model of Disease Progression Healthy Control Asymptomatic Preclinical AD Asymptomatic Prodromal AD MCI Alzheimer s Disease Dementia Tau negative Focal tau Tau spreading Extensive tau Amyloid negative Amyloid positive Amyloid positive Amyloid positive 36 6
When Does AD Start? PET imaging studies in genetic forms of AD demonstrate accumulation of Ab 15-20 years before expected age of symptom onset. Bateman RJ et al. NEJM 2012;367:795-804. Modeling of one large cohort study suggests that Ab deposition is detected 17 years before dementia diagnosis, hippocampal atrophy 4.2 years before, and memory impairment 3.3 years before (CDR 1). Villemagne VL et al. Lancet Neurol 2013;12:357-67. Right Target at Right Time Sperling RA, Jack CR, Aisen P Sci Transl Med 2011 AD Prevention Trials Focused on Amyloid b 1. Autosomal Dominant AD Treatment Trials PSEN1 E280A Kindred crenezumab sq Dominantly Inherited Alzheimer s Network (DIAN) solaneumab IV or gantenerumab sq 2. ApoE e4 Treatment Trial (e4/e4 carriers) Active immunization BACE (beta-secretase 1) inhibitor 3. Anti-Amyloid Treatment in Asymptomatic Alzheimer s disease Positive amyloid PET - solanezumab IV AD Clinical Trial Resources Prevention Trials for Alzheimer s disease (AD) Alzheimer s Prevention Registry https://www.endalznow.org GeneMatch https://www.endalznow.org/genematch Generation Study http://www.generationstudy.com Trials for Patient s with an AD diagnosis Alzheimer s Association TrialMatch https://www.alz.org http://www.clinicaltrials.gov Primary Care Management of Patients with Cognitive Impairment is Vital! Location of first contact with the healthcare system for most patients with dementia symptoms Can identify and treat conditions worsening dementia symptoms Medications are available to help many symptoms of dementia including impairments of cognition, behavior and functional abilities Can provide education, support, community resource referrals and help keep patient in home environment longer Quality Indicators in AD Care Time Line Study Time Line Dementia Dx (ICD-9 code) and continually enrolled 2 yrs Grant begins Survey Y1 Y2 Y3 Quality of Life Grant ends Data Analysis, Presentation Chart Abstraction Process of Care Receipt of Quality Indicators Outcomes Caregiver Satisfaction Costs of Care 7
1. Evaluating Dementia Symptoms Dementia Assessments % Receiving Specific Diagnosis Made 89 Lab Test (B12, TSH) 78 Brain Imaging (CT or MRI) 74 Annual assessment of cognition* 40 Annual assessment of behavior* 39 Annual assessment of function* 46 *New Consensus Quality Measure 2. Supporting Patients and Families Psychosocial Interventions % Receiving Education Provided 80 Referral to Community Resources 62 Driving Safety Addressed* 74 Alternative Decision Maker Discussed* 67 Advanced Directives Discussed* 53 *New Consensus Quality Measure 3. Medication Use in Dementia Care Pharmacologic Treatment % Receiving Cholinesterase Inhibitor Prescribed 91 Persistent Use of Cholinesterase Inhibitor 35 Memantine for Mod. to Severe AD 52 Medication Used for Severe Psychiatric Symptoms* 57 Anti-Cholinergic Medications Avoided 89 FDA-approved Medications for AD Cognex (tacrine) - 1993* Aricept (donepezil) - 1996* Exelon (rivastigmine) - 2000* Razadyne (galantamine) - 2001* Namenda (memantine) 2003* *FDA approval date *New Consensus Quality Measure Management of: Neuropsychiatric Symptoms in AD Try to understand triggers for negative behaviors Environmental changes and engaging activities are usually more effective than medications Rule out medical condition, pain, other discomfort There are no FDA-approved medications for the treatment of neuropsychiatric symptoms in AD Treatment of: Neuropsychiatric Symptoms in AD Effective antidepressant medications are available for depression, anxiety, and agitation, with low risk of side effects Severe agitation or aggressive behavior can be controlled with atypical antipsychotic medications, but with moderate risk of side effects Antipsychotic medications may decrease hallucinations, delusions, and paranoia, but with moderate risk of side effects 8
4. Managing Co-Morbid Conditions Co-Morbid Disease Mgmt. % Receiving Antiplatelet Rx (DM, CHD, CVD) 81 If Diabetes, then yearly HgA1c 87 If Diabetes, then BS control (A1c<9%) 72 If Hypertension, then BP control <140/90 63 If DM, CHD, CVD, then lipid testing 89 Lipid control (LDL<130), if high risk grp 51 Hospital Stays, Dementia & Delirium All cause admissions rates are higher for older adults with dementia than those without (OR 1.41) Patients with dementia that are hospitalized and develop delirium have poorer outcomes: longer lengths of stay, faster cognitive and functional decline, institutionalization and death. Admission rates for ambulatory care sensitive conditions are higher for patients with dementia (OR 1.78) Fink DM, J Hosp Med 2013;8:500-505. Phelan EA, JAMA 2012;307:165-172. Fong TG, Ann Intern Med 2012; 156:848-856 Patient Outcome Mean (Std. Dev.) Patient s Health Related Quality of Life Euroqol (EQ5D; 0-1 scale) 0.61 ± 0.22 Visual Analog Scale (0-100 scale) 52 ± 20.0 Satisfaction with Patient s Healthcare Satisfaction with Health Plan (0-10 scale) 8.14 ± 2.02 Satisfaction with Primary Provider (0-10) 8.10 ± 1.99 Patient s Costs of Care Two Year Total Costs (7/2003 6/2005): $21,479 ± $45,164 Annual Costs (7/2004 6/2005) Skilled Nursing Facility $296 ± $1,565 ER $614 ± $1,507 Outpatient Services $1,838 ± $1,781 Other $1,927 ± $22,212 Prescription Drug $2,182 ± $2,128 Hospitalizations $3,485 ± $8,950 Total Costs (7/2004 6/2005): $10,566 ± $24,778 Dementia Care Indexes and Outcomes Index Measure Mean +Std. Dev. Correlations with Outcomes Satisfaction (Health Plan) 2-Year Costs (Log) AD-Care IQ Index 69.5 ± 17.4 0.28-0.02 (percent of 22) p<0.01 p=0.79 Dementia Core 12 8.3 ± 2.4 0.24-0.07 (0-12) p<0.01 p=0.39 Dementia Core 6 4.5 ± 1.2 0.24-0.05 (0-6) p<0.01 p=0.49 Opportunities to Improve Care Educate providers that dementia is a chronic condition that requires ongoing assessments and disease management, not diagnose and adios. Utilize brief, assessment tools for evaluating cognition, function and psychiatric symptoms. Reimburse healthcare providers for the extra time required for dementia care in ambulatory setting. Opportunities To Improve Care Facilitate the referral of patients with dementia to community resources. Partner with caregivers and monitor their health. Consider the use of effective medications for Alzheimer s disease and related dementias, especially in patients with moderate to severe symptoms. Effectively manage co-morbid medical conditions in patients with dementia to lower the risk of hospitalization and poor outcomes 9
Learning Objectives: Understand the effects of aging on cognition and factors that can slow or accelerate decline Describe mild cognitive impairment and the most common causes of dementia List tools that can be used in evaluating cognitive decline in older adults Discuss the pathophysiology of Alzheimer s disease and experimental treatment approaches Know the important role of primary care providers in managing symptoms of dementia Questions? For questions related to this presentation you can contact Dr. Daniel Murman at dlmurman@unmc.edu, 402-559-6591 (academic office), 402-559-8600 (clinic) Appendix: Resources AD8 Mini-Cog MMSE MoCA FAQ FAST NPI-Q AD8 Brief (8 questions), informant-based questionnaire about changes in behavior or functions that may represent dementia Reliable and valid for screening for dementia Can be administered to patient directly, also Score of 2 or higher suggests need for dementia evaluation Galvin et al. Neurology 2006; 67:1942-8. Mini-Cog Brief Screening Tool (3 minutes or less) Includes two tasks: 1. Three word registration and delayed recall 2. Clock Drawing Test Scores range from 0 to 5. Scores less than 3 would indicate indicate probable dementia and the need for further evaluation. A cut point of less than 4 can be used to improve the sensitivity of this screening test. 10
Mini Mental Status Examination Evaluates orientation, memory, attention, language, visual-spatial function Take 5 10 minutes to complete Higher scores are better, 30/30 is perfect score, 24/30 or less suggests dementia Widely used and understood Average change is 2.5 to 3 points per year in patients with Alzheimer s disease Montreal Cognitive Assessment More challenging then MMSE and has more items to assess executive cognitive function, attention and visual spatial function Available online in multiple languages http://www.mocatest.org Takes about 10 minutes to complete Thirty points possible, higher scores better, scores less than 26 suggest at least mild cognitive impairment Short MoCA Functional Activities Questionaire Caregiver completed scale of functional abilities (instrumental ADLs) Rating designate whether patient is completely independent, needs some help, or is unable to complete task. Scores higher than 9 suggest significant functional impairment. Pfeffer R, et al. J Gerontol 1982;37:323-9. Functional Assessment Staging (FAST) Seven functional levels but level 6 has five items and level 7 has six items (i.e. 16 total items) Psychometric properties of scale poorly understood Levels can be divided into stages of dementia: 3,4 = Mild Dementia 5,6 = Moderate Dementia 7 = Severe Dementia Reisberg, B. Functional assessment staging (FAST). Psychopharmacology Bulletin. 1988; 24:653-659. Neuropsychiatric Inventory - Questionnaire (NPI-Q) Caregiver completed questionnaire Asks about presence and severity of neuropsychiatric symptoms in 12 domains Also measures caregiver distress related to these symptoms Can be used to identify and monitor neuropsychiatric symptoms Kaufer DI, et al. J Neuropsychiatry Clin Neursci 2000; 12:233-9. 11