Interaction of Cardiovascular Disease and Alzheimer s Disease: Implications for Cardiopulmonary Rehabilitation

Transcription

1 Interaction of Cardiovascular Disease and Alzheimer s Disease: Implications for Cardiopulmonary Rehabilitation Dereck Salisbury, PhD Assistant Professor, Clinical Exercise Physiologist Director: Laboratory of Clinical Physiology University of Minnesota, School of Nursing

2 No Disclosures

3 Objective Educate on Alzheimer s disease (AD) and apply knowledge through a core components of Cardiac Rehabilitation (CR) vantage point.

4 Focus AD The Basics Understanding AD Cognitive Domains Diagnosis and Course of AD Pathophysiology and Risk Factors of AD Current Treatments for AD Interactions of Cardiovascular Disease (CVD) and AD ExRx and Delivery Multidomain or Core Components approach with the AD patient

5 Cognition Memory Impaired ability to obtain and remember new information Language Problems with reading, speaking, or writing Executive Impaired ability to reason, handle complex tasks, and/or make poor judgement Visuospatial Having trouble finding one s way around, getting lost

6 Dementia Dementia is a general term for a decline in mental ability (i.e., cognition) severe enough to interfere with daily life. Memory loss is an example. 2019: 5.8 million Americans have AD 2050: 14 million

7 Diagnosis and Course of Dementia Prodromal research term Presence of biomarkers (PET amyloid imaging) + know risk factors for AD (ApoE4 allele) Have pathology without symptoms Cognition test - normal MCI AD Impaired performance on Cognitive test in 1 domain + positive biomarker ADLs preserved Impaired performance on Cognitive test in 2 domain + positive biomarker Impaired ADLs Exclusion of other diseases that cause cognitive impairment

8 Symptoms Triad of AD and Other Dementias Cognitive Impairment Behavioral and Psychological Symptoms of Dementia (BPSD) Inability to Perform ADLs

9 Verbal Non-verbal Verbal BPSD: Behavioral Physical Verbal Non-verbal

10 Anxious Apathetic Delusional Hallucinations BPSD: Psychological Depression Irritability Disinhibition Psychosis

11 Pathophysiology Amyloid Hypothesis Tau Hypothesis Vascular Hypothesis Cholinergic Hypothesis

12 Beta Amyloid Plaque Beta amyloid plaques aggregate APP enzymatic degradation Block cell to cell signaling Bind to post synaptic membrane receptors Triggers inflammatory response Cytotoxic to synapses

13 Tau & Neurofibrillatory Tangles Neurofibrillary tangles Twisted fibers found in neural cytoplasm Tau Protein becomes abnormal Microtubule collapses

14 What about the Vascular Component CVD Risk Factors Vascular Changes Atherosclerosis Cardiac Output Cerebral Blood Flow Glymphatic Drainage Cerebral Amyloid Angiopathy Beta Amyloid Clearance Hypoperfusion O2 and Nutrient Delivery Hypometabolism Neurodegeneration

15 What about the Vascular Component Higher Carotid-femoral PWV Inversely correlated to cog scores J Hypertens. 2005;23: Endothelial dysfunction enos is significantly lower in AD and lower activity associated with greater beta amyloid burdern Neurosci Lett 2009; 463: Low Cardiac index (cardiac output / body surface area) HR 2.87; 95% CI, ; P=0.016 Circulation. 2010;122: Circulation. 2015; 131(15): % reduced cerebral perfusion Vasc Health Risk Manag. 2012; 8: Prog Neurobiol 2001; 64: Higher incidence of AD in PAD, CHF, A-Fibrillation Vascular Medicine 2009; 14: Am J Alzheimer s Dis Other Demen. 2018; 33(1): 5-11

16 Alzheimer s Disease 5.8 Million Sporatic (90-95%) *Late Onset Familial (5-10%) *Early Onset Age Genetics Autosomal Dominant Trisomy 21 Lifestyle/Other (1%) 85 (50%) Apo E4 PSEN-1 / PSEN-2 Have additional APP gene CRF CVD Risk Factors Depression Sleep Anxiety ApoE breakdown/clear Beta Amyloid (E2 most effective, E4 least). Having 1 or 2 E4 alleles increases AD risk PSEN encode for y secretase, mutations can affect where APP is cleaved (can increase B amyloid 40, 42)

17 Treatments: FDA Approved - Pharmacological Acetylcholinesterase Inhibitors Donepezil (Aricept) All stages Rivastigmine (Exelon) Mild-moderate AD Galantamine (Razadyne) Mild-moderate AD Glutamate Inhibitor Memantine Moderate/severe AD Glutamate Inhibitor + Acetylcholinesterase Inhibitor Memantine + Donepezil (Namzaric) Moderate/severe AD

18 Treatment: Improve Aerobic Fitness

19 Through Aerobic Exercise Training

20 The Early Evidence Frequency: 3.4 days/wk Intensity: 3.7 METS Duration: 45.2 min/session Type: Primarily aerobic (65%)

21 Application to Cardiopulmonary Rehabilitation

22 Core Components Model Patient Assessment Nutritional Counseling Psychosocial Management Physical Activity Counseling Risk Factor Management Lipid Management Hypertension Management Diabetes Management Smoking Cessation Management Exercise Training

23 Common Risk Factors between AD and CVD. Risk Factor / Pathophysiology AD CVD/CBVD Age Genetic (ApoE) Hyper/Hypotension Dyslipidemia Diabetes Mellitus Obesity Poor Aerobic Fitness Smoking Depression Reduced CBF Amyloid Beta deposition Santos et al. Alzheimer s & Dementia: Diagnosis, Assessment & Disease Monitoring 7 (2017) 69-87

24 Blood Pressure Midlife hypertension is a risk factor for dementias Hypotension late in life is closely associated with AD risks Extremely low DBP ( 65 mm Hg) produced an adjusted relative risk of 1.7 (95% CI ) for AD in a prospective study of 1270 individuals aged years (Qui et al. Arch Neurol. 2003;60: ) Elasticity Chronic Hypertension Luminal Narrowing Vascular thickening Reduced CBF Brain volumes Cerebral Edema BBB Integrity

25 Diabetes Several epidemiological studies show increased risk for AD Rottenburg artery study DM increases risk for AD 2- fold Insulin dependent 4.3 fold Insulin Resistance Neuron Development Reduced insulin signal in brain Body Weight Insulin Deficiency Cognitive Processes? Ott et al. Neurology. 1999;53: ; Leibson et al. Am J Epidemiol. 1997;145:301 8; Xu et al. Diabetes. 2009;58:71 7; Arvanitakis et al. Arch Neurol. 2004;61:661 6.

26 Lipids Elevated total serum cholesterol have been associated with MCI and AD Mechanism not fully understood atherosclerosis

27 Smoking Current smokers vs non-smokers 1.79 fold risk (95% CI ) 1.59 fold risk (95% CI ) Dose-response Atherosclerosis Cerebral Blood Flow Neuronal Death Free Radicals Neuronal Excitotoxicity Austey et al. Am J Epidemiol 2007; 166( ); Barnes et al. Lancet Neurol 2011; 10:

28 Pharmacological Treatment Clinical effects in CVD Clinical effects in AD Diuretics Anti-hypertensive Long-term use may be associated with decreased incidence of AD ACE/ARB B-Blocker Statins Asa Insulin Anti-hypertensive; reduce risk of CVD events Anti-hypertensive; prevention of CVD events in high risk patients Reduce LDL, total cholesterol, antiinflammatory, reduce cardiovascular events Anti-platelet in secondary CVD prevention DM treatment, long term beneficial effects on CVD Risk May slow down progression of symptoms in mild-moderate AD Lower risk of developing cognitive impairment in older adults w/o dementia Mixed literature Mixed literature Intranasal insulin appears to improve cognition and modulate beta amyoid in early AD Yasar et al. Neurology. 2013;81: ; Khachaturian et al. Arch Neurol. 2006;63: ; Soto et al. J Am Ger Soc. 2013;61: ; Gelber et al. Neurology. 2013;81: ; Rosenberg et al. Am J Geriatr Psychiatry. 2008; 16: Feldman et al. Neurology. 2010;74: McGuinness et al. Cochrane Database Syst Rev. 2009;2:CD003160; Reger et al. Neurology. 2008;70:

29 Exercise Prescription: Base on What Patient was Referred for Disease Intensity Duration Mode PAD A Varies on Mode 30 min/session Aerobic: Treadmill or non-ischemic CAD/CHF B 40-80% HRR min/session Aerobic COPD C 60-80% peak work rate min/session Aerobic (possibly interval) A. Salisbury et al. Journal of Clinical Exercise Physiology. 2019;8(1): 1-12 B. Squires et al. Journal of Cardiopulmonary Rehabilitation and Prevention. 2018; 38(3): C. Garvey et al. Journal of Cardiopulmonary Rehabilitation and Prevention; 2016, 36: Disease Intensity Duration Mode AD 3.7 METS ( 45 min/session Aerobic (Treadmill or cycling)

30 Real World Considerations for ExRx and Delivery for the AD Patient

31 Exercise delivery Individualize based on BPSD Timing of session Sundowners Motor impairment Health history, functional tests and exercise selections Accuracy of RPE Talk test in disinhibition Small group vs individualized exercise

32 Assessments Aerobic and Physical Fitness Six minute walk test (6- MWT) Shuttle Walk Test (SWT) Timed-up-and-go (TUG) Short Physical Performance Battery (SPPB) Cardiopulmonary Exercise Test (CPET) Cognition Mini Mental State Examination (MMSE) 30 questions 5 minutes to complete Classification Normal: Mild: Moderate: Severe: <12 MiniCog ments/mini-cog.pdf s/healthcareprofessionals/cognitiveassessment

33 Due to the multifactorial nature of AD, interventions that simultaneously target multiple risk factors and disease mechanisms are needed Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) Multidomain interventional trial Aim 1: Prevent cognitive impairment Aim 2: decrease disability, CVD risk factors and related morbidities and depressive symptoms and improve QoL

34 Multidomain Approach (FINGER) Domains Intensive monitoring of metabolic and vascular risk factors Study physician guided based on current guidelines Dietary Guidance Cardioprotective dietary pattern Similar to DASH Physical Activity / Exercise Multimodal, supervised Cognitive Training and Social Activities What does this look like?

35 What else? Feedback from participants Feedback from caregivers

36 Conclusion Influence of CVD in AD is increasingly accepted As aging population increases, we will see greater dementia including AD in CR Therapy should be multidomain with exercise as a cornerstone Interventions used in CR have the potential to improve outcomes for AD

37 Thanks and Questions