A Dynamic Model of Care for Late Onset Cognitive Impairment. Linda CW Lam Department of Psychiatry The Chinese University of Hong Kong

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1 A Dynamic Model of Care for Late Onset Cognitive Impairment Linda CW Lam Department of Psychiatry The Chinese University of Hong Kong

2 Outline The pathogenesis of Late life cognitive impairment A framework of care

3 The golden age.. Age (Cambridge dictionary) The period of time someone has been alive The Life Cycle Course of developmental changes from inception as fertilized zygote to a mature reproductive state, followed by subsequent decline

4 At 85 years old, you may experience Reduced motility Reduced interests Forgetfulness Repetitiveness Mini-mental state exam 24/30 Delayed recall 2/10 1 minute animal fluency test 10 examplars

5 Brain Imaging Serial MRI brain scans, taken six months apart, show progression from mild cognitive impairment to Alzheimer's disease, with significant atrophy (blue) and ventricle enlargement (orange/red). (University of California, San Diego, UCSD)

6 Brain Imaging Klunk, W.E., et al., Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Annals of Neurology, 2004;55:306-19

7 Alzheimer s disease

Presentation by Alzheimer at conference in Tubingen (1906)

8 Alzheimer Disease Anatomical diagnosis of Auguste Deter Cerebral atrophy Arteriosclerosis of small blood vessels Presentation by Alzheimer at conference in Tubingen (1906) Fibrils with characteristics thickness (tangles) Small miliary foci (plaques)

9 Amyloid protein leads to AD. The Amyloid Cascade Hypothesis Amyloid Precursor Protein Aß plaques Aß Aß oligomer Aß Fibrils P-Tau Excitotoxicity Inflammation Oxidation Mitochondrial dysfunction Neurofibrillary tangles Synapse failure, Cell Death Cummings, Alz Dement, 2011

10 How does Alzheimer s disease develop?

11 A life course approach AGE Dementia Alzheimer disease

At conception Early onset AD Amyloid precursor gene (21) Presenilin 1 gene (14) Presenilin 2 gene (1) Late onset AD Apolipoprotein E gene (19) Gene dose effects Advance age of onset >200 genes

12 At conception Early onset AD Amyloid precursor gene (21) Presenilin 1 gene (14) Presenilin 2 gene (1) Late onset AD Apolipoprotein E gene (19) Gene dose effects Advance age of onset >200 genes identified Inflammatory pathway, energy metabolism, neuronal repair, estrogen, immune response Tanzi et al., Nature, 1987;329(6135): ; Lewy-Lahad et al., Science 1995;269: ; Sherrington et al., Nature, 1995;375 (6534): ; Corder et al., Science 1993;261(5123):

Early Life Environmental Enrichment Transgenic and wild type mice were either

Standard housed Transgenic mice Diminished hippocampal cell proliferation

Environmental enrichment reversed this genotype effect.

13 Early Life Environmental Enrichment Transgenic and wild type mice were either housed under standard conditions or in an enriched environment. Standard housed Transgenic mice Diminished hippocampal cell proliferation Reduced number of mature newborn neurons. Environmental enrichment reversed this genotype effect. Cognitive and physical stimulation Increasing the number of newborn mature hippocampal neurons in transgenic mice. Herring A, Exp Neurol. 2009;216:

14 A life course approach Dementia Alzheimer disease

15 Education High education is a protective factor for the development of dementia. Enhanced cognitive reserve? Higher education delay the onset of decline. Modulate clinical manifestations of disease burden? Valenzuela & Sachdev, Psychol Med, 2006; Wilson et al., Arch Gen Psy, 2007; Rosell F et al., Clin Neurol Neurosurg; Hall CD et al., Neurology, 2007;

16 Education, the brain and Dementia Population-based cohort studies (Epidemiological Clinicopathological Studies in Europe; EClipSE) 3 population-based studies that included 827 post-mortem brain donation and Longer years in education at early life were associated Decreased dementia risk and greater brain weight No relationship to neurodegeneration. EclipSE Collaborative Members, Brayne C, et al. Brain 2010; 133:2210-6

17 A life course approach Dementia Alzheimer disease

Early Linguistic Ability - The Nun Study A longitudinal study on aging and disability using antemortem and postmortem data collected from 678 older School Sisters of Notre Dame since 1986.

18 Early Linguistic Ability - The Nun Study A longitudinal study on aging and disability using antemortem and postmortem data collected from 678 older School Sisters of Notre Dame since The causes and prevention of Alzheimer's disease, The mental and physical disability associated with old age. Healthy Aging versus dementia AD pathology Stroke Early linguistic ability Education Snowdon. et al., JAMA. 1997;277: ; Tyas et al., Age Ageing. 2007;36:

19 Occupation In a religious order study of 517 Bavarian school sisters, risk of dementia was associated with Low education (OR 4.5, 95%CI ) Not having vocational training (OR 9.1, 95% CI ) Never been appointed to a leading position (OR 3.7, 95% CI ) Bickel & Kurz, Dement Geriatr Cogn Disord, 2009;27:

20 A life course approach Dementia Alzheimer disease

21 Mid Life Body Mass Index and AD In a meta analysis Low BMI, increased risk of AD (OR 1.96, 95% CI: ) Overweight BMI, increased risk of AD (OR 1.35, ), VaD (OR 1.26, ) U-shape curve Anstev et al, Obse Rev 2011;12:e426-37

22 Atherosclerosis and dementia Rotterdam study A population based cohort of over 6600 subjects followed up with a mean of 9 years. Atherosclerosis, especially carotid plaques, are associated with an increased risk for dementia. Van Oijen et al, Ann Neurology, 2007;

23 Cognitive activities & cognitive function Cognitive activities (reading, playing board games, musical instruments, dancing) dementia risk Late life cognitive activities delayed onset of accelerated memory decline more rapid decline after onset. Stimulating leisure activities dementia risk and AD over a 4 year period in the Three-City Study in France. Midlife cognitive activity, but not physical activity, modulated risk of dementia in monzygotic twins pairs. Verghese et al., NEJM, 2003; Hall et al., Neurology, 2009; Akbaraly et al., Neurology, 2009; Carlson et al., 2008.

24 Physical activities & cognitive function Leisure time physical activity lower mortality in a US national cohort. A 24-week home based physical activity intervention provided a modest improvement in cognition over an 18-month followup period. 6 months aerobic exercise associated sex-specific effects on cognition, glucose metabolism and hypothalamic- pituitary adrenal axis. 12 months resistance training improved executive function (Stroop test) over balance and toning. Lautenschlager et al., JAMA, 2008; Gillum & Obisesan, 2010, Ann Epidemiol, 2010; Baker et al., Arch Neurol., 2010; Liu-Ambrose et al., Arch Intern Med., 2010.

25 A life course approach Dementia Alzheimer disease

26 Amyloid ß deposition in clinical normal elders Aβ deposition in cognitively normal elders is Age-related Associated with cortical thinning Hippocampal atrophy, Aβ deposition in temporal neocortex are associated with episodic memory loss in pre-dementia stage Becker et al, Ann Neurol, 2011;69: Chetelat et al., Brain 2011;134:

27 Vascular lesions in AD brains Vascular lesions Major infarcts, lacunes, microbleeds, white matter degeneration Mixed with AD pathology Synergistic effects on clinical symptoms & disease course Jellinger. J Alz Dis., 2008;14:

28 What determines the development of AD?

29 Sperling et al, Alz Dementia; 2011

30 Hypothetical Model of AD Pathophysiological Cascade Jack CR Jr. et al, Lancet Neurol, 2010

31 A framework of care From prevention to treatment A personalized approach

32 Primary Prevention From Early to Adult Life AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Perinatal Care Health Care in early life School Education Social and Leisure enrichment Occupation Safety Substance misuse

33 Primary Prevention From Mid Life AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Optimizing cardiovascular and brain health Vascular risks Depression Physical exercise Cognitive activities Social network and support Diet

At Late Life Preclinical & Prodromal Phase AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain

34 At Late Life Preclinical & Prodromal Phase AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Optimizing cardiovascular and brain health Vascular risks Depression Physical exercise Cognitive activities Social network and support Diet Structured approach to intervention?

35 A personalized approach to dementia care Risk assessment Genetic Physical Health Cognitive reserve Early biomarker changes Intervention Stage dependent Modality Constitutional factors (Pharmacogenetics)

36 Alzheimer s disease Mild AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Optimizing physical Health Caregiver involvement Cognitive and functional maintenance Acetylcholine esterase inhibitors Functional training for IADL

37 Alzheimer s disease Moderate AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Optimizing physical Health Caregiver involvement Cognitive and functional maintenance Acetylcholine esterase inhibitors/ NMDA receptor antagonist Management of neuropsychiatric symptoms Functional training for BADL Consideration for day training

Alzheimer s disease Severe AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Optimizing physical Health

38 Alzheimer s disease Severe AGE Early factors Genes Intelligence Education Occupation Personality Midlife vascular health Exercise, Diet, Lifestyles Brain Lesions Optimizing physical Health Caregiver involvement Acetylcholine esterase inhibitors/ NMDA receptor antagonist Management of neuropsychiatric symptoms Support for BADL and physiological function Consideration for long term care

health Optimizing cognition Reduce psychiatric and physical

39 Dynamic model A patient Journey Preclinical Prodromal Clinical Enhancing Cognitive Reserve Attention to brain health Optimizing cognition Reduce psychiatric and physical morbidity Community Health care services Outpatients Hospitals Long term care

40 To tackle late life cognitive impairment.. Never too early Avoids being too late

41 Thank you

DISCLOSURES. Objectives. THE EPIDEMIC of 21 st Century. Clinical Assessment of Cognition: New & Emerging Tools for Diagnosing Dementia NONE TO REPORT

DISCLOSURES. Objectives. THE EPIDEMIC of 21 st Century. Clinical Assessment of Cognition: New & Emerging Tools for Diagnosing Dementia NONE TO REPORT Clinical Assessment of Cognition: New & Emerging Tools for Diagnosing Dementia DISCLOSURES NONE TO REPORT Freddi Segal Gidan, PA, PhD USC Keck School of Medicine Rancho/USC California Alzheimers Disease