Neurocogni*ve Deficits in Older Cancer Pa*ents. Beatrice J. Edwards, MD, MPH Central Texas Veterans Healthcare System

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2 Neurocogni*ve Deficits in Older Cancer Pa*ents Beatrice J. Edwards, MD, MPH Central Texas Veterans Healthcare System

3 Conflicts of Interest None

4 Background By 2030 close to 70% of cancer pa5ents will be 65 years of age and older Age-related diseases include cogni5ve impairment and demen5a, osteoporosis, diabetes, frailty, and sarcopenia The effect of chemotherapy on cogni5ve processes will be superimposed on age-related mild cogni5ve impairment (MCI) and demen5a Given that many cancer pa5ents have received cancer therapy, they may exhibit cogni5ve impairment and neurocogni5ve deficits earlier in life. Cultural and societal concerns

5 Defini*on Demen5a is a general term for a gradual decline in cogni5ve capacity severe enough to interfere with daily life. The prevalence of demen5a increases with age, from 15.0% of those aged years to 37.4% of those aged 90 and older Up to 74% of primary care physicians may not recognize cogni*ve impairment and when they do, the pa*ent is in the moderate to severe stage of demen*a

6 DNA damage Chronic inflamma5on Chemotherapy Androgen depriva5on therapy Mitochondrial Damage Depression Metasta5c cancer Strokes Comorbidity NEUROCOGNITIVE DEFICIT

7 Cogni*ve Impairment and Neurocogni*ve Deficits Chemotherapy induced cogni5ve impairment (CCI) may develop in any of the 3 groups listed above. Cogni5ve Impairment Depression, Delirium Organic brain syndrome, Post CVA Mild Cogni5ve Impairment (MCI) Minor neurocogni5ve Deficit Demen5a Major Neurocogni5ve Deficit

8 Criteria for Diagnosis

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11 Instrumental Ac*vi*es of Daily Living Original IADLS Heavy housekeeping Laundry Cooking Financial Management Taking own medica5ons Using the telephone Arranging for transporta5on Shopping GENDER BIAS Brody s Adapta*on Financial management Taking own medica5ons Using the telephone Arranging for transporta5on Shopping NO GENDER BIAS

12 STEPS IN DIAGNOSING NEUROCOGNITIVE DEFICITS

13 HISTORY MAJOR NEUROCOGNITIVE DEFICIT Cogni5ve deficits precede cancer diagnosis Cogni5ve deficits date back years Families will not recognize cogni5ve impairment, inquire about finances, driving, MVA, taking own medicines. etc Interpret findings in the seeng of educa5onal, occupa5onal level, and ethnicity CHEMOTHERAPY INDUCED COGNITIVE IMPAIRMENT Cogni5ve deficits follow cancer care (months) Pa5ent and/or families recognize a recent change in cogni5on

14 Mini Cog 4 items Clock drawing 3 item recall Comprehensive lit review 3 studies n= 1620 Sens 99% spec 93% Sens 76% spec 89% Sens 99% spec 83% Cochrane Database Syst Rev Feb 3;(2):CD doi: / CD pub2.

15 Montreal Cogni*ve Assessment (MoCA)

16 Cogni*ve Tes*ng in African Americans Mini Mental State Examina5on (MMSE) Blessed Orienta5on Memory Concentra5on Test (BOMC) Neurobehavior Cogni5ve Status Examina5on (NCSE) Cambridge Cogni5ve Examina5on (CAMCOG) Montreal Cogni5ve Assessment (MoCA) Lampley Dallas, JNMA 2001: 93:9

17 Folstein Mini Mental State Exam Ethnic bias In spite of educa5on-adjustment, bias con5nues Does not detect early demen5a Some studies suggest that 21 would be a beler threshold for African Americans and possibly down to 18. Bias results in higher false posi5ve rates for African Americans as compared to whites. Specificity of MMSE is lower in African Americans specific ques5ons that are biased: WORLD spelling No ifs ands or buts Lampley Dallas, JNMA 2001: 93:9

18 Blessed Orienta*on Memory Concentra*on Test It tests Orienta5on, Memory and Concentra5on 6 Item scale, takes 2-3 min and has a total score of 28. Normal score 0 to 6 or 0 to 8; 9 ques5onable, 10 + demen5a BOMC and MMSE misclassified more African Americans than whites BOMC 62% MMSE 42% misclassifica5on for African Americans Short Portable Mental Status Ques5onnaire (SPMSQ), BOMC iden5fies pa5ents at earlier stage than SPMSQ. BOMC apparently misclassified African Americans twice as open as SPMSQ Welsh, Neurology : Lampley Dallas, JNMA 2001: 93:9

19 Montreal Cogni*ve Assessment MoCA was developed in Quebec, Canada among whites with a mean 13.3 ± 3.6 years of educa5on. It is the scale best designed to iden5fy Mild cogni5ve Impairment Scores may be lower in ethnic minori5es (Score = 20) Scores may be lower in ethnic minori5es. In a community of African Americans the mean MoCA 19.8 ± 3.8. If 26 is set as a cutoff for impairment, 93.5% of subjects would be considered impaired. Among AA with HS educa5on, par5cipants who were < 55 years MoCA years 19.8 ± years of age MoCA 18.7 In La5nos with low educa5on (< 5 years of school) add 5 points Demen>a and geriatric cogni>ve disorders extra. 2015;5(1): Journal of Aging Research. 2015;2015:

20 MD Anderson Cohort N=455, mean age 86 +/- 8; MoCA screen and exam, MCI 30%, demen5a 33% Prevalence of demen5a is 2- fold higher than in noncancer pa5ents Edwards BJ hlps://doi.org/ /j.jgo

21 Factors Associated with Neurocogni*ve Deficits NCD: 33% Major NCD; 31% Minor NCD Prevalence of Neurocogni5ve Deficits Mul5morbidity (CCI > 4) p= Prior stroke p = Metastases p = percent Warfarin use p = 0.03 p=0.0 3 Minor Neurocogni5ve Deficit Major Neurocogni5ve Deficits Non cancer Edwards BJ hlps://doi.org/ /j.jgo

22 Caveats on Interpreta*on MoCA created on white HS graduates (threshold 26) in Canada Ethnic minori5es: MoCA 20 (African Americans and La5nos) If you use a cut-off of 26, you miss 90% of African Americans La5nos with less than 5 years of educa5on, you can add 5 points Repeat tes5ng should be no closer than 6 months

23 DELIRIUM Defini5on : Acute or subacute onset of alen5on and cogni5ve changes associated with fluctua5ng sensorium. It may be accompanied by hyper- or hypoac5vity. Predisposing factors: cogni5ve or sensory impairment, advanced age, male gender, Parkinson s disease, depression, Precipita5ng factors: infec5ons, SIRS, strokes, myocardial infarc5on, heart failure, acidosis, hepa5c failure, dehydra5on, advanced cancer, cor5costeroids.

24 Delirium

25 DEPRESSION Depression as a cause or risk factor for demen5a Depression as a consequence of demen5a Depression as a coincidental finding in demen5a Bennel, Maturitas 2014 Oct;79(2):184-90

26 Maturitas 2014 Oct;79(2):184-90

27 IMAGING IN ALZHEIMERS DISEASE

28 IMAGING IN VASCULAR DEMENTIAS

29 PET IMAGES IN ALZHEIMERS DISEASE Neurobiol Aging Jul;32(7):

30 RESULTS MCI and demen5a are commonly encountered in older cancer pa5ents Issues to consider: Chemotherapy induced cogni5ve impairment- is there a greater decline with cancer care if NCD is present at baseline Decisional capacity- of concern when pa5ent is in moderate stage demen5a (Major NCD) Meman5ne has been successful preven5ng Cranial XRT cogni5ve impairment Major NCD will exert an effect on clinical outcomes

31 Opera*onalizing Cogni*ve Assessment Self- administer ADL, IADL, and Pa5ent Health ques5onnaire (PHQ-9). Social support MOS History of concussions, strokes, T2DM, HTN, hyperlipidemia, substance abuse, family hx demen5a. Assess for delirium Tes5ng: quick screen Mini Cog, MoCA Tes5ng: B12, VDRL, TSH/T4 Imaging: CT brain, MRI, PET Scan Discussion about Rx.

32 RCT of Meman5ne to prevent XRT related cogni5ve impairment Neuro-Oncology 15(10): , 2013.

33 Methods Pa5ents received 37.5 Gy of WBRT (15 frac5ons of 2.5 Gy). Study drug administra5on was to commence no later than the third day of WBRT. Pa5ents were randomly assigned to receive meman5ne or placebo orally for 24 weeks and escala5ng doses over the first 4 weeks. Meman5ne was slowly 5trated to the maintenance dose of 10 mg BID. The dose was lowered to 5 mg orally twice daily if crea5nine clearance fell below 30 ml/min and was held if the crea5nine clearance was less than 5 ml/min with a weekly recheck of laboratory values. Neuro-Oncology 15(10): , 2013.

34 At 24 weeks there is Less decline in delayed recall (p=0.0587) Longer 5me to cogni5ve decline (hazard ra5o 0.78, 95% CI , p < 0.01); Superior execu5ve func5on at 8 (p < 0.008) and 16 weeks (p < 0.004) and Superior processing speed (p < 0.024) Neuro-Oncology 15(10): , Superior delayed recogni5on (p < 0.012) at 24 weeks.

35 Meta-Analyses of Efficacy of Acetyl cholinesterase inhibitors on Major NCD Strohle, Am J Geriatr Psychiatry 23:12, December 2015

36 Meta analyses to assess the Efficacy of Exercise on Minor Neurocogni*ve Deficit Strohle, Am J Geriatr Psychiatry 23:12, December 2015

37 Forest Plot Donepezil Drug treatments resulted in a small pooled effect on cogni5on (SMCR: 0.23, 95% CI: 0.20 to 0.25) in AD studies (N = 45, 18,434 pa5ents) and no effect in any of the MCI studies (N = 5, 3,693 pa5ents; SMCR: 0.03, 95% CI: 0.00 to 0.005). Strohle, Am J Geriatr Psychiatry 23:12, December 2015

38 Exercise and Major Neurocogni*ve Deficit Exercise interven5ons had a moderate to strong pooled effect size (SMCR: 0.83, 95% CI: 0.59, 1.07) Strohle, Am J Geriatr Psychiatry

39 Conclusion Neurocogni5ve deficits are common in older cancer pa5ents Demen5a is 2-fold higher in cancer pa5ents than in pa5ents without cancer Iden5fica5on is cri5cally important for decision making Management is possible Preven5on of CCI? Exercise is beneficial