The Influence of Sleep on Cognition in Breast Cancer

Transcription

1 The Influence of Sleep on Cognition in Breast Cancer Sonia Ancoli-Israel, PhD Professor of Psychiatry and Medicine University it of California i San Diego Fatigue by Rodin Supported by NIC CA112035, UL1RR (CTRI), UCSD Stein Institute for Research on Aging, the Department of Veterans Affairs Center of Excellence for Stress and Mental Health (CESAMH) and the UCSD Moores Cancer Center

2 Cognitive Function What Cancer Patients Say It's a fuzzy feeling, like trying to think through a fog. Throw in a little bit of exhaustion and fatigue, and it doesn't leave you at your cognitive best. It's hard to concentrate. It's a little bit like the feeling you get when you've had one or two or drinks too many, and you don't want to be drunk. Leroy Siever 7 years out of chemo treatments. I have been telling my oncologist for years that I am still foggy. I am terrified that I might make a terrible mistake at my job, so I live in constant fear and stress. Carolyn S Having just surpassed my 38 year old wife's two year anniversary of discovering her cancer, we have found that her chemo brain actually worsened as the time from her treatments lengthened Rick L

3 Inflammation Depression Fatigue Poor Sleep/ Disrupted Circadian Rhythms Cancer; Chemotherapy Cognitive Deficit

4 JT075 C1W-1 07/25/03 07/26/03 07/27/03 C1W1 08/01/03 08/02/03 08/03/03 C1W2 08/08/03 08/09/03 08/10/03 C1W3 08/15/03 08/16/03 08/17/03 C4W1 10/03/03 10/04/03 10/05/03 C4W2 10/13/03 10/14/03 10/15/03 C4W3 10/19/03 10/22/03 10/21/

5 Rhythmicity Over Time with Chemotherapy **** **** *** **** N=95; For comparisons between each time point vs. baseline: * p <.05; ** p <.01; *** p <.001; **** p <.0001 These data suggest that: -the first administration of chemotherapy is associated with transient circadian disruption -repeated administration of chemotherapy results in progressively worse and more enduring rhythm impairments. Savard,J. et al. Sleep 32: , 2009.

6 Design 75 women Mean age 51.8 years; SE 1.1 diagnosed with stage I-III breast cancer undergoing adjuvant or neo-adjuvant anthracycline-based chemotherapy 68 age- and education-matched women with no history of any cancer Mean age 51.8 years; SE 1.1 Neuropsychological (NP) test battery; questionnaires on fatigue, sleep quality, depressive symptoms, QOL; Patient s Assessment of Own Function (PAOF) Actigraph (Mini Mitter/Respironics/Phillips) was worn for 72 hours pre-treatment after four cycles of chemotherapy One-year post-chemotherapy Permission i obtained Blood; structural MRI for photo Each control woman was matched to and tested at the same time points as a patient.

7 Education Demographics Patients: 49% college grads; 40% some college Controls: 64% college grads; 30% some college Race/Ethnicity: Patients: 88% Caucasian; 3% AA; 9% Hispanic Controls: 88% Caucasian; 3% AA; 6% Hispanic Income (annual household ) Patients: 43% >$100, Controls: 41% >$100,000

8 Fatigue/Sleep/Circadian Rhythms Patients had significantly worse sleep, slept less at night and more during the day (naps), had more depressive symptoms and more fatigue than controls pre-chemotherapy Post-chemotherapy (end of Cycle 4), compared to controls and compared to themselves at baseline, patients had significantly worse sleep, slept less at night and more during the day (naps), had more depressive symptoms and more fatigue At one year, patients still had significantly more subjective symptoms (depressive symptoms, worse sleep quality and more fatigue) than controls at one year, but compared to themselves, were back to their own baseline levels. No significant differences in objective measures of sleep

9 Sleep/Fatigue/Mood Higher scores are worse Within groups: Patients:BL-C4 p=0.004; BL-Y ; C4-Y1 p=0.013 Controls BL-C4 p=0..227; BL-Y ; C4-Y1 p=0.269 Between groups: Baseline p=0.004; Cycle 4 p<0.001; Year one p=0.006 Within groups: Patients: BL-C4 p=0.011; 011; BL-Y1 p=0.459; C4-Y1 p= Controls BL-C4 p=0.108; BL-Y ; C4-Y1 p=0.911 Between groups: Baseline p=0.0001; Cycle 4 p<0.0001; Year one p=0.002 Within groups: Patients: BL-C4 p=0.0017; 0017; BL-Y1 p=0.322; C4-Y1 p= Controls BL-C4 p=0.0573;bl-y1 p=0.932; C4-Y1 p=0.974 Between groups: Baseline p<0.001; Cycle 4 p<0.001; Year one p=0.028 Within groups:patients:bl-c4 p=0.525;bl-y1 p=0.004;c4-y1 p=0.001 Controls BL-C ; BL-Y ; C4-Y Between groups: Baseline p=0.006; Cycle 4 p=0.0002; Year one p= th 2012 PARIS -FRANCE ICCTF International Cognition and Cancer Task Force Conference March 15-17

10 Change in Cognitive Ability Subjective j Report (PAOF) There was no difference between groups in reports prechemotherapy However, compared to their pre-chemotherapy scores patients reported significantly worse cognitive function at the end of cycle 4 and at one year Objective NP testing There no significant differences between groups at any time point Within groups, the patients had no significant change from pre- chemotherapy to cycle 4 BUT, controls significantly improved By one year, patients also showed improvement

11 Subjective Report of Cognition PAOF = Patient s Assessment of Own Function Higher score is worse function Within groups: Patients: BL-C4 p=0.025; BL-Y1 p=0.070; C4-Y1 p=0.824 Controls: BL-C4 p=0.284; BL-Y1 p=0.139; C4-Y1 p=0.548 Between groups: BL p=0.851; C4 p=0.153; Y1 p=0049 Within groups: Patients: BL-C4 p=0.0009; BL-Y1 p=0.011; C4-Y1 p=0.34 Controls: BL-C4 p=0.175; BL-Y1 p=0.274; C4-Y1 p=0.939 Between groups: BL p=0.899; C4 p=0.009; Y1 p=0.021 Within groups: Patients: BL-C4 p<0.0001; BL-Y1 p=0.0022; C4-Y1 p=0.334 Controls: BL-C4 p=0.076; 076; BL-Y1 p=0.161; C4-Y1 p=0.703 Between groups: BL p=0.527; C4 p=0.012; Y1 p=0.114

12 Change in Cognitive Ability Subjective j Report (PAOF) There was no difference between groups in reports prechemotherapy However, compared to their pre-chemotherapy scores patients reported significantly worse cognitive function at the end of cycle 4 and at one year Objective NP testing There no significant differences between groups at any time point Within groups, the patients had no significant change from pre- chemotherapy to cycle 4 BUT, controls significantly improved By one year, patients also showed improvement

13 Neuropsychological Composite Change Scores better Within groups: Patients: BL-C4 p=0.286; Controls: BL-C4 p=0.002; Between groups: NS

14 Neuropsychological Composite Change Scores better Within groups: Patients: BL-C4 p=0.286; BL-Y1 p=0.0252; C4-Y1 p=0.055 Controls: BL-C4 p=0.002; BL-Y1 p<0.001; C4-Y1 p= Between groups: NS

15 Neuropsychological Composite Change Scores Better score 0,25 NP Composite Change Scores mean change (SEM ) 0,2 0,15 BL-C4 p=0.286 BL-C4 p=0.002 BL-Y1 p= BL-Y1 p< C4-Y1 p=0.055 C4-Y1 p= patients 0,1 controls 0,05 0 Baseline-Cycle 4 Baseline-Year 1 Cycle 4-Year 1 Between groups NS

16 Percent with objective cognitive decline Baseline Cycle 4 Cycle 4 One Year Baseline-One Year % N % N % N Cancer Patients 46% 28/61 39% 16/41 29% 12/41 Controls 26% 14/53 26% 8/31 18% 6/33 Fisher s test p= p=0.30 p=0.30

17 Predictors of Changes in Cognition Composite Score (patients) t Baseline Cycle 4 Cycle 4 One Year Baseline-One Year R 2 p-value R 2 p-value R 2 p-value Rhythm Robustness (f-statistic) Sleep quality (PSQI) Night time sleep duration PAOF Total PAOF Memory PAOF Language NS: Fatigue, depressive symptoms, napping All linear regression models adjusted for age, college and BL composite NP score

18 Predictors of Changes in Cognition Episodic Learning Memory Baseline Cycle 4 Cycle 4 One Year Baseline-One Year R 2 p-value R 2 p-value R 2 p-value Rhythm Robustness (f-statistic) Fatigue (MFSI) Depressive Symptoms (CES-D) Total nap duration Number of naps PAOF Total PAOF Language NS:sleep (PSQI); PAOF memory All linear regression models adjusted for age, college and BL composite NP score

19 Predictors of Changes in Cognition Executive Function Baseline Cycle 4 Cycle 4 One Year Baseline-One Year R 2 p-value R 2 p-value R 2 p-value Rhythm Robustness (f-statistic) Sleep quality (PSQI) Night time sleep duration NS: Fatigue, depressive symptoms, nighttime sleep, napping, PAOF All linear regressioin models adjusted for age, college and BL composite NP score

20 Predictors of Changes in Cognition Attention/Working ti Memory Baseline Cycle 4 Cycle 4 One Year Baseline-One Year R 2 p-value R 2 p-value R 2 p-value Rhythm Robustness (f-statistic) Sleep quality (PSQI) Fatigue (MFSI) Total nap duration Number of naps PAOF Total PAOF Memory PAOF Language NS: depressive symptoms, nighttime sleep All linear regression models adjusted for age, college and BL composite NP score

21 Predictors of Changes in Cognition Processing Speed Baseline Cycle 4 Cycle 4 One Year Baseline-One Year R 2 p-value R 2 p-value R 2 p-value PAOF Total PAOF Memory PAOF Language NS: Rhythm robustness, sleep quality, fatigue, depressive symptoms, objective measures of sleep All linear regression models adjusted for age, college and BL composite NP score;

22 Relation of Chemobrain to Fatigue/Sleep/Rhythms: Full Model Decrease in overall cognitive ability associated with Low baseline NP composite score Not having a college degree AND Less robust circadian activity rhythm At all time points Poor sleep quality (PSQI) Night time sleep duration PAOF BUT not fatigue or depressive symptoms

23 Circadian Rhythm of one Breast Cancer Patient X-axis is clock time. Y-axis is log value. Black dots = log of activity scores calculated by the actigraphy. Blue line = best-fitting traditional cosine curve. Red line = extended cosine curve. Green line = in-bed time. This patient shows robust sleep-wake rhythm at baseline indicated by clear contrast between daytime and night time activity. The rhythm then became disrupted at C1TW and remained disrupted for the duration of chemotherapy, as indicated by lower amplitude and less contrast between bedtime and wake time

24 Summary Poor sleep and fatigue are present before but get worse during chemotherapy; by year 1 most symptoms are back to baseline levels. Note this is still worse than controls. Repeated administration of chemotherapy results in progressively worse and more enduring rhythm impairments Patients rate themselves as being more cognitively impaired immediately after chemotherapy and at one year NP testing showed that controls improve after 12 weeks (cycle 4) but patients do not; by one year they begin to show improvement

25 Summary (con t) In addition to college education and pre-chemotherapy cognitive levels, l about one-third of general cognitive dysfunction is explained by the circadian rhythm robustness, poor sleep quality, and amount of night time sleep as well as subjective reports of cognitive ability Fatigue and depressive symptoms predict change in some domains but not in overall composite scores

26 Conclusion Seated Yucatan Woman, Francisco Zúñiga Sleep and fatigue, as well as circadian rhythms and objective measures of sleep need to be explored in all patients with breast cancer. Studies are needed to determine if treating and improving these symptoms will prevent cognitive dysfunction in women with breast cancer.

27 Collaborators Joel Dimsdale, MD Lianqi Liu, MD Paul Mills, PhD Loki Natarajan, PhD Barton Palmer, PhD Barbara A. Parker, MD Georgia Robins Sadler, PhD Richard Schwab, MD Lavinia Fiorentino, PhD. Michelle Rissling, MA Sue Lawton Ariel Neikrug, MA Vera Trofimenko

28 Neuropsychological Test Battery Episodic Learning and Memory Hopkins p Verbal Learning Test - Revised (HVLT-R) Trials 1-2 = learning Trial 4 = memory Brief Visuo-Spatial Memory Test Spatial Span Test California i Verbal Learning Test (CVLT-1) Executive Functioning Wisconsin Card Sorting Test abbreviated/64-card version (WCST-64) Stroop Reading, Color and Color-Word (trail 3) Trail Making Test Part B Letter (FAS) and Category (Animals) Fluency

29 Neuropsychological Test Battery Attention WAIS Digit span Vigilance Digit Cancellation Psychomotor speed WAIS Digit Symbol, and Symbol Search Trail Making Test Part A Processing speed and flexibility Paced Auditory Serial Addition Test Self-Assessment Patient s Self Assessment of Function (PAOF)

30 Neuropsychological Test Battery A composite score was computed for the neuropsychological test btt battery. defined as the mean of the "standardized" scores on each of the 13 tests within the neuropsychological battery Each observed score was converted to a z-score standardized by subtracting the baseline mean and dividing by the standard deviation of the sample This standardization was done for each test at each of the three time points (baseline, C4; one year). The standardized scores were then averaged to yield a composite score for each time point. This composite score was used as a measure of overall neuropsychological functioning.