Participants were white, 60-year-old, right-handed female twins who were reared together. The participant who had breast cancer (twin A) was enrolled onto a research study examining the efficacy of a brief cognitive-behavioral treatment (CBT) of memory dysfunction after chemotherapy. Twin A identified her sister (no cancer), who was subsequently contacted for participation. Both had no history of head injury, stroke, or other CNS injury or disease. Neither had a smoking or substance abuse history or other systemic illnesses that could affect cognition. Both provided informed written consent for imaging and genetics testing for research approved by Dartmouth Medical School’s Committee for the Protection of Human Subjects. The consent process was in strict accordance with all US Department of Health and Human Services standards.
Twin A completed adjuvant chemotherapy for stage II breast cancer 22 months before enrollment. Treatment consisted of four cycles of doxorubicin 60 mg/m2 (108.6 mg) and cyclophosphamide 600 mg/m2 (1,086 mg), with each cycle administered every 3 weeks. She also received four cycles of docetaxel 100 mg/m2 (178 mg) over a 1-hour infusion administered every 3 weeks. Her post-treatment hormonal therapy consisted of oral tamoxifen at 20 mg/d (she had been taking this medication for 18 months at the time of study).
Monozygotic status was determined with molecular diagnostic assessment using PowerPlex 16 (Promega, Madison, WI) short tandem repeat analysis (probability of dizygosity, P
= .0000305), and genetic testing conducted as part of a larger study revealed that the twins were carriers of the ε
-4 allele of apolipoprotein E (APOE). APOE status has been associated with cognitive impairment in other populations and breast cancer patients treated with adjuvant chemotherapy.9-11
A brief battery of standardized neuropsychological tests (domains of verbal memory and processing speed) was administered to assess memory and attention.12-15
Self-reported cognitive function was assessed using the Multiple Ability Self-Report Questionnaire (MASQ), a 48-item self-report measure of cognitive function,16
and anxiety and depressive symptoms were assessed using the Spielberger State-Trait Anxiety Inventory17
and the Center for Epidemiologic Studies Depression Scale.18
Finally, structural and functional MRI scans were acquired during the same session on a GE Horizon 1.5T LX scanner (GE, Waukesha, WI). A gradient echo, echo-planar sequence was used to provide whole-brain coverage for functional MRI (repetition time [TE], 2,500 msec; echo time [TE], 40 msec; field of view [FOV], 24 cm; number of excitations [NEX], 1.29; 5-mm-thick sagittal slices with no skip, yielding a 64 × 64 matrix with 3.75 mm2
in-plane resolution). Initial volumes before spin saturation were discarded. An aurally presented verbal “3-back” task was used to probe working memory. During scanning, participants were asked to listen to a string of consonant letters (except L, W, and Y) presented at a rate of one every 3 seconds. This experiment was presented in a four-condition, blocked design. Conditions were 0, 1, 2, and 3 back. For each consonant heard, participants used a button press device (Photon Control, Burnaby, British Columbia, Canada) to signify whether the current letter was a match (ie, was the same as the designated target or the letter presented 1, 2, or 3 back in the sequence, depending on the condition instructions) or a nonmatch. The number of correct and incorrect responses was recorded, along with reaction times. Each n
-back condition was presented in 12 27-second epochs preceded by 3 seconds of instruction (eg, “the match is D” or “the match is one back”). The four experimental conditions were each presented three times in pseudorandom order. During each epoch, there was a possibility of two or three matches, and the number of matches was counterbalanced within and across conditions. In addition, non-target recurrences were presented as foils (eg, a 2-back match during the 3-back condition). Participants rehearsed practice versions of the tasks outside the scanner to ensure comprehension of task demands. We have used this paradigm in several neurologic and neuropsychiatric populations to demonstrate alterations in working memory circuitry.19-22