Accelerated vascular aging and persistent cognitive impairment in older female breast cancer survivors

Abstract

Advances in breast cancer treatment have markedly increased survivorship over the past three decades, with over 3.1 million survivors expected to live into their 70s and 80s. Without symptom relief interventions, nearly 35% of these survivors will have life-altering and distressing cognitive symptoms. This pilot study explored associations between serum markers of vascular aging, laterality in cerebral oxygenation, and severity of cognitive impairment in women, 12-18 months after chemotherapy for stage 2/3 invasive ductal breast cancer. Fifteen women (52-84 years) underwent a brief cognitive assessment (Montreal Cognitive Assessment [MOCA]) and blood draws to assess markers of vascular aging (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], C-reactive protein [CRP], and insulin growth factor-1 [IGF-1]). All underwent a computer-based test protocol that is known to increase blood flow within the frontal lobes. Percent cerebral oxyhemoglobin saturation (rcSO₂) was recorded during and after testing. Laterality in rcSO₂ was defined by ≥ 3% difference between left and right rcSO₂ (|rcSO₂ mean_{RIGHT -} mean_LEFT|). Eight participants had MOCA scores between 21 and 25 points, suggestive of mild cognitive impairment. Neither CRP (r = -.24) nor IL-6 (r = .34) nor TNF-α (r = .002) were associated with MOCA scores. Higher IL-6 was associated with greater laterality (r = .41). MOCA scores were significantly lower in subjects with laterality in rcSO₂ than in those without laterality (F_(1,14) = 13.5, p = 003). Lower IGF-1 was significantly associated with greater laterality (r = - .66, p = .007) and lower cognitive function (r = .58). These findings suggest that persistent cognitive impairment is associated with phenotypical changes consistent with accelerated vascular aging.

Keywords: Cerebral blood flow; Chemotherapy; Cognitive symptoms; Survivorship; Vascular aging.

Fig. 1

Representative plots of trends in right- and left-sided rcSO₂ in participants without (a) and with (b) laterality in rcSO₂. Note with laterality, the side with the lowest rcSO₂ remains the same across time and test conditions. The consistency in sidedness and the restoration of laterality with cognitive testing (encoding and recall) was seen in all eight participants with laterality in rcSO₂

Fig. 2

Scatter plots showing the relationships and correlation coefficients between age in years and a total scores on the Montreal Cognitive Assessment Test, as well as serum measurement of b tumor necrosis factor, c insulin growth factor 1, d high-sensitivity C-reactive protein, and e high-sensitivity interleukin-6

Fig. 3

Differences in total scores on the Montreal Cognitive Assessment Scale (MOCA) in participants with laterality and serum insulin growth factor 1 (IGF-1) < 85 ng/dL. Each filled symbol (circles and squares) marks participants with the positive predictive marker. The open symbols mark participants without the marker. Solid line marks the group mean. Stars indicate the median for each group. The dotted horizontal line extending from the X-axis indicates the clinical cutpoint for mild cognitive impairment, as measured by the MOCA