Although chemotherapy can offer long-term survival for patients with cancer, recent
reports [1] have revealed that it may induce cognitive dysfunction, such as deficits
in attention, concentration, executive function, and processing speed. Whereas such
chemotherapy-induced cognitive impairment (CICI) is usually less severe and most often
transient, it sometimes impairs activities of daily living and quality of life to
the point of debilitation. While it has been recognized as a clinically significant
issue in patients, little is known about CICI, particularly in older cancer patients
to whom chemotherapy has become more commonly proposed. CICI has been particularly
studied among middle-aged women undergoing chemotherapy for breast cancer, while only
a small number of studies have focused on older patients. Many of the candidate mechanisms
for breast cancer chemotherapy-related brain injury overlap significantly with those
involved in aging [2]. Therefore, CICI can be an interesting model for examining the
interactions in disease, aging, and neurodegeneration. Here, we introduce some proposed
mechanisms which CICI has in common with other types of dementia, and discuss the
difficulties in evaluation of cognitive function in aged cancer patients.
One proposed mechanism of CICI is direct neurotoxicity by chemotherapy itself [1].
Magnetic resonance imaging studies have demonstrated lower integrity of cerebral white
matter (the location of myelinated axons) rather than gray matter (the location of
neuronal cell bodies) in patients with CICI in comparison with healthy subjects [3].
However, these findings do not directly indicate whether the decreased integrity of
the cerebral white matter is caused by damage to axons themselves, which are the main
components of white matter, or by Wallerian axonal degeneration following neuronal
damage. Various tissues in the central nervous system (CNS), including neurons, axons,
and glia, release several lines of proteins into the cerebral spinal fluid (CSF) and/or
peripheral blood flow when damaged. Some of these proteins in the CSF and/or blood
have been explored as objective biomarkers of the severity of neuronal damage.
Recently, we evaluated in a cross-sectional study the serum level of the phosphorylated
form of the high-molecular-weight neurofilament subunit (pNF-H), a major structural
protein in central and peripheral axons, in breast cancer patients undergoing adjuvant
chemotherapy [4]. The results showed that the serum pNF-H level in patients increased
in a cumulative, dose-dependent manner. Axonal damage in the CNS can be cumulatively
caused by chemotherapy, which might eventually lead to CICI. Surprisingly, increased
pNF-H levels in CSF were also observed in a previous study [5] in patients with Alzheimer
disease when compared with age-matched controls and patients with non-Alzheimer disease-related
neurological disorders and vascular dementia. Both studies suggest that the increased
level of pNF-H could be used as a marker for neuro-degenerative disorders. Another
study showed that the pNF-H level is associated with the severity of spinal cord injury,
and may have adequate sensitivity to serve as a biomarker of treatment efficacy in
patients with such injury [6]. It might be useful, therefore, to investigate severity
indices of CICI and neural toxicity of chemotherapy on the CNS using pNF-H as a surrogate
marker, rather than subjective cognitive test batteries.
Another explanatory mechanism of CICI is the patient's genetic status, such as apolipoprotein
E (APOE), which is also associated with cognitive decline related to Alzheimer's disease
and aging [7]. APOE status influences the clearance of amyloid-beta, which is deposited
in the brain with aging and is a key element in the pathology of age-related cognitive
decline and neurodegeneration. Chemotherapy itself may increase amyloid-beta accumulation
through a rise in inflammation and oxidative stress, altered glucose metabolism, and
other factors. A previous study showed that the epsilon-4 allele of APOE may be a
potential genetic marker for increased vulnerability to chemotherapy-induced cognitive
decline [7]. Further studies combining APOE status and amyloid-beta are needed to
examine the interactions between aging, amyloid-beta accumulation, genetic risk, and
chemotherapy.
The evaluation of CICI is also challenging. CICI is moderate and often transient,
so many cognitive screening tests used in oncogeriatry, such as the Comprehensive
Geriatric Assessment in Oncology and Mini Mental State Examination, are not sensitive
enough to detect CICI in both young and aged cancer patients. Therefore it may be
promising to use biomarkers such as pNF-H as prognostic markers, rather than subjective
cognitive tests, to detect CICI, or to employ them as predictive markers to distinguish
which patients would develop CICI before symptoms are recognized.
In summary, although the effects and mechanisms of chemotherapy on the cognitive functions
remain unclear, some may be similar to the neurodegenerative disorders associated
with aging. Further studies of biomarkers, such as pNF-H, might help us to understand
the mechanisms of both CICI and brain aging, measure the severity of CICI, and predict
who may develop CICI.