NT is a poorly characterized, but frequent consequence, of cancer related therapy, and the pathophysiology remains largely unknown. Most of the previous studies evaluating the neurotoxic effects of treatment on cancer patients have concentrated on structural or functional changes. Studies examining relationships between NP testing and structural changes on MRI have yielded inconsistent results. A noninvasive method for early detection of structural changes that correlates with NP function would be clinically useful in the management of these patients. Proton magnetic resonance imaging is a relatively recent clinical advance that has proven useful in the evaluation of neoplasms [32
] and central nervous system diseases such as white matter disease [34
], Alzheimer's disease [36
], and attention deficit/hyperactive disorder (ADHD) [14
]. The relationship between metabolic profiles in proton MRS and NP function has not been well-characterized. Previous research on NP function and proton MRS has applied single voxel techniques [8
]. This study describes relationships between cognitive function and multi-voxel 1
H-MRSI metabolic data in cancer patients.
NAA, an amino acid derivative found predominantly in neurons [35
], is considered a marker of neuronal integrity and implicated in cognitive function [43
]. NAA is reduced in pathological states with neuronal loss or injury such as brain tumor [32
], head trauma [17
], and infection [7
]. Phosphocholine and glycerophosphocholine are known precursors of cell membrane synthesis and components of membrane breakdown products [22
]. Increased Cho is associated with membrane turnover and reflects cellular density [21
]. Lactate (Lac) and lipids (Lip) are also detectable at long TEs but are not seen in normal brain tissue [31
]. Lac is a reflection of anaerobic metabolism. Prominent lipid peaks have been reported in MRS studies of multiple sclerosis [33
], Tay-Sachs disease [2
], and Sjögren-Larsson syndrome [42
] and are attributed to demyelination or membrane breakdown. Because neuronal loss and demyelination have been associated with NT, we hypothesized that changes in the metabolites that reflect these conditions would be markers of NT.
In this study, metabolite ratios (Cho/Cr, Cho/NAA, and NAA/Cr) were compared to NP test results. We investigated areas of the brain that are known to be involved in selected domains of NP function. Relationships between 1
H-MRSI metabolite ratios and lower NP functioning were identified in this study. IQ appears to be the most robust measure for 1
H-MRSI comparisons. Comparisons between metabolite ratios in subcortical regions and lower IQ scores yielded significant relationships. Increased levels of choline or lipids, both reflections of membrane turnover or demyelination, are related to lower IQ scores and overall cognitive deficits. This metabolic profile has been observed in other patient groups who present with decreased cognitive function, including patients with head trauma [17
] or white matter disease [34
]. Studies using proton MRS techniques to evaluate patients with traumatic brain injury and HIV disease have also shown that decreased NAA, indicating either neuronal loss or dysfunction, is associated with poor cognitive outcome [17
]. In patients with Tay-Sachs disease and Sjögren-Larsson syndrome [24
], populations at risk for impaired cognitive function, memory and executive function [44
], increased levels of choline and prominent lipid peaks have been observed and associated with active demyelination [2
] and white matter abnormalities. The relationships identified between poorer NP function and metabolite ratios in our study may reflect changes in myelin metabolism that are not consistently perceptible on MRIs.
The development of NT in cancer patients is variable with regards to clinically detectable onset. When these changes in metabolites and detection of lipid peaks develop in relation to treatment remains to be determined. A prospective, longitudinal study may yield additional information about this unique metabolic profile and its relationship to NP function.
This study shows that 1H-MRSI is a potential tool for early identification of neurological and NP complications in cancer patients. Limitations of this study include cross sectional design, small sample size, multiple comparisons, and heterogeneous population. Thus, our findings will need to be confirmed in additional studies. Further studies using 1H-MRSI and NP assessment are warranted to determine if this method can be used to noninvasively identify, predict, and better characterize NT.