Relationship of cerebrospinal fluid glucose metabolites to MRI deep white matter hyperintensities and treatment resistance in bipolar disorder patients

Abstract

Objectives Both diabetes mellitus and magnetic resonance image (MRI) deep white matter hyperintensities (WMHs) are more common in bipolar disorder (BD) patients than in matched controls. Deep—as opposed to periventricular—WMHs and diabetes are associated with treatment resistance and poorer outcome. This study investigated whether brain glucose metabolism by the polyol pathway—a pathway linked to nervous tissue disease in diabetes—is related to deep WMH volume and treatment resistance in BD patients. Methods Volumes of fluid-attenuated inversion recovery WMHs were quantified and correlated with cerebrospinal fluid (CSF) concentrations of glucose metabolites in 20 nondiabetic patients with BD and nondiabetic comparison subjects with schizophrenia (n = 15) or transient neurologic symptoms (neurologic controls, n = 15). Results BD patients, but not schizophrenic patients, had significantly greater volumes of deep but not periventricular WMHs compared to neurologic controls. BD subjects also had significantly greater CSF concentrations of sorbitol and fructose (the polyol pathway metabolites of glucose) compared to controls. Significant positive correlations between CSF metabolites and WMH volumes were found only in the BD group and were between deep WMH volumes and CSF sorbitol (ρ = 0.487, p = 0.029) and fructose (ρ = 0.474, p = 0.035). An index of treatment resistance correlated significantly with deep WMH volume (ρ = 0.578, p = 0.008), sorbitol (ρ = 0.542, p = 0.013), and fructose (ρ = 0.692, p = 0.001) in BD subjects but not in other subjects. Conclusions This is the first reported evidence of relationships between abnormal brain glucose metabolism and both deep WMHs and treatment resistance in a group of BD patients. Further studies are necessary to determine the significance of these findings to BD pathophysiology.

A role for white matter abnormalities in the pathophysiology of bipolar disorder

“…An increased number and/or severity of white matter hyperintensities (WMH), which are hyper-intense bright spots that may be detected in T2-weighted and fluid-attenuated inversion recovery (FLAIR) MR images, is one of the most consistently reported abnormalities in bipolar disorder (Ahn et al, 2004; Altshuler et al, 1995; Aylward et al, 1994; de Asis et al, 2006; Dupont et al, 1990; Dupont et al, 1995; Figiel et al, 1991; Gulseren et al, 2006; Kempton et al, 2008; Lloyd et al, 2009; Lyoo et al, 2002; McDonald et al, 1991; McDonald et al,1999; Moore et al, 2001a; Moore et al, 2001b; Pillai et al, 2002; Regenold et al, 2008; Silverstone et al, 2003; Swayze et al, 1990; Tamashiro et al, 2008; Woods et al, 1995), although several negative reports have appeared (Botteron et al, 1995; Breeze et al, 2003; Brown et al, 1992; Chang et al, 2005; Dolan et al, 1990; Krabbendam et al, 2000; Lewine et al, 1995; López-Larson et al, 2002; Persuad et al, 1997; Sassi et al, 2003; Strakowski et al, 1993b; Zanetti et al, 2008). Regarding these negative findings, however, Ahn et al (2004) have pointed out that studies using thinner MR imaging slices, a larger sample size, and that have rated the severity of WMH, in addition to their presence or absence according to an established rating scale, tend to produce more consistent, positive results.…”

“…In unipolar depression (UD) and BD, increased deep WMH, but not necessarily periventricular WMH, have been frequently noted (Ahn et al, 2004; de Asis et al, 2006; Figiel et al, 1991; McDonald et al, 1999; Moore et al, 2001b; Regenold et al, 2008; Thomas et al, 2002a; Thomas et al, 2002b), although the opposite has also been reported (Altshuler et al, 1995). An association between increased rates of periventricular WMH and previous suicide attempts among patients with affective disorders has been reported (Pompili et al, 2008), suggesting that periventricular WMH may be potential neurological markers of suicidal behavior.…”

Neuroimaging Data in Bipolar Disorder: An Updated View

“…Neuroimaging research in BD has already produced several data documenting the involvement of different cortical and subcortical regions in different phases of the illness. In particular, published studies explored structural and functional abnormalities present in BD and tried to establish specific correlations with outcome (Moore et al, 2001;Wingo et al, 2009) as well as difficult-to-treat conditions such as treatment resistant forms (Regenold et al, 2008). The possibility to study cognitive function in BD through fMRI represents another major acquisition of neuroimaging in psychiatric research.…”

Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder

“…Positron emission tomography studies show resting prefrontal hypometabolism and simultaneous resting limbic/paralimbic hypermetabolism in patients with bipolar disorder [6,7]. Nuclear magnetic resonance studies have revealed significantly elevated concentrations of sorbitol and fructose in the cerebrospinal fluid [8] and lower levels of N-acetylaspartate in frontal lobe structures and hippocampi [9,10]. Moreover, treatment with lithium increased levels of N-acetylaspartate in patients with bipolar disorder [11,12].…”