Hyperintensities on T2-weighted images in the basal ganglia of patients with major depression: Cerebral perfusion and clinical implications
Introduction
White matter hyperintensities on T2-weighted images (WMH T2-WI) are magnetic resonance imaging (MRI) brain findings appearing bright on T2 and proton density (PD) images. Putative pathophysiological mechanisms contributing to the development of WMH T2-WI include atherosclerotic or ischemic disease, microinfarcts (Krishnan and McDonald, 1995, Alexopoulos et al., 1997), demyelination (Thomas et al., 2002), cerebral edema (Lenze et al., 1999), astrocyte proliferation and deposition of brain toxic materials (Thomas et al., 2002).
Also found in the brains of healthy individuals, such brain findings are particularly prevalent in elderly patients with major depressive disorder (MDD). WMH T2-WI in MDD are found with the highest frequency in the frontal lobe (Krishnan, 1993, Aylward et al., 1994) and basal ganglia (Coffey et al., 1990). A landmark post mortem (PM) brain pathology study (Thomas et al., 2002) revealed that WMH T2-WI lesions in depressed patients almost exclusively reflect arthrosclerosis or ischemic damage whereas in healthy controls these same lesions mostly arise from dilation of perivascular spaces and demyelination with no evidence of ischemia.
The term “vascular depression”, coined by Alexopoulos et al., 1997, Krishnan et al., 1997, denotes this subtype of depression and is associated with high rates of hypertension, diabetes, and coronary disease (Krishnan and McDonald, 1995), and history of stroke or silent stroke (Krishnan, 1993). The location of these lesions is related to the distribution of the perforating arteries, which supply blood to the basal ganglia or to watershed areas (boundary regions between vascular territories). Damage to the striato-pallido-thalamo-cortical pathway is considered central in the development of this type of depression (Alexopoulos et al., 1997, Krishnan et al., 1997, Kimura et al., 2003).
The presence and location of WMH T2-WI in depression have clinical and prognostic implications. A higher prevalence of WMH T2-WI was found in depressed patients with cognitive impairment compared with depressed patients without cognitive impairment (Alexopoulos et al., 1997, Ebmeier et al., 1997, Krishnan et al., 2006, Krishnan et al., 1997). MDD with anger attacks was associated with a higher prevalence and severity of subcortical but not periventricular WMH T2-WI (Versluis et al., 2006, Iosifescu et al., 2007). Depressive patients with subcortical WMH T2-WI exhibit lassitude and deficits in the instrumental activities of daily life (Krishnan et al., 2004). The association between presence of WMH T2-WI and prognosis is not clearly established. Taylor et al. (2003) found a correlation between progression in severity of WMH T2-WI and negative long-term outcome in depressed patients. Cognitive dysfunction in depression in older patients associated with WMH T2-WI in the prefrontal area predicts poor or delayed antidepressant response (Kalayam and Alexopoulos, 1999). Poor treatment outcome was associated with subcortical and basal ganglia, but not periventricular, hyperintensities (Steffens et al., 2002). In contrast, other studies report no difference in treatment response between elderly patients with and without WMH T2-WI (Salloway et al., 2002), or prevalence of WMH T2-WI and prognosis (Krishnan et al., 2004).
Altered regional cerebral blood flow (rCBF) is a consistent finding in MDD (Drevets, 2003, Mayberg, 2003). Perfusion anomalies have been found in frontal, prefrontal, parietal, limbic and subcortical structures (Mayberg, 2003). However, only limited effort has been made to link CBF deficiencies with structural brain findings such as WMH T2-WI. Lesser et al. (1994) did not find a correlation between WMH T2-WI and whole brain CBF but noted that in patients with the largest total area of WMH T2-WI whole brain CBF was equal to or lower than that of depressed patients. Kimura et al. (2003) found reduced rCBF in frontotemporal regions in patients with vascular depression. Oda et al. (2003) found that depressed patients with WMH T2-WI in deep white matter show decreases in rCBF in the occipital lobe, midbrain, basal ganglia and thalamus WMH T2-WI.
In the current study we used single photon emission computed tomography (SPECT) with Technetium-99m hexamethylpropyleneamineoxime (Tc-99m HMPAO) and MRI to study depressed patients before treatment with antidepressant medication or electroconvulsive therapy (ECT). Previous analysis of the MRI data revealed that depressed patients with WMH T2-WI in the basal ganglia were more severely depressed and more cognitively impaired than depressed patients with no WMH T2-WI or WMH T2-WI in other locations (Agid et al., 2003). We hypothesized that this subgroup of depressed patients would also demonstrate the most severe perfusion deficits and the poorest response to antidepressant treatment
Section snippets
Subjects
Thirty-seven (21 women) patients suffering from MDD (diagnosis conferred using the structured clinical interview for DSM-IV (SCID) (Spitzer et al., 1995)) aged 55 ± 16.3 (mean ± S.D.; range 22–83) and 27 healthy controls (14 women) aged 50 ± 11.2 (range 24–64) participated in the study. No significant differences in age, and sex socioeconomic, demographic or educational background were observed between the two groups. Subjects' characteristics are described in more detail elsewhere (Agid et al.,
Response to treatment
Rates of response (defined as a decrease of at least 50% in the 21-item HAM-D) to antidepressant treatment and of remission (defined as HAM-D score equal to or lower than seven) are similar in severely depressed cognitively compromised patients with WMH T2-WI in the basal ganglia, patients with WMH T2-WI in other locations and patients with no WMH T2-WI (see Table 2).
An improvement in MMSE score, nearing significance levels (p = 0.06, paired, 2-tailed), was noted in the WMH T2-WI-BG group after
Discussion
We have shown that severely depressed, cognitively compromised patients with WMH T2-WI in the basal ganglia area display more extensive cerebral perfusion deficits than depressed patients with WMH T2-WI in other regions or depressed patients with no WMH T2-WI. Since SPM comparisons were performed on images normalized to mean global brain activity we do not know whether these deficits represent absolute lower cerebral blood flow or only relatively lower perfusion. We have also shown that these
Acknowledgments
This study was supported by grant no. 391/95 from the Israel Science Foundation to Dr Lerer, and a NARSAD Young Investigator Award to Dr Bonne.
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