Part I of the present study conducted a volumetric assessment in patients with NPH using automated segmentation techniques. Total brain volume and volumes of subcortical structures in NPH patients were compared to healthy controls; and associations between volumetric data and cognitive function/ outcome were investigated.
4.5.1. Pre-operative total brain volume
Total brain, GM, and WM volumes were extracted at pre-shunt in the NPH group. As would be expected, age was significantly negatively correlated with WM volume and total brain volume in the NPH group. However, ventricular volume was not significantly correlated with total brain, GM, or WM volume. The average total brain, GM, and WM volumes of the NPH group were smaller than those for the control group but the differences were not statistically significant.
84 One previous study (Serulle et al., 2014) compared GM, WM, and ventricular volumes in patients with NPH, patients with Alzheimer’s disease (AD), and healthy controls. They found a statistically significant reduction in GM volume in patients with AD compared to NPH patients and controls. Although the mean GM volume for the NPH group was smaller than the control group mean, the difference was not statistically significant. No significant differences in WM volume were observed across the three groups. Ventricular volume in the NPH group was significantly larger than in the two remaining groups. Therefore, the results of the present study support the findings by Serulle et al.
These results might suggest that, despite the ventriculomegaly, total brain volume in patients with NPH is not markedly reduced, or that brain atrophy is absent or mild in NPH. However, as the sample sizes in these studies were small, a larger study is needed to verify this finding. Another explanation could be that the patients in the present study and in the previous study had relatively short disease durations but that brain atrophy could occur as the disease progresses. The relationship between disease duration and total brain volume in NPH would be an interesting topic for future research. Finally, brain atrophy may only occur in a subgroup of NPH patients, such as those with comorbid AD (Serulle et al., 2014).
The present study also investigated whether total brain, GM, and WM volumes were associated with cognitive performance. After controlling for the effect of age, WM volume was significantly negatively correlated with HVLT delayed score, and there was a trend towards a significant negative correlation between WM volume and HVLT learning score. That is, reduced WM volume was associated with better performance on a measure of delayed recall. The reason for this relationship is unclear and warrants further investigation. However, GM and total brain volume did not significantly correlate with scores in any of the cognitive tests.
4.5.2. Subcortical deep grey matter structure volumes
Volumetric assessment of SDGM structures was conducted in patients with NPH at both pre- and post-shunt. At baseline, mean volume of the caudate nucleus was significantly reduced in NPH patients compared to healthy controls after controlling for age and ventricular volume. Correlations between subcortical volumes and neuropsychological test scores in the NPH patient group at pre-shunt revealed that greater caudate volume was associated with better performance on the MMSE, and greater nucleus accumbens volume was associated with better performance on the HVLT immediate subtest. However, after controlling for IQ, the
85 relationship between caudate volume and MMSE score was no longer significant. At post- shunt, volumes of the putamen, pallidum, hippocampus and nucleus accumbens were significantly reduced in the NPH group compared to controls after controlling for age and ventricular volume. Additionally, at post-shunt, greater caudate volume was associated with better semantic fluency performance and less severe levels of apathy; and greater nucleus accumbens volume was associated with better performance on the MMSE as well as better performance on the immediate, learning and delayed subtests of the HVLT. After controlling for IQ, the relationship between caudate volume and semantic fluency was no longer significant.
Reduced caudate volume was previously noted by our laboratory in a group of NPH patients who had not yet undergone shunt surgery (DeVito et al., 2007). While the previous study segmented the caudate nuclei only, in the present study, volumes for a greater range of SDGM structures were extracted. Despite this, at pre-shunt, the caudate was the only SDGM structure showing a statistically significant volume reduction compared to controls. DeVito et al. (2007) further hypothesised that caudate volume loss may contribute to cognitive decline and apathy in NPH. In the present study, caudate volume was associated with apathy at post- shunt.
At post-shunt, while there was no significant difference in mean caudate volume compared to pre-shunt, mean caudate volume was no longer significantly reduced compared to controls. Instead, the putamen, pallidum, hippocampus, and nucleus accumbens showed significant volume reductions compared to controls. Further, volume of the nucleus accumbens was associated with performance on the MMSE at post-shunt, and with verbal learning and memory at pre- and post-shunt. The nucleus accumbens forms part of the ventral striatum and has been linked to learning and memory (Setlow, 1997), and dementia (de Jong et al., 2012). Thus, the associations between caudate and nucleus accumbens volume with scores on neuropsychological tests and apathy suggest that striatal volume reductions in NPH may be related to functional impairment of these areas. While volumes of the putamen and pallidum did not correlate with performance in cognitive tests, both of these regions have been shown to play a role in movement (DeLong et al., 1984; Heimer, Switzer, & Van Hoesen, 1982; Marchand et al., 2008; Mogenson, Jones, & Yim, 1980). Therefore, future studies should investigate whether gait dysfunction in NPH is related to volumes of the pallidum and putamen. Although there were significant group improvements in tests of semantic fluency, and verbal learning and memory following shunt surgery; as well as significant volume increases
86 in the thalamus, and hippocampus, percent change in these variables were not significantly correlated. Therefore, SDGM volumetric change following shunt surgery cannot account for the observed cognitive improvement in the present study. However, regional volumetric changes following shunt may be associated with other measures of cognitive or functional outcome.
It is unclear why volumes of specific SDGM structures might increase following shunt surgery. While percent increase in volume of the thalamus was significantly correlated with percent reduction in ventricular volume, reduced ventricular volume was not significantly correlated with increased volume of the hippocampus. Therefore, ventricular reduction may not be the sole mechanism leading to SDGM volumetric changes. A previous study investigating whole brain volume change following diagnostic CSF removal found an increase in global brain volume which was particularly evident in periventricular, frontal, and temporal regions (Singer et al., 2012). The researchers hypothesised that increased brain volume may be due to increased cerebral blood volume, and that this in turn might lead to improved cerebral perfusion. However, further research is needed to investigate whether regional volumetric changes are associated with changes in rCBF.
Overall, the results suggest there is reduction of volumes of subcortical structures both before and following shunt surgery in NPH that is not solely due to ventricular enlargement. Striatal volumes in particular appear to be associated with cognitive performance and apathy in NPH. These results suggest that at least some of the cognitive decline in patients with NPH may be due to subcortical dysfunction.
4.5.3. Rationale for Part II
There was a significant negative correlation between caudate volume and apathy at post-shunt (that is, a reduction in caudate volume was associated with increased apathy severity), but this relationship was not observed at pre-shunt. However, due to problems with caudate segmentation in particular (due to ventriculomegaly), caudate volumetric information was not available for five of the patients at pre-shunt, and three of the patients at post-shunt, considerably reducing the sample size for caudate volume analyses. Therefore, in order to further investigate the relationship between caudate volume and apathy in NPH patients (at pre- and post-shunt), Part II of the present study was conducted in which the caudate nuclei were segmented manually for the NPH group. Specifically, Part II aimed to investigate whether
87 caudate volume is related to apathy at pre-shunt (I.e. whether the reduced sample size explains the lack of a relationship at pre-shunt in Part I), as well as at post-shunt.
88