As a group, the NPH patients in this study had larger total intracranial volumes than other subjects, an observation consistent with past reports of increased head-size among adult NPH patients [22
]. Despite the fact that NPH patients had significantly larger ventricular volumes than all other groups including AD, there was overlap in this measure between the NPH and AD participants (). The Evans Index also failed to differentiate between groups, as several AD and one older NC participant scored above the cutoff for ventricular enlargement. This is consistent with the observation that it is difficult to distinguish ventriculomegaly due to NPH and AD based on ventricular size alone. NPH patients also showed a large degree of overlap with other groups in measures of global or regional cortical thickness. The AD group has significantly different total cortical thickness and middle temporal thickness than the other groups, but these measures did not distinguish all AD patients from the other patient groups. Accordingly, neither ventricular volume nor cortical thickness alone would be expected to adequately serve as the basis for differential diagnosis of NPH individual patients. However, when both VentVol and TCortTh were considered together as in , subjects with an NPH diagnosis can be more clearly separated from NC and patients with AD and PD.
The volumetric analysis techniques employed in this study have become more widely available, efficient, and user friendly in recent years. Fully automated measurements of cortical thickness and ventricular volume may be less subject to interrater variations and therefore more suitable for clinical use. Limitations to the present study include the small number of subjects and the use of images obtained with different MRI platforms and sequences. Although these factors are likely to have influenced the absolute values of our ventricular volume and cortical thickness measurements, the outcomes obtained for these parameters in this study are consistent with those in the literature [21
Differential diagnosis of NPH from AD and other neurologic disorders might be assisted by additional biomarkers. Positron emission tomography (PET) imaging with amyloid tracers detects amyloid plaques in the brain, which are characteristic of AD [23
]. This technique could be used to confirm this study's findings in individual cases, but it would require carrying out an expensive, additional test. The 42-amino acid subtype of the amyloid beta protein is present in cerebrospinal fluid (CSF) and is associated with AD [24
]. Other CSF biomarkers include total tau and phosphorylated tau [24
]. Amyloid PET and CSF biomarkers, however, have not been shown to conclusively distinguish AD from NPH, although ongoing studies can help to address this [26
]. Future research can combine the MRI measures examined in the current study with other biomarkers to further improve the accuracy of the differential diagnosis of NPH.
Future follow-up studies with larger samples can use parametric statistics such as logistic regression to further establish the separation of NPH from other groups based on ventricular volume and cortical thickness. In addition, future studies can examine cortical thickness and/or volume changes in specific structures that are vulnerable to AD to further improve the differential diagnosis of NPH relative to AD. Hippocampal volume, however, may not be as useful in differentiating the two diseases because it can be reduced in NPH due to compression by the expanded temporal horn of the lateral ventricle. Cortical structures, being farther removed from the ventricles, might better contribute to the differential diagnosis of NPH. In this study, middle temporal thickness was not as effective as total cortical thickness in distinguishing groups, since NPH patients showed thinning of this area. Further research is needed to identify specific areas of the cortex that can contribute to the differential diagnosis of NPH.
Another possible confounder to this analytic strategy in practice is the simultaneous occurrence of NPH and AD or PD in the same patient. Such cases were excluded from the present analysis but are often encountered in clinical practice. Further studies will be required to determine if patients with dual diagnoses can be identified by these methods.