Pathological studies have revealed the histological heterogeneity and severities of WMH. These include myelin pallor, enlargement of perivascular spaces, discontinuity of ependyma, infarctions, gliosis, and axonal loss [13, 18-20]. Nevertheless, these pathologic changes induce similar signals via FLAIR or T2WI and are difficult to distinguish. Some studies have suggested that pathological differences exist between periventricular WMHs and deep WMHs [21-24]. Our results demonstrated that microstructural changes around the frontal periventricular WMHs were significantly different from those in other regions, Meanwhile, the structural changes within parietal-occipital periventricular WMHs resembled those of deep white matter.
There were significantly lower FA values, but higher DA, DR, and MD values in frontal periventricular WMHs compared to other regions. These results underscore the pathological heterogeneity of WMHs in different regions. Studies with magnetization transfer imaging also showed a lower magnetization transfer ratio in frontal periventricular WMHs compared to parieto-occipital periventricular WMHs [16, 17]. As there were no such differences in DTI metrics among different brain regions that featured normal white matter. Therefore, these heterogeneities were likely not due to anatomical heterogeneities.
Frontal periventricular WMHs might correspond with more severe pathological processes than other regions. Frontal WMHs appeared at an earlier age and demonstrated less age-related progression than WMHs in other regions . This may lead to inconsistencies between the extent of WMHs and their respective pathological severities. The underlying pathological changes may be aggravated, even with little volumetric expansion. These findings suggest that future studies should consider, not only the volume of WMH, but also their pathological severities.
Previous studies have mostly assessed the relationship between volumetric measures of WMH and functional decline. Fazekas et al.  categorized periventricular WMHs into three grades. Moderate and severe (grades 2 and 3) periventricular WMHs were believed to be related to ischemia, whereas mild (grade 1) periventricular WMHs were considered non-ischemic, mainly due to a partial loss of the ependymal lining . However, correlations between the volume of WMHs and cognitive performance were modest. Therefore, many clinical variations cannot be explained by volumetric measurements.
Some studies [4-6] have elucidated links between cognitive decline and periventricular WMHs in the frontal lobe, parieto-occipital lobe, and other parts of the brain. However, the underlying pathological mechanisms of WMHs in different regions that might explain cognitive decline (other than anatomical locations) remain scarcely studied .
Some pathological studies suggested that periventricular WMHs occurred because of fluid accumulation within the extracellular space that was related to the loss of ventricular ependyma [25-27]. Although increases in interstitial water content might have led to significant increases in MD, these changes could not explain the more immediate changes in DR values, compared to DA values. Thus, demyelination may have contributed to these pathological changes. Further, these changes may have led to rapid increases in DR and relatively mild changes in DA .
Immunohistochemical findings revealed that periventricular WMHs demonstrated more severe demyelination than deep WMHs . A past neuropathological study found a stronger relationship between the extent of WMHs on MRI and the extent of myelin rarefaction in the frontal lobe, compared to the parietal lobe . These findings suggested that even Fazekas grade 1 WMHs may correspond to clinically significant pathological changes around the frontal lateral ventricle. Frontal white matter microstructural changes began before the appearance of hyperintensities that could be found using conventional MRI.
A recent DTI study  showed that, in patients with hypertension, anterior thalamic radiations, the superior longitudinal fasciculus, and the forceps minor had significantly lower FA and significantly higher MD, AD, and RD values; these changes corresponded with measures of cognitive impairment. In Duering's study  of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), anterior thalamic radiations and frontal forceps were also considered key sites of cognitive impairment. These results suggested that frontal WMHs may contribute to functional impairments.
There were some limitations to our study. First, normal white matter FA values decreased with age, while MD values increased with age. Our control group was significantly younger, on average, than our patient group. However, the differences between WMHs and standard DTI metrics were greater than the normal variation observed with age . Second, to minimize the influence of DTI parameters caused by anatomical variations, we selected ROIs within identical white matter tracts, according to the color maps; however, variations may still exist. Third, since the structural changes reflected by DTI parameters were non-specific and may have been affected by many factors, relevant pathological changes remain poorly elucidated.