This study demonstrates white matter tract degeneration in the superior cerebellar peduncles, corpus callosum, and association fibers in PSP and shows that this degeneration is associated with clinical dysfunction in PSP.
The superior cerebellar peduncles were the tracts that showed the most significant decreases in FA and increases in MD in PSP compared to controls, and provided excellent discrimination between groups. This finding confirms previous DTI studies8–10, 26
, and concurs with the fact that demyelination and microgliosis have both been observed in these structures at pathology2, 27, 28
. Volume loss of the superior cerebellar peduncles has also been observed in PSP4, 29, 30
. This finding contrasts with the relative preservation of the middle cerebellar peduncle. In this study we found significant correlations between FA values in the superior cerebellar peduncles and performance on tests of disease severity, including the PSPRS, FBI, MMSE and MDS-UPDRS. While each of these tests measures different aspects of motor, cognitive and behavioral ability, they were all highly correlated to PSPRS suggesting that performance on each test is associated with disease severity. Our results therefore suggest that FA measures in the superior cerebellar peduncle could be an excellent marker of disease severity in PSP. These results also demonstrate disruption of the dentatorubrothalamic tract which runs through the superior cerebellar peduncles to the contralateral ventrolateral nucleus of the thalamus31
. In fact, the TBSS analysis demonstrated reduced FA in the thalamus which likely reflects degeneration of this system. While the thalamus is predominantly a grey matter structure and so was not sampled in the ROI-based analysis, it does contain a system of myelinated fibers (internal medullary lamina) that separate thalamic subdivisions32
and were likely detected by TBSS. Previous studies have only been able to demonstrate increased MD in the grey matter of the thalamus in PSP9, 33, 34
Significantly reduced FA and increased MD were also both observed in the body of the corpus callosum in PSP, yet no changes were observed in the splenium or genu. These findings may reflect degeneration of the commisural fibers connecting adjacent regions of grey matter loss in the posterior frontal and premotor cortex that are commonly observed in PSP6
. Previous studies have similarly identified changes in diffusivity and volume loss in anterior-middle portions of the corpus callosum 11, 12, 26, 35, 36
. Measurements of FA and MD in the body of the corpus callosum did not correlate with any clinical measures however suggesting that it is not directly associated with the clinical symptoms of PSP.
Diffusivity changes were also observed in association fibers, namely the inferior longitudinal fasciculus and superior longitudinal fasciculus. Correlations were identified between both FA and MD values in inferior longitudinal fasciculus and scores on the MDS-UPDRS parts II and III which assess motor function. Interestingly, a couple of recent DTI studies investigating healthy aging have similarly found associations between abnormalities in the inferior longitudinal fasciculus and motor function37
and visuomotor dexterity38
. The inferior longitudinal fasciculus connects visual cortices to the inferior, middle and superior temporal lobes, and has been suggested to subserve a “direct short-latency pathway” of visual processing39
. Visual-motor coordination is indeed likely to play a role in performance on a number of the items assessed using the MDS-UPDRS, such as toe and finger tapping and hand movements. Performance on the MDS-UPDRS parts II and III did however also correlate with diffusivity in the superior cerebellar peduncles suggesting that motor function may involve a complex network of systems in PSP.
Reductions in FA were observed in both the anterior descending tracts and the horizontal superior tracts of the superior longitudinal fasciculus. These tracts project to the posterior frontal lobes; regions that are atrophic in PSP6
. Anterior superior longitudinal fasciculus FA correlated with performance on the PSP Saccadic Impairment Scale which attempts to grade severity of eye movement abnormalities that occur in PSP (Box 1
). This is a novel finding, yet plausible since although several structures in the brainstem determine the direction, amplitude, and velocity of saccades40, 41
, fMRI and PET studies demonstrate that voluntary saccades are under cortical control42, 43
and the frontal and supplemental eye fields are known to play a role in saccadic eye movements44
. Our results suggest a possible cortical element to saccadic abnormalities in PSP, perhaps involving the frontal eye fields and premotor cortices, mediated by the superior longitudinal fasciculus.
It is clear from the TBSS analysis that reductions in FA were more severe than increases in MD in our PSP cohort, suggesting that directional diffusivity, and hence degeneration of the white matter tracts, is predominantly affected in PSP. There are a number of pathological mechanisms which could be contributing to breakdown of diffusion along white matter tracts: 1) tau deposition observed within axons and the outer mesaxon of myelinated fibers 3, 45, 46
, 2) phagocytosis of myelin by macrophages (activate microglia) that are found in white matter tracts in PSP27, 47
, and 3) wallerian degeneration. The degree of demyelination in the superior cerebellar peduncle has been shown to correlate to tau burden, not microglial burden, in PSP 27
, suggesting that tau pathology may be responsible for the degeneration of white matter tracts although further pathological studies will be needed in order to understand these biological mechanisms.
Strengths of this manuscript include the fact that all patients were prospectively assessed with a standardized battery of clinical assessments and the number of subjects was large, especially for a rare disorder like PSP. In addition, we utilized two independent DTI analysis techniques. One could argue that results from small ROIs placed on specific tracts may not be representative of the entire tract, although the similarity across the ROI-based and TBSS analyses supported the validity of the data. Furthermore, the TBSS analysis showed significant findings after correction for multiple comparisons, increasing confidence in the results. A limitation of using DTI to assess white matter tract dysfunction in PSP, however, is that the resolution of the scans limits the ability to identify and measure very small tracts that may also be playing important roles in the disease, such as the subthalamic fasciculus connecting subthalamic nuclei to basal ganglia. Our analysis of maximum FA demonstrated that the ROI results were unlikely to be confounded by partial volume averaging, although this could still be a problem in the TBSS analysis for thin tracts such as the fornix.