This study investigated white matter damage in the main language tracts and in their subcomponents in the three major variants of primary progressive aphasia using DTI tractography. Results showed that primary progressive aphasia variants are associated with significant white matter changes in specific networks that are fundamental to language processing. Furthermore, each variant showed a distinct pattern of alteration in the different DTI metrics considered.
Many previous studies that used DTI in neurodegenerative diseases have mainly considered fractional anisotropy values in voxels or tracts of interest (Chua et al., 2008
; Matsuo et al., 2008
; Damoiseaux et al., 2009
; Mielke et al., 2009
; Smith et al., 2010
). In this study, we considered different tracts and their anatomical subcomponents, and also quantified other important DTI metrics such as axial, radial and mean diffusivity. Classically, decreases in fractional anisotropy have been used as a marker of myelin injury with axonal loss. This would result in sphere-like diffusion tensor, instead of the usual ellipsoid, because of increased radial diffusivity and a much smaller or no change in axial diffusivity. However, other situations, such as fibre reorganization, could occur in neurodegenerative disease resulting in a decrease in fractional anisotropy, but via a different mechanism, such as a reduction in axial diffusivity with an increase of radial diffusivity (Beaulieu, 2002
; Song et al., 2002
). Furthermore, other conditions such as glial alterations, increased membrane permeability and diffusivity, destruction of intracellular structures, alterations in the cytoskeleton and axonal transport, could influence different DTI metrics in ways that are not well understood (Beaulieu, 2002
; Song et al., 2002
). The presence of these pathological changes makes the understanding of the DTI alterations in neurodegenerative conditions complicated, but could explain, for instance, why fractional anisotropy changes are not always found (Agosta et al., 2009
; Acosta-Cabronero et al., 2010
). In this context, we discuss our findings of differential changes of the various DTI metrics in the specific language-related tracts in the primary progressive aphasia variants. We argue that our findings of differential anatomical and microstructural involvement warrant further investigation as possible markers of disease.
The non-fluent patients showed changes in DTI metrics in all the SLF components (). Damage in this fundamental dorsal temporoparietal–frontal language tract and network was quite severe and might be partially responsible for some of the language features typical of this variant, such as motor speech difficulties and agrammatism. In comparison, the ventral tracts were relatively spared. The sparing of the inferior longitudinal fasciculus is consistent with these patients’ good performance in single-word comprehension and semantic tasks. Interestingly, the uncinate was also spared in this variant, reflecting sparing of the anterior temporal to orbitofrontal network, which is possibly involved in behavioural and social functioning (Bramham et al., 2009
) and in name retrieval (Papagno et al., 2011
). A study by Rosen et al. (2006)
showed that non-fluent patients had less behavioural symptoms than did those with the semantic variant.
When considering DTI metrics in the non-fluent variant, fractional anisotropy reduction and mean diffusivity increase were observed in all the tracts that showed significantly abnormal DTI results (SLF and its subcomponents, ). Axial diffusivity was never significantly different from controls, while radial diffusivity changes were present in all tracts that showed fractional anisotropy and mean diffusivity abnormalities. This pattern of DTI changes is suggestive of more severe myelin injury or a change in structures that create barriers for water diffusion along the direction perpendicular to the main axis of the axons. Only one previous study looked at DTI changes in the non-fluent variant (Whitwell et al., 2010
). Using a region of interest-based approach, this study located abnormalities in the SLF, although tractography was not performed. No subcomponents of the different tracts were considered and relative changes in DTI metrics were not identified.
In summary, our DTI data showed that the non-fluent variant primary progressive aphasia is associated with severe white matter changes in the dorsal language network and this may be contributing to the phenotype. Clinicopathological correlation studies have shown that the non-fluent variant is most often, although not exclusively, associated with a tauopathy and in a minority of cases with TDP-43 type 3 Sampathu (Mackenzie type 1) (Josephs et al., 2006
; Snowden et al., 2007
; Yokota et al., 2009
; Grossman, 2010
). Progressive supranuclear palsy and corticobasal degeneration, classic tauopathies, both exhibit extensive glial pathology in white matter (Dickson et al., 2002
; Zhukareva et al., 2006
). Significant white matter pathology has also been reported in Pick’s disease and in some areas was more extensive than in the adjacent grey matter (Zhukareva et al., 2002
). Our findings of specific white matter changes in the non-fluent variant might thus be a marker of these pathological changes. Future pathological studies are needed to investigate this hypothesis.
Semantic variant patients showed severe involvement of the uncinate fasciculus bilaterally and of the inferior longitudinal fasciculus, especially the anterior portion bilaterally and the middle section in the left hemisphere ( and ). The components of the SLF that connect the temporal lobe to the dorsal language network (left arcuate fasciculus and temporoparietal component) were also involved, while the parietofrontal SLF components were relatively spared ( and ). A dysfunction of the ventral language system, with relative sparing of the dorsal network, accounts for the typical combination of impaired semantics and spared phonology, grammar and fluency language domains in semantic variant, as previously hypothesized (Agosta et al., 2009
). The changes in the uncinate fasciculus might instead be related to the behavioural changes that often accompany language symptoms in semantic variant but the role of this tract is still debated (Papagno et al., 2011
In the semantic variant, the tracts involved showed changes in all DTI metrics, including axial diffusivity, although radial diffusivity had the largest alteration, explaining the decrease of fractional anisotropy and the increase of mean diffusivity. Interestingly, as reported by Agosta and colleagues (2009)
in a previous study of a different group of semantic variant patients, fractional anisotropy did not change in the inferior longitudinal fasciculus when the tract was considered in its entirety, although mean diffusivity changes were evident ( and ). In our study, partitioning the inferior longitudinal fasciculus into anterior, middle and posterior portions revealed significant fractional anisotropy differences in the more anterior portions. Therefore, the less apparent change in fractional anisotropy with clear change in mean diffusivity in the entire inferior longitudinal fasciculus could be explained by the fact that pathology is most severe in the anterior temporal lobe and also by the particular pattern of DTI metrics changes, characterized by both axial and radial diffusivity increases.
In the semantic variant, the temporal lobe is so damaged that all tracts that connect to it are altered, including the left arcuate, consistent with previous studies (Kertesz et al., 2005
; Seeley et al., 2005
; Borroni et al., 2007
; Snowden et al., 2007
; Grossman et al., 2008
; Agosta et al., 2009
; Brambati et al., 2009
; Whitwell et al., 2010
). DTI changes decreased in severity while moving posteriorly along the inferior longitudinal fasciculus, with the left middle portion showing significant fractional anisotropy and mean diffusivity differences and the most posterior portion showing only a trend for axial diffusivity increase. The anterior–posterior axis of decreased severity in white matter changes is consistent with previous grey matter longitudinal findings showing atrophy moving posteriorly and contralaterally as disease progresses (Brambati et al., 2009
). The changes in all DTI metrics suggest that the white matter injury in semantic patients may be more severe than in non-fluent and logopenic patients, especially in the anterior temporal regions where ventral language and behavioural pathways relay in the temporal lobe. As in the case of the non-fluent variant, these changes are likely to be primary contributors to the disease process, together with grey matter changes.
Clinicopathological correlations have shown that the semantic variant clinical syndrome is reliably associated with frontotemporal lobar degeneration-TDP pathology (Kertesz et al., 2005
; Snowden et al., 2007
), almost invariably Sampathu frontotemporal lobar degeneration-TDP 1 (Mackenzie type 2) (Mackenzie et al., 2006
; Sampathu et al., 2006
). Frontal and temporal lobe white matter pathology has been seen in the three frontotemporal lobar degeneration-TDP subtypes (Neumann et al., 2007
). TDP-43-positive glial inclusions were found in the frontal and temporal lobes and these inclusions were thought to occur in oligodendrocytes. In a small study, Tartaglia et al. (2010)
investigated more extensively the distribution of the pathology in the three frontotemporal lobar degeneration-TDP subtypes and found that affected white matter regions showed reduced myelin staining, axonal loss, reactive gliosis, microglial activation and TDP-43 glial inclusions and threads. The degree of white matter pathology varied significantly among cases and across different anatomical regions. Frontotemporal lobar degeneration-TDP 3 (Mackenzie type 1) cases with clinical syndromes of behavioural frontotemporal dementia and non-fluent variant primary progressive aphasia showed the greatest white matter degeneration in the deep frontal lobe. In cases with frontotemporal lobar degeneration-TDP 1 (Mackenzie type 2), all having semantic variant primary progressive aphasia, the anterior temporal lobe white matter showed the most damage. Cases with frontotemporal lobar degeneration-TDP 2 (MacKenzie type 3) had the least white matter degeneration with frontal and anterior temporal regions equally affected. The degree of reduced myelin staining and axonal loss correlated strongly. Cases with frontotemporal lobar degeneration-TDP 3 (Mackenzie type 1) had the most white matter TDP-43 pathology; however, this did not correlate with degree of white matter degeneration. The extensive white matter pathology suggests that glial TDP-43 white matter pathology is a characteristic feature of frontotemporal lobar degeneration-TDP and that glial TDP-43 pathology also contributes to the neurodegenerative process and the cognitive and motor impairments seen in patients affected by frontotemporal lobar degeneration-TDP. Our results, together with previous evidence, suggest that DTI might become an in vivo
marker of this process.
Logopenic patients showed the most consistent DTI changes in the left SLF temporoparietal component, but also abnormalities in the left arcuate fasciculus, in SLF-II and III and in the right temporoparietal SLF ( and ). These results are consistent with volumetric studies demonstrating grey matter atrophy and demonstrate how patients with the logopenic variant have involvement of tracts that connect regions important for sentence repetition and phonological short-term memory (Gorno-Tempini et al., 2008
; Hu et al., 2010
A close look at the pattern of change in the DTI metrics in logopenic patients revealed that the temporoparietal component of the left SLF was the most injured with all DTI metrics showing significant changes. The fractional anisotropy was significantly lower than in controls because of a larger increase of radial than axial diffusivity (). Mean diffusivity was altered in left frontoangular SLF (SLF-II) and arcuate fasciculus as well as the right temporoparietal SLF (). Radial diffusivity showed changes that paralleled the mean diffusivity increase in these tracts, while only axial diffusivity was altered in the left SLF-III and left middle inferior longitudinal fasciculus. One interpretation is that the only tract that showed changes on the shape of the diffusion ellipsoid (temporoparietal SLF), could be the most damaged, as demyelination and axonal loss could be at play. The rest of the dorsal language network showed only diffusivity increases but no change in fractional anisotropy, suggesting less severe damage without disruption of directionality.
Taken together, these results suggest that diffusivities, including axial and radial diffusivity as well as their average may be more sensitive than fractional anisotropy to the pathological changes occurring in logopenic variant. Interestingly, similar qualitative DTI results were demonstrated, even if in different tracts or regions, in patients with early Alzheimer’s disease suggesting that absolute diffusivities were more sensitive than fractional anisotropy in defining the white matter damage in these patients (Acosta-Cabronero et al., 2010
). Several studies have shown that the logopenic variant is most often associated with Alzheimer’s disease pathology (Grossman et al., 2008
; Josephs et al., 2008
; Mesulam et al., 2008
) and Pittsburgh compound B-positive PET scans (Rabinovici et al., 2008
). It has also been suggested that the logopenic variant is a left-lateralized form of early-age-of-onset Alzheimer’s disease thus explaining why these patients have DTI changes similar to those already described for Alzheimer’s disease but in a language-related location (Migliaccio et al., 2009
). In support of this hypothesis, seven out of eight of the logopenic patients included in this study had a positive Pittsburgh compound B scan.
Pathologically, Alzheimer's disease is also associated with white matter damage but seemingly of a different nature than in frontotemporal lobar degeneration. Two types of white matter pathology have been observed in Alzheimer's disease, excluding the vascular changes related to infarcts and ischaemia: Wallerian degeneration and white matter disease (Englund, 1998
). Wallerian degeneration, a secondary phenomenon, tends to be seen adjacent to the atrophied grey matter. The white matter was atrophied and the tissue rarefied and collapsed when the disease was advanced. The temporal lobes had the greatest amount of white matter changes but this was present in a milder form elsewhere. They noted a mild decrease of axons, myelin and oligodendrocytes with some astrocytosis and the pathology was symmetrical. The second type of white matter pathological change was white matter rarefaction related to an angiopathy in the deep hemispheric regions. It had a preferential location in the frontal lobes and did not follow the regional extension of the grey matter changes. They observed a decrease in myelin with a parallel decrease in axonal density. They saw a partial loss of oligodendrocytes and the vessels showed a hyalinized sclerosis. Some patients with Alzheimer’s disease showed both types of white matter injury and others showed one or the other. Amyloid plaques have been described in the white matter, most adjacent to the grey matter but at a considerable distance (Braak et al., 1989
). The different and maybe less primary damage of white matter pathology in Alzheimer's disease could contribute to the different patterns of DTI changes that we observed in our logopenic patients.
Our study therefore indicates that each primary progressive aphasia clinical phenotype shows different patterns of white matter damage with focal involvement of specific portions of the language pathways and that these changes can be assessed using DTI. Different patterns of changes in DTI metrics observed in the different groups likely reflected differences in the underlying biological and pathological process. The precise relationship between the different pathological substrates seen in primary progressive aphasia patients and the different DTI metrics is currently unknown. One could speculate that post-mortem radiological–pathological studies will reveal patterns associated with primary progressive aphasia that could be used for in vivo diagnosis of the specific molecular pathology. Hence, beyond subtype tracking, DTI could play a role as an in vivo biomarker of specific molecular pathologies. This would be particularly important when treatments directed at specific molecular pathologies become available.
There are limitations in this study mainly related to the use of a diffusion tensor-based technique. One issue relates to the undetermined influence that tissue pathology can have on the correct alignment of the major eigenvector with the axons of the underlying white matter (Wheeler-Kingshott and Cercignani, 2009
). This concern is somewhat mitigated by the fact that imperfect alignment of eigenvectors should not influence fractional anisotropy and mean diffusivity. Another limitation is that the diffusion tensor model deals poorly with crossing fibres, which result in a more spherical shape of the diffusion tensor ellipsoid, even in the absence of white matter damage. This limitation could be an issue and could make tractography less accurate, for instance, when we separate the SLF into the different components, resulting in a partial overlap between the components. The last issue is that our results lack post-mortem pathological–radiological correlations that would be required to definitively relate biological substrates to the changes in the various DTI metrics.
In conclusion, this is the first study to compare the three main variants of primary progressive aphasia using DTI tractography. The results demonstrate that distinct patterns of white matter alteration occur in the three primary progressive aphasia subtypes at both anatomical and micro-structural levels. How these changes are related to different pathological substrates has yet to be established.