Imaging biomarkers of brain anatomy, function, and molecular composition are already essential tools for diagnosis of most neurodegenerative diseases and will almost certainly be critical for monitoring progression. For the purposes of clinical trials, these tools can be thought of as useful for identifying a relatively homogenous sample of participants (i.e., for the identification of disease-specific brain abnormalities and the exclusion of those lacking typical disease-associated abnormalities, much as is done in stroke or multiple sclerosis). They can also be thought of as potential outcome measures, although the clinical validation requirements called for by the Food and Drug Administration make this a taller hurdle. Readers interested in a detailed discussion of some of these issues in the field of Alzheimer’s disease are referred to recent publications (Dickerson and Sperling 2005
; Hampel et al. 2010
Although routine clinical MRI scans in patients with mild PPA are often interpreted as within normal limits, careful visual inspection of specific cortical regions can often provide the clinician with evidence of subtle atrophy in critical nodes of the language network. The ability to see these regions clearly depends heavily on the type of MRI scan obtained, and we typically employ a high-resolution (1 mm isotropic) coronal T1-weighted scan, which is a sequence that is becoming much more widely available on common MRI platforms; this type of sequence should be requested in the MRI protocol, and clinicians should review the results directly themselves in consultation with a radiologist or other imaging expert (see for case examples).
Fig. 3 Representative ultrahigh-resolution T1-weighted MRI scans (0.38 mm in-plane), illustrating asymmetric inferior frontal opercular atrophy in non-fluent/agrammatic PPA (left), temporopolar atrophy in semantic PPA (middle), and inferior parietal atrophy (more ...)
There has been great progress aimed at mapping focal brain abnormalities in PPA and relating these abnormalities to types of language deficits by comparing groups of clinically characterized patients to controls or to other disease groups (Rohrer et al. 2009
; Gorno-Tempini et al. 2004
; Peelle et al. 2008
). Most of the techniques used in such studies that aim to map atrophy and rates of progression in PPA are at present still basic imaging neuroscience research methodology, not yet tools that are available for clinical use. One such technique under development in our group consists of cortical thickness mapping, which has the ability to measure the thickness of the cerebral cortex with submillimeter precision. This method can be used to localize regions of cortical atrophy in patient groups compared to controls. In contrast to AD, in which the “signature” of regional cortical atrophy includes medial and lateral temporal, medial and lateral parietal, and often frontal atrophy with a relatively symmetric pattern (Dickerson et al. 2009
), PPA typically has a distinct asymmetric perisylvian atrophy pattern (), which correlates with the overall degree of impairment on the PASS clinical instrument (see ).
Fig. 4 Quantitative analysis of MRI data is still a research tool but it is becoming more apparent that these methods need to be translated into clinically efficient tools since measures of neuroanatomic abnormalities can be very useful as biomarkers for diagnosis (more ...)
Fig. 5 The PPA-signature of cortical atrophy as measured from MRI scans is a valid reflection of the level of clinical impairment. Correlation between PPA-signature MRI biomarker and PASS Sum-of-Boxes measure of clinical impairment, with higher ratings on this (more ...)
Beyond this global pattern of perisylvian atrophy, the three major subtypes of PPA have distinct atrophy patterns in specific nodes of the language network which relate to impairment in the specific domains of language function that are most compromised in types subtypes (see ). Although these patterns appear to be quite consistent across centers (Mesulam et al. 2009
; Rohrer et al. 2009
; Sapolsky et al. 2010
), there has been little effort aimed at localizing and quantifying abnormalities in single individuals. If we aim to use quantitative imaging measures as diagnostic markers, the translation of these imaging methods into tools that can be applied to individual patients will be crucial. Some of these research imaging methods could potentially be translated into tools that can be used clinically in individual patients, but the appropriate reliability and validity studies need to be performed.
Fig. 6 The three PPA subtypes are associated with distinct patterns of cortical atrophy. PPA-non-fluent/agrammatic patients exhibit primarily left prefrontal atrophy with relative sparing of temporal lobe cortex (left); PPA-semantic patients demonstrate anterior (more ...)
Although both structural MRI and FDG-PET metabolic measures have been used in studies of PPA, there has never been a systematic head-to-head comparison of the relative sensitivity and specificity of these imaging measures in PPA. Do they provide complementary or redundant information? In the field of AD, it appears that MRI and FDG-PET provide complementary information that, together, improve the sensitivity and specificity of diagnosis beyond that provided by either modality alone (Mosconi et al. 2007
). Since FDG-PET is becoming more widely available and is approved by Medicare for reimbursement for the differential diagnosis of AD vs. frontotemporal dementia (of which PPA is considered a subtype), it is important to determine the potential benefits of this type of scanning in PPA, particularly since it is still costly.
In addition to FDG-PET, there are several emerging MRI-based measures of brain function, including task-related functional MRI (fMRI), functional connectivity MRI (fcMRI), and perfusion MRI (arterial spin-labeled or ASL MRI). For the most part, these are all currently innovative basic imaging science techniques being used to investigate aspects of brain function, and have not yet been subjected to reliability, validity, or longitudinal studies to determine their potential for translation into useful tools for clinical trials.
As mentioned above, recent post-mortem studies of the pathologic substrates of PPA and related disorders have demonstrated that a substantial portion of patients have AD pathology (Alladi et al. 2007
; Mesulam et al. 2008
), which has been shown in vivo using PiB PET amyloid imaging (Rabinovici et al. 2008
), a novel imaging marker of fibrillar amyloid pathology being used in a variety of research settings but not yet in clinical use. Although a small percentage of patients with the semantic variant of PPA have evidence of AD pathology, it appears that most patients with the logopenic subtype of PPA harbor AD pathology, suggesting that this form of PPA may be an atypical variant of AD. While there are a large number of questions that deserve investigation as follow-up to these initial studies, it is clear that investigations attempting to identify in vivo clinical and imaging markers for use in clinical trials need to include measures that aim to determine whether there are specific characteristics unique to the PPA patients with Alzheimer pathology. Ultimately, it will be important to decide whether these patients should be directed toward disease-modifying clinical trials for AD even though their clinical phenotype is in most cases quite different from that of typical AD. Thus, this imaging method needs to be included in the translational efforts aimed at identifying an optimal set of imaging markers for use in PPA clinical trials.
Efforts are ongoing to develop PET ligands that label fibrillar tau protein, with initial efforts beginning to show promise (Okamura et al. 2005
; Small et al. 2006
). Ultimately, it may be possible to use molecular markers to “triangulate” the three major subtypes of PPA with the goal of determining whether (1) non-fluent/agrammatic patients exhibit tau-positive PET signals but absent PiB signal consistent with underlying tau pathology, (2) logopenic patients exhibit elevated PiB and tau signal consistent with AD pathology, while (3) semantic patients exhibit no uptake of PiB or tau ligands suggestive of underlying TDP-43 pathology. These PET findings could then be investigated in relation to the quantitative MRI measures described above to determine how well the MRI measures predict molecular abnormalities. The impact of this type of analysis would be to determine whether these additional but expensive molecular markers are needed to increase the specificity of diagnosis, or whether specificity is nearly is good using MRI (and possibly FDG-PET) measures alone. This will be essential information for the planning of treatment trials of compounds that are targeted toward specific molecular abnormalities, which is the case for a growing number of compounds.
If our long-term goal is to intervene in PPA using forms of disease-modifying therapy, or even to investigate potential plastic responses to forms of speech and language therapy, we need markers of brain structure and function that are sensitive to disease progression. We know that different types of PPA progress at different rates; new data indicate that the non-fluent/agrammatic variant progressing relatively rapidly and the semantic variant more slowly (Hodges et al. 2010
). Furthermore, individual patients clearly vary with respect to each other in the level of impairment at initial presentation and in rate of progression. Our preliminary work comparing rate of change on the clinical PASS measure with rate of change in cortical atrophy supports the idea that MRI will provide a clinically valid imaging biomarker of progression (see ).
Fig. 7 Longitudinal change in the PPA-signature MRI biomarker is a valid reflection of progression of clinical impairment. Preliminary evidence indicates that, while there is substantial variability between patients in the rate of decline, there is a reasonable (more ...)
Several natural history studies are ongoing in which longitudinal MRI and in some cases PET data are being collected in patients with PPA and related disorders. One goal is to generate data that would enable power calculations to be performed to estimate sample size for disease-modifying clinical trials, much as has been done in AD research; initial data in PPA look promising (Knopman et al. 2009
; Gordon et al. 2010
). Baseline imaging measures are also being investigated for their potential as predictive markers of clinical or functional-anatomic change, with the goal of determining whether some of these measures could be indicators of patients who may be “rapid progressors”, since this population would be an ideal target for clinical trials.