Impairments in patients with PPA are heterogenous, and quantification is essential for monitoring and the ultimate evaluation of potential treatments. PPA impairments are typically quantified using language test performance measures.5,13,17,18
Here we have extended recent work to quantify the overall impairment of language functions through the judgment of trained clinicians, an approach that has traditionally played an important role in AD clinical research and trials. We developed a method for clinician judgment-based grading of overall impairment in fluency, grammar/syntax, and single word comprehension, since these are hallmark language abnormalities in PPA and are often dissociated from each other. The present study demonstrated that this approach is reliable between raters and is valid against performance-based measures. Since performance-based and clinician-rated measures of cognitive impairment are not completely redundant in AD,6
it stands to reason that they may provide complementary information in PPA, although this deserves further study. Furthermore, the clinician-graded impairments in fluency/grammar/syntax and comprehension are strongly dissociated with respect to neuroanatomic abnormalities in cortical thickness, also supporting their validity. Both hypothesis-driven and exploratory analyses demonstrated sensitive and specific relationships between impaired syntax/grammar and ventrolateral prefrontal atrophy, and between impaired word comprehension and temporopolar atrophy.
We have previously shown through longitudinal clinical research in prodromal AD that measures grading both symptom severity in daily life and in the office and performance abilities on psychometric testing can provide complementary information with respect to present level of impairment as well as prognosis.6
Every clinician has worked with a patient who exhibits prominent symptoms in daily life yet who performs relatively well on office-based tests. Conversely, there are many patients who have relatively subtle symptoms, maintaining generally good function in complex activities of daily life, yet who perform strikingly poorly on tests. This can be particularly true in some patients with fluent, word comprehension-centered forms of PPA. Thus, we believe it is critical for the field to continue to develop and apply a rich set of instruments for clinical assessment,4
ideally tailored to the PPA population and including patient- and informant-rated questionnaires, performance-based instruments, and clinician-graded measures. A comprehensive battery of such measures will likely be of great value for clinical research and ultimately treatment trials. We hope that the PASS instrument described here is of use for that goal, and that the specific anatomic relationships found here provide data to support its validity.
Previous studies of PPA have demonstrated the relationships between semantic deficits and left temporopolar atrophy19,20
as well as deficits in syntactic processing and inferior frontal atrophy.21
Yet there have been few investigations of these dissociable relationships within a single sample of patients with PPA.5,13,22
The investigation of dissociated deficits in single samples of patients with PPA has revealed valuable findings regarding some aspects of language dysfunction in PPA, particularly naming deficits with temporopolar atrophy and nonfluent/agrammatic speech with middle and inferior frontal atrophy.13
A recent study employed cortical thickness analysis in comparison with performance-based measures of grammar and semantic processing and found that the patterns of localization of cortical thinning for the 3 subtypes were remarkably similar to those identified here.5
Notably, the caudal middle temporal gyrus/superior temporal sulcus—a critical region for linking speech sounds to word meaning23
—is involved in all 3 variants. Another recent study employing cortical thickness analysis showed a similar pattern of thinning for the PPA-semantic subtype but a somewhat different pattern for PPA-nonfluent subtype, raising questions about whether that sample was truly clinically comparable to the present one.24
One advantage of cortical thickness analysis in this type of work is that the measures can be obtained from single individuals using an a priori ROI approach,12
and cortical thickness measures are directly related to morphometric measures that can be made in postmortem brain specimens.11,12
Although the cellular and pathologic correlates of cortical thickness have received little study,25
some histologic data indicate that cortical thinning is present in regions that harbor AD pathology.26,27
Yet while regional cortical thinning identified via in vivo MRI measures in patients with presumed neurodegenerative syndromes is undoubtedly valuable in localizing pathologic change, it seems much less likely that these regional measures will provide specific evidence regarding the molecular nature of that pathology.28
The congruence between the anatomic classification of patients with PPA using inferior frontal, temporopolar, and superior temporal sulcal thickness and clinical subtyping is impressively good (), as has similarly been demonstrated using atrophy pattern classification analyses.29
Such findings suggest that these types of quantitative MRI-based measures deserve a place in new clinical diagnostic criteria since they can be applied at the individual level, similarly to recently reported performance-based measures.5
Limitations of the present study include the lack of additional domains in the PASS rating scale. It is clear that patients with PPA can exhibit a variety of other relevant symptoms beyond impaired fluency, grammar/syntax, and comprehension. Fluency can be impaired for a variety of reasons (such as impairments in grammar/syntax, phonology, or word retrieval), so this measure may ultimately need to be refined or replaced, but it is useful at present. We have developed ratings for other domains of language function, including word retrieval, repetition, articulation, and others, and are currently testing these measures (the current scale is available upon request). It is also not clear how readily the PASS approach used here will generalize within the community of PPA investigators, but studies are being planned to evaluate its performance at multiple centers. It is not clear how well the PASS will perform in differentiating types of impairment in patients with more advanced stages of illness; it seems to perform very well in mildly to moderately impaired patients. Finally, we do not yet know how well the clinical or anatomic measures employed here will perform in longitudinal analyses, but these investigations are underway. Ultimately, we hope that further investigation will demonstrate that the types of measures studied here can be translated into clinical and imaging markers for use in diagnosis, monitoring, and prognostication, and will prove useful in clinical trials of novel therapeutics for these devastating diseases.