Research Article: A language-based sum score for the course and therapeutic intervention in primary progressive aphasia

Date Published: April 25, 2018

Publisher: BioMed Central

Author(s): Elisa Semler, Sarah Anderl-Straub, Ingo Uttner, Janine Diehl-Schmid, Adrian Danek, Beate Einsiedler, Klaus Fassbender, Klaus Fliessbach, Hans-Jürgen Huppertz, Holger Jahn, Johannes Kornhuber, Bernhard Landwehrmeyer, Martin Lauer, Rainer Muche, Johannes Prudlo, Anja Schneider, Matthias L. Schroeter, Albert C. Ludolph, Markus Otto.


With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions.

We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials.

Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures.

Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.

The online version of this article (10.1186/s13195-018-0345-3) contains supplementary material, which is available to authorized users.

Partial Text

Primary progressive aphasia (PPA) comprises a group of neurodegenerative disorders in which language problems are the principal cause of impaired daily living activities, whereas other neurobehavioral or cognitive deficits are rare during the initial stages of the illness [1]. PPA can be classified into three clinical subtypes [2]. The nonfluent/agrammatic variant (nfvPPA) presents with agrammatism in speech production and/or apraxia of speech with additional impaired comprehension of syntactically complex sentences, while object knowledge and single-word comprehension are spared [2]. Patients with the semantic variant (svPPA) have progressive deficits in comprehending single words as a widespread semantic memory deficit, often combined with impaired object knowledge and surface dyslexia or dysgraphia [2]. The logopenic variant (lvPPA) is specified by difficulties finding words and impaired sentence repetition [2, 3]. Typically, nfvPPA and svPPA are syndromes with underlying frontotemporal lobar degeneration (FTLD) pathology, i.e., nfvPPA is frequently linked to FTLD-tau, whereas svPPA is associated with FTLD-TDP [4]. In contrast, lvPPA often has an underlying Alzheimer’s disease pathology [5].

The overall aim of this analysis was to provide a clinical score that can be used as an outcome measure in clinical trials. With the aim of covering a range of important aspects of language to provide one score for all PPA subtypes, we identified eight cognitive tests, merging them into one overall sum score. The two variants of this score, one comprising a simple summation of all raw scores obtained, the second a balanced version precluding unbalanced weights for single scores, showed overall high progressive decline between –9% and –13% at 1 year, which is in line with the results of Hsieh et al. [7], who reported an approximate 10% reduction in a cognitive screening tool (Addenbrooke’s Cognitive Examination-Revised) in PPA patients. We did not find any meaningful differences in sum score decreases between the PPA subgroups, preventing a differentiation between the diagnostic groups. At baseline, the sum scores and clinical rating scale FTLD-CDR showed relevant correlations with r ≈ –0.6, suggesting a good overall representation of cognitive status. A correlation between sum score and volumetric changes showed slightly higher relations for the balanced score version, including both the left frontal lobe (r = 0.647) and the left putamen (r = 0.593). Although it has to be noted here that the quite high correlations seem to be reinforced by a strong progressive decline in single patients, we also see evidence that the cognitive decline measured by the sum score reflects atrophy progression.

Our results show overall high decline in language-specific neuropsychological tests within 1 year for all PPA subtypes and progressive atrophy in frontal and temporal regions. Based on our cohort, we combined the most informative neuropsychological assessments covering different aspects of language to a new sum score, which showed high correlations with the frontal atrophy rate. Subsequent sample size calculations showed feasible numbers; therefore, we believe that we now hold a practical tool for investigating PPA patients, especially with a focus on nfvPPA patients at follow-up, which can be used for clinical trials.




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