The non-fluent/agrammatic variant of primary progressive aphasia

Abstract

The non-fluent/agrammatic variant of primary progressive aphasia (naPPA) is a young-onset neurodegenerative disorder characterised by poor grammatical comprehension and expression and a disorder of speech sound production. In an era of disease-modifying treatments, the identification of naPPA might be an important step in establishing a specific cause of neurodegenerative disease. However, difficulties in defining the characteristic language deficits and heterogeneity in the anatomical distribution of disease in naPPA have led to controversy. Findings from imaging studies have linked an impairment of this uniquely human language capacity with disruption of large-scale neural networks centred in left inferior frontal and anterior superior temporal regions. Accordingly, the pathological burden of disease in naPPA is anatomically focused in these regions. Most cases of naPPA are associated with the spectrum of pathological changes found in frontotemporal lobar degeneration involving the microtubule-associated protein tau. Knowledge of these unique clinical-pathological associations should advance care for patients with this important class of neurodegenerative diseases while supplementing our knowledge of human cognitive neuroscience.

FIGURE 1. SEMISTRUCTURED SPEECH SAMPLE OF naPPA

1. Speech sample of a patient with naPPA narrating the children’s wordless picture story Frog, Where Are You?. The narrative accompanying each of the three pictures is below the corresponding picture. While description of the content is accurate, the grammatical structure of the utterances is distorted and simplified, containing many errors. There are also speech sound errors. Pauses longer than 2 seconds are noted in parentheses in the transcript.

FIGURE 2. GRAY MATTER ATROPHY AND WHITE MATTER DISEASE IN naPPA

1. Patients (n=12) meeting published criteria for naPPA with CSF totaltau: amyloid-beta ratio <0.34 consistent with FTD spectrum pathology . UPPER PANEL: Red areas show significant gray matter atrophy at p<0.0025 (FDRcorrected) that is most evident in the left frontal lobe, including inferior, opercular, dorsolateral regions, extending into insula and anterior-superior temporal regions. There is also involvement of the right frontal lobe. LOWER PANEL: Solid areas show significantly reduced fractional anisotropy at p<0.01 (FDRcorrected) that is more prominent on the left than the right. This includes left inferior frontal-occipital fasciculus as it courses through the external capsule (solid green), bilateral inferior frontal-occipital fasciculus, arcuate fasciculus and anterior thalamic radiations coursing through the anterior corona radiata and most anterior portion of the internal capsule bilaterally (solid red), and interhemispheric fibers of the corpus callosum (solid blue).blue=corpus callosum, red=internal capsule, green=external/extreme capsule, orange=fornix.

FIGURE 3. PATHOLOGY IN naPPA

1. Upper panel shows gross specimen of a patient with naPPA, illustrating significant inferior frontal and anterior-superior temporal atrophy. Lower panel left shows H & E preparation of histopathology demonstrating neuronal cytoplasmic inclusions consistent with Pick bodies; lower panel right shows tauimmunoreactive staining of neuronal inclusions.