A wealth of neuroimaging research has associated semantic variant primary progressive aphasia with distributed cortical atrophy that is most prominent in the left anterior temporal cortex; however, there is little consensus regarding which region within the anterior temporal cortex is most prominently damaged, which may indicate the putative origin of neurodegeneration. In this study, we localized the most prominent and consistent region of atrophy in semantic variant primary progressive aphasia using cortical thickness analysis in two independent patient samples (n = 16 and 28, respectively) relative to age-matched controls (n = 30). Across both samples the point of maximal atrophy was located in the same region of the left temporal pole. This same region was the point of maximal atrophy in 100% of individual patients in both semantic variant primary progressive aphasia samples. Using resting state functional connectivity in healthy young adults (n = 89), we showed that the seed region derived from the semantic variant primary progressive aphasia analysis was strongly connected with a large-scale network that closely resembled the distributed atrophy pattern in semantic variant primary progressive aphasia. In both patient samples, the magnitude of atrophy within a brain region was predicted by that region's strength of functional connectivity to the temporopolar seed region in healthy adults. These findings suggest that cortical atrophy in semantic variant primary progressive aphasia may follow connectional pathways within a large-scale network that converges on the temporal pole.

“Functional communication” refers to an individual’s ability to communicate effectively in his or her everyday environment, and thus is a paramount skill to monitor and target therapeutically in people with aphasia. However, traditional controlled-paradigm assessments commonly used in both research and clinical settings often fail to adequately capture this ability. In the current study, facets of functional communication were measured from picture-elicited speech samples from 70 individuals with mild primary progressive aphasia (PPA), including the three variants, and 31 age-matched controls. Building upon methods recently used by Berube et al. (2019), we measured the informativeness of speech by quantifying the content of each patient’s description that was relevant to a picture relative to the total amount of speech they produced. Importantly, form-based errors, such as mispronunciations of words, unusual word choices, or grammatical mistakes are not penalized in this approach. We found that the relative informativeness, or efficiency, of speech was preserved in non-fluent variant PPA patients as compared with controls, whereas the logopenic and semantic variant PPA patients produced significantly less informative output. Furthermore, reduced informativeness in the semantic variant is attributable to a lower production of content units and a propensity for self-referential tangents, whereas for the logopenic variant, a lower production of content units and relatively ”empty” speech and false starts contribute to this reduction. These findings demonstrate that functional communication impairment does not uniformly affect all the PPA variants and highlight the utility of naturalistic speech analysis for measuring the breakdown of functional communication in PPA.

Despite the important role of written language in everyday life, abnormalities in functional written communication have been sparsely investigated in Primary Progressive Aphasia (PPA). Prior studies have analyzed written language separately in the three variants of PPA - nonfluent (nfvPPA), logopenic (lvPPA), and semantic (svPPA) - but have rarely compared them to each other or to spoken language. Manual analysis of written language can be a time-consuming process. We developed a program which uses a language parser and quantifies content units (CU) and total units (U) in written language samples. The program was used to analyze written and spoken descriptions of the WAB Picnic scene, based on a pre-defined CU corpus. We then calculated the ratio of CU to U (CU/U Ratio) as a measure of content density. Our cohort included 115 participants (20 control participants for written, 20 control participants for spoken, 28 participants with nfvPPA, 30 with lvPPA, and 17 with svPPA). We compared written language between patients with PPA and control participants and written to spoken language in patients with the three variants of PPA. Finally, we analyzed CU and U in relation to the Progressive Aphasia Severity Scale Sum of Boxes and the Clinical Dementia Rating Sum of Boxes. Our program identified CU with a validity of 99.7% (95%CI 99.5 to 99.8) compared to manual annotation of the samples. All patients with PPA wrote fewer total units than controls (p<0.001). Patients with lvPPA (p=0.013) and svPPA (0.004) wrote fewer CU than controls. The CU/U Ratio was higher in nfvPPA and svPPA than controls (p=0.019 in both cases), but no different between lvPPA patients and controls (p=0.962). Participants with lvPPA (p<0.001) and svPPA (p=0.04) produced fewer CU in written samples compared to spoken. A two-way ANOVA showed all groups produced fewer units in written samples compared to spoken (p<0.001). However, the decrease in written CU compared to spoken was smaller than the decrease in written units compared to spoken in participants with PPA, resulting in a larger written CU/U Ratio when compared to spoken language (p<0.001). nfvPPA patients produced correlated written and spoken CU (R=0.5, p=0.009) and total units (R=0.64, p<0.001), but this was not the case for lvPPA or svPPA. Considering all PPA patients, fewer CU were produced in those with greater aphasia severity (PASS SoB, R=-0.24, p=0.04) and dementia severity (CDR SoB, R=-0.34, p=0.004). In conclusion, we observed reduced written content in patients with PPA compared to controls, with a preference for content over non-content units in patients with nfvPPA and svPPA. When comparing written to spoken language, we observed a similar "telegraphic" style in both modalities in patients with nfvPPA, which was different from patients with svPPA and lvPPA, who use significantly less non-content units in writing than in speech. Lastly, we show how our program provides a time-efficient tool, which could enable feedback and tracking of writing as an important feature of language and cognition.

No abstract

Agrammatism is characterized by short sentences, the omission of function words, a higher ratio of heavy to light verbs, and a decreased use of verbs relative to nouns. Despite the observation of these phenomena more than two centuries ago, there has been no unifying theory to explain all features of agrammatism. Here, by first examining the language of patients with primary progressive aphasia, we show that the seemingly heterogeneous features of agrammatism can be explained by a process that selects lower frequency words over their higher frequency alternatives in the context of a limitation in sentence production, likely to increase the informational content of sentences. We further show that when healthy speakers are constrained to produce short sentences, features of agrammatism emerge in their language. Finally, we show that these findings instantiate a general property in healthy language production in which shorter sentences are constructed by selecting lower frequency words.

Background and Objectives.Patients with Primary Progressive Aphasia (PPA) have gradually progressive language deficits during the initial phase of the illness. As the underlying neurodegenerative disease progresses, PPA patients start losing independent functioning due to the development of non-language cognitive or behavioral symptoms. The timeline of this progression from the mild cognitive impairment stage to the dementia stage of PPA is variable across patients. Here, in a sample of PPA patients, we measured the magnitude of cortical atrophy within functional networks thought to subserve diverse cognitive and affective functions. We then evaluated the utility of this measure as a predictor of time to subsequent progression to dementia in PPA.Methods.PPA patients with largely independent daily function were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit. All patients underwent an MRI scan at baseline. Cortical atrophy was then estimated relative to a group of amyloid-negative cognitively normal control participants. For each patient, we measured the time between the baseline visit and the subsequent visit at which dementia progression was documented or last observation. Simple and multivariable Cox regression models were used to examine the relationship between cortical atrophy and the likelihood of progression to dementia.Results:Forty-nine PPA patients (mean age = 66.39 ± 8.36 years, 59.2% females) and 25 controls (mean age = 67.43 ± 4.84 years, 48% females) were included in the data analysis. Greater baseline atrophy in not only the left language network (hazard ratio [HR] = 1.47, 95% CI = 1.17-1.84) but also in the frontoparietal control (1.75, 1.25-2.44), salience (1.63, 1.25-2.13), default mode (1.55, 1.19-2.01), and ventral frontotemporal (1.41, 1.16-1.71) networks was associated with a higher risk of progression to dementia. A multivariable model identified contributions of the left frontoparietal control (1.94, 1.09-3.48) and ventral frontotemporal (1.61, 1.09-2.39) networks in predicting dementia progression, with no additional variance explained by the language network (0.75, 0.43-1.31).Discussion:These results suggest that baseline atrophy in cortical networks subserving non-language cognitive and affective functions is an important predictor of progression to dementia in PPA. This measure should be included in precision medicine models of prognosis in PPA.

Highlights Default mode network connectivity is disrupted in svPPA. Dorsal attention to visual association network connectivity is increased in svPPA. Focal neurodegeneration can alter large-scale cognitive networks.

ObjectiveNonfluent aphasia is characterized by simplified sentence structures and word‐level abnormalities, including reduced use of verbs and function words. The predominant belief about the disease mechanism is that a core deficit in syntax processing causes both structural and word‐level abnormalities. Here, we propose an alternative view based on information theory to explain the symptoms of nonfluent aphasia. We hypothesize that the word‐level features of nonfluency constitute a distinct compensatory process to augment the information content of sentences to the level of healthy speakers. We refer to this process as lexical condensation.MethodsWe use a computational approach based on language models to measure sentence information through surprisal, a metric calculated by the average probability of occurrence of words in a sentence, given their preceding context. We apply this method to the language of patients with nonfluent primary progressive aphasia (nfvPPA; n = 36) and healthy controls (n = 133) as they describe a picture.ResultsWe found that nfvPPA patients produced sentences with the same sentence surprisal as healthy controls by using richer words in their structurally impoverished sentences. Furthermore, higher surprisal in nfvPPA sentences correlated with the canonical features of agrammatism: a lower function‐to‐all‐word ratio, a lower verb‐to‐noun ratio, a higher heavy‐to‐all‐verb ratio, and a higher ratio of verbs in ‐ing forms.InterpretationUsing surprisal enables testing an alternative account of nonfluent aphasia that regards its word‐level features as adaptive, rather than defective, symptoms, a finding that would call for revisions in the therapeutic approach to nonfluent language production. ANN NEUROL 2023