Introduction Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.

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Background Aphasic syndromes caused by neurodegenerative disease are known as Primary Progressive Aphasias (PPA). The most recent consensus criteria have classified PPA into the non‐fluent variant (nfPPA), semantic variant (svPPA) and the logopenic variant (lvPPA). Few longitudinal studies have explored the prognosis of patients with PPA. This study aims to give an overview of the clinical profile divided into different domains, the progression into other diagnoses and mortality of the different subtypes of PPA. Method Twenty‐two patients diagnosed with nfPPA, 24 with svPPA and 18 with lvPPA between 2011 and 2019 were retrospectively collected and followed‐up for a maximum of over 6 years. Biomarkers and neuroimaging were acquired at baseline. Reported additional symptoms, neurological signs and outcomes on different neuropsychological tests during follow‐up period were collected and compared for baseline and longitudinal results. Kaplan‐ Meier survival analysis was performed for mortality rate. Result As expected, a language disorder was the main problem of all PPA patients at the first assessment. However, over the disease course, the subtypes exhibited a different progression pattern. Behavioural problems were prominent in svPPA whereas patients with lvPPA exhibited a greater executive and visuospatial dysfunction and episodic memory impairment (p<0.05). Unlike svPPA and lvPPA, nfPPA subjects presented a relatively pure aphasia profile initially. However, 50% of the subjects developed extrapyramidal and pyramidal signs within 4 years and progressed into other diagnoses such as corticobasal degeneration, progressive supranuclear palsy, motor neuron disease, behavioural variant frontotemporal dementia and Alzheimer’s disease. Furthermore, in this group the mortality rate was significantly higher in comparison to the other subtypes (median years 3.04 [1.06 – 5.62], p=0.001). By contrast, none of the svPPA patients progressed into another diagnosis whereas 78% of the lvPPA patients progressed to Alzheimer’s disease within 3 years (Figure 1). Conclusion To our knowledge, this is the first study to determine the progression profiles and the entire course of the disease from the diagnosis to the death. Our results show that prognosis differs widely per PPA subgroup. Disclosing the risk of developing motor symptoms should be considered in the case of nfPPA.