The present study, based on data gathered in the BNA, showed an incidence of PPA of 1.14/100,000 person-year, which is consistent with that was previously reported in FTLD and can be estimated in PPA [5, 12, 13].

Median age at first diagnosis was significatively lower in the PPA than in the AD group, which is in agreement with other studies that have shown that symptoms onset happened at a younger age in PPA than in AD [16]. However, the onset of PPA is known to occur before the age of 65 [17] and the disease is described as a progressive language deficit occurring between 45 and 70 years old [14]. So, our results are not aligned to those of previous studied cohort and indicates possible bias of recruiting older people in memory centres, because they are mostly known as a diagnostic facility for memory and not language disorders.

The other possible explanation would be the proportion of different PPAs in the database and the lack of literature on the age of onset of an lvPPA.

Sex ratio was more balanced in the PPA than in the AD group, with 55.7% of females. Unless a majority of women was described as usual, sex ratio varies from one cohort to another in AD, in PPA group our results are in agreement with the literature [3].

The educational level was higher in the PPA than in the AD group, which is more than described in other studies [3] but in agreement with the fact of early onset dementia patients are more educated than patients with late onset dementia [18]. So, compared to other studies, we can suppose that PPA will be able to cope better with greater brain damage than AD [19].

The mean MMSE score (in 2-point difference) at first diagnosis was not statistically different in the PPA than in the AD group, which is in agreement with the elements found in the literature [20]. MMSE’s item scores could be useful to discriminate PPA patients and AD [21, 22] but it was not possible to test this in this study [21, 22].

About evolution of PPA diagnosis, the most frequently, the diagnosis stays PPA (72.7%), including temporal variant of FTLD, then AD then behavioural variant of FTLD. These results are in agreement with literature values [3].

Regarding the initially diagnosed PPA patients, the natural evolution to a FTD in temporal or frontal variant diagnosis is concordant as the language impairment will be accompanied by a more global cognitive deficit. In cognitively impaired patients, the appearance of a global cognitive deficit or behavioural symptoms announces a future onset of dementia in the six following years of evolution, mostly with a frontal phenotype (75%) [23].

The second evolution observed in our study is AD with 13.8%. These results are in agreement with the fact of due to similar neuropathology and the clinical phenotype presented after the aphasic state, the logopenic subtype of PPA is considered as an atypical form of AD [24].

Other evolutive profile are also reported in our study like Lewy body dementia (0.5%), corticobasal degeneration (CBD) (0.5%) and progressive supranuclear palsy (0.5%) in agreement with literature [25, 26].

Indeed, some authors consider PPA-plus syndromes when aphasia is still not the only major deficit. They report that disinhibition by familiarity, blunted judgement and difficulty in problem solving result in a personality change. Personality change and asymmetric extrapyramidal deficit occur frequently considering the PPA anatomical dysfunction evolution, which is supposed to be close to behavioural variant of FTD or CBD [27].

Also, initial language deficits are reported in one third of corticobasal dementia.

However, in our study, some results are surprising, as the percentage of evolution in subjective complaint which is not a mode of evolution of PPAs and can bring into question on a possible diagnostic error at the beginning.

Our secondary objectives were to determine if diagnosis of PPA is more difficult to establish and more delayed than AD and what are the related prescribed treatment over 7 years of follow-up.

For patients diagnosed of PPA at the end of the follow-up, the first diagnosis was 12.7% Alzheimer’s dementia, 7.1% subjective memory complaint and 4.4% non-amnestic mild cognitive impairment. Subjective memory complaint in the cohort is corresponding to the first consultation of the patient that could, at this time, stay at a subjective cognitive impairment report. We know that PPA patients can complain of memory loss and may perform poorly in standard tests of memory [28]. However, percentage of patients initially diagnosed with AD or with a pending diagnosis (49.6%) seem to support the hypothesis that diagnosis of PPA is more difficult and more delayed than AD.

Other results seem to support this hypothesis, like:

  • The delay between the first consultation for cognitive troubles and the first diagnosis that is significantly longer than in the AD group.

  • The number of different diagnoses before the diagnosis of interest that is significantly higher in the PPA group than in the AD group.

  • The percentage of patients with more than one diagnosis that was higher in the PPA group than in the AD group.

To summarize, despite the evolution of the diagnostic criteria of primary progressive aphasia over time [14, 15], their diagnostic still does not seem optimal.

Our study shows also that PPA diagnosis is particularly important because it modifies pharmacological and nonpharmacological interventions.

Indeed, the number of patients under pharmacological treatment increases of more than 50% after the diagnosis of PPA. Also, non-pharmacological treatments increase after the diagnosis and especially speech therapy (22.7% before and 66.0% after).

In the field of pharmacological interventions, to date, no medications have been shown to improve or stabilize cognitive deficits in patients with PPA [29]. Indeed, clinical trials on patients with FTD and controlled trials on PPA patients with bromocriptine [30] and memantine [31] have not demonstrated any efficiency. Studies on limited patient samples with galantamine, rivastigmine and selegiline have shown no results [32]. Also, although some patients with PPA, particularly with a logopenic subtype, may suffer from atypical AD, cholinesterase inhibitors have shown no results. No effect is expected as cholinergic deficit has been specifically identified in AD’s physiopathology. Worsening of behavioural variant of FTD is also suspected under anticholinerterasic treatment. So on, actual recommendation is not favourable for anticholinesterase inhibitors’ use in FTD [33].

However, benefits have been found on behaviour but not on cognition with the cholinesterase inhibitor rivastigmine and the MAO-B inhibitor selegiline [34].

The use of antidepressants, such as trazadone, is known to be effective on the behavioural symptoms but no impact on cognition is reported in FTD [35]. Antipsychotics with careful and limited use could improve behavioural symptoms but their side effect on wake and cognition limits their use. It is suspected that high-frequency repetitive transcranial magnetic stimulation (hf-rTMS) applied to the left prefrontal cortex produces improvement on language test that seems to last; other magnetic stimulations are suspected to maintain some language capacities [36].

In summary, although no drugs have shown an effectiveness on PPA, but, on behavioural disorders, some drugs have been deleterious, and others had positive effects. It thus appears essential to establish a diagnosis of PPA to set up an adapted medical treatment.

A key intervention on the PPA population is speech and language therapy (SLT): a specific form of cognitive intervention that evaluates communication skills and designs a personalized intervention plan to improve communication abilities. This type of intervention has been shown to be effective and advised to be implemented in a more systematic way [37].

Also, in addition to the take care of language disorders, speech therapy is particularly important for swallowing disorders, which represent vital risks. Indeed, all variants showed swallowing difficulties and they were more frequent in PPA-S [38].

Finally, the put of diagnosis is essential whether it is for more adapted pharmacological or non-pharmacological interventions.

Logopenic variant of PPA (lv-PPA) is a neurodegenerative syndrome frequently associated with biomarkers of AD. Lv-PPA patients display characteristic linguistic deficits, a pattern of brain atrophy, and possibly genetic susceptibility, which warrant considering this variant as a discrete AD endophenotype [39]. Also, recent diagnostic criteria include lvPPA as an atypical early onset variant of AD because sporadic lvPPA clinical syndrome is both associated with AD biomarkers and AD pathological changes in about 85–90% of cases [8, 40,41,42]. For these reasons, patients with PPAs are often included in studies on AD.

However, it has been shown that the classification of lvPPA does not successfully differentiate PPA due to AD from PPA due to other pathologies [43]. Furthermore, several underlying neurodegenerative etiologies have been reported in a few lvPPA cases, which can be linked to Lewy body disorder [44] and coexisting disorders or to biomarkers discordant with the clinical syndrome, especially in older individuals [42, 45].

Understanding in vivo pathological prediction is crucial in neurodegenerative diseases because therapeutic pharmacological strategies are, or soon will be, directed towards decreasing or clearing toxic molecules, such as amyloid, tau or TDP. This study highlights importance to improve early diagnosis of PPA to better understand links with AD.

Finally, studies have demonstrated that toxic proteins including amyloid, tau and TDP43 spread transneuronally through connected networks in a prion-like manner [46, 47]. In PPA neuroimaging support these findings by showing network-specific damage. The studies comparing PPAs and ADs seem even more of interest because they permit to investigate the intricate relationship between protein deposition patterns and network susceptibility in neurodegenerative diseases. In summary, the comparison of clinical characteristics between PPA and AD patients could provide a better understanding of the reasons for network susceptibility generating clinical disorders increased on the language or memory.

Limitations of the present study

Despite BNA represents a valuable epidemiologic tool because it grants access to many patients with dementia and permits follow-up studies, several limitations should be noted.

First, data are entered into the BNA by different physicians and even though they all follow standard criteria for diagnosis, there is no external validation that those criteria were met. Also, criteria for diagnosis of PPA have be modified since 2010. Second, even though the BNA includes the great majority of individuals with PPA and associated disorders who are referred to specialized centres (French memory units), individuals included in the BNA are not fully representative of the total French population with PPA. Indeed, one part of the population with PPA is under general practitioner (GP) supervision only (GPs do not currently have access to the BNA), and another part of the population is referred to specialists (geriatricians, neurologists, psychiatrists) who are not using the BNA database. Finally, the data reported in the BNA do not include the information on the PPA variants and thus do not allow to perform separate analyses for different patients’ groups.

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