The course of primary progressive aphasia diagnosis: a cross-sectional study

Participants of the present study were recruited from the French National data Bank (BNA) which is part of the French strategy to fight against dementia [11] and records information since the end of 2009. This database was created to provide information about the medical activity of the French memory centres in order to adapt healthcare provision, and generate epidemiologic knowledge on the diseases and the medical practices. The BNA includes a limited set of demographic, diagnostic and clinical information, selected by a national consensus group. The number of collected variables was limited to facilitate and enhance care providers to participate to this national database. Data are collected from 536 memory units in France: 434 memory centres (secondary level), 28 resource and research memory centres (tertiary level) and 74 independent neurologists who expressed the willingness to participate.

Each time a person consults one of these centres, a clinical record is generated and transferred to the database. Therefore, one patient can figure more than once in the BNA, depending on the number of medical acts he/she underwent.

The following variables were considered in the present study: gender, age, living conditions, education (five levels according to the French education system, corresponding to the following categories: no formal education, primary school level [equivalent to 1–5 years of education], secondary school level with 6–9 years of education, secondary school level with 10–12 years of education and university level [over 12 years of education]), type of medical centre, referring modalities, score on the Mini Mental Score Examination (MMSE) [12] date of consultation, medical diagnosis and recommended treatments.

The BNA differentiates 38 diagnostic groups, based on International Classification of Diseases, Tenth Revision, ICD-10. For the AD diagnosis, ICD-10 criteria include insidious and irreversible onset dementia and clinical examination or special investigation that do not suggest any other aetiology of the disorders (metabolic disorder, cerebral haematoma…). Therefore, AD diagnosis was established on clinical, biological and cerebral imaging results. As the BNA is a large databank, reflecting usual clinical practice, on the period studied (2010 to 2016), no metabolic imaging or amyloid proof was required. For treatments, the BNA records the presence of a prescription at the time of the consultation for 6 groups of psychotropic drugs classified as follows, using ATC codes: antidepressant (N06A), anxiolytic (N05B), hypnotic (N05C), antipsychotic (N05A), cholinesterase Inhibitors (ChEIs) (N06DA) and N-Methyl-D-aspartate receptor antagonist (NMDA antagonist) (N06DX01). No data is available on drug generics or brand names, nor on dosage. Psychosocial intervention and rehabilitation are recorded too. More details on this database are described in Le Duff et al. [13].

Patients were selected in the BNA from January 1, 2010, to December 31, 2016. Patients with at least once a diagnosis of PPA according to the diagnostic criteria including progressive language disorders were included in the PPA group (including all PPA subtypes) [14, 15]. Patients with at least once a diagnosis of AD, but never of PPA were included in the AD group.

Individuals who already had the diagnosis of interest when first registered in the database were included only if their first consultation for memory problems was in the same year or the year before the first visit. This was intended to exclude patients who had a diagnosis established for a long time, and to collect data at the time of the first diagnosis. To describe the whole population included in the study, we selected data at the first diagnosis of interest. Given the importance of cognitive status, only patients with at least one existing MMSE evaluation at less than 1 year before or after the first diagnosis of interest were considered in the analyses (see Fig. 1).

Incident cases were defined as those first diagnosed during the study period. Incidence was calculated by dividing the total number of incident cases by the total number of person-years for the catchment area population over 7 years (data from the French national institute for statistical and economic studies INSEE).

Descriptive analyses were conducted using percent and frequency for qualitative variables and mean with SD for quantitative variables. Variables associated with diagnosis (i.e., PPA, AD) were analysed using Student t-test for quantitative variables and chi-squared tests for qualitative variables. The change in treatment and the change in psychosocial interventions were determined using the McNemar test. In all analyses, a p value less than 0.05 was considered significant.

In addition, because of the large size of our cohort, we decided to run a second type of analysis: Bayesian analysis. This analysis was also performed as a simple way to deal with significantly labelled differences between large-sized groups. Here we used a burn-in of 1000 iterations (to allow Markov chains to reach stationary distribution) and 4000 useful iterations for estimates. Furthermore, the Bayesian techniques allow acceptance of a null hypothesis (not only rejection), which is not only a comparison with 0 (for example, for a difference). Statistical analyses were done with SAS Enterprise Guide software, version 5.1 (SAS Institute, Cary, NC, USA). Bayesian analyses were done with WinBugs 1.4 software.

The PPA and the AD groups respectively included 5186 and 162,005 patients. The incidence rate of PPA was 1.14 per 100,000 person-years, while the incidence rate of AD was 35.7 per 100,000 persons-years. Demographic characteristics of the two groups are presented in Table 1, and the results of Bayesian analysis are reported in Additional file 1: Table S1. Patients with PPA were significantly younger (mean = 73.7; SD = 9.1 years) than those with AD (mean = 81.4; SD = 8.0 years (p<0.001)), and this was observed in all age groups, except for the patients aged 80 years and older for which the opposite pattern was observed. As shown in Table 1, the sex ratio was more balanced in the PPA than in the AD group, and the educational level was higher in the PPA than in the AD group, with a larger proportion of patients with more than 6 years of education (secondary second school level).

Compared to the AD group, the patients of the PPA group were more often referred by neurologists and less by general practitioners. In PPA more often than in AD, the diagnosis was established in a tertiary centre, and patients lived farther from the centre.

In the PPA group, the MMSE score at first diagnosis was significantly different than in AD. Using Bayesian analytical methods, we found that there was a significant difference of 1 point between the two groups, while the difference of 2 points for MMSE was not significant. Patients were more to live in community compared to the patients with AD.

As shown in Additional file 1: Table S2, the delay between the first consultation for cognitive disorders (that could be prior the first record in the BNA) and the first diagnosis visit was significantly longer in the PPA than in the AD group.

The number of different diagnoses before the diagnosis of interest was significantly different in the PPA group than in the AD group. Indeed, the mean number of diagnoses before the diagnosis of interest was 0.54 (SD=0.69) in the PPA group, and 0.45 in the AD group (SD=0.62). The mean time between the first consultation and the first diagnosis was 0.7 years in the PPA group and 0.6 years in the AD group (p<0.001) (see Additional file 1: Table S2).

We analysed the diagnoses made before the diagnosis of interest in each group (Table 2). Except “pending diagnosis”, the most frequent diagnosis given before PPA diagnosis were AD (12.6%) then subjective cognitive complaint, followed by non-amnestic mild cognitive impairment. Though before AD diagnosis, except “pending diagnosis”, it was most often amnestic mild cognitive impairment (14%) then cognitive complaint then non-amnestic mild cognitive impairment.

The proportion of patients having received no other diagnosis after PPA was identified was lower than after an AD diagnosis was made (see Additional file 1: Table S2).

However, the proportion of patients having received more than one diagnosis after the first diagnosis visit was higher in the PPA than in the AD group. Diagnoses registered after a PPA diagnosis were most often PPA (72.7%), then AD then behavioural variant of frontotemporal neurocognitive disorder then mixed neurocognitive disorder. And after AD diagnosis, it was most frequent AD diagnosis (90.7%) then mixed neurocognitive disorder (Table 2).

Patients with at least one BNA record before and after the diagnosis of interest and for whom the data about pharmacological (N=1622) and non-pharmacological treatment (N=1605) were registered were selected. The number of patients under pharmacological treatment was significantly higher after, than before the diagnosis of PPA, and this is true for the different psychotropic drugs and for anti-dementia treatments. After diagnosis, the treatment that was mainly added in the PPA group was antidepressants (for 20,6% of the patients). More patients received non-pharmacological treatments after a PPA compared to before the diagnosis, with the most common intervention being speech-language therapy (see Table 3). The delay between diagnosis and starting speech-language therapy was 6.9 (± 6.3) months.

In the AD group too, the number of patients under pharmacological treatment (N=42,571) was significantly higher after, than before the diagnosis (Table 3), and this is also true for the different psychotropic drugs and for anti-dementia treatments. After diagnosis, the treatment that was mainly added was cholinesterase inhibitors (for 46.4%of the AD patients). As for the PPA group, more patients received non-pharmacological treatments after receiving an AD diagnosis compared to before the diagnosis. The delay between diagnosis and starting speech-language therapy was 9.0 (± 9.6) months.

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.