Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia

Frontotemporal dementia (FTD) is a presenile neurodegenerative disorder, leading to a heterogeneous clinical presentation, involving behavioural (behavioural variant FTD; bvFTD) and/or language deterioration (primary progressive aphasia; PPA) [1]. FTD has an autosomal dominant pattern of inheritance in 30 percent of cases, with mutations in the progranulin (GRN) and microtubule-associated protein tau (MAPT) genes as its two main causes [2]. The cognitive profile of FTD varies depending on the clinical phenotype and the underlying genotype. Patients with bvFTD are characterized by deficits in executive function, social cognition and language, whereas memory and visuoconstruction are initially spared [3‐5]. Non-fluent variant PPA (nfvPPA) patients show agrammatism and speech sound distortions, while semantic variant PPA (svPPA) patients experience deficits in confrontation naming and word comprehension [6]. GRN mutations often lead to a clinical diagnosis of bvFTD, nfvPPA or parkinsonism. In MAPT mutations, bvFTD is the main phenotype, and semantic and memory impairments can be prominent neuropsychological symptoms [7].

Research in familial FTD has demonstrated the presence of a presymptomatic stage in which subtle cognitive changes have been identified [8‐12]. More specifically, cognitive decline can start as early as 8 years prior to estimated symptom onset and shows mutation-specific patterns, with GRN mutation carriers declining in memory, and MAPT mutation carriers declining in language, social cognition and memory [8, 10]. This suggests that cognitive measures could function as disease-tracking biomarkers in the presymptomatic stage. However, it is currently unknown what the long-term cognitive profiles of presymptomatic FTD mutations are, whether neuropsychological assessment can be used to track disease progression to the symptomatic stage, and what the prognostic value is of cognitive trajectories in the presymptomatic and early symptomatic stage of FTD.

In this study, we investigated longitudinal cognitive decline on neuropsychological assessment in presymptomatic mutation carriers (MAPT or GRN) and controls from the same families within our longitudinal presymptomatic Dutch familial FTD Risk Cohort (FTD-RisC). Second, we assessed the difference in cognitive course between converters’ genotypes (i.e. MAPT vs. GRN) and phenotypes (i.e. bvFTD vs. nfvPPA) versus non-converters. Lastly, we investigated the prognostic value of neuropsychological trajectories in predicting symptom onset within 2–4 years.

This study examined a large cohort of at-risk participants from GRN and MAPT FTD families by means of neuropsychological assessment during a 4-year follow-up. Within the study time window, eight mutation carriers became symptomatic. Converters with a MAPT and GRN mutation had mutual as well as gene-specific profiles of cognitive decline. Cognitive decline on categorical fluency between 2 years before conversion and symptom onset was predictive for an underlying MAPT mutation, and decline on ScreeLing phonology and letter fluency was predictive for conversion to nfvPPA. These results suggest that neuropsychological assessment could provide sensitive clinical biomarkers to identify and track FTD mutation carriers at-risk of converting to the symptomatic stage. These findings hold potential for improving early clinical diagnosis by identifying the most sensitive neuropsychological tests for conversion, and use in upcoming disease-modifying clinical trials.

Following the MAPT mutation carriers over a 4-year period, we found significant decline in language, social cognition and memory. This is consistent with findings from previous presymptomatic familial FTD studies, in which both cross-sectional [9‐11, 33] and longitudinal [8] decline was found. Specifically, in our first follow-up study [8], we demonstrated decline in the domains language, social cognition and memory 5–8 years before estimated symptom onset. It should be taken into account that this study made use of estimated onset as a proxy, instead of actual symptom onset as in the present study—but the similar profile of decline confirms the presence of early changes in these three domains. As in our previous study, the present results are largely driven by the converters. This could suggest that neuropsychological test scores remain static while mutation carriers are presymptomatic, and cognitive decline starts only near or at symptom onset [34‐36], suggesting an explosive rather than gradual start of the symptomatic disease stage. Alternatively, we might be unable to pick up subtle cognitive changes in presymptomatic mutation carriers due to lack of power. Also, although well-validated, most of our neuropsychological tests were not developed for repeated administration in a preclinical population [37]. We therefore cannot rule out that familiarity and/or practice effects are obscuring subtle cognitive decline, a notion that seems to be underwritten by improvement in social cognition and memory in controls, but not mutation carriers.

In our exploratory analyses in converters, we discovered both common as well as mutation-specific profiles of cognitive decline in MAPT and GRN. In both mutations, decline in attention, mental processing speed and executive function was found—while only converters with a MAPT mutation demonstrated decline on language, memory and social cognition. Previous studies in familial FTD also point to distinct profiles for MAPT and GRN [8, 10‐12], and are largely consistent with our present findings. Another important aspect is the longitudinal tracking of the different clinical phenotypes. The similar patterns of cognitive decline in bvFTD as MAPT, and nfvPPA as GRN are related to the dominant genotype in each group (e.g. all nfvPPA converters have a GRN mutation). These findings suggest that neuropsychological assessment can be used to track the different mutations and phenotypes from the presymptomatic to the symptomatic stage, which is advantageous considering the need for good clinical endpoints in future disease-modifying trials.

Extending the findings from our first follow-up study [8], we demonstrated significant decline on the RAVLT recall in presymptomatic MAPT mutation carriers. The additional finding that lower memory scores over time were also found in MAPT, and not GRN converters—suggesting a mutation-specific aetiology—corroborate this. Although memory loss has been described in GRN [38, 39], this is usually a later symptom, while episodic memory impairment has been found as the presenting and most prominent symptom in MAPT [7, 40, 41]. Interestingly, the Genetic Frontotemporal dementia Initiative (GENFI) consortium revealed hippocampal atrophy in presymptomatic MAPT from 15 years before estimated symptom onset [10], and as this medial temporal structure is critical for episodic memory processing [42] this offers a good explanation for our findings. In line with earlier studies [42, 43], we did find deficits in verbal recall but not visual associative memory. Semantically loaded tasks such as the RAVLT can be particularly more difficult than visual memory tasks like the VAT, as a result of the prominent semantic impairments seen early in MAPT-associated FTD [44]. Our results contribute to the present thinking that memory deficits can be an integral part of the clinical spectrum [42], and comprehensive memory tasks should therefore be incorporated in the standard diagnostic work-up.

Knowing the cognitive profile of decline indicative for conversion is important to get more insight into the timing of clinical changes in the earliest disease stage. We found that conversion can be predicted based on cognitive decline in the 2 years prior to symptom onset, but not earlier. As the cognitive decline was part of the diagnostic process of determining conversion, this is not a surprising finding. However, it does suggest a more explosive disease development with cognitive decline accelerating rapidly in proximity of symptom onset, which is in line with evidence from a large familial Alzheimer’s disease cohort [45]. By selectively choosing tests within the domains that have prognostic abilities, the neuropsychological battery can be shortened, which would benefit patient burden and helps cutting healthcare expenses. Especially fluency tasks seem to be promising candidates, as they were able to distinguish accurately between future phenotype and underlying genotype. The latter is essential for patient stratification in future clinical trials targeting specific pathologies, and ideally these interventions should be applied in the presymptomatic stage [46]. Reliable phenotypic prediction furthermore optimizes the diagnostic process by shortening the current diagnostic delay [47], and is helpful for the patient, caregiver and clinician in knowing what disease presentation and course to expect. Verbal fluency tests are widely used in dementia diagnosis setting [48], and are affected in both presymptomatic [8, 11] and symptomatic FTD [49, 50]. Future research could additionally investigate the use of qualitative assessment of verbal fluency (e.g. clustering, switching between clusters), as recent research [49] points to differences between FTD and PPA subtypes—making this a promising application of verbal fluency for a precise clinical differentiation in presymptomatic and early stage FTD.

Key strengths of our study constitute our longitudinal design, spanning a 4-year follow-up of at-risk participants from both MAPT and GRN families. Although our group of converters is currently small, this is the first study tracking FTD mutation carriers from the presymptomatic to symptomatic disease stage. Being aware of the caveats of small sample sizes and administering a large amount of neuropsychological tests with respect to statistical power, our results warrant replication in our cohort as well as larger international cohorts such as GENFI [10], in which with the passing of time more mutation carriers will approach symptom onset and/or convert to clinical FTD. The dropout rate is very low, creating balanced datasets across the three time points. Additionally, use of multilevel linear modeling further handles efficiently with missing data. Directions for future research entail the development of neuropsychological tasks more suited to administer in the presymptomatic phase (robust to ceiling effects) and repeated administration (robust to practice and able to measure small changes). More extensive quantification tools of behavioural functioning are also needed to capture the entire clinical spectrum of (presymptomatic) FTD, as well as assessment methods that rely less on the accuracy of informant report [37]. A disadvantage of the study is the fact that the neuropsychological assessment was part of the clinical assessment with which we determined conversion to the symptomatic stage. This has likely led to a circular reasoning, as we demonstrated that converters declined over time, while cognitive decline was considered a prerequisite for conversion. Ideally, the tests assessed in our study should not have been used in the diagnosis of conversion. However, in our multidisciplinary meeting, we followed the international consensus criteria for bvFTD [3] and PPA [6], using all available clinical information—e.g. MR imaging of the brain, anamnestic and heteroanamnestic information, behavioural and neuropsychiatric questionnaires, unblinding of genetic status—so that symptom onset did not solely depend on the neuropsychological assessment. Furthermore, as the multilevel model assumes a linear relationship between genetic status and cognitive decline over time, we could have missed non-linear effects over time. Lastly, the analyses on the non-converters and controls were performed using the original baseline and follow-up visits, regardless of, e.g. age and time to estimated symptom onset. It is possible that these analyses therefore lost some sensitivity to detect cognitive decline over time. However, as between-group analyses on age and estimated years to symptom onset in converters, non-converters, and controls did not show significant differences (respectively, p = 0.99 and p = 0.19), we believe this effect is minimal.

Our study investigates longitudinal neuropsychological performance in a large cohort of at-risk individuals from genetic FTD families. We provide evidence of mutation-specific cognitive decline when moving from the presymptomatic into symptomatic stage, and of neuropsychological trajectories predicting symptom onset. These results suggest the potential biomarker value of neuropsychological assessment in both disease-monitoring and predicting conversion to clinical FTD.