Multicentric Clinical Data Collection: A Game-Changer for Rare Neurological Diseases

Frontotemporal degeneration (FTD) is an umbrella term encompassing several rare neurodegenerative diseases causing changes in behavior, executive function, speech, and language. The classic neuropsychiatric symptoms associated with the behavioral variant of FTD are disinhibition, apathy, loss of sympathy or empathy, ritualistic-compulsive behavior, and appetite change [1]. However, other neuropsychiatric symptoms such as depression, delusions, hallucinations, impaired sleep, and agitation are also common [2]. The underlying proteinopathy or genetic cause may play a role in the neuropsychiatric presentation, for instance hallucinations are more common in patients with a C9orf72 repeat expansion [3]. Although a myriad of neuropsychiatric symptoms can occur due to FTD, there is a lack of evidence on the optimal therapeutic management of these symptoms [4]. The rarity of FTD combined with the phenotypical and neuropathological heterogeneity likely play an important role in this knowledge gap.

In this issue, Katisko et al. [5] report on the use of psychopharmacological medication at the time of diagnosis in 222 patients with genetic or sporadic FTD. This multicentric Finnish study used an equally sized cohort of Alzheimer’s disease (AD) patients as a reference group. Compared to the AD group, newly diagnosed FTD patients received more antidepressants, antipsychotics, and mood stabilizers [5]. The proportion of newly diagnosed FTD patients on psychopharmacological medication was high: 50% of the female patients and 39% of the male patients were receiving such drugs. As expected, the overall percentage was highest in the behavioral variant subtype (52%). The work of Katisko et al. [5] is very valuable as it demonstrates the highly frequent need for pharmacological management of neuropsychiatric symptoms caused by FTD. Choosing the right drug may be challenging because data indicating the optimal therapeutic approach are not available. Because of the lack of evidence-based guidelines, this real-world data report can offer insight into the current practices of clinicians caring for patients with FTD. An exchange of current practices can lead to converging on a more standardized approach of patients.

For rare diseases such as FTD, reporting real-world data about therapeutic management contributes to knowledge sharing between clinicians caring for these patients around the world. The systematic collection of clinical data on rare neurological diseases across centers has been vital to making scientific progress. This has been demonstrated by the consortia focusing on genetic FTD such as the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium (merging The Advancement in Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL); focused on sporadic and familial frontotemporal lobar degeneration, and the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS); focused on familial frontotemporal lobar degeneration), The Genetic FTD Initiative (GENFI), the Multi-partner consortium to expand dementia research in Latin America (ReD-Lat) and other international cohorts. Several consortia have now joined forces to create the FTD Prevention Initiative (FPI) to create an international database of participants eligible for trials and to develop uniform standards for conducting such trials [6]. In this way, new drugs under development for genetic FTD can be tested rigorously and the field should not be confronted again with underpowered clinical trials providing no more than preliminary answers.

But where does this leave rare neurodegenerative diseases other than genetic FTD? Based on the Orphanet database, Wakap et al. estimated that rare diseases affect at least between 3.5 to 5.9% of the worldwide population, with many of these rare diseases resulting in neurological symptoms [7]. For a lot of these rare diseases, questions remain regarding the real-world prevalence, full phenotypical spectrum and optimal therapeutic management resulting in several unmet medical needs in the affected patient groups. Such questions can only be resolved by multicentric sharing of medical knowledge, ideally through dedicated consortia or platforms such as registries containing core clinical information. Registries can be used to study the natural history of rare diseases, assist in the evaluation of treatments and establish disease-specific uniform standards as well as evidence-based guidelines. Registries can also play an important role in assessing the impact of preventive strategies or novel treatments on the individual and societal level, including health economic aspects. Additionally, patients may indicate their interest to participate in new disease-specific trials through such platforms. Several frameworks have been suggested to set up registries for rare diseases. For instance, a clinical registry containing physician-entered information has been proposed by the European Reference Network for Rare Neurological Diseases [8], and a natural history repository generating patient-reported data has been put forward by the National Organization for Rare Disorders [9]. Regardless of the exact format, the registries can facilitate a coherent and integrated approach for rare neurological diseases. By means of major international collaborations, we can then arrive at a point of global knowledge sharing and optimally work towards the long-term goal of curing or preventing FTD and other rare neurological diseases.