Genetics and Environment intersection In the Amyotrophic Lateral Sclerosis - FrontoTemporal Dementia spectrum: an Italian Twins cohort study with a Multi-Omics approach (Geniality)

Rationale
The Amyotrophic Lateral Sclerosis-FrontoTemporal Dementia (ALS-FTD) spectrum encompasses a heterogeneous group of clinical syndromes sharing some pathological and genetic features, with different phenotypes characterized by impairment of motor, cognitive, behavioural functions that may be unpredictably overlapped. Progression of disease is extremely variable among affected individuals and, despite the advancement in comprehension of ALS/FTD pathomechanisms, what drives disease onset, phenotypic variability and progression remains largely unknown.
Nowadays, twins studies may offer the unique possibility of studying genetics and environment as risk/protective factors driving diseases features, especially if deep phenotyping is combined with a multi-omics approach.
Currently, studies on ALS/FTD twins are limited to single or small series descriptions, or to retrospective linkage among registers to define heritability. Apart from biotechnological limitations of the past years, the main drawbacks of existing studies rely on the very small series, the lack of longitudinal follow up, the narrow spectrum of biological variables examined, the absence of an integrated vision.
Prospective cohort studies are lacking as well as researches on biological signatures through a multi-omics approach or on exposome through in-depth questionnaires or with laboratory tests.
Broad objectives
This study is aimed at creating a longitudinal cohort of Italian ALS/FTD twins and a virtual biobank with collection of different samples for a multi-omics study, to pursue the following objectives: I to find environmental/genetic risk/protective factors driving twins discordance by the classical monozygotic (MZ) twins design; II to find ALS/FTD early signatures by studying unaffected MZ as pre/asymptomatic carriers of the same genetic background of affected co-twins; III to find post-twinning ALS/FTD-related alterations by exploring parent-offspring trios.
Design and methods
In this national prospective cohort study on ALS/FTD twins, three Italian centers will enroll patients with co-twins and their parents (parent-offspring trios studies).
Based on our epidemiological data, we estimate to collect 45 twin pairs (15 MZ) by taking advantage from Italian MND network (referral from other Italian centers), by creating a website and with media and public campaigns to involve patients. At baseline, all affected or unaffected twins will undergo deep phenotyping, neuropsychological, neurophysiological and multimodal imaging studies, in-depth questionnaires on environmental factors including occupational/residential exposures to toxins, drugs, vaccinations, and diet. We will collect blood, saliva, stool, skin, hair, and CSF for biobanking (for future research) and multi-omics study embracing genomics, epigenetics, proteomics, microbiome, immune system, biomarkers, metabolites, pesticides, metals and metalloids. Twins will be followed longitudinally with biobanking to assess discordance and identify early disease signatures in the unaffected ones.
Expected results
We expect to identify biological and environmental signatures specifically correlated with ALS/FTD. Multi-omics approach, longitudinal twins follow up and sampling will help to understand which factors, and how and when, drive disease onset, heterogeneity and progression. Thanks to advancements in omics sciences, we could define different patients' biological profiles to be targeted by personalized treatments.