“IT TAKES AWAY WHAT MADE A PERSON THAT PERSON”: RECONSTRUCTING IDENTITY IN RESPONSE TO GENETIC RISK OF BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA

There is limited research considering the personal experiences of individuals living with or at risk for developing behavioral variant frontotemporal dementia (bvFTD). FTD is known to have a significant genetic contribution. With advances in understanding the genetic component of FTD, rates of predictive and symptomatic genetic testing will increase. Though FTD is the second most prevalent cause of early-onset dementia after Alzheimer disease (AD), there is substantially more literature related to AD experiences. In dementia research broadly, care partners rather than persons diagnosed tend to be the informants. The data presented in this paper are derived from an exploratory project called Voices of Individuals: Challenges and Experiences of Behavioral Variant Frontotemporal Dementia (VOICE Of bvFTD) that qualitatively explores the specific experience of living with bvFTD diagnosis and risk from the perspective of the persons diagnosed and at-risk. Semi-structured telephone interviews were conducted to qualitatively explore how bvFTD may influence an individual’s sense of identity, individuals’ experiences of loss, how individuals cope and adapt to the challenges they face, and other factors that might be perceived to influence these processes. Participants with a diagnosis of bvFTD (n=6) and with genetic testing results conferring high risk of developing bvFTD (n=14) were recruited through two academic medical centers, the National Institutes of Health, ClinicalTrials.gov, and through FTD support resources. Interviews were transcribed and underwent thematic analysis. This paper considers how identity was shaped by the threat of developing FTD among the at-risk subset of VOICE Of bvFTD participants (n=14). Participants varied in their conceptualizations of their status, how they integrated FTD risk information into their current identity, and how they anticipated changes to their identity in the future. FTD risk raised fundamental issues related to what constitutes the essence of a person, challenged people to wrestle with Cartesian dualism, and exposed the roles of time, social relationships, and social roles in the understanding of the nature of self. Understanding how at-risk individuals reconstruct their identities in response to their FTD risk status can inform clinical care, resource development, and future research

The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs

Isoform-specific patterns of tau burden and neuronal degeneration in MAPT-associated frontotemporal lobar degeneration

Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0-4) and separate burden of glial and neuronal tau inclusions (i.e. 0-3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that FTLD-MAPT isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct isoform-related mechanisms of genetic tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers