In vivo tracking of TDP43 in ALS: cognition as a new biomarker for brain pathology

Lulé, Dorothée; Ludolph, Albert C.

doi:10.1136/jnnp-2019-321940

Cited by 6 publications

(6 citation statements)

References 6 publications

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“…(10) Can we confirm suggestions for the staging of FTLD, both neuropathologically and clinically?. 36,37 FRONTIERS will be equipped to address these questions, as the study is population based, and all the new cases in a defined period of time and in a defined geographical area will be collected for comprehensive analysis of demographics, phenotypes, and outcomes across different geographic regions. 25 FRONTIERS will allow us to determine the distribution of clinical phenotypes and genotypes, as well as the relative weight of each in each country in Europe.…”

Section: Expected Results and Impactmentioning

confidence: 99%

See 1 more Smart Citation

FRONTotemporal dementia Incidence European Research Study—FRONTIERS: Rationale and design

Borroni

Graff

Hardiman

et al. 2021

Alzheimer's & Dementia

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Introduction The incidence of Frontotemporal Lobar Degeneration (FTLD)–related disorders and their characteristics are not well known. The “FRONTotemporal dementia Incidence European Research Study” (FRONTIERS) is designed to fill this gap. Methods FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long‐lasting experience in FTLD‐related disorders and comprehensive regional referral networks, enabling incidence estimation over well‐defined geographical areas. Endpoints The primary endpoints are (1) the incidence of FTLD‐related disorders across Europe; (2) geographic trends of FTLD‐related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD‐related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. Expected impacts FRONTIERS will improve the understanding of FTLD‐related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies.

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Section: Expected Results and Impactmentioning

confidence: 99%

“…(10) Can we confirm suggestions for the staging of FTLD, both neuropathologically and clinically?. 36 , 37 …”

Section: Expected Results and Impactmentioning

confidence: 99%

FRONTotemporal dementia Incidence European Research Study—FRONTIERS: Rationale and design

Borroni

Graff

Hardiman

et al. 2021

Alzheimer's & Dementia

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“…Further intra-regional pathophysiological variation is also suggested by the atrophy of specific amygdala nuclei on imaging (26). Indeed, other ECAS domains are highly predictive of brain region abnormalities on imaging (27,28).…”

Section: Discussionmentioning

confidence: 97%

Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis

Rifai,

Waldron,

O’Shaughnessy

et al. 2024

Preprint

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BackgroundCognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALSFTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43.MethodsHere we examinepost-mortemtissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS).ResultsOverall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell type predominance, and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43APT), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron.ConclusionsIntra-neuronal pTDP-43 and cytoplasmic TDP-43APTpathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43APTstaining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43APTpathology, representing a potential region-specific imaging biomarker of early disease in ALS.Key MessagesWhat is already known on this topicThe amygdala is a key brain region in regulating behavior and emotional cognition and has been shown recently, through imaging studies, to be affected in ALS and FTD patients.What this study addsHere we examine the underlying pathology driving the association between the amygdala and behavioural symptoms in sporadic ALS demonstrating that region specific TDP-43 pathology and brain iron accumulation could represent potential early biomarkers of dysfunction.How this study might affect research, practice, or policyThe correlation between early TDP-43 pathology (detected by RNA aptamer) and increased ferritin (brain iron accumulation) occurring upstream of clinical manifestation represents a potential, region-specific (amygdala), early imaging biomarker in ALS. This means that people at risk could be identified early and stratified for clinical trials prior to substantial neuronal cell loss and symptom onset.

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“…As ALS is increasingly recognized as a metabolic disorder (42) (65), metabolic dysfunction (42), memory deficits (59,74). Imaging in ALS has also been instrumental to link disability profiles to pathological TDP-43 burden patterns (36,53,(75)(76)(77)(78) (88), and quantitative Magnetization Transfer Imaging (qMTi) and data analysis approaches such as Event-Based Modeling (EBM). A shared aspiration of both "wet" and "dry" biomarker studies is the transition from describing group-level observations to the precision categorization and tracking of individual patients (53,76,83,84,(89)(90)(91).…”

Section: Wet Biomarkersmentioning

confidence: 99%

Editorial: Biomarkers and Clinical Indicators in Motor Neuron Disease

Bede

2019

Front. Neurol.

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In vivo tracking of TDP43 in ALS: cognition as a new biomarker for brain pathology

Cited by 6 publications

References 6 publications

FRONTotemporal dementia Incidence European Research Study—FRONTIERS: Rationale and design

FRONTotemporal dementia Incidence European Research Study—FRONTIERS: Rationale and design

Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis

Editorial: Biomarkers and Clinical Indicators in Motor Neuron Disease

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