Biology subjects

Read, F. L.

Publications and source records attributed to Read, F. L..

3 recordsLinked to original sources

bioRxiv2025

Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer's Disease and Amyotrophic Lateral Sclerosis

BackgroundTDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated the burden of brain TDP-43 pathology across ageing, Alzheimers disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology. MethodsPathological TDP-43 was detected using an HDGFL2 cryptic exon in situ hybridisation probe and a TDP-43 RNA aptamer, providing greater sensitivity and specificity than antibody-based approaches. Amygdala, hippocampus, and frontal cortex tissue was analysed from non-neurological controls (ages 40-80), AD cases, and ALS cases. Ferritin (as a proxy for iron accumulation) was quantified in parallel to assess its association with TDP-43 pathology. FindingsTDP-43 pathology was detectable from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after age 60 years. In AD, pathology was present in 90% of cases and distinguished from ageing by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Regional ferritin strongly predicted TDP-43 burden: amygdala ferritin explained 87% of TDP-43 variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin explained between 43-81% of regional TDP-43 variance. InterpretationTDP-43 brain pathology emerges in midlife with increased involvement after age 60 years, exhibits disease-specific regional signatures in AD and ALS, and is closely linked to ferritin accumulation. As TDP-43 confers a worse prognosis in AD, the capacity of ferritin, detectable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its promise as a biomarker for disease stratification and prognosis. Short AbstractHere we show that pathological TDP-43 emerges during normal ageing from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after 60 years. In Alzheimers disease (AD), TDP-43 pathology was present in 90% of cases and distinguished from ageing by disproportionate amygdala involvement, while in amyotrophic lateral sclerosis (ALS) it was nearly ubiquitous across hippocampus, amygdala, and frontal cortex. Using sensitive detection tools, we demonstrate that region-specific ferritin strongly predicts TDP-43 burden: amygdala ferritin explained 87% of variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin levels in all three regions explained 43-81% of TDP-43 variance. As TDP-43 pathology confers a worse prognosis in AD, the ability of ferritin, quantifiable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its potential as a biomarker for disease stratification and prognostic assessment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/680028v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@9c54b3org.highwire.dtl.DTLVardef@17cb415org.highwire.dtl.DTLVardef@12dabeorg.highwire.dtl.DTLVardef@1d72f95_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITDP-43 brain pathology occurs in normal ageing from early in the fourth decade, characterised by a 4.5-fold increase in hippocampus pathology from the sixth decade. C_LIO_LITDP-43 brain pathology is detectable in 90% of AD cases, with a disease-signature of increased amygdala pathology relative to age-matched controls. C_LIO_LIIn ALS, TDP-43 is nearly ubiquitous in amygdala, hippocampus and frontal cortex. C_LIO_LIHippocampus high brain ferritin distinguishes AD from and age-matched controls C_LIO_LIBrain ferritin is a brain region-specific marker of TDP-43 pathology in ageing and disease, with amygdala ferritin explaining 87% of the variance in amygdala TDP-43 pathology in ALS, and 66% of amygdala TDP-43 pathology in AD C_LIO_LIIn AD, ferritin levels for all three brain regions explain between 43-81% of variance in their TDP-43 pathology levels C_LI

neuroscience↗

bioRxiv2025

Improved detection of pre-symptomatic, non-central nervous system TDP-43 pathology in amyotrophic lateral sclerosis using RNA aptamer

The recognition that disease-associated proteinopathies can manifest in peripheral organs outside the central nervous system preceding the onset of neurological symptoms, has transformed our understanding of Parkinsons disease, in wide terms of pathogenesis, detection and diagnosis. For amyotrophic lateral sclerosis, non-motor symptoms, and non-central nervous system pathologies are gaining increased recognition but remain incompletely understood. Here, using a TDP-43 RNA aptamer and a Stathmin-2 cryptic exon transcript BaseScopeTM ISH probe, we identify widespread peripheral organ TDP-43 pathology prior to motor symptom onset in a discovery cohort of ante-mortem tissues from people who went on to develop ALS. Peripheral organs exhibiting both TDP-43 toxic gain- and loss-of function include muscle, lymph node, gallbladder, colon and with notably high incidence, skin. Given the accessibility of skin as a readily biopsiable tissue, representing a promising substrate for the detection of disease-associated proteinopathies and the development of minimally invasive biomarkers, we established an extended cohort of ante-mortem skin samples for TDP-43 pathology validation and further investigation. In skin biopsies taken during life from 17 individuals who went on to develop ALS we identify TDP-43 pathology from all 17 individuals in a wide distribution of anatomical sites, up to 26.5 years before ALS diagnosis - a presymptomatic period comparable to that observed for skin -synucleinopathy in Parkinsons disease. TDP-43 pathology was most abundant in skin biopsies from the back and shoulder, with sweat and sebaceous glands showing the highest involvement. TDP-43 pathology was also associated with structural changes. As skin -synucleinopathy has been established as a biomarker for both the detection of Parkinsons disease and the differentiation of Parkinsons disease from multiple system atrophy, we propose that skin TDP-43 likewise holds diagnostic and discrimination potential for diseases characterised by TDP-43 proteinopathy. Short AbstractPeripheral manifestations of neurodegenerative disease can precede neurological symptoms and serve as biomarkers, as shown by -synuclein in the skin of individuals who later develop Parkinsons disease. In amyotrophic lateral sclerosis (ALS), however, the distribution and diagnostic potential of peripheral TDP-43 pathology remain unclear. Using a TDP-43 RNA aptamer and a cryptic STMN2 BaseScope probe, we examined ante-mortem tissues from individuals who later developed ALS. In a discovery cohort, we detected widespread pre-symptomatic TDP-43 pathology across multiple organs, with skin emerging as the most consistent site. We then validated these findings in a validation cohort comprising 17 individuals, all of whom exhibited TDP-43 pathology enriched in sweat glands and structural changes detectable up to 26.5 years before ALS diagnosis. These findings establish skin as a robust and accessible site of pre-symptomatic TDP-43 pathology, supporting its potential as a minimally invasive biomarker for early diagnosis and disease stratification in ALS. SummaryMuch like skin -synucleinopathy has transformed biomarker development in Parkinsons disease, this study identifies skin TDP-43 pathology as a promising early marker of ALS. The results open avenues for earlier diagnosis and stratification in a disease where intervention is most needed before symptoms appear. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/648122v2_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@14cc6c0org.highwire.dtl.DTLVardef@18c69f7org.highwire.dtl.DTLVardef@1811265org.highwire.dtl.DTLVardef@dea8bc_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPresymptomatic TDP-43 pathology occurs across a range on non-CNS peripheral organ systems including skin, gastrointestinal tract and lymph nodes prior to motor symptom onset in people who went on to develop ALS. C_LIO_LIIn skin, presymptomatic TDP-43 pathology is associated with structural changes and can be detected up to 26.5 years prior to motor symptoms in ALS. C_LIO_LIAs for Parkinsons disease, shoulder and back represents optimal skin sampling sites for pre-symptomatic pathology in ALS. C_LIO_LISweat and sebaceous glands present with high levels of TDP-43 pathology, offering a promising biomarker target for early pathology detection. C_LI One Sentence SummaryUsing distinct biomarker discovery and validation ante-mortem tissue cohorts, we provide evidence of pre-symptomatic TDP-43 pathology across diverse non-CNS peripheral tissues, including skin decades before ALS symptom onset, highlighting skin TDP-43 pathology as a potential early biomarker for ALS and related TDP-43 proteinopathies

pathology↗

bioRxiv2024

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

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 examine post-mortem tissue 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-43APT pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43APT staining 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-43APT pathology, representing a potential region-specific imaging biomarker of early disease in ALS. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSThe 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.

neuroscience↗