Song, Yuping

Abstract TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer’s disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.

Objective Immunohistochemically (IHC) measured transactive response DNA‐binding protein 43 (TDP‐43) inclusions are observed in Alzheimer's disease (AD) and are associated with medial temporal lobe atrophy. Accumulation of cryptic exons occurs in AD in response to TDP‐43 pathology. We aimed to assess relationships between IHC and biochemically measured insoluble TDP‐43 and cryptic exons and assess associations with hippocampal and amygdala volume loss and atrophy rates on magnetic resonance imaging (MRI). Methods Eighty‐one neuropathologically diagnosed AD cases were analyzed. For biochemistry, insoluble TDP‐43 was quantified using a Meso‐scale discovery (MSD) immunoassay. IHC‐TDP burden was quantified with digital histopathology. Cryptic RNAs were assessed via quantitative real‐time polymerase chain reaction (qRT‐PCR). Thirty‐eight cases had serial brain MRI. Hippocampal and amygdala volumes were calculated using FreeSurfer. Regression models were used to investigate associations among IHC‐TDP‐43 status/burden, MSD‐TDP status/levels, cryptic RNAs, and hippocampal and amygdala volumes and atrophy rates. Results IHC‐TDP(+) cases exhibited elevated levels of MSD‐TDP and cryptic RNAs ( KCNQ2 , STMN2 , and UNC13A ) and increased MSD‐TDP levels were associated with increased cryptic RNA levels, in the hippocampus and amygdala. IHC‐TDP(+) cases had smaller hippocampal and amygdala volumes compared to IHC‐TDP(−) cases. MSD‐TDP(+) cases had smaller hippocampal volumes and faster amygdala rates of atrophy compared with MSD‐TDP(−) cases. Higher KCNQ2 and UNC13A levels were associated with smaller amygdala volumes. Interpretation MSD‐TDP level is a reliable surrogate for IHC‐based TDP‐43 status. Both TDP‐43 and cryptic RNA levels are associated with reduced medial temporal volumes, suggesting cryptic exons may be playing a role in brain volume loss in AD. ANN NEUROL 2026;100:193–205

ABSTRACT Objective This study aims to identify both fluid and neuroimaging biomarkers for CSF1R‐RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression. Methods Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers ( N = 14), symptomatic CSF1R pathogenic variant carriers ( N = 17), and healthy controls ( N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1‐weighted MPRAGE scans, providing a highly valuable physiological component to our analyses. Results Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early‐stage CSF1R‐RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms. Interpretation Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R‐RD.

Spinocerebellar ataxia type 7 (SCA7), a rare form of ataxia, possesses a wide phenotypic spectrum ranging from classic ataxic symptoms to blindness, multiorgan failure, cardiomyopathy, and early death among younger age groups. Biomarkers associated with disease progression and severity could aid in disease prognostication. We evaluated the utility of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in distinguishing patients with SCA7 from healthy controls and estimating patient prognosis. GFAP and NfL levels were measured in 23 plasma and 20 cerebrospinal fluid (CSF) samples from asymptomatic (N = 3) and symptomatic SCA7 participants (N = 10) and from healthy controls (N = 8). GFAP concentrations were elevated in the plasma (82.7 pg/mL) and CSF (9318 pg/mL) of patients with SCA7 compared to controls (plasma: 48.0 pg/mL; CSF: 89,056 pg/mL). Similarly, NfL plasma (21.6 pg/mL) and CSF (2615.0 pg/mL) levels were also significantly upregulated in SCA7 compared to controls (plasma: 8.2 pg/mL; CSF: 414.6 pg/mL). Higher levels of NfL, but not of GFAP, significantly discriminated symptomatic SCA7 patients from controls (area under de curve, AUC: 0.898, p = 0.0059, in plasma, and AUC: 1.0, p = 0.0012, in CSF). The levels of both biomarkers increased overtime, with plasma NfL levels strongly associated with a worse score in the scale for the assessment and rating of ataxia (SARA) (Spearman r: 0.8354, p = 0.0007; regression analysis: β: 0.021, 95% CI: 0.008–0.035, p = 0.0048). These findings suggest that NfL could serve as a valuable biomarker for monitoring disease progression and prognosis in SCA7 patients.

Abstract Background Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin ( DCTN1 ). PS brains accumulate inclusions positive for ubiquitin, transactive‐response DNA‐binding protein of 43 kDa (TDP‐43), and to a lesser extent dynactin. Objectives Little is known regarding the contributions of TDP‐43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP‐43 dysfunction in two regions of PS brains. Methods We evaluated the levels of insoluble pTDP‐43 and TDP‐43‐regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology, and 11 cognitively healthy controls without TDP‐43 pathology. Results Insoluble pTDP‐43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP‐43‐regulated cryptic RNAs ( ACTL6B , CAMK2B , STMN2 , UNC13A , KCNQ2 , ATG4B , GPSM2 , and HDGFL2 ) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A , reached significance in the substantia nigra despite similar pTDP‐43 levels. Conclusion We detected TDP‐43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP‐43 dysfunction across different brain regions and determine the targets that are specific and common to TDP‐43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.

Abstract Numerous reports have suggested that infectious agents could play a role in neurodegenerative diseases, but specific etiological agents have not been convincingly demonstrated. To search for candidate agents in an unbiased fashion, we have developed a bioinformatic pipeline that identifies microbial sequences in mammalian RNA-seq data, including sequences with no significant nucleotide similarity hits in GenBank. Effectiveness of the pipeline was tested using publicly available RNA-seq data and in a reconstruction experiment using synthetic data. We then applied this pipeline to a novel RNA-seq dataset generated from a cohort of 120 samples from amyotrophic lateral sclerosis patients and controls, and identified sequences corresponding to known bacteria and viruses, as well as novel virus-like sequences. The presence of these novel virus-like sequences, which were identified in subsets of both patients and controls, were confirmed by quantitative RT-PCR. We believe this pipeline will be a useful tool for the identification of potential etiological agents in the many RNA-seq datasets currently being generated.

PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele may serve to specifically target mutant ATXN3 .

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606