Citations

Abstract Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

Abstract Different MRI image contrasts are designed to highlight various tissue properties and combining them allows extension of probabilistic segmentation beyond the commonly used “gray-white-CSF” models. This work describes a fully automated method that combines T1-weighted, T2-FLAIR, and conventional T2-weighted images to provide internal consistency across prediction of tissue segmentations including segmentation of superficial and deep gray matter, white matter hyperintensities, and MR-visible perivascular spaces. Results from 773 imaging datasets from 403 participants in the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center (ADRC) are presented.

Abstract INTRODUCTION We examined when Alzheimer's disease biomarkers become informative by identifying age‐related breakpoints with slope‐changing trajectories. METHODS In 2082 Mayo Clinic Study of Aging participants, we modeled plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid/tau positron emission tomography (PET), hippocampal volume (HVa), and global cognition. Generalized additive models described age trends; Davies' test and piecewise linear regression estimated breakpoints. A C2N subsample ( n = 462) provided mass‐spectrometry plasma markers (p‐tau181, p‐tau217, their ratios, Aβ42/40). RESULTS In the full cohort, Aβ42/40, HVa, and cognition declined with age; p‐tau181, NfL, GFAP, and amyloid/tau PET increased. We observed single breakpoints (years, 95% CI): GFAP 68.1 (63.5–71.8), NfL 70.7 (65.9–75.6), p‐tau181 67.2 (60.3–70.3), amyloid PET 62.3 (56.2–69.3), HVa 68.1 (63.1–71.9), cognition 59.8 (55.4–66.0); tau PET showed none. In the mass‐spectrometry subset, p‐tau217 and p‐tau181 broke at 72.6; their ratios and Aβ42/40 showed no breakpoints. DISCUSSION Breakpoints cluster near late midlife, suggesting windows for screening and monitoring.

ABSTRACT Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by antibody‐mediated platelet destruction, often driven by long‐lived plasma cells (LLPCs) resistant to conventional therapies. While most patients respond to corticosteroids and intravenous immunoglobulin (IVIG), a subset develops life‐threatening refractory disease. In this case series, we describe three patients aged 39, 85, and 58 with life‐threatening, multi‐agent refractory ITP and platelet nadirs < 2 × 10 9 /L who failed corticosteroids, IVIG, and thrombopoietin receptor agonists (TPO‐RAs). Following salvage therapy with daratumumab, a monoclonal antibody targeting CD38, all three patients achieved rapid hematologic recovery, with platelet count normalization within 1 week. This accelerated response allowed for urgent clinical stabilization, including safe anticoagulation and surgical intervention. The efficacy of daratumumab likely stems from a dual mechanism: the depletion of CD38+ LLPCs and the immediate modulation of Fc‐receptor‐mediated platelet clearance. These observations suggest that CD38‐targeted therapy can bypass traditional treatment resistance to achieve near‐immediate remission in high‐complexity, high‐risk clinical settings. While these results are compelling, prospective clinical trials are warranted to define the long‐term safety, durability, and optimal dosing of anti‐CD38 therapies in refractory ITP populations.

ABSTRACT BACKGROUND Increasing evidence suggests that accurate prediction of Alzheimer’s disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) Aβ42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING National Institute on Aging, Alzheimer’s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.

Abstract Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated &gt;40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

Abstract INTRODUCTION Visual perceptual difficulties occur in dementia with Lewy bodies (DLB). Normative data and cut scores for DLB and mild cognitive impairment with Lewy bodies (MCI‐LB) are needed for the 20‐item Noise Pareidolia Task. METHODS Participants included 344 cognitively unimpaired (CU), 112 DLB, and 105 MCI‐LB. Cumulative percentile ranking was used for normative classification. Receiver operating characteristic analyses, convergent validity, and associations with visual hallucinations (VH) were assessed. RESULTS In CU participants, a perfect score was average, one error was low average, and two or more errors fell below average. A cut score of one or more errors optimally distinguished CU participants from DLB (Total score area under the curve [AUC]: 0.82, Noise score AUC: 0.77) and MCI‐LB (Total score AUC: 0.75, Noise score AUC: 0.74). A cut score of two or more errors lowered sensitivity but increased specificity to 94%. Performance was associated with VH in DLB, but not MCI‐LB. DISCUSSION Results establish normative data for the 20‐item Noise Pareidolia Task and support its use in DLB and MCI‐LB.

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.