👤 Gill Farrar

Dementia with Lewy Bodies (DLB) is a neurodegenerative disorder characterised by α-synuclein pathology, causing cognitive decline, motor and non-motor symptoms. This review explores the clinical and neuropathological heterogeneity of DLB, which complicates its early diagnosis, prognosis, and treatment. The staging of Lewy body (LB) pathology varies, with both brain-first and body-first hypotheses suggesting different origins and pathways for disease progression. Co-pathologies, such as amyloid-β plaques, tau tangles, and cerebrovascular changes, further influence the clinical presentation and rate of disease progression in DLB patients, contributing to significant variability. In this review, the role of genetic factors, particularly APOE ε4 and GBA mutations, in shaping DLB's clinical and pathological diversity is also emphasized. Heterogeneous manifestations, including REM sleep behavior disorder (RBD), mild cognitive impairment, and psychiatric-onset DLB, highlight the need for improved biomarkers to guide early diagnosis. Neuroimaging techniques such as [ Overall, the paper explores the complexity of DLB's heterogeneous nature, advocating for deeper exploration of its diverse pathological pathways, genetic predispositions, and clinical profiles to improve diagnosis and treatment outcomes. Understanding this heterogeneity is crucial for the development of personalized therapeutic strategies and effective management of the disease. Show less

MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions: 104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: (2 each of DDX3X and TEC), with 6 partners (DDX3Y, CEP164, SCN2B, TREH, NAP1L1, and XPO1) observed in single patients. Patients with MLLT10 (n = 127) demonstrated adverse outcomes, with 5-year event-free survival (EFS) of 18.6% vs 49% in patients without MLLT10 (n = 1953, P < .001), inferior 5-year overall survival (OS) of 38.2% vs 65.7% (P ≤ .001), and a higher relapse risk of 76% vs 38.6% (P < .001). Patients with KMT2A::MLLT10 had an EFS from study entry of 19.5% vs 12.7% (P = .628), and an OS from study entry of 40.4% vs 27.6% (P = .361) in those with other MLLT10 fusion partners. Patients with PICALM::MLLT10 had an EFS of 9.2% vs 20% in other MLLT10- without PICALM (X::MLLT10; P = .788). Patients with PICALM::MLLT10 and X::MLLT10 fusions exhibit a DNA hypermethylation signature resembling NUP98::NSD1 fusions, whereas patients with KMT2A::MLLT10 bear aberrations primarily affecting distal regulatory elements. Regardless of the fusion partner, patients with AML harboring MLLT10 fusions exhibit very high-risk features and should be prioritized for alternative therapeutic interventions. Show less