👤 R N Lippert

White matter hyperintensities (WMH) on T2-weighted brain magnetic resonance imaging (MRI) are common in aging and associated with small vessel cerebrovascular disease. Standard segmentation methods treat these lesions as uniform binary entities, fundamentally reducing WMH signal by flattening a complex spectrum of tissue damage into a single label. Most WMH methods threshold voxel intensities to estimate lesion volume, missing richer characterization achievable by combining fluid-attenuated inversion recovery (FLAIR) with diffusion MRI. We introduce Voxel-wise Correlation of Neighbors (VCON), a cross-modal framework that quantifies voxel-level relationships between intensity values on T2-weighted FLAIR scans and fractional anisotropy (FA) on diffusion MRI within individuals. VCON generates hypothesis-driven WMH labels by identifying regions where increased FLAIR signal is negatively correlated with FA, suggesting underlying microstructural damage. Using MRI data from over 2,500 participants in community-based aging cohorts, we validated VCON through multi-scale analysis, age-association modeling, scanner comparisons, and intensity-based clustering of WMH into spatially coherent zones with distinct microstructural profiles. VCON revealed a gradient of WMH signal variation that tracks with age and diffusion metrics across scanners and segmentation methods. These results demonstrate that binary WMH masks may obscure clinically important variation in lesion characteristics. VCON reframes lesion segmentation as characterizing microstructural heterogeneity, offering additional structure-informed characterization beyond conventional binary methods by leveraging multimodal MRI signal variation. Show less

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM₀₀₁₀₀₉₉₉₉.3:c.136G > A:p.G46S, and likely pathogenic NM₀₀₁₀₀₉₉₉₉.3:exon6:c.865₈₆₆del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A. Show less

In adult organisms, a number of receptors have been identified which modulate metabolic processes related to peptides derived from the intestinal tract. These receptors play significant roles in glucose homeostasis, food intake and energy balance. Here we assess these classical metabolic receptors and their expression as well as their potential role in early development of hypothalamic neuronal circuits. Chow-fed C57BL6/N female mice were mated and hypothalamic tissue was collected from offspring across postnatal development (postnatal day 7-21). Subsequent qPCR and Western Blot analyses were used to determine mRNA and protein changes in gut-derived peptide hormone receptors. Correlations to body weight, blood glucose and circulating leptin levels were analyzed. We describe the gene expression and dynamic protein regulation of key gut-derived peptide hormone receptors in the early postnatal period of the mouse brain. Specifically, we show changes to Gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide 1 receptor (GLP1R), and cholecystokinin receptor 2 (CCK2R) in the developing hypothalamus. The changes to GIPR and InsR seem to be strongly negatively correlated with body weight. This comprehensive analysis underscores the need to understand the roles of maternal-derived circulating gut hormones and their direct effect on offspring brain development. Show less

The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well-characterized melanocortin-4 receptor (MC4R), little is known regarding the organization of MC3R-expressing neural circuits. To increase our understanding of the intrinsic organization of MC3R neural circuits, identify specific differences between males and females, and gain a neural systems level perspective of this circuitry, we conducted a brain-wide mapping of neurons labeled for MC3R and characterized the distribution of their projections. Analysis revealed MC3R neuronal and terminal labeling in multiple brain regions that control a diverse range of physiological functions and behavioral processes. Notably, dense labeling was observed in the hypothalamus, as well as areas that share considerable connections with the hypothalamus, including the cortex, amygdala, thalamus, and brainstem. Additionally, MC3R neuronal labeling was sexually dimorphic in several areas, including the anteroventral periventricular area, arcuate nucleus, principal nucleus of the bed nucleus of the stria terminalis, and ventral premammillary region. Altogether, anatomical evidence reported here suggests that MC3R has the potential to influence several different classes of motivated behavior that are essential for survival, including ingestive, reproductive, defensive, and arousal behaviors, and is likely to modulate these behaviors differently in males and females. Show less

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ( We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funded by Roche Sequencing Solutions, Inc. Show less

Like most homeostatic systems, adiposity in mammals is defended between upper and lower boundary conditions. While leptin and melanocortin-4 receptor (MC4R) signaling are required for defending energy set point, mechanisms controlling upper and lower homeostatic boundaries are less well understood. In contrast to the MC4R, deletion of the MC3R does not produce measurable hyperphagia or hypometabolism under normal conditions. However, we demonstrate that MC3R is required bidirectionally for controlling responses to external homeostatic challenges, such as caloric restriction or calorie-rich diet. MC3R is also required for regulated excursion from set point, or rheostasis, during pregnancy. Further, we demonstrate a molecular mechanism: MC3R provides regulatory inputs to melanocortin signaling, acting presynaptically on agouti-related protein neurons to regulate γ-aminobutyric acid release onto anorexigenic MC4R neurons, exerting boundary control on the activity of MC4R neurons. Thus, the MC3R is a critical regulator of boundary controls on melanocortin signaling, providing rheostatic control on energy storage. Show less

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements. Show less

The PICALM-MLLT10 fusion gene, generated by the t(10;11)(p12-13;q14-21) translocation, is a rare but recurrent event in acute leukemias. In this study, we assessed the characteristics and outcome of 18 PICALM-MLLT10 AML patients. As compared with non PICALM-MLLT10 patients (n=72), PICALM-MLLT10 AML were characterized by more frequent extramedullary diseases, CD7 expression and higher platelet counts. Three out of four therapy-related PICALM-MLLT10 AMLs had been previously treated for diffuse large B-cell lymphoma. The complete response rate was 71% after intensive chemotherapy. PICALM-MLLT10 patients had a shorter median overall survival than patients with favorable cytogenetics (12 months vs. not reached, p=0.07) but not significantly different from those of intermediate (26 months, p=0.32) or unfavorable cytogenetic groups (8 months, p=0.13). Long term responses were achieved in a subset of patients after allogeneic stem-cell transplantation but also after high-dose cytarabine. Show less