👤 Kaitlin Driscoll

To determine whether long-term residential air pollution [AP; ozone (O₃) and fine particulate matter (PM₂.₅)] is associated with (1) incident mild cognitive impairment (MCI) or Alzheimer’s disease (AD), (2) biomarkers of core and AD-relevant pathology, and (3) whether these relationships are moderated by APOE4+/- (carrier/non-carrier of one or both ε4 alleles) status or mediated by neuroinflammation. Sample included 795 participants (Mage 68.7 ± 7.9; 68% female) from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention parent studies, both enriched for AD risk at enrollment based on parental AD history. Residential zip code and 2009–2021 EPA-based annual AP reports were used to estimate individual exposure. Cox proportional hazards models assessed MCI/AD risk. Linear regressions examined the relationships between AP exposure and biomarkers of core and AD-relevant pathology, with and without APOE4 + stratification. Causal mediation analysis examined whether markers of inflammation mediated the AP-AD pathology relationships. Neither O₃ nor PM₂.₅ exposure predicted MCI/AD incidence nor core AD pathology (Ps > 0.05). Higher PM₂.₅ was associated with higher CSF GFAP levels ( Show less

Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes. Show less

Attention-deficit-hyperactivity disorder (ADHD) is highly heritable and increases the likelihood of nicotine dependence (ND). The self-medication hypothesis of nicotine use in ADHD proposes that ADHD patients seek nicotine for its ability to improve their symptoms, and they have less success quitting, possibly due to the worsening of ADHD symptoms in withdrawal. The present analysis compared transcriptomic data from the brains of rodent models of ADHD and those of ND, with a focus on striatal gene expression. Differential expression analysis, pathway enrichment analysis, and gene-network mapping identified signaling networks and candidate genes that may contribute to the high co-occurrence between ADHD and ND. We identified novel differentially expressed genes (PRKAG2, MAPK1), and genes with known associations to either ADHD or ND (ANK3, CALD1, CHRNA4, CHRNA7, CMTM8, DLG4, DUSP6, GNG3, GNG11, GRIK5, GRINA2, GRM5, ICAM2, KCNJ6, PRKAB1, SNAP25, SYNPO, SYT1, VAMP2). In addition, synaptic transmission (hsa04728, R-HAS-112315, R-HSA-442755) and MAPK signaling pathways (hsa04010, hsa04014, hsa04015, R-HSA-5673001, R-HSA-5684996) were enriched in both ADHD and ND. The signaling pathways implicated by this analysis mediate neurological mechanisms known to contribute to ND. The association of analogous differently expressed genes and common signaling pathways suggests an important causal relationship between ND and ADHD that may be clinically important. Show less

The aim of this study was to review bariatric procedure outcomes among patients with Prader-Willi syndrome (PWS), melanocortin 4 receptor (MC4R) mutations, Bardet-Biedl syndrome, and hypothalamic obesity. Systematic published literature review used the following search terms: "Prader-Willi syndrome," "Bardet-Biedl syndrome," "hyperphagia," "bariatric surgery," "MC4R"/"melanocortin 4 receptor", "hypothalamic obesity," and "bariatric procedure." Information collected included demographics, genetics, anthropometry, procedure type, outcomes, and complications, with inclusion of case series and clinical reports given the rarity of the disorders. For PWS, postoperative weight-change percentage and BMI up to 14 years following surgery were analyzed using general linear mixed models, with descriptive outcomes for other conditions. A total of 54 publications were identified, with variable follow-up periods for 202 patients (114 with PWS, 43 with MC4R mutations, 7 with Bardet-Biedl syndrome, and 38 with hypothalamic obesity) among bariatric procedures. Weight loss of patients with PWS was greatest within 1 year of surgery, with weight-change percentage not significantly different from 0 at 5 years. Long-term results in other conditions were variable and featured suboptimal weight loss and increased reoperation risk. Bariatric procedures among hyperphagic individuals, including those with PWS, report variable results and outcomes. Benefits of bariatric surgery may be less durable in hyperphagic disorders in comparison with other patients with severe obesity. Show less

Bardet-Biedl syndrome (BBS) and autosomal dominant polycystic kidney disease (ADPKD) are two genetically distinct ciliopathies but share common phenotypes such as renal cysts. Seven BBS proteins form a complex called the BBSome which is localized at the basal body or ciliary axoneme and regulates the ciliary entry or flagellar exit of several signaling molecules. Here, we demonstrate that, unlike the seven-span somatostatin receptor 3 or the leptin receptor that interacts with all subunits of the BBSome, the ADPKD protein polycystin-1 (PC1) interacts with BBS1, BBS4, BBS5 and BBS8, four of the seven components of the BBSome. Only depletion or mutation of BBS1, but not depletion of BBS5 and BBS8, or knockout of BBS4, impairs ciliary trafficking of PC1 in kidney epithelial cells. Depletion of these BBS proteins affects neither the ciliary length nor the plasma membrane targeting of PC1. Expression of a pathogenic BBS3/Arl6 mutant (T31R) that locks Arl6 in the GDP form leads to stunted cilia and inhibition of PC1 on primary cilia. We propose that the 11-span membrane protein PC1 is a BBSome cargo and that the components of the BBSome may possess subunit-specific functions. Moreover, physical interactions between the BBS and ADPKD proteins may underline the overlapping renal phenotypes in these two diseases. Show less