Faculty Bibliography

BACKGROUND:Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here we present testing results from a large cohort with suspected MSD. METHODS:Subjects with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing (tMPS) panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. RESULTS:Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and 2 digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in 10 or more families were: AGXT, HOGA1, SLC34A3, CYP24A1, SLC3A1, and CLCN5. Compared to the unresolved group, MSD probands had a lower baseline and last visit estimated glomerular filtration rate (eGFR), earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those less than 16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, primary hyperoxaluria patients had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. CONCLUSIONS:Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of MSD patients were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.

Formaldehyde, a reactive aldehyde widely present in the environment and associated with occupational exposure, has been linked to cognitive impairment and Alzheimer's disease (AD) in multiple epidemiological and animal studies. However, its contribution to AD-like pathology in human neural models remains poorly understood. We utilized a 3D culture system of human neural progenitor cells (ReNcell VM) differentiated into neurons and glial cells to model chronic formaldehyde exposure. Additionally, we established a 3D human AD model by transducing ReN cells with APP and PSEN1 mutations to assess the effects of formaldehyde in an AD genetic background. Long-term formaldehyde exposure (up to 12 weeks) induced a dose-dependent increase in Aβ40, Aβ42, APP, and phosphorylated tau levels in both wild-type and AD-mutant 3D cultures. These changes mimic hallmark features of AD neuropathology, suggesting that formaldehyde acts as a pathological driver in both sporadic and familial contexts. Our study provides direct evidence that chronic formaldehyde exposure may initiate and accelerate amyloid and tau pathologies in 3D human neural cell models. These findings support growing concerns about formaldehyde as a modifiable risk factor in neurodegeneration.

Dopamine (DA) is essential for the production of vigorous actions, but how DA modifies the gain of motor commands remains unclear. Here we show that subsecond DA transients in the striatum of mice are neither required nor sufficient for specifying the vigor of ongoing forelimb movements. Our findings have important implications for our understanding of how DA contributes to motor control under physiological conditions and in Parkinson's disease.

BACKGROUND:Children born very preterm (VPT) are at high risk for attention problems. This study's purpose was to describe the Conners Kiddie Continuous Performance Test (K-CPT) assessment in children born VPT, including rates of clinically elevated scores, change over time, and associations between K-CPT scores and parent reported attention problems. METHODS:We studied 305 children from a multi-site study of children born VPT who completed at least one K-CPT assessment at age 5, 6, and/or 7 years. Parent-reported ADHD symptoms and diagnosis were also collected. We calculated K-CPT completion rates, mean scores, and rates of clinically elevated scores at each timepoint. Linear mixed models examined change over time in K-CPT scores. Correlations and generalized linear models investigated associations between K-CPT scores and ADHD symptoms and diagnoses. RESULTS:K-CPT scores showed expected age-related improvements from age 5-7, with significant intra- and inter-individual variability. Up to 1/3 of children had clinically elevated attention problems and another 1/3 had subclinical elevations. K-CPT scores were modestly correlated with parent-rated ADHD symptoms and children with a parent-reported ADHD diagnosis performed worse on nearly all K-CPT metrics. CONCLUSION/CONCLUSIONS:Performance-based measures like the K-CPT can be useful for research and clinical practice in VPT populations. IMPACT/CONCLUSIONS:Attention problems are a specific area of weakness for children born very preterm. Performance-based tests of attention have benefits and drawbacks compared to parent report measures yet are understudied in this population. We examined one performance-based measure (the Conners Kiddie Continuous Performance Test [K-CPT]) in 305 children born very preterm. We observed improving task scores from age 5-7 years with significant intra- and inter-individual variability, a sizable proportion of children with clinically and subclinically elevated scores, and modest associations between K-CPT scores and parent reported attention problems. The K-CPT could be a useful clinical and research tool in this population.

OBJECTIVE:To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms. METHODS:We conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms according to genetic exposure. RESULTS:By the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status. INTERPRETATION/CONCLUSIONS:Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.

Lewy body dementia is a heterogeneous disease that is underdiagnosed and poorly understood. Pathologically, Lewy body dementia is characterised by the accumulation of intraneuronal aggregates of misfolded α-synuclein, known as Lewy bodies and Lewy neurites. The genetic architecture of Lewy body dementia is complex, involving both common genetic variants with small risk effects and rare genetic variants with large effects. Alzheimer's disease pathology frequently coexists with Lewy body pathology and influences the clinical presentation. A deeper understanding of the pathophysiological pathways, including mitochondrial dysfunction, lysosomal dysfunction, and neuroinflammation, can enhance disease modelling, and this knowledge will ultimately facilitate the development of therapeutic interventions. The biological relationships that Lewy body dementia shares with other neurodegenerative and psychiatric disorders might also be crucial for the development of therapeutic strategies.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Only a minority of renal oncocytic tumors are aggressive. These tumors' behavior is difficult to predict by histopathological evaluation; consequently, many patients experience anxiety upon diagnosis and may undergo unnecessary treatment. Our aim was to derive genomic and epigenomic signatures to distinguish clinically indolent renal oncocytic tumors from aggressive chromophobe renal cell carcinoma (ChRCC). METHODS:We performed molecular profiling of nephrectomies from 68 patients: 44 with indolent renal oncocytic tumors (19 renal oncocytoma, two oncocytic renal neoplasm of low malignant potential, and 23 indolent ChRCC) and 24 with aggressive ChRCC. We performed targeted exome sequencing, gene expression profiling, and whole-genome methylation sequencing of formalin-fixed, paraffin-embedded (FFPE) samples. We also analyzed The Cancer Genome Atlas Kidney Chromophobe data from 66 ChRCC patients in silico. Genomic and epigenomic signatures linked to aggressive ChRCC-obtained from sampling morphologically nonsarcomatoid foci-from both cohorts were derived using the least absolute shrinkage and selection operator method. KEY FINDINGS AND LIMITATIONS/UNASSIGNED:Aggressive ChRCC was distinguished from indolent ChRCC and other indolent renal oncocytic tumors using a focused seven- to 11-gene expression signature (ten-fold cross-validation [CV] area under the curve [AUC] = 0.77-0.85) with an external validation AUC of 0.88, and an eight-CpG methylation signature (ten-fold CV AUC = 0.86) with an external validation AUC of 0.91. TP53 and PTEN mutations substantially increased the probability of aggressive ChRCC. Limitations include the small sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:Focused genomic and epigenomic signatures from routinely processed FFPE tumor tissues can help distinguish aggressive ChRCC from indolent renal oncocytic tumors, including indolent ChRCC. This forms the basis for replication studies to inform appropriate patient management, provide reassurance, and guide follow-up.

Gonadal hormones act throughout the brain and modulate psychiatric symptoms. Yet how hormones influence cognitive processes is unclear. Exogenous 17β-estradiol, the most potent estrogen, modulates dopamine in the nucleus accumbens core, which instantiates reward prediction errors (RPEs), the difference between received and expected reward. Here we show that following endogenous increases in 17β-estradiol, dopamine RPEs and behavioral sensitivity to previous rewards are enhanced, and nucleus accumbens core dopamine reuptake proteins are reduced. Rats adjusted how quickly they initiated trials in a task with varying reward states, balancing effort against expected rewards. Nucleus accumbens core dopamine reflected RPEs that influenced rats' initiation times. Higher 17β-estradiol predicted greater sensitivity to reward states and larger RPEs. Proteomics revealed reduced dopamine transporter expression following 17β-estradiol increases. Finally, knockdown of midbrain estrogen receptors suppressed sensitivity to reward states. Therefore, endogenous 17β-estradiol predicts dopamine reuptake and RPE signaling, and causally dictates the impact of previous rewards on behavior.

Consciousness Science is entering an age of unprecedented opportunity, thanks to recent empirical and theoretical advances, increasing interest in the topic, and technological advances in neuroscience. The role theories will play in a maturing science of consciousness deserves a closer look.