Faculty Bibliography

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.

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.

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: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.

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.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

BACKGROUND:Despite the high potential of transcranial ultrasound stimulation (TUS) for non-invasive brain therapy and interrogation, real-time monitoring of brain responses to TUS remains a challenge. Traditional methods to monitor direct neural responses are invasive and mostly incompatible with precise TUS delivery while other non-invasive approaches to visualize the induced responses suffer from poor penetration depth, lack of sensitivity, or low temporal resolution. OBJECTIVE:We present an integrated approach for high precision delivery of ultrasound into the mouse brain and simultaneous whole-brain oximetry with functional optoacoustic tomography to characterize the hemodynamic response elicited by TUS. METHODS:A spherically focused ultrasound array was employed to non-invasively deliver holographic TUS and simultaneously detect multispectral optoacoustic signals from the brains of anesthetized mice. Ultrasound pressure and pulse duration were varied, while the number of stimuli (5), stimulation duration (15 s), and ultrasound frequency (3 MHz) were kept constant. The acquired optoacoustic data were tomographically reconstructed and spectrally unmixed to render three-dimensional maps of oxygenated and deoxygenated hemoglobin in real time. RESULTS:TUS-evoked brain-wide hemodynamics were efficiently monitored via spectroscopic optoacoustic imaging with high spatial and temporal resolution. Holographic TUS targeted to the somatosensory cortex elicited distinct hemodynamic responses, which extended beyond the stimulated region, involving subcortical arteries and pial veins. CONCLUSIONS:Our method provides new transformative non-invasive capabilities to study the effects of ultrasound on a living brain thus help unleash the strong potential of TUS in neuroscience and medicine.

Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high-frequency oscillations (HFOs, defined as 250-500Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2^-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.