Citations

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

ABSTRACT The initiation and sustained expression of motivated behaviour is strongly regulated by mesolimbic dopamine (DA) release within the nucleus accumbens (NAc). Deep brain stimulation (DBS) has demonstrated efficacy in treating refractory psychiatric disorders characterised by dysfunctional motivated drive and related behaviours. However, the neurobiological mechanisms underlying DBS effects at the local and circuit levels remain unclear. This study aimed to investigate the effects of NAc DBS on effort‐based decision‐making and local phasic DA neurotransmission in male Wistar rats. Male Wistar rats ( N = 8) were trained on a concurrent fixed ratio 5/chow effort‐related choice task (ERCT) until stable baseline performance was reached. On the test day, animals underwent a 2‐h session of high‐frequency NAc DBS (130 Hz; 90 μs pulse width; 500 μA) immediately prior to behavioural testing, with additional testing conducted on subsequent days to assess prolonged effects. In a separate experiment, the effects of identical NAc DBS parameters (or sham) on ventral tegmental area (VTA)‐evoked (120 pulses; 60 Hz; 2 ms pulse width; 200–500 μA) DA release in the NAc core were quantified using fast‐scan cyclic voltammetry in urethane‐anesthetised rats ( N = 12). Acute bilateral NAc DBS transiently reduced overall food‐related motivation while maintaining effort‐based choice bias. In parallel, NAc DBS significantly suppressed VTA‐evoked NAc DA release compared to sham, although a moderate reduction was also observed in sham controls. DA reuptake kinetics remained unchanged across groups. NAc DBS transiently suppresses overall food‐related motivation while maintaining effort‐based decision‐making. Attenuated phasic DA neurotransmission with active DBS may contribute to this behavioural effect. image

Abstract Pick’s disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Pick’s disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Mapping and Annotation of GWAS (FUMA) platform, followed by co-localisation analyses using the METABRAIN dataset and statistical finemapping using FINEMAP and SuSiE. After exclusion of 3 cases of MAPT mutations, no variants were associated with risk of PiD at genome-wide significance ( p < 5 × 10 -8 ). The strongest association was on chromosome 4 (4p13, lead SNP rs112161979, OR = 7.53, 95% Confidence Interval (CI) = 3.62-15.65, p = 6.37 × 10 -8 ) followed by chromosome 11 (11p15.4, lead SNP rs66481907, OR = 2.10, 95% CI = 1.54-2.84, p = 1.83 × 10 -6 ). rs112161979 is an intronic SNP in the KCDT8 gene, encoding a potassium channel tetramerization domain that acts as an auxiliary subunit for GABA B receptors, whilst rs66481907 is an intronic SNP in TRIM22 , encoding an E3 ubiquitin-protein ligase. Our GWAS provides the first evidence of possible genetic risk for PiD that implicate the modulation of GABA B receptor signalling and inflammation, in disease pathogenesis. Replication of these findings will be important, but our results suggest that, if present, the genetic risk of PiD beyond MAPT mutations is low.

Maternal infection with Zika virus (ZIKV) is associated with a distinct pattern of birth defects, known as congenital Zika syndrome (CZS). In ZIKV-exposed children without CZS, it is often unclear whether they were protected from in utero infection and neurotropism. Early neurodevelopmental assessment is essential for detecting neurodevelopmental delays (NDDs) and prioritizing at-risk children for early intervention. We compared neurodevelopmental outcomes between ZIKV-exposed and unexposed children at 1, 3 and 4 years to assess exposure-associated NDD risk. A total of 384 mother–child dyads were enrolled during a period of active ZIKV transmission (2016–2017) in Grenada, West Indies. Exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. Neurodevelopment was assessed using the Oxford Neurodevelopment Assessment, the NEPSY® Second Edition and Cardiff Vision Tests, at 12 (n = 66), 36 (n = 58) and 48 (n = 59) months, respectively. There were no differences in NDD rates or vision scores between ZIKV-exposed and unexposed children. Rates of microcephaly at birth (0.88% vs. 0.83%, p = 0.81), and childhood stunting and wasting did not differ between groups. Our results show that Grenadian ZIKV-exposed children, the majority of whom were without microcephaly, had similar neurodevelopmental outcomes to unexposed controls up to at least an age of 4 years.

Abstract Background: Hsp90 is a molecular chaperone protein required for the stabilization and activation of many proteins, referred to as Hsp90 ‘clients’, such as HER2, HIF1-a, EGFR, ER, PI3K, AKT, P53 and VEGFR. The drug candidate, ganetespib is a novel triazolone inhibitor of Hsp90, with over 700 patients treated to date. Ganetespib has shown activity in preclinical models of HER2+, ER+/PR+ and TNBC. Early clinical trials documented ganetespib single agent activity in heavily pretreated HER2+ and TNBC patients. Ganetespib has been well tolerated in clinical trials with a favorable safety profile. This efficacy-screening study is designed to provide further evidence of ganetespib activity and identify potentially predictive biomarkers in metastatic breast cancer (BC). Methods: The ENCHANT-1 Trial is an international, first-line 2-cohort Phase 2 study in BC patients: Cohort A, HER2 amplified (n = 35), and Cohort B, TNBC (n = 35). Patients who present with previously untreated metastatic disease are eligible for treatment with ganetespib at 150 mg/m2 twice weekly on 3 out of 4 wks, for a total of up to 12 wks. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include metabolic response as assessed by PET/CT at wk 3 utilizing modified EORTC criteria. Disease progression (PD) at wk 3 by PET imaging indicates discontinuation of study therapy, and is performed to quickly offer patients with metabolic PD a standard of care treatment. The study is designed as Simon 2-stage requiring at least one OR in 15 patients for the respective cohort to expand to 35 patients. A Steering Committee is established to oversee the overall study and review the interim results. Results: The study was initiated in 23 centers globally. At the time of submission, a total of 17 patients had been enrolled; TNBC (n = 15) and HER2 (n = 2). Here we report the interim analysis in the TNBC cohort. The median age was 54 years (range 30 -77) with ECOG PS 0 (n = 7/15). Most patients (n = 9) presented with de novo metastatic disease. 5 patients were not evaluable for PET assessment (3 had not yet reached wk 3 and 2 withdrawn before wk 3 for clinical progression), and 9 patients were not evaluable for objective response at wk 6 (3 withdrawn before or at wk 3 for clinical progression and 6 had not yet reached wk 6 evaluation). In the 10 patients with evaluable PET imaging, 9 patients achieved metabolic (m) response (2 mPR, 4 mSD with dominant tumor shrinkage and 3 SD) and one patient with mPD. In the 6 patients evaluable for OR at wk 6, one patient achieved PR, 2 SD and 3 PD. Treatment with ganetespib was well tolerated; the most common AEs were mild or moderate diarrhea (8/15, 53%), fatigue (5/15, 33%), decreased appetite (4/15, 27%), insomnia (4/15, 27%), and nausea (4/15, 27%). Conclusion: Ganetespib single agent was generally well tolerated and showed anti-tumor activity TNBC patients as early as 3 weeks following treatment. PET seems to be a good tool to screen antitumor activity of new agents in early settings rather that in heavily pretreated patients. The TNBC cohort has met the protocol criteria for proceeding to stage 2. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-23.

Despite advances in evidence‐based treatments (EBTs), research suggests these interventions are not utilized in practice settings. This study examined implementation of multi‐family psychoeducational psychotherapy (MF‐PEP), an EBT for childhood mood disorders, in two outpatient community clinics. Fifteen community therapists facilitated MF‐PEP. Twenty community clinicians referred 40 children ages 8–12 with mood disorders and their parents who participated in MF‐PEP. Preliminary descriptive findings based on observations and self‐report questionnaires demonstrated implementation outcomes of acceptability, adoption, appropriateness, feasibility, implementation cost, penetration, and sustainability of MF‐PEP at these clinics. Parents also demonstrated significant improvement in knowledge of mood disorders posttreatment. Preliminary results support implementation of MF‐PEP in practice settings and suggest community‐based MF‐PEP may be associated with improvement in clinical outcomes.