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ABSTRACT IMPACT: This work will help to understand a novel therapeutic approach to a common type of acute myeloid leukemia. OBJECTIVES/GOALS: FMS-like tyrosine kinase 3 (or FLT3) mutations occur in ˜30% of acute myeloid leukemia (AML) cases. FLT3 tyrosine kinase domain (TKD) mutations are particularly important in relapsed/refractory FLT3 mutant AML, which portends poor prognosis. This study describes a therapeutic approach to overcoming resistance conferred by FLT3-TKD mutations. METHODS/STUDY POPULATION: To understand the efficacy of a novel type 1 FLT3 inhibitor (NCGC1481), as a monotherapy and combination therapy, several assays were utilized to interrogate functionality of these therapies. Cell lines and patient samples containing aspartate 835 to tyrosine mutations (D835Y, the most common TKD alteration) and phenylalanine 691 to leucine (F691L) were utilized to examine the effects of NCGC1481 with and without other targeted therapies like MEK inhibitors. Specifically, assays measuring viability, cell death using flow cytometry, in vitro clonogenicity, cellular signaling, and xenograft survival were examined in these FLT3-TKD AML models. Synergy was also measured using well described methods, which also allowed for appropriate dose finding for drug combination experiments. RESULTS/ANTICIPATED RESULTS: Our novel type 1 FLT3 inhibitor (NCGC1481) was particularly effective in the most common FLT3 TKD mutant, D835Y. NCGC1481 reduced viability and cell signaling, while also inducing cell death and prolonging xenograft survival in the FLT3-D835Y model system. In contrast, clinically approved FLT3 inhibitors were less effective at suppressing AML cells expressing FLT3-D835Y. In the case of FLT3-F691L, most of the FLT3 inhibitors tested, including NCGC1481, suppressed canonical FLT3 signaling, but did not significantly reduce viability or leukemic clonogenicity. However, when NCGC1481 was combined with other targeted agents like MEK inhibitors, at synergistic doses, eradication of the FLT3-F691L AML clone was substantially increased. DISCUSSION/SIGNIFICANCE OF FINDINGS: In AML, response to FLT3 inhibitor therapy is often short-lived, with resistance sometimes occurring via FLT3-TKD mutations. Given the dismal prognosis of relapsed FLT3 mutant AML, novel therapies are necessary. This study describes efficacy of a novel FLT3 inhibitor, along with its synergistic activity when combined with other targeted agents.
Cholinergic deficits are a hallmark of Alzheimer’s disease (AD) and Lewy body dementia (LBD). The nucleus basalis of Meynert (NBM) provides the major source of cortical cholinergic input; studying its functional connectivity might, therefore, provide a tool for probing the cholinergic system and its degeneration in neurodegenerative diseases. Forty-six LBD patients, 29 AD patients, and 31 healthy age-matched controls underwent resting-state functional magnetic resonance imaging (fMRI). A seed-based analysis was applied with seeds in the left and right NBM to assess functional connectivity between the NBM and the rest of the brain. We found a shift from anticorrelation in controls to positive correlations in LBD between the right/left NBM and clusters in right/left occipital cortex. Our results indicate that there is an imbalance in functional connectivity between the NBM and primary visual areas in LBD, which provides new insights into alterations within a part of the corticopetal cholinergic system that go beyond structural changes.
Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain.
To provide robust prospective evidence of the diagnostic accuracy of dopaminergic imaging at the MCI stage to either support or refute its inclusion as a biomarker for the diagnosis of MCI with Lewy bodies.
We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computerised tomography (123I-FP-CIT SPECT) in 144 patients with MCI. Images were rated as normal or abnormal by a panel of experts with access to striatal binding ratio results. Follow-up consensus diagnosis based on the presence of core features of Lewy body disease was used as the reference standard.
At latest assessment (mean 2 years) 61 patients had probable MCI with Lewy bodies, 26 possible MCI with Lewy bodies and 57 MCI due to Alzheimer's disease. The sensitivity of baseline FP-CIT visual rating for probable MCI with Lewy bodies was 66% (95% CI 52–77%), specificity 88% (76–95%) and accuracy 76% (68–84%), with positive likelihood ratio 5.3.
It is over five times as likely for an abnormal scan to be found in probable MCI with Lewy bodies than MCI due to Alzheimer's disease. Dopaminergic imaging appears to be useful at the MCI stage in cases where Lewy body disease is suspected clinically.
The Rapid ASKAP Continuum Survey (RACS) is the first large-area survey to be conducted with the full 36-antenna Australian Square Kilometre Array Pathfinder (ASKAP) telescope. RACS will provide a shallow model of the ASKAP sky that will aid the calibration of future deep ASKAP surveys. RACS will cover the whole sky visible from the ASKAP site in Western Australia and will cover the full ASKAP band of 700–1800 MHz. The RACS images are generally deeper than the existing NRAO VLA Sky Survey and Sydney University Molonglo Sky Survey radio surveys and have better spatial resolution. All RACS survey products will be public, including radio images (with
15 arcsec resolution) and catalogues of about three million source components with spectral index and polarisation information. In this paper, we present a description of the RACS survey and the first data release of 903 images covering the sky south of declination
made over a 288-MHz band centred at 887.5 MHz.
Recently published diagnostic criteria for mild cognitive impairment with Lewy bodies (MCI-LB) include five neuropsychiatric supportive features (non-visual hallucinations, systematised delusions, apathy, anxiety and depression). We have previously demonstrated that the presence of two or more of these symptoms differentiates MCI-LB from MCI due to Alzheimer's disease (MCI-AD) with a likelihood ratio >4. The aim of this study was to replicate the findings in an independent cohort.
Participants ⩾60 years old with MCI were recruited. Each participant had a detailed clinical, cognitive and imaging assessment including FP-CIT SPECT and cardiac MIBG. The presence of neuropsychiatric supportive symptoms was determined using the Neuropsychiatric Inventory (NPI). Participants were classified as MCI-AD, possible MCI-LB and probable MCI-LB based on current diagnostic criteria. Participants with possible MCI-LB were excluded from further analysis.
Probable MCI-LB (n = 28) had higher NPI total and distress scores than MCI-AD (n = 30). In total, 59% of MCI-LB had two or more neuropsychiatric supportive symptoms compared with 9% of MCI-AD (likelihood ratio 6.5, p < 0.001). MCI-LB participants also had a significantly greater delayed recall and a lower Trails A:Trails B ratio than MCI-AD.
MCI-LB is associated with significantly greater neuropsychiatric symptoms than MCI-AD. The presence of two or more neuropsychiatric supportive symptoms as defined by MCI-LB diagnostic criteria is highly specific and moderately sensitive for a diagnosis of MCI-LB. The cognitive profile of MCI-LB differs from MCI-AD, with greater executive and lesser memory impairment, but these differences are not sufficient to differentiate MCI-LB from MCI-AD.
Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series.
This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences.
We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions.
The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs.
Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.
To assess the utility of an automated, statistically-based outbreak detection system to identify clusters of hospital-acquired microorganisms.
Multicenter retrospective cohort study.
The study included 43 hospitals using a common infection prevention surveillance system.
A space–time permutation scan statistic was applied to hospital microbiology, admission, discharge, and transfer data to identify clustering of microorganisms within hospital locations and services. Infection preventionists were asked to rate the importance of each cluster. A convenience sample of 10 hospitals also provided information about clusters previously identified through their usual surveillance methods.
We identified 230 clusters in 43 hospitals involving Gram-positive and -negative bacteria and fungi. Half of the clusters progressed after initial detection, suggesting that early detection could trigger interventions to curtail further spread. Infection preventionists reported that they would have wanted to be alerted about 81% of these clusters. Factors associated with clusters judged to be moderately or highly concerning included high statistical significance, large size, and clusters involving Clostridioides difficile or multidrug-resistant organisms. Based on comparison data provided by the convenience sample of hospitals, only 9 (18%) of 51 clusters detected by usual surveillance met statistical significance, and of the 70 clusters not previously detected, 58 (83%) involved organisms not routinely targeted by the hospitals’ surveillance programs. All infection prevention programs felt that an automated outbreak detection tool would improve their ability to detect outbreaks and streamline their work.
Automated, statistically-based outbreak detection can increase the consistency, scope, and comprehensiveness of detecting hospital-associated transmission.
The COVID-19 pandemic has disrupted the traditional practice of psychiatric assessment and treatment via face-to-face interaction. Telepsychiatry, the delivery of psychiatric care remotely through telecommunications technology, is an existing and under-utilised tool that may help to minimise disruption to patient care. Technological advancement is at a stage where it can facilitate widespread use of this practice; however, concerns that limited its expansion previously were not unfounded. This article discusses the use of telepsychiatry in the context of the COVID-19 pandemic.
Stratified medicine has been successfully used in many areas of medicine, perhaps most notably oncology. There is now both a growing evidence base and mounting enthusiasm, supported at a governmental level and across industry, academia and clinical medicine, to apply this approach to neurodegenerative illnesses, including dementia, as these provide the greatest clinical and social challenge of our times. In this article we consider definitions of stratified medicine, look at its application in other medical specialties, review the national context in the UK and consider the current state, future potential and specific considerations of applying stratified medicine to dementia.
Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD).
A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function.
Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline.
These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms – particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.
Late-life depression (LLD) is associated with poor social functioning. However, previous research uses bias-prone self-report scales to measure social functioning and a more objective measure is lacking. We tested a novel wearable device to measure speech that participants encounter as an indicator of social interaction.
Twenty nine participants with LLD and 29 age-matched controls wore a wrist-worn device continuously for seven days, which recorded their acoustic environment. Acoustic data were automatically analysed using deep learning models that had been developed and validated on an independent speech dataset. Total speech activity and the proportion of speech produced by the device wearer were both detected whilst maintaining participants' privacy. Participants underwent a neuropsychological test battery and clinical and self-report scales to measure severity of depression, general and social functioning.
Compared to controls, participants with LLD showed poorer self-reported social and general functioning. Total speech activity was much lower for participants with LLD than controls, with no overlap between groups. The proportion of speech produced by the participants was smaller for LLD than controls. In LLD, both speech measures correlated with attention and psychomotor speed performance but not with depression severity or self-reported social functioning.
Using this device, LLD was associated with lower levels of speech than controls and speech activity was related to psychomotor retardation. We have demonstrated that speech activity measured by wearable technology differentiated LLD from controls with high precision and, in this study, provided an objective measure of an aspect of real-world social functioning in LLD.
The rupture of atherosclerotic plaques is the prerequisite for adverse cardiovascular events. Calcification morphology plays a critical role in plaque stability, therefore accurate calcification classification is essential for favourable patient management. Blood biomarkers may be a worthwhile approach to stratify patients based on calcification phenotype. Vitamin K-dependent Matrix γ-carboxyglutamate (Gla) protein (MGP) is a potent inhibitor of vascular calcification. Recent studies have demonstrated the potential utility of circulating non-functional MGP (dp-ucMGP) measurements to determine arterial stiffness and calcification levels. The objective of this study was to examine the relationship between circulating dp-ucMGP and calcification phenotype within symptomatic atherosclerotic lesions. Consenting patients undergoing standard endarterectomy procedures were recruited (n = 29). Fasting venous blood was collected preoperatively. Circulating plasma levels of dp-ucMGP were quantified using the inaKtif MGP (dp-ucMGP) iSYS kit. A bicinchoninic acid assay was used to standardise the total protein content present in each sample. High-resolution micro-CT imaging was conducted on the excised atherosclerotic specimens postoperatively. ImageJ post-processing was used to accurately quantify the calcification volume (≥ 130 Hounsfield Units) and determine the total number of calcified particles (3D objects counter plugin). Thirteen carotid (average age 71 years, 9 male) and fourteen peripheral lower limb (average age 65 years, 12 male) patients were examined. One patient had a carotid and a peripheral lower limb plaque (age 79, male). Peripheral lower limb specimens have larger volumes of calcification and higher numbers of calcified particles than carotid samples (472 ± 310 vs 85 ± 113mm3, p < 0.0005; 13919 ± 16034 vs 3476 ± 6208, p = 0.061.) While a higher dp-ucMGP value was noted in carotid than peripheral lower limb patients (214 ± 52 vs 169 ± 36pmol/L, p = 0.014) there was no correlation between circulating dp-ucMGP and calcification volume or number of calcified particles (rs = -0.329 and rs = 0.046). Previous research also found that peripheral lower limb lesions contain higher volumes of calcification than carotid lesions. There is currently no published data on calcified particle comparisons. Patients with symptomatic carotid disease are assumed to have a degree of peripheral arterial disease, this could explain the higher levels of circulating dp-ucMGP in carotid patients. The current study did not examine the dietary patterns of individuals with regards to Vitamin K intake or analyse other areas of the vasculature for additional calcification. This may interfere with dp-ucMGP measurements. This study serves as a preliminary investigation into the potential of dp-ucMGP as a blood based biomarker to distinguish between symptomatic atherosclerotic calcification phenotypes.
Alzheimer's disease and vascular dementia are associated with overlapping symptoms of anxiety and depression. More accurate discrimination between emerging neuropsychiatric and cognitive symptoms would better assist illness detection. The potential for protection against cognitive decline and dementia following early identification and intervention of neuropsychiatric symptoms warrants investigation.
To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups – probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer’s disease (probable MCI-AD) – as well as associations with clinical features.
Memory clinics and dementia services.
Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20).
Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated.
There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026).
There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.
Bipolar disorder is less prevalent in older people but accounts for 8–10% of psychiatric admissions. Treating and managing bipolar disorder in older people is challenging because of medical comorbidity. We review the cognitive problems observed in older people, explore why these are important and consider current treatment options. There are very few studies examining the cognitive profiles of older people with bipolar disorder and symptomatic depression and mania, and these show significant impairments in executive function. Most studies have focused on cognitive impairment in euthymic older people: as in euthymic adults of working age, significant impairments are observed in tests of attention, memory and executive function/processing speeds. Screening tests are not always helpful in euthymic older people as the impairment can be relatively subtle, and more in-depth neuropsychological testing may be needed to show impairments. Cognitive impairment may be more pronounced in older people with ‘late-onset’ bipolar disorder than in those with ‘early-onset’ disorder. Strategies to address symptomatic cognitive impairment in older people include assertive treatment of the mood disorder, minimising drugs that can adversely affect cognition, optimising physical healthcare and reducing relapse rates.
After reading this article you will be able to:
• understand that cognitive impairment in euthymic older people with bipolar disorder is similar to that in working-age adults with the disorder, affecting attention, memory and executive function/processing speeds
• recognise that cognitive impairment in older people is likely to be a major determinant of functional outcomes
• Implement approaches to treat cognitive impairment in bipolar disorder.
DECLARATION OF INTEREST
B.J.S. consults for Cambridge Cognition, PEAK (www.peak.net) and Mundipharma.
Infant protein intake has been associated with child growth, however, research on maternal protein intake during pregnancy is limited. Insulin-like growth factors (IGF) play a role in early fetal development and maternal protein intake may influence child body composition via IGF-1. The aim of this study was to investigate the association of maternal protein intake throughout pregnancy on cord blood IGF-1 and child body composition from birth to 5 years of age. Analysis was carried out on 570 mother–child dyads from the Randomised cOntrol trial of LOw glycaemic index diet study. Protein intake was recorded using 3-d food diaries in each trimester of pregnancy and protein intake per kg of maternal weight (g/d per kg) was calculated. Cord blood IGF-1 was measured at birth. Infant anthropometry was measured at birth, 6 months, 2 and 5 years of age. Mixed modelling, linear regression, and mediation analysis were carried out. Birth weight centiles were positively associated with early-pregnancy protein intake (g/d per kg), while weight centiles from 6 months to 5 years were negatively associated (B=−21·6, P<0·05). These associations were not mediated by IGF-1. Our findings suggest that high protein intake in early-pregnancy may exert an in utero effect on offspring body composition with a higher weight initially at birth but slower growth rates into childhood. Further research is needed to elucidate the exact mechanisms by which dietary protein modulates fetal growth.