Subsequent Indications in Oncology Drugs: Pathways, Timelines, and the Inflation Reduction Act.

INTRODUCTION: Recent research has raised questions about potential unintended consequences of the Inflation Reduction Act's Drug Price Negotiation Program (DPNP), suggesting that the timelines introduced by the law may reduce manufacturer incentives to invest in post-approval research towards additional indications. Given the role of multiple indications in expanding treatment options in patients with cancer, IRA-related changes to development incentives are especially relevant in oncology. This study aimed to describe heterogeneous drug-level trajectories and timelines of subsequent indications in a cohort of recently approved, multi-indication oncology drugs, including overall, across subgroups of drugs characterized by the timing and pace of additional indications, and by drug type (i.e., small molecule vs. biologic). METHODS: This cross-sectional study evaluated oncology drugs first approved by the FDA from 2008 to 2018 and later approved for one or more additional indications. Numbers, types, and approval timelines of subsequent indications were recorded at the drug level, with drugs grouped by quartile based on the pacing of post-approval development (i.e., "rapid pace" to "measured pace"). RESULTS: Multi-indication oncology drugs (N = 56/86, 65.1%) had one or more subsequent indication approved in a new: cancer type (60.7%), line of treatment (50.0%), combination (41.1%), mutation (32.1%), or stage (28.6%). The median time between FDA approvals for indications increased from 0.6 years (IQR: 0.48, 0.74) in the "rapid pace" group to 1.6 years (IQR: 1.32, 1.66), 2.4 years (IQR: 2.29, 2.61), and 4.9 years (IQR: 3.43, 6.23) in the "moderate," "measured-moderate," and "measured" pace groups, respectively. Drugs in the "rapid pace" group often received their first subsequent indication approval within 9 months of initial approval (median: 0.7 years; IQR: 0.54, 1.59), whereas the "measured pace" group took a median of 5.7 years (IQR: 3.43, 6.98). Across all multi-indication drugs, the median time to the most recent approval for a subsequent indication was 5.5 years (IQR: 3.18, 7.95). One quarter (25%) of drugs were approved for their most recent subsequent indication after the time at which they would be DPNP-eligible. CONCLUSION: Approval histories of new oncology drugs demonstrate the role of post-approval indications in expanding treatment options towards new cancer types, stages, lines, combinations, and mutations. Heterogeneous clinical development pathways provide insights into potential unintended consequences of IRA-related changes surrounding post-approval research and development.

Regulation of Cx36 trafficking through the early secretory pathway by COPII cargo receptors and Grasp55.

Gap junctions formed by the major neuronal connexin Cx36 function as electrical synapses in the nervous system and provide unique functions such as synchronizing neuron activities or supporting network oscillations. Although the physiological significance of electrical synapses for neuronal networks is well established, little is known about the pathways that regulate the transport of its main component: Cx36. Here we have used HEK293T cells as an expression system in combination with siRNA and BioID screens to study the transition of Cx36 from the ER to the cis Golgi. Our data indicate that the C-terminal tip of Cx36 is a key factor in this process, mediating binding interactions with two distinct components in the early secretory pathway: the COPII complex and the Golgi stacking protein Grasp55. The C-terminal amino acid valine serves as an ER export signal to recruit COPII cargo receptors Sec24A/B/C at ER exit sites, whereas the PDZ binding motif "SAYV" mediates an interaction with Grasp55. These two interactions have opposing effects in their respective compartments. While Sec24 subunits carry Cx36 out of the ER, Grasp55 stabilizes Cx36 in the Golgi as shown in over expression experiments. These early regulatory steps of Cx36 are expected to be essential for the formation, function, regulation and plasticity of electrical synapses in the developing and mature nervous system.

Associations Between Neuropsychiatric Symptoms and Inflammation in Neurodegenerative Dementia: A Systematic Review.

Background: Neuropsychiatric symptoms are common in dementia and linked to adverse outcomes. Inflammation is increasingly recognized as playing a role as a driver of early disease progression in Alzheimer's disease (AD) and related dementias. Inflammation has also been linked to primary psychiatric disorders, however its association with neuropsychiatric symptoms in neurodegenerative dementias remains uncertain. Methods: We conducted a systematic literature review investigating associations between inflammation and neuropsychiatric symptoms in neurodegenerative dementias, including AD, Lewy body, Frontotemporal, Parkinson's (PD) and Huntington's disease dementias. Results: Ninety-nine studies met our inclusion criteria, and the majority (n = 59) investigated AD and/or mild cognitive impairment (MCI). Thirty-five studies included PD, and only 6 investigated non-AD dementias. Inflammation was measured in blood, CSF, by genotype, brain tissue and PET imaging. Overall, studies exhibited considerable heterogeneity and evidence for specific inflammatory markers was inconsistent, with lack of replication and few longitudinal studies with repeat biomarkers. Depression was the most frequently investigated symptom. In AD, some studies reported increases in peripheral IL-6, TNF-a associated with depressive symptoms. Preliminary investigations using PET measures of microglial activation found an association with agitation. In PD, studies reported positive associations between TNF-a, IL-6, CRP, MCP-1, IL-10 and depression. Conclusion: Central and peripheral inflammation may play a role in neuropsychiatric symptoms in neurodegenerative dementias; however, the evidence is inconsistent. There is a need for multi-site longitudinal studies with detailed assessments of neuropsychiatric symptoms combined with replicable peripheral and central markers of inflammation.

Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.

BACKGROUND AND OBJECTIVES: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aß1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition. METHODS: This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aß1-42, P-tau181, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal). RESULTS: A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aß1-42 (ß = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aß1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aß1-42 (indirect effect: ß = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau181 (indirect effect: ß = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: ß = -0.10 ± 0.03; ß = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: ß = -0.16 ± 0.03) through CSF Aß1-42. DISCUSSION: In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aß1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Differences in Grey Matter Concentrations and Functional Connectivity between Young Carriers and Non-Carriers of the APOE ε4 Genotype.

Background: The pathophysiology of Alzheimer's disease (AD) may begin developing years or even decades prior to the manifestation of its first symptoms. The APOE ε4 genotype is a prominent genetic risk for AD that has been found to be associated with brain changes across the lifespan since early adulthood. Thus, studying brain changes that may occur in young adults with an APOE ε4 status is highly relevant. Objective: Examine potential differences in grey matter (GM) and functional connectivity (FC) in brains of cognitively healthy young APOE ε4 carriers and non-carriers, denoted here as ε4(+) and ε4(-), respectively. Methods: Three Tesla magnetic resonance imaging (MRI) brain scans were acquired from cognitively healthy young participants aged approximately 20 years (n = 151). Voxel-based morphometry (VBM) analysis was employed to identify potential structural differences in GM between ε4(+) and ε4(-). In a subsequent seed-based connectivity (SBC) analysis, brain regions that structurally differed in the VBM analysis were considered as seeds and correlated with all the remaining voxels across the brains to then measure the differences in FC between groups. Results: The VBM analysis suggested that ε4(+) (n = 28) had greater GM densities relative to ε4(-) (n = 123) in the left hippocampus and the left posterior insula (puncorr < 0.001). However, the effect did not survive the correction for multiple comparisons, suggesting minimal structural differences in this age range. In contrast, the SBC analysis indicated that ε4(+) exhibited significantly decreased FC between the left hippocampus and areas of the left middle temporal gyrus (n = 27) compared to ε4(-) (n = 102). These results remained significant after multiple comparisons (pFDR < 0.05). Lastly, no statistically significant differences in FC between groups were observed for the left insular seed (pFDR > 0.05). Discussion: These results suggest early structural and functional brain changes associated with the APOE ε4 genotype on young adults. Yet, they must be cautiously interpreted and contrasted with both older adults with genetic risk for AD and patients diagnosed with AD.

The accelerated approval program for oncology drugs: celebrating more than 250,000 life-years gained and counting.

This commentary explores how 2 recently published studies evaluating the clinical benefit of the FDA's accelerated approval program for oncology drugs came to different conclusions.

Characterizing ER Retention Defects of PDZ Binding Deficient Cx36 Mutants Using Confocal Microscopy.

Overexpression of proteins in transiently transfected cells is a simple way to study basic transport mechanisms and the underlying protein-protein interactions. While expression systems have obvious drawbacks compared to in vivo experiments, they allow a quick assessment of more conserved functions, for instance, ER export or sorting of proteins in the Golgi. In a previous study, our group described the formation of ER-derived removal vesicles for the gap junction protein Cx36 in transfected HEK293T cells. These removal vesicles, termed "whorls" because of their concentric structure, were formed by Cx36 channels that failed to escape the ER. In this article, we describe an imaging protocol that can be used to determine these ER retention defects for Cx36 expressed in cultured cells. The protocol we provide here employs regular confocal microscopy, which allows for sufficient resolution to reveal the characteristic shape of ER whorls.

Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration.

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationship with central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers as these will reduce the time, risk, and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with FTLD as compared to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A sub-group of patients underwent 11C-PK11195 TSPO PET imaging, as an index of microglial activation. A Principal Component Analysis (PCA) was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components, to compare each patient cohort to controls, and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the PCA (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 TSPO PET. A permutation-based Canonical Correlation Analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner. This data-driven approach identified a pro-inflammatory profile across the FTLD clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies.

Association of optic disc pallor and RNFL thickness with cerebral small vessel disease in the PREVENT-Dementia study.

INTRODUCTION: We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]). METHODS: We used PallorMetrics to quantify optic disc pallor from fundus photographs, and pRNFL thickness from optical coherence tomography scans. Linear and logistic regression assessed relationships between retinal measures and SVD markers. Participants (N = 108, mean age 51.6) were from the PREVENT Dementia study. RESULTS: Global optic disc pallor was linked to ePVSs in the basal ganglia in both left (ß = 0.12, standard error [SE] = 0.05, P < 0.05) and right eyes (ß = 0.13, SE = 0.05, P < 0.05). Associations were also noted in different disc sectors. No pRNFL associations with SVD markers were found. DISCUSSION: Optic disc pallor correlated with ePVSs in the basal ganglia, suggesting retinal examination may be a useful method to study brain health changes related to SVD. Highlights: Optic disc pallor is linked to enlarged perivascular spaces in basal ganglia.There is no association between peripapillary retinal nerve fiber layer thickness and cerebral small vessel disease markers.Optic disc examination could provide insights into brain health.The sample included 108 midlife adults from the PREVENT Dementia study.

Neuroimaging and Clinical Findings in Healthy Middle-Aged Adults With Mild Traumatic Brain Injury in the PREVENT Dementia Study.

Importance: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI. Objective: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals. Design, Setting, and Participants: This cross-sectional analysis used baseline data from the PREVENT Dementia program collected across 5 sites in the UK and Ireland between 2014 and 2020. Eligible participants were cognitively healthy midlife adults aged between 40 and 59 years. Data were analyzed between January 2023 and April 2024. Exposure: Lifetime TBI history was assessed using the Brain Injury Screening Questionnaire. Main Outcomes and Measures: Cerebral microbleeds and other markers of cerebral small vessel disease (white matter hyperintensities [WMH], lacunes, perivascular spaces) were assessed on 3T magnetic resonance imaging. Clinical measures were cognition, sleep, depression, gait, and cardiovascular disease (CVD) risk, assessed using Computerized Assessment of Information Processing (COGNITO), Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, clinical interviews, and the Framingham Risk Score, respectively. Results: Of 617 participants (median [IQR] age, 52 [47-56] years; 380 female [61.6%]), 223 (36.1%) had a history of TBI. TBI was associated with higher microbleed count (ß = 0.10; 95% CI, 0.01-0.18; P = .03), with a dose-response association observed with increasing number of TBI events (ß = 0.05; 95% CI, 0.01-0.09; P = .03). Conversely, TBI was not associated with other measures of small vessel disease, including WMH. Furthermore, TBI moderated microbleed associations with vascular risk factors and clinical outcomes, such that associations were present only in the absence of TBI. Importantly, observations held when analyses were restricted to individuals reporting only mild TBI. Conclusions and Relevance: In this cross-sectional study of healthy middle-aged adults, detectable changes in brain imaging and clinical features were associated with remote, even mild, TBI in the general population. The potential contribution of vascular injury to TBI-related neurodegeneration presents promising avenues to identify potential targets, with findings highlighting the need to reduce TBI through early intervention and prevention in both clinical care and policymaking.

Texture-based morphometry in relation to apolipoprotein ε4 genotype, ageing and sex in a midlife population.

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross-sectional study, we investigated textural properties of T1-weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT-Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel-based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non-carriers. Textural maps were generated and were subsequently harmonised using voxel-wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non-carriers at midlife and have established associations of textural features with ageing and sex.

Deuterium Metabolic Imaging of Alzheimer Disease at 3-T Magnetic Field Strength: A Pilot Case-Control Study.

Background Impaired glucose metabolism is characteristic of several types of dementia, preceding cognitive symptoms and structural brain changes. Reduced glucose uptake in specific brain regions, detected using fluorine 18 (18F) fluorodeoxyglucose (FDG) PET, is a valuable diagnostic marker in Alzheimer disease (AD). However, the use of 18F-FDG PET in clinical practice may be limited by equipment availability and high cost. Purpose To test the feasibility of using MRI-based deuterium (2H) metabolic imaging (DMI) at a clinical magnetic field strength (3 T) to detect and localize changes in the concentration of glucose and its metabolites in the brains of patients with a clinical diagnosis of AD. Materials and Methods Participants were recruited for this prospective case-control pilot study between March 2021 and February 2023. DMI was performed at 3 T using a custom birdcage head coil following oral administration of deuterium-labeled glucose (0.75 g/kg). Unlocalized whole-brain MR spectroscopy (MRS) and three-dimensional MR spectroscopic imaging (MRSI) (voxel size, 3.2 cm cubic) were performed. Ratios of 2H-glucose, 2H-glutamate and 2H-glutamine (2H-Glx), and 2H-lactate spectroscopic peak signals to 2H-water peak signal were calculated for the whole-brain MR spectra and for individual MRSI voxels. Results A total of 19 participants, including 10 participants with AD (mean age, 68 years ± 5 [SD]; eight males) and nine cognitively healthy control participants (mean age, 70 years ± 6; six males) were evaluated. Whole-brain spectra demonstrated a reduced ratio of 2H-Glx to 2H-glucose peak signals in participants with AD compared with control participants (0.41 ± 0.09 vs 0.58 ± 0.20, respectively; P = .04), suggesting an impairment of oxidative glucose metabolism in AD. However, there was no evidence of localization of these changes to the expected regions of metabolic impairment at MRSI, presumably due to insufficient spatial resolution. Conclusion DMI at 3 T demonstrated impairment of oxidative glucose metabolism in the brains of patients with AD but no evidence of regional signal differences. © RSNA, 2024 Supplemental material is available for this article.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Association of Food and Housing Insecurity on Outcomes in Pregnant Patients With Substance Use Disorder.

OBJECTIVES: Food insecurity (FI) may be associated with worsened neonatal abstinence syndrome severity in infants born to individuals with substance use disorder. This study evaluates FI and housing insecurity (HI) influence on maternal and neonatal outcomes. METHODS: This was a cohort study of patients receiving obstetric care through a multispecialty program in Kentucky from 2015 to 2023. Inclusion criteria were: (1) program participants over age 18 consenting to observational research, (2) delivering at University of Kentucky, and (3) not withdrawing from research at any time. Initially, a subset of patients for whom FI and HI concerns were heightened were screened. In 2019, FI and HI screening became standard of care at the clinic. Housing was assessed on enrollment. A validated 2-question Hunger Vital Sign FI screen was utilized for a subset of patients. Maternal and neonatal outcomes, including adverse delivery outcomes, maternal comorbidities, and birth complications, were observed. Fisher's exact and 2 sample t tests were performed. RESULTS: Of 494 participants, 188 (38%) identified at risk for HI. At enrollment, 221 (45%) individuals reported owning their primary residence, 85 (17%) were in group residential treatment, 34 (6.9%) had no housing, and 134 (27%) lived at another's residence. Disposition of a child to a relative or not the patient's own care was greater with HI, 51% versus 47%. Of 155 respondents, 96 (62%) reported FI, associated with increased neonatal intensive care unit (NICU) admission, 86% versus 74%. Using the validated tool, Abuse Assessment Screen, abuse was significantly greater with FI, 76% versus 58%. Edinburgh Postpartum Depression Scales >12 indicating depression were more common with FI, 63% versus 32%, P < .05. Anxiety scores were also higher with FI, P < .05. Patients with FI were more likely to experience abuse. CONCLUSIONS: FI and HI were health-related needs associated with increased anxiety, depression, infant NICU admission, and loss of child custody.

Outcomes of Patients With Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease at 3 and 5 Years After Diagnosis.

BACKGROUND AND OBJECTIVES: Retrospective studies indicate that dementia with Lewy bodies (DLB) may be preceded by a mild cognitive impairment (MCI) prodrome. Research criteria for the prospective identification of MCI with Lewy bodies (MCI-LB) have been developed. We aimed to assess the prognosis of a prospectively identified MCI-LB cohort at 2 key milestones, 3- and 5 years after diagnosis, to examine classification stability over time and rates of adverse outcomes (dementia or death). METHODS: This was a retrospective examination of data from 2 longitudinal observational cohort studies where participants with MCI were prospectively recruited from North East England and differentially classified as MCI due to Alzheimer disease (MCI-AD), possible MCI-LB, or probable MCI-LB. Adverse outcomes (DLB/other dementia or death) and stability of disease-specific classifications were examined in each group. RESULTS: Of 152 participants with baseline MCI (54 MCI-AD, 29 possible MCI-LB, and 69 probable MCI-LB), 126 were followed for up to 3 years (mean age 75.3 years; 40% female). We found that prospective probable MCI-LB classifications were both sensitive (91%) and specific (94%) to classifications either remaining as probable MCI-LB or progressing to DLB (in some cases autopsy confirmed) for 3 or more years after. Classifications were at least as stable as those in MCI-AD. In this cohort with disease-specific MCI classifications, rates of progression to dementia were high: 55% of MCI-LB had developed DLB within 3 years. Dementia occurred in 47% of MCI-AD over the same duration (odds ratio 1.68, 95% CI 0.66-4.26, p = 0.278). Premature death was a common competing risk, occurring in 9% of MCI-AD and 11% of MCI-LB within 3 years. DISCUSSION: These findings support that prospectively identified probable MCI-LB is a prodromal presentation of DLB and that disease-specific classifications of MCI may reliably identify different prodromal dementias.

The PREVENT dementia programme: baseline demographic, lifestyle, imaging and cognitive data from a midlife cohort study investigating risk factors for dementia.

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological samples (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery and are imaged using multi-modal 3-T MRI scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies that supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data include 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ± 5.47), with the majority female (n = 433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% versus 48.6%) and a relatively high prevalence of APOEɛ4 carriers (n = 264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry (n = 672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (total score 95.6 ± 4.06). Mean white matter hyperintensity volume at recruitment was 2.26 ± 2.77 ml (median = 1.39 ml), with hippocampal volume being 8.15 ± 0.79 ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel data set to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer's Disease Data Initiative platform and Dementia Platforms UK platform pending approval of the data access request from the PREVENT steering group committee.

The Mediterranean diet is not associated with neuroimaging or cognition in middle-aged adults: a cross-sectional analysis of the PREVENT dementia programme.

BACKGROUND AND PURPOSE: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. METHODS: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. RESULTS: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. CONCLUSIONS: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

Identification of N-pyrrolidino protonitazene in powders sold as heroin and associated with overdose clusters in Dublin and Cork, Ireland.

Synthetic opioids have been associated globally with adverse effects in drug users. The nitazene group of drugs is a relatively new addition to the synthetic opioid class emerging in Europe in 2019. Some nitazenes have been shown to be more potent than fentanyl. Overdose clusters in heroin users in Dublin (57 cases) and Cork (20 cases), Ireland, in November and December 2023, respectively, prompted a rapid response from a number of Irish laboratories to identify the substance(s) of concern. Light brown (tan) powders were obtained from cases associated with overdoses, and the results from these analyses by collaboration of four laboratories are reported here. The samples were found to contain N-pyrrolidino protonitazene (protonitazepyne), caffeine, paracetamol, benzoic acid and mannitol.

Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.

Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.

Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.