The development and validation of a conceptual definition of avoidable transitions from long-term care to the emergency department: A mixed methods study.

Background/Objectives: Transitions to and from Emergency Departments (EDs) can be detrimental to long-term care (LTC) residents and burden the healthcare system. While reducing avoidable transfers is imperative, various terms are used interchangeably including inappropriate, preventable, or unnecessary transitions. Our study objectives were to develop a conceptual definition of avoidable LTC-ED transitions and to verify the level of stakeholder agreement with this definition. Methods: The EXamining Aged Care Transitions study adopted an exploratory sequential mixed-method design. The study was conducted in 2015-2016 in 16 LTC facilities, 1 ED, and 1 Emergency Medical Service (EMS) in a major urban center in western Canada. Phase 1 included 80 participants, (healthcare aides, licensed practical nurses, registered nurses, LTC managers, family members of residents, and EMS staff). We conducted semistructured interviews (n = 25) and focus groups (n = 19). In Phase 2, 327 ED staff, EMS staff, LTC staff, and medical directors responded to a survey based on the qualitative findings. Results: Avoidable transitions were attributed to limited resources in LTC, insufficient preventive care, and resident or family wishes. The definition generated was: A transition of an LTC resident to the ED is considered avoidable if: (a) Diagnostic testing, medical assessment, and treatment can be accessed in a timely manner by other means; (b) the reasons for a transfer are unclear and the transition would increase the disorientation, pain, or discomfort of a resident, outweighing a clear benefit of a transfer; and (c) the transition is against the wishes expressed by the resident over time, including through informal and undocumented conversations. There was a high level of agreement with the definition across the four participant groups. Conclusions and Implications: To effectively reduce LTC resident avoidable transitions, stakeholders must share a common definition. Our conceptual definition may significantly contribute to improved care for LTC residents.

Strand asymmetry in the repair of replication dependent double-strand breaks.

Single-strand breaks (SSBs) are one of the most common endogenous lesions and have the potential to give rise to cytotoxic double-strand breaks (DSBs) during DNA replication. To investigate the mechanism of replication fork collapse at SSBs and subsequent repair, we employed Cas9 nickase (nCas9) to generate site and strand-specific nicks in the budding yeast genome. We show that nCas9-induced nicks are converted to mostly double-ended DSBs during S-phase. We find that repair of replication-dependent DSBs requires homologous recombination (HR) and is independent of canonical non-homologous end joining. Consistent with a strong bias to repair these lesions using a sister chromatid template, we observe minimal induction of inter-chromosomal HR by nCas9. Using nCas9 and a gRNA to nick either the leading or lagging strand template, we carried out a genome-wide screen to identify factors necessary for the repair of replication-dependent DSBs. All the core HR genes were recovered in the screen with both gRNAs, but we recovered components of the replication-coupled nucleosome assembly (RCNA) pathway with only the gRNA targeting the leading strand template. By use of additional gRNAs, we find that the RCNA pathway is especially important to repair a leading strand fork collapse.

Detection of the synthetic cathinone N,N-dimethylpentylone in seized samples from prisons.

Drug use is prevalent in prisons with drugs associated with depressant effects found to be more prevalent than stimulants. Synthetic cathinones (SCats; often sold as "bath salts", "ecstasy", "molly", and "monkey dust") are the second largest category of new psychoactive substances (NPS) currently monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and are commonly used as substitutes for regulated stimulants, such as amphetamine, cocaine, and MDMA. N,N-dimethylpentylone (also known as dimethylpentylone, dipentylone, and bk-DMBDP) was detected for the first time in the Scottish prisons in seven powder samples seized between January and July 2023. Samples were analyzed using gas chromatography-mass spectrometry (GC-MS), ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-QToF-MS), and nuclear magnetic resonance imaging (NMR). Dimethylpentylone was detected alongside other drugs in four samples, including the novel benzodiazepine desalkylgidazepam (bromonordiazepam) and the synthetic cannabinoid receptor agonists (SCRAs) MDMB-INACA and MDMB-4en-PINACA.

Premenopausal bilateral oophorectomy and brain white matter brain integrity in later-life.

INTRODUCTION: Premenopausal bilateral oophorectomy (PBO) is associated with later-life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity. METHODS: Female participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40-45 years; 39 with PBO 46-49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype. RESULTS: Females with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity. DISCUSSION: Females who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later-life. These results are important for females considering PBO for noncancerous conditions. HIGHLIGHTS: Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents. Females with PBO < 40 years had higher MD in many regions versus referents. Adjusting for estrogen replacement therapy use did not attenuate results. Females with PBO 45-49 years also had some white matter changes versus referents.

White Matter Abnormalities Track Disease Progression in Multiple System Atrophy.

BACKGROUND: White matter (WM) abnormalities have been implicated in clinically relevant functional decline in multiple system atrophy (MSA). OBJECTIVE: To identify the WM and gray matter (GM) abnormalities in MSA and assess the utility of longitudinal structural and diffusion changes as surrogate markers for tracking disease progression in MSA. METHODS: Twenty-seven participants with early MSA [15 with clinically predominant cerebellar (MSA-C) and 12 with clinically predominant parkinsonian features (MSA-P)] and 14 controls were enrolled as a part of our prospective, longitudinal study of synucleinopathies. Using structural magnetic resonance imaging (MRI) and diffusion MRI (diffusion tensor and neurite orientation and dispersion density imaging), we analyzed whole and regional brain changes in these participants. We also evaluated temporal imaging trajectories based on up to three annual follow-up scans and assessed the impact of baseline diagnosis on these imaging biomarkers using mixed-effect models. RESULTS: MSA patients exhibited more widespread WM changes than GM, particularly in the cerebellum and brainstem, with greater severity in MSA-C. Structural and diffusion measures in the cerebellum WM and brainstem deteriorated with disease progression. Rates of progression of these abnormalities were similar in both MSA subtypes, reflecting increasing overlap of clinical features over time. CONCLUSION: WM abnormalities are core features of MSA disease progression and advance at similar rates in clinical MSA subtypes. Multimodal MRI imaging reveals novel insights into the distribution and pattern of brain abnormalities and their progression in MSA. Selected structural and diffusion measures may be useful for tracking disease progression in MSA clinical trials.

Prescription Opioids and Brain Structure in Community-Dwelling Older Adults.

OBJECTIVE: To evaluate the associations between prescription opioid exposures in community-dwelling older adults and gray and white matter structure by magnetic resonance imaging. METHODS: Secondary analysis was conducted of a prospective, longitudinal population-based cohort study employing cross-sectional imaging of older adult (≥65 years) enrollees between November 1, 2004, and December 31, 2017. Gray matter outcomes included cortical thickness in 41 structures and subcortical volumes in 6 structures. White matter outcomes included fractional anisotropy in 40 tracts and global white matter hyperintensity volumes. The primary exposure was prescription opioid availability expressed as the per-year rate of opioid days preceding magnetic resonance imaging, with a secondary exposure of per-year total morphine milligram equivalents (MME). Multivariable models assessed associations between opioid exposures and brain structures. RESULTS: The study included 2185 participants; median (interquartile range) age was 80 (75 to 85) years, 47% were women, and 1246 (57%) received opioids. No significant associations were found between opioids and gray matter. Increased opioid days and MME were associated with decreased white matter fractional anisotropy in 15 (38%) and 16 (40%) regions, respectively, including the corpus callosum, posterior thalamic radiation, and anterior limb of the internal capsule, among others. Opioid days and MME were also associated with greater white matter hyperintensity volume (1.02 [95% CI, 1.002 to 1.036; P=.029] and 1.01 [1.001 to 1.024; P=.032] increase in the geometric mean, respectively). CONCLUSION: The duration and dose of prescription opioids were associated with decreased white matter integrity but not with gray matter structure. Future studies with longitudinal imaging and clinical correlation are warranted to further evaluate these relationships.

Microstructural Mapping of Neural Pathways in Alzheimer's Disease using Macrostructure-Informed Normative Tractometry.

Introduction: Diffusion MRI is sensitive to the microstructural properties of brain tissues, and shows great promise in detecting the effects of degenerative diseases. However, many approaches analyze single measures averaged over regions of interest, without considering the underlying fiber geometry. Methods: Here, we propose a novel Macrostructure-Informed Normative Tractometry (MINT) framework, to investigate how white matter microstructure and macrostructure are jointly altered in mild cognitive impairment (MCI) and dementia. We compare MINT-derived metrics with univariate metrics from diffusion tensor imaging (DTI), to examine how fiber geometry may impact interpretation of microstructure. Results: In two multi-site cohorts from North America and India, we find consistent patterns of microstructural and macrostructural anomalies implicated in MCI and dementia; we also rank diffusion metrics' sensitivity to dementia. Discussion: We show that MINT, by jointly modeling tract shape and microstructure, has potential to disentangle and better interpret the effects of degenerative disease on the brain's neural pathways.

Influences of amyloid-ß and tau on white matter neurite alterations in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-ß with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-ß, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-ß exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

Phosphate environment and phosphate uptake studies: past and future.

The present review explains briefly the importance of phosphorus in the biological activities and states that the most phosphorus of living organisms is absorbed by plants from the soil. Next, previous studies on the mechanisms of phosphate uptake by plants are reviewed as H+-dependent or Na+-dependent co-transport systems and the phosphate environment in which plants grow is discussed. The evolution of transporter genes and their regulation mechanisms of expression is discussed in relation to the phosphorus environment.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Genetic basis and selection of glyceollin elicitation in wild soybean.

Glyceollins, a family of phytoalexins elicited in legume species, play crucial roles in environmental stress response (e.g., defending against pathogens) and human health. However, little is known about the genetic basis of glyceollin elicitation. In the present study, we employed a metabolite-based genome-wide association (mGWA) approach to identify candidate genes involved in glyceollin elicitation in genetically diverse and understudied wild soybeans subjected to soybean cyst nematode. In total, eight SNPs on chromosomes 3, 9, 13, 15, and 20 showed significant associations with glyceollin elicitation. Six genes fell into two gene clusters that encode glycosyltransferases in the phenylpropanoid pathway and were physically close to one of the significant SNPs (ss715603454) on chromosome 9. Additionally, transcription factors (TFs) genes such as MYB and WRKY were also found as promising candidate genes within close linkage to significant SNPs on chromosome 9. Notably, four significant SNPs on chromosome 9 show epistasis and a strong signal for selection. The findings describe the genetic foundation of glyceollin biosynthesis in wild soybeans; the identified genes are predicted to play a significant role in glyceollin elicitation regulation in wild soybeans. Additionally, how the epistatic interactions and selection influence glyceollin variation in natural populations deserves further investigation to elucidate the molecular mechanism of glyceollin biosynthesis.

Detection of anabolic-androgenic steroids in e-cigarettes seized from prisons: A case study.

The administration of new psychoactive substances (NPS), in particular synthetic cannabinoid receptor agonists (SCRAs), via e-cigarettes, within prison settings has been well publicized. This study provides an overview of five e-cigarette case samples seized from Scottish prisons between May 2022 and July 2023 where the anabolic-androgenic steroids (AASs) mestanolone and oxandrolone were identified following gas chromatography-mass spectrometry (GC-MS) analysis. These e-cigarette samples represented 2.9% of all samples containing e-cigarette cartridges (n = 170) and 9.4% of all samples found to contain AASs (n = 53) seized during the same time period. The AASs were detected in combination with other drugs, including cocaine, Δ9-tetrahydrocannabinol (Δ9-THC), SCRAs and nicotine. This represents a new and novel route of administration for AASs.

Functional recovery following traumatic brain injury in rats is enhanced by oral supplementation with bovine thymus extract.

Traumatic brain injury (TBI) is one of the leading causes of death worldwide. There are currently no effective treatments for TBI, and trauma survivors suffer from a variety of long-lasting health consequences. With nutritional support recently emerging as a vital step in improving TBI patients' outcomes, we sought to evaluate the potential therapeutic benefits of nutritional supplements derived from bovine thymus gland, which can deliver a variety of nutrients and bioactive molecules. In a rat model of controlled cortical impact (CCI), we determined that animals supplemented with a nuclear fraction of bovine thymus (TNF) display greatly improved performance on beam balance and spatial memory tests following CCI. Using RNA-Seq, we identified an array of signaling pathways that are modulated by TNF supplementation in rat hippocampus, including those involved in the process of autophagy. We further show that bovine thymus-derived extracts contain antigens found in neural tissues and that supplementation of rats with thymus extracts induces production of serum IgG antibodies against neuronal and glial antigens, which may explain the enhanced animal recovery following CCI through possible oral tolerance mechanism. Collectively, our data demonstrate, for the first time, the potency of a nutritional supplement containing nuclear fraction of bovine thymus in enhancing the functional recovery from TBI.

Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors.

Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme polynucleotide kinase 3'-phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.

Flavonols improve thermotolerance in tomato pollen during germination and tube elongation by maintaining ROS homeostasis.

Elevated temperatures impair pollen performance and reproductive success, resulting in lower crop yields. The Solanum lycopersicum anthocyanin reduced ( are ) mutant has a FLAVANONE 3 HYDROXYLASE ( F3H ) gene mutation resulting in impaired synthesis of flavonol antioxidants. The are mutant has reduced pollen performance and seed set relative to the VF36 parental line, which is accentuated at elevated temperatures. Transformation of are with the wild-type F3H gene, or chemical complementation with flavonols, prevented temperature-dependent ROS accumulation in pollen and reversed are's reduced viability, germination, and tube elongation to VF36 levels. VF36 transformed with an F3H overexpression construct prevented temperature driven ROS increases and impaired pollen performance, revealing thermotolerance results from elevated flavonol synthesis. Although stigmas of are had reduced flavonols and elevated ROS, the growth of are pollen tubes were similarly impaired in both are and VF36 pistils. RNA-Seq was performed at optimal and stress temperatures in are , VF36, and the VF36 F3H overexpression line at multiple timepoints across pollen tube elongation. Differentially expressed gene numbers increased with duration of elevated temperature in all genotypes, with the largest number in are . These findings suggest potential agricultural interventions to combat the negative effects of heat-induced ROS in pollen that leads to reproductive failure. One sentence summary: Flavonol antioxidants reduce the negative impacts of elevated temperatures on pollen performance by reducing levels of heat induced reactive oxygen species and modulation of heat-induced changes in the pollen transcriptome.

Shifting gears: Creating equity informed leaders for effective learning health systems.

Leadership is vital to a well-functioning and effective health system. This importance was underscored during the COVID-19 pandemic. As disparities in infection and mortality rates became pronounced, greater calls for equity-informed healthcare emerged. These calls led some leaders to use the Learning Health System (LHS) approach to quickly transform research into healthcare practice to mitigate inequities causing these rates. The LHS is a relatively new framework informed by many within and outside health systems, supported by decision-makers and financial arrangements and encouraged by a culture that fosters quick learning and improvements. Although studies indicate the LHS can enhance patients' health outcomes, scarce literature exists on health leaders' use and incorporation of equity into the LHS. This article begins addressing this gap by examining how equity can be incorporated into LHS activities and discussing ways leaders can ensure equity is considered and achieved in rapid learning cycles.

Latent Class Groups of Concurrent Substance Use Among Adolescents in an Urban Community: Correlates With Mental Health, Access to Drugs and Alcohol, and Risk Perception.

BACKGROUND: Concurrent substance use among adolescents has been associated with an increase in physical and mental health problems. These outcomes tend to be exacerbated among adolescents of color in underserved urban settings. The purpose of this study was to understand alcohol and concurrent drug use patterns among adolescents in an underserved urban community to provide targeted prevention and treatment recommendations. METHOD: This study examined data among adolescents in an underserved urban community (N = 1789; 56.90% female; 70.86% Hispanic/Latino/a; meanage = 15.96 ± 1.56). Using latent class analysis (LCA) and multinomial logistic regression modeling, analyses identified independent correlates of latent class membership. RESULTS: Five latent classes (LC) were identified including LC group 1: Predominant alcohol use and limited to no concurrent-drug use (n = 213; 11.9%); LC group 2: Concurrent drug and alcohol use including methamphetamine, marijuana and synthetic marijuana use, and alcohol use (n = 74; 4.2%); LC group 3: Concurrent drug and alcohol use, with no marijuana use (n = 204; 11.39%); LC group 4: High Concurrent drug use and alcohol use (n = 204; 11.40%); and LC group 5: Concurrent drug use without alcohol use (n = 1101; 61.52%). Significant between group differences were noted between latent class groups and sociodemographic characteristics. Multinomial logistic regression models identified the associations between sociodemographic characteristics and corollary clinical features of substance use on latent class groupings of alcohol and concurrent drug use. CONCLUSION: Understanding concurrent substance use LC groups among adolescents is essential to providing targeted interventions and treatment programs, as well as early intervention programs that may help reduce substance use during adolescence.

In vitro cannabinoid receptor activity, metabolism, and detection in seized samples of CH-PIATA, a new indole-3-acetamide synthetic cannabinoid.

The rapidly evolving synthetic cannabinoid receptor agonist (SCRA) market poses significant challenges for forensic scientists. Since the enactment of a generic ban in China, a variety of new compounds have emerged capable of evading the legislation by carrying new structural features. One recent example of a SCRA with new linker and head moieties is CH-PIATA (CH-PIACA, CHX-PIATA, CHX-PIACA). CH-PIATA bears an additional methylene spacer in the linker moiety between the indole core and the traditional carbonyl component of the linker. This study describes detections in 2022 of this new SCRA in the United States, Belgium, and Scottish prisons. CH-PIATA was detected once in a seized powder by Belgian customs and 12 times in Scottish prisons in infused papers or resin. The metabolites of CH-PIATA were investigated via in vitro human liver microsome (HLM) incubations and eight metabolites were identified, dominated by oxidative biotransformations. A blood sample from the United States was confirmed to contain a mixture of SCRAs including CH-PIATA via presence of the parent and at least five of the metabolites identified from HLM incubations. Furthermore, this paper evaluates the intrinsic in vitro cannabinoid 1 and 2 (CB1 and CB2) receptor activation potential of CH-PIATA reference material and the powder seized by Belgian customs by means of ß-arrestin 2 recruitment assays. Both the reference and the seized powder showed a weak activity at both CB receptors with signs of antagonism found. Based on these results, the expected harm potential of this newly emerging substance remains limited.

Neurite-based white matter alterations in MAPT mutation carriers: A multi-shell diffusion MRI study in the ALLFTD consortium.

We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor imaging (DTI) (fractional anisotropy; FA, mean diffusivity; MD) and neurite orientation dispersion and density imaging (NODDI) (neurite density index; NDI, orientation and dispersion index; ODI). Linear mixed-effects models accounting for age and family relatedness revealed alterations across DTI and NODDI metrics in all mutation carriers and in symptomatic carriers, with the most significant differences involving fronto-temporal WM tracts. Asymptomatic carriers showed higher entorhinal MD and lower cingulum FA and patterns of higher ODI mostly involving temporal areas and long association and projections fibers. Regression models between estimated time to or time from disease and DTI and NODDI metrics in key regions (amygdala, cingulum, entorhinal, inferior temporal, uncinate fasciculus) in all carriers showed increasing abnormalities with estimated time to or time from disease onset, with FA and NDI showing the strongest relationships. Neurite-based metrics, particularly ODI, appear to be particularly sensitive to early WM involvement in asymptomatic carriers.