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The selective vulnerability of brain networks in individuals at risk for Alzheimer’s disease (AD) may help differentiate pathological from normal aging at asymptomatic stages, allowing the implementation of more effective interventions. We used a sample of 72 people across the age span, enriched for the APOE4 genotype to reveal vulnerable networks associated with a composite AD risk factor including age, genotype, and sex. Sparse canonical correlation analysis (CCA) revealed a high weight associated with genotype, and subgraphs involving the cuneus, temporal, cingulate cortices, and cerebellum. Adding cognitive metrics to the risk factor revealed the highest cumulative degree of connectivity for the pericalcarine cortex, insula, banks of the superior sulcus, and the cerebellum. To enable scaling up our approach, we extended tensor network principal component analysis, introducing CCA components. We developed sparse regression predictive models with errors of 17% for genotype, 24% for family risk factor for AD, and 5 years for age. Age prediction in groups including cognitively impaired subjects revealed regions not found using only normal subjects, i.e. middle and transverse temporal, paracentral and superior banks of temporal sulcus, as well as the amygdala and parahippocampal gyrus. These modeling approaches represent stepping stones towards single subject prediction.

Aim Drivers of extant population genetic structure include past climate-driven range shifts and vicariant events, as well as gene flow mediated by dispersal and habitat continuity. Their integration as alternative or complementary drivers is often missing or incomplete, potentially overlooking relevant processes and time scales. Here we ask whether it is the imprint of past range shifts or habitat connectivity driven by oceanographic transport that best explain genetic structure in a poorly understood model, a forest-forming African kelp. Location Southwestern coast of Africa (Benguela current region). Taxon Laminaria pallida. Methods We estimated genetic variability along the species distributional range using 14 microsatellite markers. This genetic variability was compared to estimates of past range shifts derived from species distribution modelling for the Last Glacial Maximum (LGM), the mid-Holocene (MH) and the present, and estimates of habitat connectivity derived from oceanographic biophysical modelling. Results The species is structured in two clusters, a southern cluster with much richer (allelic richness A: 10.40 +/- 0.33) and unique (private alleles PA: 56.69 +/- 4.05) genetic diversity, and a northern cluster (A: 4.75 +/- 0.17; PA: 6.70 +/- 1.45). These clusters matched well-known biogeographical regions and their transition coincided with a dispersal barrier formed by upwelled offshore transport. No major range shifts or vicariant events were hindcasted along the present range, suggesting population stability from the LGM to the present. Main conclusions Habitat connectivity, rather than past range shifts, explains the extant population structure. Future environmental requirements of the species along the Benguela upwelling system are projected to persist or even intensify, likely preserving the observed genetic patterns for the years to come. Yet, the differentiation and endemicity between clusters, and the isolation structured by the regional oceanography, implies high conservation value for genetic biodiversity, and even more if considering the ecological, social and economic services provided by kelp forests. info:eu-repo/semantics/acceptedVersion

Understanding the interplay between genotype, age, and sex has potential to reveal factors that determine the switch between successful and pathological aging. APOE allelic variation modulate brain vulnerability and cognitive resilience during aging and Alzheimer disease (AD). The APOE4 allele confers the most risk and has been extensively studied with respect to the control APOE3 allele. The APOE2 allele has been less studied, and the mechanisms by which it confers cognitive resilience and neuroprotection remain largely unknown. Using mouse models with targeted replacement of the murine APOE gene with the human major APOE2 alleles we sought to identify changes during a critical period of middle to old age transition, in a mouse model of resilience to AD. Age but not female sex was important in modulating learning and memory estimates based on Morris water maze metrics. A small but significant 3% global brain atrophy due to aging was reflected by regional atrophy in the cingulate cortex 24, fornix and hippocampal commissure (>9%). Females had larger regional volumes relative to males for the bed nucleus of stria terminalis, subbrachial nucleus, postsubiculum (~10%), and claustrum (>5%), while males had larger volumes for the orbitofrontal cortex, frontal association cortex, and the longitudinal fasciculus of pons (>9%). Age promoted atrophy in both white (anterior commissure, corpus callosum, etc.), and gray matter, in particular the olfactory cortex, frontal association area 3, thalamus, hippocampus and cerebellum. A negative age by sex interaction was noted for the olfactory areas, piriform cortex, amygdala, ventral hippocampus, entorhinal cortex, and cerebellum, suggesting faster decline in females. Fractional anisotropy indicated an advantage for younger females for the cingulate cortex, insula, dorsal thalamus, ventral hippocampus, amygdala, visual and entorhinal cortex, and cerebellum, but there was faster decline with age. Interestingly white matter tracts were largely spared in females during aging. We used vertex screening to find associations between connectome and traits such as age and sex, and sparse multiple canonical correlation analysis to integrate our analyses over connectomes, traits, and RNA-seq. Brain subgraphs favored in males included the secondary motor cortex and superior cerebellar peduncle, while those for females included hippocampus and primary somatosensory cortex. Age related connectivity loss affected the hippocampus and primary somatosensory cortex. We validated these subgraphs using neural networks, showing increased accuracy for sex prediction from 81.9% when using the whole connectome as a predictor, to 94.28% when using the subgraphs estimated through vertex screening. Transcriptomic analyses revealed the largest fold change (FC) for age related genes was for Cpt1c (log2FC = 7.1), involved in transport of long-chain fatty acids into mitochondria and neuronal oxidative metabolism. Arg1, a critical regulator of innate and adaptive immune responses (log2FC = 4.9) also showed age specific changes. Amongst the sex related genes, the largest FC were observed for Maoa (log2FC = 4.9) involved in the degradation of the neurotransmitters serotonin, epinephrine, norepinephrine, and dopamine, and implicated in response to stress. Four genes were common for age and sex related vulnerability: Myo1e (log2FC = −1.5), Creld2 (log2FC = 1.4), Ptprt (log2FC = 2.9), and Pex1 (log2FC = 3.6). We tested whether blood gene expression help track phenotype changes with age and sex. Genes with the highest weight after connectome filtering included Ankzfp1 with a role in maintaining mitochondrial integrity under stress, as well as Pex1, Cep250, Nat14, Arg1, and Rangrf. Connectome filtered genes pointed to pathways relate to stress response, transport, and metabolic processes. Our modeling approaches using sparse canonical correlation analysis help relate quantitative traits to vulnerable brain networks, and blood markers for biological processes. Our study shows the APOE2 impact on neurocognition, brain networks, and biological pathways during a critical middle to old age transition in an animal model of resilience. Identifying changes in vulnerable brain and gene networks and markers of resilience may help reveal targets for therapies that support successful aging.

The brown algal genus Lobophora (Dictyotales, Phaeophyceae) is an important ecological component of tropical marine systems. Although still scantily sampled, 35 species of Lobophora were discovered previously from the western Indian Ocean. This study updates previous diversity estimates by incorporating recent collections from Madagascar, Mozambique, and the Red Sea, considerably improving our knowledge of Lobophora diversity and biogeography in this region. Eight additional species are identified from the western Indian Ocean, raising the total number of Lobophora species to 43. Fifteen species are new to science and described herein. With ca. 40% of the global diversity, the western Indian Ocean is second only to the Central IndoPacific. Of the species identified to date, 29 appear to be restricted to the western Indian Ocean, three are shared with the Atlantic (four including L. lessepsiana introduced to the western Mediterranean Sea) and 12 have a wider distribution in the Indo-Pacific. The western Indian Ocean supports a high diversity with ca. 67% of its Lobophora restricted to this region, which is comparable to the Central Indo-Pacific (62%) and the Caribbean (61%). The presence of several putative endemic species in the western Indian Ocean islands and the Red Sea illustrates that these provinces played an important role in Lobophora species diversification within the western Indian Ocean by producing locally new species. The small number of species shared between the western Indo-Pacific and Atlantic indicates that this oceanic boundary - associated with the temperate Agulhas marine province, and the Benguela current and upwelling - acts as an effective dispersal barrier. info:eu-repo/semantics/publishedVersion

We extend the scope of full configuration interaction quantum Monte Carlo (FCIQMC) to be applied to coupled fermion-boson hamiltonians, alleviating the a priori truncation in boson occupation which is necessary for many other wave function based approaches to be tractable. Detailing the required algorithmic changes for efficient excitation generation, we apply FCIQMC in two contrasting settings. The first is a sign-problem-free Hubbard--Holstein model of local electron-phonon interactions, where we show that with care to control for population bias via importance sampling and/or reweighting, the method can achieve unbiased energies extrapolated to the thermodynamic limit, without suffering additional computational overheads from relaxing boson occupation constraints. Secondly, we apply the method as a `solver' within a quantum embedding scheme which maps electronic systems to local electron-boson auxiliary models, with the bosons representing coupling to long-range plasmonic-like fluctuations. We are able to sample these general electron-boson hamiltonians with ease despite a formal sign problem, including a faithful reconstruction of converged reduced density matrices of the system.

Age-related macular degeneration (AMD) is a prevalent disease impeding vision. More recently, AMD has also been linked to cognitive impairment, such as deficits in language and memory skills. In order to better understand the extent of AMD-related changes in the whole brain structure and connectivity, we have conducted an MRI diffusion acquisition study on 40 participants (20 diagnosed with AMD and 20 controls). These acquisitions were then performed again in a follow up two years later. We developed novel analysis methods for diffusion based tractography and connectomes to better determine which, if any, brain region connections saw the greatest changes between the AMD and the age-matched control groups. Using voxel-based analysis, we identified atrophy in AMD participants in the cuneate gyrus, which has been associated with vision, and the left superior temporal gyrus, which has been associated with language, while later acquisitions compounded this with a deficiency in the bilateral cingulate gyrus, itself linked to higher cognition and memory. These regional atrophy findings support that people with AMD experience widespread neuronal degradation that is not limited to retinal neurons. Regions that saw drastically lowered fractional anisotropy among AMD vs. control included the visual cortex, such as the bilateral occipital lobe and the frontoparietal cortex. Tensor Network Principal Component Analysis (TN-PCA) isolated lingual and temporal connections as important differentiators of AMD connectomes compared to controls, thus supporting our morphometric and texture findings in regions related to vision, but also connectopathies of language and memory brain regions. Bundle based analyses in baseline data revealed that the lingual gyrus had greater spread of tracts overall in the AMD participants, which may be explained by prior reorganization in this area, demonstrating a connection between retinal health and lingual structure. Moreover, we noted group differences in the interhemispheric temporal connections, and lingual cerebellar connections, supporting extensive downstream effects of vision loss. Our bundle-based analyses expand the toolset available for neuroimaging-based phenotyping, and reveal widespread changes in AMD participants beyond brain regions and tractography networks directly involved in vision processing, including those involved in language and memory.

Brain connectomes provide untapped potential for identifying individuals at risk for Alzheimer’s disease (AD), and can help provide novel targets based on selective circuit vulnerability. Age, APOE4 genotype, and female sex are thought to contribute to the selective vulnerability of brain networks in Alzheimer’s disease, in a manner that differentiates pathological versus normal aging. These brain networks may predict pathology otherwise hard to detect, decades before overt disease manifestation and cognitive decline. Uncovering network based biomarkers at prodromal, asymptomatic stages may offer new windows of opportunity for interventions, either therapeutic or preventive. We used a sample of 72 people across the age span to model the relationship between Alzheimer’s disease risk and vulnerable brain networks. Sparse Canonical Correlation analysis (SCCA) revealed relationships between brain subgraphs and AD risk, with bootstrap based confidence intervals. When constructing a composite AD risk factor based on sex, age, genotype, the highest weight was associated with genotype. Next, we mapped networks associated with auditory, visual, and olfactory memory, and identified networks extending beyond the main nodes known to be involved in these functions. The inclusion of cognitive metrics in a composite risk factor pointed to vulnerable networks, and associated with the specific memory tests. These regions with the highest cumulative degree of connectivity in our studies were the pericalcarine, insula, banks of the superior sulcus and cerebellum. To help scale up our approach, we extended Tensor Network Principal Component Analysis (TNPCA) to evaluate AD risk related subgraphs, introducing CCA components and sparsity. When constructing a composite AD risk factor based on sex, age, and genotype, and family risk factor the most significant risk was associated with age. Our sparse regression based predictive models revealed vulnerable networks associated with known risk factors. The prediction error was 17% for genotype, 24% for family risk factor, and 5 years for age. Age prediction in groups including MCI and AD subjects involved several regions that were not prominent for age prediction otherwise. These regions included the middle and transverse temporal, paracentral and superior banks of temporal sulcus, as well as the amygdala and parahippocampal gyrus. The joint estimation of AD risk and connectome based mappings involved the cuneus, temporal, and cingulate cortices known to be associated with AD, and add new candidates, such as the cerebellum, whose role in AD is to be understood. Our predictive modeling approaches for AD risk factors represent a stepping stone towards single subject prediction, based on distances from normative graphs.

G Protein-Coupled Receptor Kinase-Interacting Protein-1 (GIT1) regulates neuronal functions, including cell and axon migration and synapse formation and maintenance, and GIT1 knockout (KO) mice exhibit learning and memory deficits. We noted that male and female GIT1-KO mice exhibit neuroimaging phenotypes including microcephaly, and altered cortical layering, with a decrease in neuron density in cortical layer V. Micro-CT and magnetic resonance microscopy (MRM) were used to identify morphometric phenotypes for the skulls and throughout the GIT1-KO brains. High field MRM of actively-stained mouse brains from GIT1-KO and wild type (WT) controls (n = 6 per group) allowed segmenting 37 regions, based on co-registration to the Waxholm Space atlas. Overall brain size in GIT1-KO mice was ~32% smaller compared to WT controls. After correcting for brain size, several regions were significantly different in GIT1-KO mice relative to WT, including the gray matter of the ventral thalamic nuclei and the rest of the thalamus, the inferior colliculus, and pontine nuclei. GIT1-KO mice had reduced volume of white matter tracts, most notably in the anterior commissure (~26% smaller), but also in the cerebral peduncle, fornix, and spinal trigeminal tract. On the other hand, the basal ganglia appeared enlarged in GIT1-KO mice, including the globus pallidus, caudate putamen, and particularly the accumbens - supporting a possible vulnerability to addiction. Volume based morphometry based on high-resolution MRM (21.5 μm isotropic voxels) was effective in detecting overall, and local differences in brain volumes in GIT1-KO mice, including in white matter tracts. The reduced relative volume of specific brain regions suggests a critical, but not uniform, role for GIT1 in brain development, conducive to brain microcephaly, and aberrant connectivity.

The species diversity of Callithamnion sensu lato in South Africa is re-visited using existing literature, morphology and DNA. The identity of a putative new species is confirmed as distinct using DNA and is described here as Callithamnion africanum sp. nov. Callithamnion africanum differs molecularly and morphologically from a similar species, C. cordatum with which it shares a similar habitat and distribution range in South Africa. Callithamnion africanum is resolved in the Callithamnion sensu stricto clade and is sister to the type species of the genus, Callithamnion corymbosum. Additionally, Callithamnion stuposum, a species described from South Africa and a common component of the seaweed flora, was recovered in the larger, unresolved Callithamnion sensu lato clade. An updated species inventory of Callithamnion sensu lato in South Africa is provided, and indicates a lack of sequence data for the large majority of species. Furthermore, a global rbcL phylogeny highlights a number of taxonomic concerns regarding the classification of taxa circumscribed to Callithamnion sensu lato and calls for a global revision using DNA, type specimens or material collected from near type localities.

The seaweed industry of temperate Southern Africa was last reviewed in 2003. Since then there have been considerable changes. There are three main uses of kelp (mostly Ecklonia maxima, with some Laminaria pallida) in South Africa. The collection of wash-up for drying and exporting for alginate extraction has drastically reduced to very small amounts in recent years. The boat harvest of fresh kelp for abalone feed in land-based farms has reached a plateau of between 4000 and 5000 t fresh per annum. The diver harvest of E. maxima for agricultural liquid plant growth enhancer shows a constant increase over several years, is still growing, and is currently over 3000 t fresh per annum. The small intertidal collection of Gelidium pristoides as export for agar production has maintained a small, sustainable production of around 100 t dry for many years. Former Gracilaria industries in sheltered bays in both South Africa and Namibia have collapsed, and there is currently no commercial collection. There was commercial raft aquaculture production of Gracilaria in Lüderitz Bay, Namibia for a number of years, but this is no longer practised. Currently, the only commercial seaweed use in Namibia is of L. pallida. Annually, ca. 150 t of fresh wash-up is collected, in Lüderitz, to be used as feed in land-based abalone aquaculture. There are a number of small start-up companies experimenting with seaweed products for cosmetics and nutritional products in both countries, some involving species of Ulva and Porphyra. The former species is a major aquaculture product, with around 2000 t fresh yr–1 being produced in integrated land-based systems with abalone.

Since its reinstatement, the diversity of the genus Pyropia has never been fully assessed in the Benguela Marine Province in southern Africa (South Africa and Namibia), although it has been included in previous, more general biodiversity assessments. The aim of the present study was to revisit the diversity and identity of species of Pyropia from the region, using an integrative taxonomic approach, including a multigene phylogeny, morphological characterisation and ecological data. The phylogenetic affinities of southern African Pyropia to other species around the world were assessed using three unlinked loci (cox1, rbcL, nSSU rDNA). A species first collected on the South African coast ca. 60 years ago is described as a new species, Pyropia meridionalis, and extended descriptions and further information provided on the distribution and ecology for two previously described species endemic to the Benguela Marine Province: Py. saldanhae and Py. aeodis. Lastly, the identity and occurrence of Py. gardneri, a species widely distributed in North America, could not be confirmed in South Africa, while the cosmopolitan Py. suborbiculata likely occurs in the region but is currently lacking molecular data. The phylogenetic relationships between species from southern Africa and other species occurring in the Southern Hemisphere support the notion of historic connectivity in the Southern Ocean, but also indicate a much more complex historical biogeographical history as some clades are deeply divergent while others are more closely related.

The Mediterranean mussel Mytilus galloprovincialis is the most significant invasive alien marine species in South Africa and, although not normally found subtidally, has recently been observed colo...

Introduction Giant pituitary tumor, defined as >4cm, comprise 6-10% of all pituitary tumors. Giant GH-secreting pituitary tumors are rare and difficult to treat. They typically invade surrounding structures ​such as the cavernous sinus, making ​complete resection challenging or impossible. This report highlights a case of giant GH-secreting pituitary tumor with an unusual clinical presentation.CLINICAL CASE: A 56 Y/O male with hypertension, cardiomyopathy, obesity, and OSA presented to the ER with stroke-like symptoms. Brain CT and MRI revealed small acute to subacute infarcts within the left occipital, left frontal, right frontal, right parietal areas, and right cerebellum. An incidental finding was a 4.3 cm T2 hyperintense enhancing mass centered within the skull base with involvement of the sella, extension into bilateral cavernous sinuses, clivus, encasement of bilateral carotid arteries, and invasion through the sphenoid sinus into the nasopharyngeal space resulting in a preoperative CSF. He was overtly acromegalic with coarse facial features, prominent frontal bossing, early prognathism, and macroglossia. Hands and feet were enlarged, but non-edematous. Visual field testing was normal. Laboratory values: IGF-1, 317 ng/mL (NL Conclusion This patient had the unique presentation of florid acromegaly and CSF leak mainly related to his delay in seeking medical care. Absence of visual defects has been noted in only 15% of reported patients with giant GH-secreting adenomas. Massive replacement of the sphenoid sinus by a giant pituitary tumor causing a CSF leak with invasion into the ​cavernous sinuses and clivus has been rarely reported. Trans-sphenoidal resection is the preferred first-line treatment for patients with acromegaly. The remission rate decreases and can reach almost 0% for giant GH-secreting tumors. Somatostatin receptor analogs (SRA) are the preferred first-line pharmacological treatment as an adjuvant therapy for residual tumor. Our patient likely will need continued SRA and potentially other modalities to control acromegaly due to unresectable tumor anatomy. This case also highlights the complications of delayed detection and benefits of extensive TSS surgical resection with the goal to enhance his response to SRA. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer's disease, and even in cognitively normal individuals at risk for Alzheimer's disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer's disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric was sensitive to sex differences, supporting increased vulnerability in females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer's disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer's disease.

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease.

We investigate fully self-consistent multiscale quantum-classical algorithms on current generation superconducting quantum computers, in a unified approach to tackle the correlated electronic structure of large systems in both quantum chemistry and condensed matter physics. In both of these contexts, a strongly correlated quantum region of the extended system is isolated and self-consistently coupled to its environment via the sampling of reduced density matrices. We analyze the viability of current generation quantum devices to provide the required fidelity of these objects for a robust and efficient optimization of this subspace. We show that with a simple error mitigation strategy and optimization of compact tensor product bases to minimize the number of terms to sample, these self-consistent algorithms are indeed highly robust, even in the presence of significant noises on quantum hardware. Furthermore, we demonstrate the use of these density matrices for the sampling of non-energetic properties, including dipole moments and Fermi liquid parameters in condensed phase systems, achieving a reliable accuracy with sparse sampling. It appears that uncertainties derived from the iterative optimization of these subspaces is smaller than variances in the energy for a single subspace optimization with current quantum hardware. This boosts the prospect for routine self-consistency to improve the choice of correlated subspaces in hybrid quantum-classical approaches to electronic structure for large systems in this multiscale fashion.

Advanced biophysical models like neurite orientation dispersion and density imaging (NODDI) have been developed to estimate the microstructural complexity of voxels enriched in dendrites and axons for both in vivo and ex vivo studies. NODDI metrics derived from high spatial and angular resolution diffusion MRI using the fixed mouse brain as a reference template have not yet been reported due in part to the extremely long scan time required. In this study, we modified the three-dimensional diffusion-weighted spin-echo pulse sequence for multi-shell and undersampling acquisition to reduce the scan time. This allowed us to acquire several exhaustive datasets that would otherwise not be attainable. NODDI metrics were derived from a complex eight shell diffusion (1000 – 8000 s/mm(2)) dataset with 384 diffusion gradient encoding directions at 50 μm isotropic resolution. These provided a foundation for exploration of tradeoffs among acquisition parameters. A three-shell acquisition strategy covering low, medium, and high b values with at least angular resolution of 64 is essential for ex vivo NODDI experiments. The good agreement between neurite density index (NDI) and the orientation dispersion index (ODI) with the subsequent histochemical analysis of myelin and neuronal density highlights that NODDI could provide new insight into the microstructure of the brain. Furthermore, we found that NDI is sensitive to microstructural variations in the corpus callosum using a well-established demyelination cuprizone model. The study lays the ground work for developing protocols for routine use of high resolution NODDI method in characterizing brain microstructure in mouse models.

IntroductionDiabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD.Methods and analysisVeterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period.Ethics and disseminationThis study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal.Trial registration numberNCT03625648.