Multisystem pathology in McLeod syndrome.

We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.

Identifying healthy individuals with Alzheimer's disease neuroimaging phenotypes in the UK Biobank.

BACKGROUND: Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimer's disease (AD) in particular, to identify populations suitable for preventive and early disease-modifying trials. Evidence from genetic and other studies suggests the neurodegeneration of Alzheimer's disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be used to reliably detect prediagnostic sporadic disease. METHODS: We trained a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD score representing the probability of AD using structural MRI data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real-world dataset of the National Alzheimer's Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80) and demonstrate the correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimer's disease. RESULTS: We show that the cohort with a neuroimaging Alzheimer's phenotype has a cognitive profile in keeping with Alzheimer's disease, with strong evidence for poorer fluid intelligence, and some evidence of poorer numeric memory, reaction time, working memory, and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking. CONCLUSIONS: This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimer's disease.

Spotting people with dementia early is challenging, but important to identify people for trials of treatment and prevention. We used brain scans of people with Alzheimer's disease, the commonest type of dementia, and applied an artificial intelligence method to spot people with Alzheimer's disease. We used this to find people in the Healthy UK Biobank study who might have early Alzheimer's disease. The people we found had subtle changes in their memory and thinking to suggest they may have early disease, and we also found they had high blood pressure and smoked for longer. We have demonstrated an approach that could be used to select people at high risk of future dementia for clinical trials.

Association between Elevated Urine Neutrophil Gelatinase-Associated Lipocalin and Postoperative Acute Kidney Injury in Neonates.

OBJECTIVE: To examine the incidence of postoperative neonatal acute kidney injury (AKI) following general surgical procedures and to test the hypothesis that postoperative urine neutrophil gelatinase-associated lipocalin (uNGAL) concentrations predict AKI. The secondary objective was to evaluate for an association between AKI and hospital mortality. STUDY DESIGN: Prospective observational study of infants undergoing abdominal and thoracic surgical procedures in the neonatal intensive care unit from October 2018 to March 2020. The primary outcome was incidence of neonatal AKI (defined by the neonatal modified Kidney Diseases Improving Global Outcomes criteria) following each procedure to postoperative day 5. Severe AKI was defined as stage 2 or 3 AKI. Urine samples were obtained pre- and postoperatively at 6 time points to evaluate for levels of uNGAL. Secondary outcomes were in-hospital mortality and length of stay. RESULTS: Subjects (n = 141) underwent a total of 192 general surgical procedures during the study period. Neonatal AKI and severe AKI occurred following 36 (18%) and 15 (8%) procedures (n = 33 subjects). Percent change of uNGAL from 24 hours preoperatively to 24 hours postoperatively was greater in subjects with neonatal AKI (190.2% [IQR 0.0, 1666.7%] vs 0.7% [IQR -31.2%,140.2%], P = .0374). The strongest association of uNGAL and AKI occurred at 24 hours postoperatively (area under the receiver operator curves of 0.81, 95% CI 0.72, 0.89). Increased mortality risk was observed in subjects with any postoperative AKI (aOR 11.1 95% CI 2.0, 62.8, P = .0063) and severe AKI (aOR 13.8; 95% CI 3.0, 63.1, P = .0007). CONCLUSION: Elevation in uNGAL 24 hours postoperative was associated with AKI. Neonates with postoperative AKI had increased mortality.

A case report of metastatic renal cell carcinoma causing corticobasal syndrome.

We present a case report of a patient with a history of renal cell carcinoma in which corticobasal syndrome had been diagnosed ante-mortem. However, distinguishing features of corticobasal degeneration pathology were absent at post-mortem. Instead, neuropathological examination revealed features consistent with the patient's history of renal cell carcinoma: micrometastatic renal cell carcinoma in cerebellar and cerebral white matter, including within the gyral white matter of the primary motor and somatosensory cortices. There was also Purkinje cell loss and mild lymphocytic inflammation in the cerebellum, but the significance of this was unclear. A number of "corticobasal degeneration mimics" have been described in the literature, but micrometastatic carcinoma causing corticobasal syndrome is a novel finding. This case expands the range of clinical disorders which may mimic corticobasal degeneration to include micrometastatic carcinoma.

Clinicopathological co-occurrence of Fahr's disease and dementia with Lewy bodies.

We present the clinicopathological findings of a case of combined Fahr's disease (FD) and dementia with Lewy bodies (DLB), associated with a novel pathogenic mutation. The patient presented with visual hallucinations, fluctuating confusion and parkinsonism, leading to a presumptive diagnosis of DLB. CT scan showed extensive bilateral parenchymal calcifications, suggestive of FD. DNA sequencing identified a novel missense variant (c.92A>T p.(Asn31Ile)) in the SLC20A2 gene, a gene known to be associated with FD. This change has not been previously recorded in genetic repositories, and in silico analyses classified it as likely to be disease-causing. The patient died aged 77, four years after symptom onset. Neuropathological examination revealed, macroscopically and microscopically, extensive calcification in the striatum, globus and cerebellar white matter. There was also neuronal loss in the substantia nigra and residual neurones contained alpha-synuclein-positive Lewy bodies. The neuropathology was therefore consistent with DLB and FD. A literature review identified 3 other cases of co-existing Fahr's and Lewy body pathology, thus the frequency of dual pathology (44%) is higher than expected by random association. Further studies are needed to determine whether alpha-synucleinopathy is linked mechanistically to FD and/or represents a phenotypic subtype.

Evidence of a Causal Association Between Cancer and Alzheimer's Disease: a Mendelian Randomization Analysis.

While limited observational evidence suggests that cancer survivors have a decreased risk of developing Alzheimer's disease (AD), and vice versa, it is not clear whether this relationship is causal. Using a Mendelian randomization approach that provides evidence of causality, we found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84-0.99, p = 0.019), leukemia (OR 0.98, 95% CI 0.96-0.995, p = 0.012), and breast cancer (OR 0.94, 95% CI 0.89-0.99, p = 0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of AD, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of AD (OR 0.98, 95% CI 0.96-0.988, p = 0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with AD than non-smoking related cancers (OR 0.95, 95% CI 0.92-0.98, p = 0.0026, vs. OR 0.98, 95% CI 0.97-0.995, p = 0.0091).

Early microglial activation and peripheral inflammation in dementia with Lewy bodies.

Inflammation is increasingly recognized as part of the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, but its role in dementia with Lewy bodies remains unclear. Using multimodal imaging and peripheral cytokine analysis, we therefore investigated central and peripheral inflammation in this common form of dementia. Nineteen participants with probable dementia with Lewy bodies and 16 similarly aged controls underwent 3 T MRI and PET imaging with 11C-PK11195, a marker of microglial activation in vivo. Peripheral blood inflammatory cytokines were also measured in all subjects, as well as in an additional 10 controls, using the Mesoscale Human Cytokine 36 plex panel and additional assays for high sensitivity c-reactive protein, tumour necrosis factor receptor 1, IL-34, YKL-40 (chitinase-3-like protein 1) and colony stimulating factor 1. To test for the presence of in vivo amyloid, 11C-Pittsburgh compound B PET imaging was also performed in 16 of the dementia with Lewy body participants. Microglial activation was elevated in dementia with Lewy bodies subjects with mild disease when compared to those with moderate/severe impairment, where disease severity was indexed by cognitive performance on the revised Addenbrooke's Cognitive Examination. In patients, strong correlations were found between cognitive performance and 11C-PK11195 non-displaceable binding potential in several regions including the caudate nucleus (R = 0.83, P = 0.00008) and cuneus (R = 0.77, P = 0.0005). Several inflammatory cytokines were altered in the patients compared to controls, with elevated macrophage inflammatory protein-3 (P = 0.001), IL-17A (P = 0.008) and IL-2 (P = 0.046) and reduced IL-8 (P = 0.024). There was no correlation between cortical 11C-Pittsburgh compound B standardized uptake value ratio and clinical features, regional 11C-PK11195 binding or peripheral cytokine levels. Nor was there any regional correlation between 11C-PK11195 non-displaceable binding potentials and 11C-Pittsburgh compound B standardized uptake value ratios. Our findings provide evidence for both central and peripheral inflammatory changes in dementia with Lewy bodies, with microglial activation occurring early in the disease in key regions known to be associated with pathology, before declining as cognition declines. Raised peripheral cytokines associated with T cell function further suggest a role for the adaptive immune system in the pathogenesis of the disease.

Abscisic acid regulates root growth under osmotic stress conditions via an interacting hormonal network with cytokinin, ethylene and auxin.

Understanding the mechanisms regulating root development under drought conditions is an important question for plant biology and world agriculture. We examine the effect of osmotic stress on abscisic acid (ABA), cytokinin and ethylene responses and how they mediate auxin transport, distribution and root growth through effects on PIN proteins. We integrate experimental data to construct hormonal crosstalk networks to formulate a systems view of root growth regulation by multiple hormones. Experimental analysis shows: that ABA-dependent and ABA-independent stress responses increase under osmotic stress, but cytokinin responses are only slightly reduced; inhibition of root growth under osmotic stress does not require ethylene signalling, but auxin can rescue root growth and meristem size; osmotic stress modulates auxin transporter levels and localization, reducing root auxin concentrations; PIN1 levels are reduced under stress in an ABA-dependent manner, overriding ethylene effects; and the interplay among ABA, ethylene, cytokinin and auxin is tissue-specific, as evidenced by differential responses of PIN1 and PIN2 to osmotic stress. Combining experimental analysis with network construction reveals that ABA regulates root growth under osmotic stress conditions via an interacting hormonal network with cytokinin, ethylene and auxin.

Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.

Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.

Personality predicts the brain's response to viewing appetizing foods: the neural basis of a risk factor for overeating.

Eating is not only triggered by hunger but also by the sight of foods. Viewing appetizing foods alone can induce food craving and eating, although there is considerable variation in this "external food sensitivity" (EFS). Because increased EFS is associated with overeating, identifying its neural correlates is important for understanding the current epidemic of obesity. Animal research has identified the ventral striatum, amygdala, hypothalamus, medial prefrontal and premotor cortices as key interacting structures for feeding. However, it is unclear whether a similar network exists in humans and how it is affected by EFS. Using functional magnetic resonance imaging, we showed that viewing appetizing compared with bland foods produced changes in connectivity among the human ventral striatum, amygdala, anterior cingulate and premotor cortex that were strongly correlated with EFS. Differences in the dynamic interactions within the human appetitive network in response to pictures of appetizing foods may determine an individual's risk of obesity.

Phase 1 single dose studies to optimize the pharmacokinetics of DG17, a novel HIV-protease inhibitor pro-drug, using sodium bicarbonate and ritonavir.

DG17 is an orally available prodrug of DG35 (a novel HIV protease inhibitor with variable pharmacokinetics). These studies aimed to optimize DG17 pharmacokinetics by gastric acid neutralization and ritonavir pharmacoenhancement. Both studies were conducted using a randomized, cross-over design in which 6 healthy individuals were administered a single dose of 100mg or 200mg DG17, half with the study intervention (sodium bicarbonate solution in the first study, low dose ritonavir in the second). After a one week washout period, each subject was then administered a second dose of DG17, with the study intervention only administered to the other half. Cmax and AUC increases with gastric acid neutralization were greatest in those with the lowest absorption of DG17 alone. All doses were subsequently given with sodium bicarbonate solution in the second study. Low-dose ritonavir co-administration with DG17 increased DG35 C(max) (median 1437 versus 100 ng/ml, p=0.028) and AUC (median 6975 versus 154ng/ml*hr, p=0.028) compared with DG17 without ritonavir. Plasma DG35 exceeded the IC(90) for HIV for > or = 12 hours following a single DG17/ritonavir dose. No significant adverse events occurred. Single dose DG17 is safe and best administered in a manner preventing gastric acid degradation and with low-dose ritonavir.