Sheryl Foster

Chronic effects of dietary Vitamin D deficiency without increased calcium supplementation on the progression of experimental polycystic kidney disease

Increasing evidence indicates that vitamin D deficiency exacerbates chronic kidney injury, but its effects on renal enlargement in polycystic kidney disease (PKD) are not known. In this study, male Lewis polycystic kidney disease (LPK) rats received a normal diet (ND; AIN-93G) supplemented with or without cholecalciferol (vitamin D-deficient diet, VDD; both 0.5% calcium), commenced at either postnatal week 3 (until weeks 10-20; study 1) or from week 10 (until week 20; study 2). Levels of 25-hydroxy vitamin D were reduced in groups receiving the VDD (12 ± 1 nmol/l vs. 116 ± 5 in ND; P < 0.001). In study 1, food intake and weight gain increased by ∼25% in LPK rats receiving the VDD ad libitum, and at week 20 this was associated with a mild reduction in the corrected serum calcium (SCa(2+), 7.4%) and TKW:BW ratio (8.8%), and exacerbation of proteinuria (87%) and hypertension (19%; all P < 0.05 vs. ND). When LPK rats were pair-fed for weeks 3-10, there was a further reduction in the SCa(2+) (25%) and TKW:BW ratio (22%) in the VDD group (P < 0.05 vs. ND). In study 2, the VDD did not alter food intake and body weight, reduced SCa(2+) (7.7%), worsened proteinuria (41.9%), interstitial monocyte accumulation (26.4%), renal dysfunction (21.4%), and cardiac enlargement (13.2%, all P < 0.05), but there was a trend for a reduction in the TKW:BW ratio (13%, P = 0.09). These data suggest that chronic vitamin D deficiency has adverse long-term actions on proteinuria, interstitial inflammation, renal function, and cardiovascular disease in PKD, and these negate its mild inhibitory effect on kidney enlargement.

Young Australian adults with NF1 have poor access to health care, high complication rates, and limited disease knowledge†

Neurofibromatosis type 1 (NF1) is a multisystem disease associated with a lifelong risk of debilitating and potentially life‐limiting complications, however many adults with NF1 have no regular health surveillance. We interviewed and examined 17 young adults with NF1 between the ages of 25 and 33. Most had not been assessed for NF1‐related complications within the previous 8 years, including patients with known serious vascular complications, for example, renal artery stenosis. Acute and/or chronic pain, particularly back and plexiform‐related pain were common symptoms, and despite a significant impact on quality of life, was untreated in most instances. Symptom and examination‐directed imaging revealed serious complications in 41% of the cohort. These included severe spinal cord compression (two cases), a highly SUV avid lesion suggestive of malignancy (one case), and a Juvenile Pilocytic Astrocytoma in a patient without any previous NF1‐related complications. Few study participants had a good understanding of NF1, its associated risks and complications, and many had not sought appropriate medical advice as questions or problems arose. NF1‐related cognitive deficits in some participants, and the lack of a clear source of expert medical advice for adults with NF1 likely contributed to poor health surveillance and management in this population. Overall, these findings suggest that many Australian adults with NF1 are at risk of serious and life‐threatening medical complications, but are not accessing and receiving adequate health care. Access to multidisciplinary adult clinics that specialize in NF1 may address many of the unmet health needs of young adults with NF1.

Cognitive control network anatomy correlates with neurocognitive behavior: A longitudinal study.

Cognitive control is the process of employing executive functions, such as attention, planning or working memory, to guide appropriate behaviors in order to achieve a specific goal. Functional magnetic resonance imaging studies suggest a superordinate cognitive control network, comprising the dorsal regions of the lateral prefrontal cortex (DLPFC), anterior cingulate cortex (dACC) and parietal cortex (DPC). How gray matter structure changes across this network throughout neurodevelopment and how these changes impact cognitive control are not yet fully understood. Here we investigate changes in gray matter volume of the key nodes of the cognitive control network using structural MRI scans from 176 participants aged 8–38 years. One hundred and eleven of these also completed a longitudinal follow‐up at two years. We compare these with performance on a cognitive battery also measured at these two time points. We found that volume decreases in the cognitive control network were associated with improved performance in executive function (in left DLPFC and bilateral DPC), information processing (in bilateral dACC and right DPC) and emotion identification tasks (left DLPFC). These results were significant after controlling for age. Furthermore, gray matter changes were coordinated across the network. These findings imply age‐independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains. This study provides insight into the direct impact of structural changes on behavior within this network during neurodevelopment and provides a normative evidence base to better understand development of cognitive dysfunction in brain disorders. Hum Brain Mapp 38:631–643, 2017.

Potential structural and functional biomarkers of upper motor neuron dysfunction in ALS

Abstract Assessment of upper motor neuron (UMN) function in amyotrophic lateral sclerosis (ALS) remains clinically based. Given the potential difficulties in identifying UMN signs, objective biomarkers of UMN dysfunction are important. Consequently, the present study assessed utility of cortical thickness analysis combined with threshold tracking transcranial magnetic stimulation (TMS) as biomakers of UMN dysfunction in ALS. Cortical thickness analysis and threshold tracking TMS studies were undertaken on 25 ALS patients and results were compared to healthy control subjects, with different control groups used for each technique. Structural and functional abnormalities were evident in both motor cortices in the ALS cohort and were heralded by marked reduction of short-interval intracortical inhibition (SICI RAPB 1.4 ± 2.4%; SICI LAPB 3.6 ± 1.9%; SICI CONTROLS10.5 ± 1.1%, p <0.01), resting motor threshold (p <0.05) and cortical silent period duration (p <0.001) combined with increase in MEP amplitude (p <0.05) and intracortical facilitation (p <0.05). Significant cortical thinning was evident in the bitemporal regions (p <0.05), while precentral gyrus cortical thinning was evident in 56% of cases and when combined with TMS abnormalities disclosed UMN dysfunction in 88% of cases. In conclusion, findings from the present study establish that a combination of structural and functional assessment of corticomotoneurons may increase the yield of objectively identifying UMN dysfunction in ALS.

Pharyngeal mucosal wall folds in subjects with obstructive sleep apnea

Mechanical processes underlying pharyngeal closure have not been examined. We hypothesized that the pharyngeal mucosal surface would fold during closure, and lowering the upper airway lining liquid surface tension would unfold areas of mucosal apposition, i.e., folds. We compared baseline pharyngeal fold numbers and response to reduction in upper airway liquid surface tension in healthy and obstructive sleep apnea (OSA) subjects. Awake, gated magnetic resonance pharyngeal airway images of 10 healthy and 11 OSA subjects were acquired before and after exogenous surfactant administration (beractant). Upper airway liquid surface tension was measured at the beginning and end of image acquisition and averaged. Velopharyngeal and oropharyngeal images were segmented and analyzed separately for average cross-sectional area, circumference, and fold number. Compared with healthy subjects, at baseline, velopharynx for OSA subjects had a smaller cross-sectional area (98.3 ± 32.5 mm(2) healthy, 52.3 ± 23.6 mm(2) OSA) and circumference (46.5 ± 8.1 mm healthy, 30.8 ± 6.1 mm OSA; both P < 0.05, unpaired t-test), and fewer folds (4.9 ± 1.6 healthy, 3.1 ± 1.8 OSA, P < 0.03). There were no differences in oropharynx for cross-sectional area, circumference, or folds. Reduction in upper airway liquid surface tension from 61.3 ± 1.2 to 55.3 ± 1.5 mN/m (P < 0.0001) did not change cross-sectional area or circumference for velopharynx or oropharynx in either group; however, in OSA subjects, oropharyngeal folds fell from 6.8 ± 3.1 to 4.7 ± 1.2 (n = 8, P < 0.05), and velopharyngeal folds from 3.3 ± 1.9 to 2.3 ± 1.2 (P = 0.08), and were unchanged in healthy subjects. Subjects with OSA have fewer velopharyngeal wall folds, which decrease further when surface tension falls. We speculate that reduced pharyngeal wall folds contribute to an increase in pharyngeal collapsibility.

Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD)

Introduction Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1–3) due to ADPKD. Methods and analysis A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. Ethics and dissemination The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. Trial registration number ANZCTR12614001216606.

Effects of TORC1 inhibition during the early and established phases of polycystic kidney disease

The disease-modifying effects of target of rapamycin complex 1 (TORC1) inhibitors during different stages of polycystic kidney disease (PKD) are not well defined. In this study, male Lewis Polycystic Kidney Disease (LPK) rats (a genetic ortholog of human NPHP9, phenotypically characterised by diffuse distal nephron cystic growth) and Lewis controls received either vehicle (V) or sirolimus (S, 0.2 mg/kg by intraperitoneal injection 5 days per week) during the early (postnatal weeks 3 to 10) or late stages of disease (weeks 10 to 20). In early-stage disease, sirolimus reduced kidney enlargement (by 63%), slowed the rate of increase in total kidney volume (TKV) in serial MRI by 78.2% (LPK+V: 132.3±59.7 vs. LPK+S: 28.8±12.0% per week) but only partly reduced the percentage renal cyst area (by 19%) and did not affect the decline in endogenous creatinine clearance (CrCl) in LPK rats. In late-stage disease, sirolimus reduced kidney enlargement (by 22%) and the rate of increase in TKV by 71.8% (LPK+V: 13.1±6.6 vs. LPK+S: 3.7±3.7% per week) but the percentage renal cyst area was unaltered, and the CrCl only marginally better. Sirolimus reduced renal TORC1 activation but not TORC2, NF-κB DNA binding activity, CCL2 or TNFα expression, and abnormalities in cilia ultrastructure, hypertension and cardiac disease were also not improved. Thus, the relative treatment efficacy of TORC1 inhibition on kidney enlargement was consistent at all disease stages, but the absolute effect was determined by the timing of drug initiation. Furthermore, cystic microarchitecture, renal function and cardiac disease remain abnormal with TORC1 inhibition, indicating that additional approaches to normalise cellular dedifferentiation, inflammation and hypertension are required to completely arrest the progression of PKDs.

Brain functional connectome abnormalities in amyotrophic lateral sclerosis are associated with disability and cortical hyperexcitability

The present study utilized a multimodal approach encompassing connectome networks combined with brain volume analysis, and assessment of cortical excitability to provide novel insights into amyotrophic lateral sclerosis (ALS) pathogenesis.

Cognitive ability is associated with changes in the functional organization of the cognitive control brain network

Cognitive control is one of the most important skills in day‐to‐day social and intellectual functioning but we are yet to understand the neural basis of the group of behaviors required to carry this out. Here, we probed changes over time in the brain network associated with cognitive control (the dorsolateral prefrontal cortex, the dorsal posterior parietal cortex, and the dorsal anterior cingulate cortex) using both behavioral assays and functional brain imaging during a selective working memory task in 69 healthy participants within the age range 18–38 years (mean: 25, SD: ±6), assessed twice, 2 years apart. We aimed to explore the relationship of changing network activation and connectivity with behavioral tasks associated with cognitive control in this otherwise neurodevelopmentally stable group. We found that increased connectivity between frontoparietal cognitive control network regions during the working memory task was associated with improved memory and executive functions over the 2‐year period and that this association was not impacted by age, gender, or baseline performance. These results provide evidence that changes in the functional organization of the cognitive control brain network occur despite the absence of neurodevelopment, aging or targeted cognitive training effects, and could modulate cognitive performance in early to mid‐adulthood. Understanding how and why this change is occurring could provide insights into the mechanisms through which cognitive control ability is cultivated over time. This could aid in the development of interventions in cases where cognitive control is impaired.

Amygdala activation and connectivity to emotional processing distinguishes asymptomatic patients with bipolar disorders and unipolar depression

BACKGROUND Mechanistically based neural markers, such as amygdala reactivity, offer one approach to addressing the challenges of differentiating bipolar and unipolar depressive disorders independently from mood state and acute symptoms. Although emotion-elicited amygdala reactivity has been found to distinguish patients with bipolar depression from patients with unipolar depression, it remains unknown whether this distinction is traitlike and present in the absence of an acutely depressed mood. We addressed this gap by investigating patients with bipolar disorder (BP) and unipolar major depressive disorder (MDD) in remission. METHODS Supraliminal and subliminal processing of faces exhibiting threat, sad, happy, and neutral emotions during functional magnetic resonance imaging was completed by 73 participants (23 BP patients and 25 MDD patients matched for age and gender, number of depressive episodes and severity; 25 age- and gender-matched healthy control subjects). We compared groups for activation and connectivity for the amygdala. RESULTS BP patients had lower left amygdala activation than MDD patients during supraliminal and subliminal threat, sad, and neutral emotion processing and for subliminal happy faces. BP patients also exhibited lower amygdala connectivity to the insula and hippocampus for threat and to medial orbitofrontal cortex for happy supraliminal and subliminal processing. BP patients also demonstrated greater amygdala-insula connectivity for sad supraliminal and subliminal face processing. Both patient groups were distinct from control subjects across several measures for activation and connectivity. CONCLUSIONS Independent of valence or level of emotional awareness, amygdala activation and connectivity during facial emotion processing can distinguish BP patients and MDD patients. These findings provide evidence that this neural substrate could be a potential trait marker to differentiate these two disorders largely independent of illness state.