A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics

O’Reilly, Michael; Westgate, Connar; Hornby, Catherine; Botfield, Hannah; Taylor, Angela E.; Markey, Keira; Mitchell, James; Scotton, William; Mollan, Susan P; Yiangou, Andreas; Jenkinson, Carl; Gilligan, Lorna C; Sherlock, Mark; Gibney, James; Tomlinson, Jeremy; Lavery, Gareth G.; Hodson, David J.; Arlt, Wiebke; Sinclair, Alexandra J

doi:10.1172/jci.insight.125348

Cited by 82 publications

(121 citation statements)

References 41 publications

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“…This pathway is also often aggravated by thrombophilic exogenous oestrogens. In addition, further studies on the associations between CCL2 on inflammation of the arachnoid villi, hyperandrogenism and PCOS, may highlight a possible role in the cause of increased resistance to CSF drainage and elevated ICP in female IIH patients with obesity [37][38][39].…”

Section: Resistance To Csf Drainagementioning

confidence: 98%

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

Alimajstorovic

Pascual-Baixauli

Hawkes

et al. 2020

Fluids Barriers CNS

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Background: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by raised cerebrospinal fluid (CSF) pressure in the absence of any intracranial pathology. IIH mainly affects women with obesity between the ages of 15 and 45. Two possible mechanisms that could explain the increased CSF pressure in IIH are excessive CSF production by the choroid plexus (CP) epithelium or impaired CSF drainage from the brain. However, the molecular mechanisms controlling these mechanisms in IIH remain to be determined. Methods:In vivo ventriculo-cisternal perfusion (VCP) and variable rate infusion (VRI) techniques were used to assess changes in rates of CSF secretion and resistance to CSF drainage in female and male Wistar rats fed either a control (C) or high-fat (HF) diet (under anaesthesia with 20 μl/100 g medetomidine, 50 μl/100 g ketamine i.p). In addition, CSF secretion and drainage were assessed in female rats following treatment with inflammatory mediators known to be elevated in the CSF of IIH patients: C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-17 (IL-17), IL-6, IL-1β, tumour necrosis factor-α (TNF-α), as well as glucocorticoid hydrocortisone (HC). Results:Female rats fed the HF diet had greater CSF secretion compared to those on control diet (3.18 ± 0.12 μl/ min HF, 1.49 ± 0.15 μl/min control). Increased CSF secretion was seen in both groups following HC treatment (by 132% in controls and 114% in HF) but only in control rats following TNF-α treatment (137% increase). The resistance to CSF drainage was not different between control and HF fed female rats (6.13 ± 0.44 mmH 2 O min/μl controls, and 7.09 ± 0.26 mmH 2 O min/μl HF). and when treated with CCL2, both groups displayed an increase in resistance to CSF drainage of 141% (controls) and 139% (HF) indicating lower levels of CSF drainage. Conclusions:Weight loss and therapies targeting HC, TNF-α and CCL2, whether separately or in combination, may be beneficial to modulate rates of CSF secretion and/or resistance to CSF drainage pathways, both factors likely contributing to the raised intracranial pressure (ICP) observed in female IIH patients with obesity.

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Section: Resistance To Csf Drainagementioning

confidence: 98%

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

Alimajstorovic

Pascual-Baixauli

Hawkes

et al. 2020

Fluids Barriers CNS

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“…Idiopathic intracranial hypertension is characterized by a unique profile of androgen excess affecting the cerebrospinal fluid dynamics. 11 Androgen excess is a key driver of increased cardiovascular risk. 12 , 13 , 14 , 15 , 16 , 17 We hypothesized that patients with IIH may have an increased risk of cardiometabolic disease compared with a cohort matched for obesity (BMI), age, and sex.…”

Section: Introductionmentioning

confidence: 99%

Association Between Idiopathic Intracranial Hypertension and Risk of Cardiovascular Diseases in Women in the United Kingdom

et al. 2019

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Key PointsQuestionIs the risk of cardiovascular disease greater in women with idiopathic intracranial hypertension than in women of the same age and body mass index but without idiopathic intracranial hypertension?FindingsIn this population-based matched controlled cohort study of 2760 female patients with idiopathic intracranial hypertension and 27 125 control patients, women with this condition had twice the risk for cardiovascular disease compared with their counterparts with similar body mass index and age. Between 2005 and 2017, the incidence and prevalence of idiopathic intracranial hypertension have tripled.MeaningIdiopathic intracranial hypertension appeared to be a risk factor for cardiovascular disease in women; changing patient management to address the risk factors for cardiovascular disease may reduce long-term morbidity.

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“…A diagnostic feature is the presence of increased peri-optic CSF determined by neuroimaging [137]. O'Reilly et al [138] examined the systemic and CSF androgen metabolome in patients with IIH and found a unique signature of androgen excess and provide evidence that this may affect CSF secretion. There is also evidence that these patients may have defects in CSF drainage due to increased sagittal sinus venous pressure [139] and that there may be BBB dysfunction as measured by extravasated fibrinogen in the brain [136].…”

Section: Idiopathic Intracranial Hypertension (Iih)mentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

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Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics

Cited by 82 publications

References 41 publications

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

Association Between Idiopathic Intracranial Hypertension and Risk of Cardiovascular Diseases in Women in the United Kingdom

This was the year that was: brain barriers and brain fluid research in 2019

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