Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.
Abstract Clinical trials in Alzheimer’s disease (AD) aim to reduce the rate of progression of disease. This is heavily dependent on a consensus of a minimum clinically important difference as well as the ability of the cognitive and functional measures used to accurately measure progression. In this study we perform a systematic review and meta-regression to assess the precision of measurement of AD clinical progression in clinical trials of therapeutic interventions in patients with known positive amyloid status prior to trial entry. Meta analyses of randomised controlled trials (RCT) in AD, with amyloid positive status (Aβ+) as an inclusion criterion, were undertaken with functional, cognitive, and composite measures included in the analyses. Twenty-five RCTs were eligible for inclusion. Whilst most RCTS enrolled prodromal or mild AD patients with an average MMSE score at baseline of 27, several included average MMSE scores as low as 22. We performed meta regressions, correcting for age, gender, and stage of disease in R version 4.2.0, using the metafor and emmeans libraries. Of the progression measures included in the meta-analyses, the FAQ, a functional measure, had the largest weighted mean change over 12-weeks followed by MMSE, whilst the most commonly used neuropsychiatric battery, NPI, failed to show sensitivity to change in the given time period. This study emphasises the necessity of appropriate composite progression measures that weigh cognitive, functional and neuropsychiatric symptoms according to their ability to detect meaningful change in symptoms and thus have a better chance of detecting meaningful change in participants of interventional RCTs. Summary Background Alzheimer’s disease (AD) is a slowly progressive disease. It is now widely recognised that there is a pre-clinical phase. This phase of the disease may be apparent via biomarker testing up to 20 years before clinically evident AD. Pre-clinical AD is then followed by clinically significant cognitive decline ranging from MCI to severe AD. The aim of randomised controlled trials (RCT) is to reduce or halt the rate of clinical progression of AD. Most of these trials have been unsuccessful. To determine the effectiveness of treatments there must be robust and reliable tools for measuring AD progression. For at least 30 years there has been recognition that the measures of progression used in AD clinical trials are problematic. A significant concern is that current measures of clinical progression are potentially not sensitive enough in early and preclinical stages of AD and so are not reliable indicators of AD progression. In this systematic review and meta-regression we aimed to assess the precision of measurements of clinical progression in AD clinical trials of therapeutic interventions in patients with known positive amyloid status prior to trial entry. Methods Meta analyses of RCTs in AD with amyloid positive status (Aβ+) as an inclusion criterion was undertaken with functional, cognitive, and composite measures included in the analyses. Twenty-five RCTs were eligible for inclusion. Statistical analyses were performed using R version 4.2.0 and the metafor and emmeans libraries. Findings Of the progression measures commonly reported in RCTs, the FAQ, had the largest weighted mean change over 12-weeks followed by MMSE. Other cognitive measures were amongst the least sensitive measures over the chosen time period. As a composite score, both the iADRS and CDRSB appear to be performing better than the cognitive components they comprise. The neuropsychiatric battery analysed in this study appeared to be the least sensitive of measures of progression. Interpretation Functional measures, with the exception of QoL-AD, perform better than other groups of measures. Measures which rely on purely cognitive domains are not optimal for sole use in AD trials. Ideally, measures should include both cognitive and functional components to enhance sensitivity. New composite measures address the poorer performance of composite scores, as compared to their comprising functional measures, by assigning different weights to cognitive and functional change.
The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats.We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate.At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999).Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.
Purpose To use perfusion and magnetic resonance (MR) spectroscopy to compare the diffusion tensor imaging (DTI)‐defined invasive and noninvasive regions. Invasion of normal brain is a cardinal feature of glioblastomas (GBM) and a major cause of treatment failure. DTI can identify invasive regions. Materials and Methods In all, 50 GBM patients were imaged preoperatively at 3T with anatomic sequences, DTI, dynamic susceptibility perfusion MR (DSCI), and multivoxel spectroscopy. The DTI and DSCI data were coregistered to the spectroscopy data and regions of interest (ROIs) were made in the invasive (determined by DTI), noninvasive regions, and normal brain. Values of relative cerebral blood volume (rCBV), N‐acetyl aspartate (NAA), myoinositol (mI), total choline (Cho), and glutamate + glutamine (Glx) normalized to creatine (Cr) and Cho/NAA were measured at each ROI. Results Invasive regions showed significant increases in rCBV, suggesting angiogenesis (invasive rCBV 1.64 [95% confidence interval, CI: 1.5–1.76] vs. noninvasive 1.14 [1.09–1.18]; P < 0.001), Cho/Cr (invasive 0.42 [0.38–0.46] vs. noninvasive 0.35 [0.31–0.38]; P = 0.02) and Cho/NAA (invasive 0.54 [0.41–0.68] vs. noninvasive 0.37 [0.29–0.45]; P = < 0.03), suggesting proliferation, and Glx/Cr (invasive 1.54 [1.27–1.82] vs. noninvasive 1.3 [1.13–1.47]; P = 0.028), suggesting glutamate release; and a significantly reduced NAA/Cr (invasive 0.95 [0.85–1.05] vs. noninvasive 1.19 [1.06–1.31]; P = 0.008). The mI/Cr was not different between the three ROIs (invasive 1.2 [0.99–1.41] vs. noninvasive 1.3 [1.14–1.46]; P = 0.68). In the noninvasive regions, the values were not different from normal brain. Conclusion Combining DTI to identify the invasive region with perfusion and spectroscopy, we can identify changes in invasive regions not seen in noninvasive regions. J. Magn. Reson. Imaging 2016;43:487–494.
Abstract To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy–Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy–Richardson, 52 with a progressive supranuclear palsy–cortical variant (progressive supranuclear palsy–frontal, progressive supranuclear palsy–speech/language, or progressive supranuclear palsy–corticobasal), and 17 with a progressive supranuclear palsy–subcortical variant (progressive supranuclear palsy–parkinsonism or progressive supranuclear palsy–progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a ‘subcortical’ subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a ‘cortical’ subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy–subcortical cases and 81% of progressive supranuclear palsy–Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy–cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the ‘subcortical’ subtype was associated with worse clinical severity scores compared to the ‘cortical subtype’ (progressive supranuclear palsy rating scale and Unified Parkinson’s Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.
Idiopathic intracranial hypertension (IIH) causes headaches, vision loss, and reduced quality of life. Sustained weight loss among patients with IIH is necessary to modify the disease and prevent relapse.
Objective
To compare the effectiveness of bariatric surgery with that of a community weight management (CWM) intervention for the treatment of patients with active IIH.
Design, Setting, and Participants
This 5-year randomized clinical trial (Idiopathic Intracranial Hypertension Weight Trial) enrolled women with active IIH and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or higher at 5 National Health Service hospitals in the UK between March 1, 2014, and May 25, 2017. Of 74 women assessed for eligibility, 6 did not meet study criteria and 2 declined to participate; 66 women were randomized. Data were analyzed from November 1, 2018, to May 14, 2020.
Interventions
Bariatric surgery (n = 33) or CWM intervention (Weight Watchers) (n = 33).
Main Outcomes and Measures
The primary outcome was change in intracranial pressure measured by lumbar puncture opening pressure at 12 months, as assessed in an intention-to-treat analysis. Secondary outcomes included lumbar puncture opening pressure at 24 months as well as visual acuity, contrast sensitivity, perimetric mean deviation, and quality of life (measured by the 36-item Short Form Health Survey) at 12 and 24 months. Because the difference in continuous outcomes between groups is presented, the null effect was at 0.
Results
Of the 66 female participants (mean [SD] age, 32.0 [7.8] years), 64 (97.0%) remained in the clinical trial at 12 months and 54 women (81.8%) were included in the primary outcome analysis. Intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, −6.0 [1.8] cm cerebrospinal fluid [CSF]; 95% CI, −9.5 to −2.4 cm CSF;P = .001) and at 24 months (adjusted mean [SE] difference, −8.2 [2.0] cm CSF; 95% CI, −12.2 to −4.2 cm CSF;P < .001) compared with the CWM arm. In the per protocol analysis, intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, −7.2 [1.8] cm CSF; 95% CI, −10.6 to −3.7 cm CSF;P < .001) and at 24 months (adjusted mean [SE] difference, −8.7 [2.0] cm CSF; 95% CI, −12.7 to −4.8 cm CSF;P < .001). Weight was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, −21.4 [5.4] kg; 95% CI, −32.1 to −10.7 kg;P < .001) and at 24 months (adjusted mean [SE] difference, −26.6 [5.6] kg; 95% CI, −37.5 to −15.7 kg;P < .001). Quality of life was significantly improved at 12 months (adjusted mean [SE] difference, 7.3 [3.6]; 95% CI, 0.2-14.4;P = .04) and 24 months (adjusted mean [SE] difference, 10.4 [3.8]; 95% CI, 3.0-17.9;P = .006) in the bariatric surgery arm.
Conclusions and Relevance
In this randomized clinical trial, bariatric surgery was superior to a CWM intervention in lowering intracranial pressure. The continued improvement over the course of 2 years shows the impact of this intervention with regard to sustained disease remission.
Aims and methods Patients with idiopathic intracranial hypertension (IIH) often report significant morbidity associated with lumbar punctures. We therefore aimed to assess the patient’s experience of diagnostic lumbar puncture (LP) in IIH using an online survey designed in collaboration with IIH: UK (a leading UK charity). Results 463 patients responded to the survey, and were eligible for analysis, over a 2 month period in 2015. 40% of patients described severe pain during the LP (VRS≥8), and the median pain score during the LP was 7 (VRS, IQR 5–7). The majority of patients felt they received insufficient pain relief (85%). Levels of anxiety about future LP’s were high (median VRS 7, IQR 4–10), with 47% being extremely anxious (VRS≥8). LPs performed as an emergency were associated with significantly greater pain scores compared to elective procedures (median 7, IQR 5–7 vs 6, IQR 4–8, p=0.012). Higher LP pain scores (VRS) were significantly associated with poorly informed patients (Spearman correlation, r=−0.32, p<0.001). Conclusions This study has shown that a significant number of these patients are experiencing significant morbidity from pain and anxiety. This morbidity is associated with both inadequate pre-procedural information, as well as the setting the LP is performed in.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
