Intracranial myxoid angiomatoid fibrous histiocytoma with "classic" histology and EWSR1:CREM fusion providing insight for reconciliation with intracranial myxoid mesenchymal tumors.

Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft tissue neoplasm that can exhibit diverse morphological features, including myxoid change. Rarely, the tumor occurs intracranially and poses considerable diagnostic challenges to neuropathologists. This is compounded by a recently coined entity, referred to as intracranial myxoid mesenchymal tumor (IMMT). These tumors show significant overlaps with intracranial myxoid AFH from clinicopathological and molecular genetic viewpoints. We described an unusual intracranial tumor in a 30-year-old man. The tumor exhibited "classic" histological features of myxoid AFH and EWSR1:CREM fusion, a relatively novel variant of EWSR1:CREB family fusion, first identified in IMMT. We also performed a comprehensive literature review comparing the clinicopathological features of intracranial AFHs and IMMTs. Peritumoral lymphoplasmacytic cuffing appears to be the only morphological finding that is consistently absent in reported cases of IMMT while being present in most intracranial AFHs. Otherwise, both tumors showed considerable overlaps in clinical, histological, and immunohistochemical features and have a common molecular genetic signature of EWSR1:CREB family fusion, including EWSR1:CREM fusion. Our case appeared to be the first described EWSR1:CREM-fused intracranial tumor to show prominent peritumoral lymphoplasmacytic cuffing and myxoid change in addition to most of the other "classic" morphologic features of AFH. As such, while the current literature appears to be lacking when it comes to defining intracranial myxoid AFH and IMMT as separate nosological entities, they likely represent a morphological spectrum of a common entity characterized by EWSR1 rearrangement, akin to solitary fibrous tumors and hemangiopericytomas with the signal transducer and activator of transcription 6 gene (STAT6) rearrangement.

The impact of luteinizing hormone and testosterone on beta amyloid (Aß) accumulation: Animal and human clinical studies.

This article is part of a Special Issue "SBN 2014". Hormonal changes associated with ageing have been implicated in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia. Reductions in serum testosterone and increases in luteinizing hormone (LH) are established AD risk factors for dementia in men and have important roles in modulating AD pathogenesis. One of the defining features of AD is the accumulation of amyloid-beta (Aß) in the brain, which has a key role in the neurodegenerative cascade. Both testosterone and LH have been shown to modulate CNS Aß accumulation in animal studies, and associations with cerebral amyloid load in human studies have supported this. The underlying mechanisms by which these hormones modulate Aß accumulation and contribute to neurodegeneration are not completely understood, however they have been shown to regulate Aß metabolism, enhance its clearance and alter the processing of its parent molecule, the amyloid precursor protein. This review will discuss underlying mechanisms by which testosterone and LH modulate Aß and provide an update on therapeutic approaches targeting these hormones.

Direct exposure of guinea pig CNS to human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels.

BACKGROUND/AIMS: Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aß), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aß metabolism. However, whether LH can directly modulate cerebral Aß levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aß levels. METHODS: Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aß levels measured via ELISA. Levels of the Aß precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. RESULTS: An increase in CSF Aß40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aß40 levels observed in brain homogenates. No change was observed in plasma Aß40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. CONCLUSION: These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aß levels, perhaps due to altered APP expression/metabolism.

A case series and review of the mononostril endoscopic transnasal transsphenoidal approach: Safe and effective in a low resource setting.

BACKGROUND: A transnasal transsphenoidal (TNTS) approach can be performed through a binostril or mononostril technique. The binostril technique is generally preferred, however the mononostril may be an underutilized approach with significant benefits. METHODS: All (n = 521) pituitary adenoma transsphenoidal surgeries performed from March 2008 until July 2017 at a university hospital in Indonesia were isolated. The majority (n = 512) were performed through a mononostril approach with no nasal speculum by a single experienced neurosurgeon. A PubMed literature review researching the differences in indications, techniques, and outcomes for both approaches supplements the case series. The mononostril surgical technique is described in detail. RESULTS: The average mononostril operating time was 105 min. The most prevalent surgical complications were CSF leak (4.1 %), diabetes insipidus (3.7 %) and cacosmia (2.1 %). Visual field deficits noted in 85 %, 89 % improved. Length of stay was less than 2 days for 90 %, with 13 ICU admissions (average one day). Recurrence rate was 8.2 % at follow up (1-10 years). CONCLUSIONS: Based on a literature review, binostril TNTS surgeries have longer operative time and a higher risk of epistaxis. According to our experience, post-operative patient comfort and satisfaction are higher with the monostril approach. Furthermore, this technique is easier to teach, ENT assistance unnecessary, and thus especially advantageous in low resource settings. Our CSF leak and tumor recurrence rates were lower than reported binostril rates in the literature. The mononostril technique is both safe and effective and should be strongly considered for an appropriately pre-selected subset of pituitary adenomas.

Global incidence of brain and spinal tumors by geographic region and income level based on cancer registry data.

While obtaining accurate estimates of tumor incidence volume is a difficult technical problem because it requires collating and analyzing data from dozens of world-wide sources curated under different conditions, our study aims to determine the global incidence of brain and spinal tumors. We analyzed 207 tumor registries on five continents, and calculated age-standardized rates to compare tumor incidence between geographic regions and income levels. Based on data available in current cancer registries, the apparent global incidence of malignant brain tumors was 4.25 cases per 100,000 person-years (95% CI [4.21-4.29]), and varied by region from 6.76 [6.71-6.80] in Europe to 2.81 [2.64-2.99] in Africa. Incidence also varied by World Bank income group, ranging from 6.29 [6.26-6.32] cases per 100,000 in high income countries (HICs), to 4.81 [4.77-4.86] in low and middle-income countries (LMICs). Malignant spinal tumors were much less frequent globally (0.098 [0.093-0.104]) and varied similarly by region and income group. The incidence of brain and spinal tumors varies by region and income group, although case ascertainment bias driven by limited resources in low income regions likely plays a role in variance. The burden of neurosurgical disease in LMICs is large, and similar in scale to HICs.

Distinct effects of testosterone on plasma and cerebrospinal fluid amyloid-beta levels.

The effect of testosterone on the levels of the Alzheimer's disease amyloid-beta peptide (Abeta) was investigated in guinea pigs. Castrated guinea pigs (GPX) were administered testosterone at two different dosages, following which plasma and cerebrospinal fluid (CSF) Abeta_{40} levels were measured. Plasma Abeta_{40} levels were reduced in GPX in the early stages of low-dose testosterone treatment, whereas CSF Abeta_{40} levels were only reduced by the time circulating testosterone had returned to untreated GPX levels. The supraphysiological testosterone dose did not reduce CSF Abeta_{40} levels significantly until circulating testosterone was back to uncastrated levels, whereas plasma Abeta_{40} levels significantly increased over time in these animals. These results indicate that the extent of testosterone-induced changes to Abeta_{40} levels and their response rates depend on both the tissue examined and testosterone dosage.

Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies.

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-ß peptide (also known as Aß or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aß peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aß.

The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men.

Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer's disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively determine the significance of testosterone treatment.

Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety.

Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.