Differentiating comorbidities and predicting prognosis in idiopathic normal pressure hydrocephalus using cerebrospinal fluid biomarkers: a review

Idiopathic normal pressure hydrocephalus (iNPH) is a condition resulting from impaired cerebrospinal fluid (CSF) absorption and excretion characterized by a triad of symptoms comprising dementia, gait disturbance (impaired trunk balance), and urinary incontinence. CSF biomarkers not only assist in diagnosis but are also important for analyzing the pathology and understanding appropriate treatment indications. As the neuropathological findings characteristic of iNPH have yet to be defined, there remains no method to diagnose iNPH with 100% sensitivity and specificity. Neurotoxic proteins are assumed to be involved in the neurological symptoms of iNPH, particularly the appearance of cognitive impairment. The symptoms of iNPH can be reversed by improving CSF turnover through shunting. However, early diagnosis is essential as once neurodegeneration has progressed, pathological changes become irreversible and symptom improvement is minimal, even after shunting. Combining a variety of diagnostic methods may lead to a more definitive diagnosis and accurate prediction of the prognosis following shunt treatment. Identifying comorbidities in iNPH using CSF biomarkers does not contraindicate shunting-based intervention, but does limit the improvement in symptoms it yields, and provides vital information for predicting post-treatment prognosi

Neuropathological findings in possible normal pressure hydrocephalus : A post-mortem study of 29 cases with lifelines

Publisher Copyright: © 2022, University of Muenster. All rights reserved.Aims: There are very few detailed post-mortem studies on idiopathic normal-pressure hydrocephalus (iNPH) and there is a lack of proper neuropathological criteria for iNPH. This study aims to update the knowledge on the neuropathology of iNPH and to develop the neuropathological diagnostic criteria of iNPH. Methods: We evaluated the clinical lifelines and post-mortem findings of 29 patients with possible NPH. Premortem cortical brain biopsies were taken from all patients during an intracranial pressure measurement or a cerebrospinal fluid (CSF) shunt surgery. Results: The mean age at the time of the biopsy was 70±8 SD years and 74±7 SD years at the time of death. At the time of death, 11/29 patients (38%) displayed normal cognition or mild cognitive impairment (MCI), 9/29 (31%) moderate dementia and 9/29 (31%) severe dementia. Two of the demented patients had only scarce neuropathological findings indicating a probable hydrocephalic origin for the dementia. Amyloid-β (Aβ) and hyperphosphorylated τ (HPτ) in the biopsies predicted the neurodegenerative diseases so that there were 4 Aβ positive/low Alzheimer’s disease neuropathological change (ADNC) cases, 4 Aβ positive/intermediate ADNC cases, 1 Aβ positive case with both low ADNC and progressive supranuclear palsy (PSP), 1 HPτ/PSP and primary age-related tauopathy (PART) case, 1 Aβ/HPτ and low ADNC/synucleinopathy case and 1 case with Aβ/HPτ and high ADNC. The most common cause of death was due to cardiovascular diseases (10/29, 34%), followed by cerebrovascular diseases or subdural hematoma (SDH) (8/29, 28%). Three patients died of a postoperative intracerebral hematoma (ICH). Vascular lesions were common (19/29, 65%). Conclusions: We update the suggested neuropathological diagnostic criteria of iNPH, which emphasize the rigorous exclusion of all other known possible neuropathological causes of dementia. Despite the first 2 probable cases reported here, the issue of “hydrocephalic dementia” as an independent entity still requires further confirmation. Extensive sampling (with fresh frozen tissue including meninges) with age-matched neurologically healthy controls is highly encouraged.Peer reviewe

Multiplexed Molecular Profiling of Lung Cancer Using Pleural Effusion

Introduction:Pleural effusion is frequently observed in patients with advanced lung cancer. Although effusion can be obtained less invasively and repeatedly, its use in multiplexed molecular profiling has not been fully investigated.Methods:Between July 2011 and April 2013, pleural effusion samples were obtained from patients with lung cancer at Shizuoka Cancer Center. They were analyzed for EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 mutations, EGFR, MET, FGFR1, FGFR2, and PIK3CA amplifications, and ALK, ROS1, and RET fusion genes using pyrosequensing and/or capillary electrophoresis, quantitative reverse-transcriptase polymerase chain reaction, and reverse-transcriptase polymerase chain reaction, respectively.Results:One hundred and two samples from 84 patients were analyzed. Adenocarcinoma was the most common histological subtype (82%). Genetic abnormalities were detected in 42% of patients. The most common abnormality was EGFR mutation (29%), followed by EML4-ALK rearrangement (5%), KRAS mutation, and EGFR amplification (4%, each). Concordance rates between pleural effusion and matched formalin-fixed, paraffin-embedded samples were 88%. Among 11 patients who provided samples at multiple time points, changes in molecular profile over the course of treatment were observed in five patients.Conclusions:The use of pleural effusion for multiplexed molecular testing and real-time monitoring in lung cancer was demonstrated

Total transferrin in cerebrospinal fluid is a novel biomarker for spontaneous intracranial hypotension

Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Patients with SIH experience postural headaches, nausea, etc., due to CSF hypovolemia. Imaging studies and clinical examinations, such as radioisotope (RI) scintigraphy, are useful for diagnosing SIH. However, 20-30% of patients do not show typical morphology and clinical test results. We previously reported that CSF contains transferrin (Tf) isoforms:"brain-type" Tf derived from the choroid plexus and "serum-type" Tf derived from blood. We showed that both isoforms increased in the CSF of patients with SIH by Western blotting. In the present study, we demonstrate that conventional ELISA for quantifying total Tf is useful for diagnosing SIH more accurately than Western blotting. In addition, SIH with chronic subdural hematoma (CSDH) was also accurately diagnosed. Total Tf in the CSF can serve as a useful biomarker for diagnosing SIH with or without CSDH

In Orbit Timing Calibration of the Hard X-Ray Detector on Board Suzaku

The hard X-ray detector (HXD) on board the X-ray satellite Suzaku is designed to have a good timing capability with a 61 $\mu$s time resolution. In addition to detailed descriptions of the HXD timing system, results of in-orbit timing calibration and performance of the HXD are summarized. The relative accuracy of time measurements of the HXD event was confirmed to have an accuracy of $1.9\times 10^{-9}$ s s$^{-1}$ per day, and the absolute timing was confirmed to be accurate to 360 $\mu$s or better. The results were achieved mainly through observations of the Crab pulsar, including simultaneous ones with RXTE, INTEGRAL, and Swift.Comment: Accepted for publication on PASJ Vol.60, SP-1, 200

The ASTRO-H X-ray Observatory

The joint JAXA/NASA ASTRO-H mission is the sixth in a series of highly successful X-ray missions initiated by the Institute of Space and Astronautical Science (ISAS). ASTRO-H will investigate the physics of the high-energy universe via a suite of four instruments, covering a very wide energy range, from 0.3 keV to 600 keV. These instruments include a high-resolution, high-throughput spectrometer sensitive over 0.3-2 keV with high spectral resolution of Delta E < 7 eV, enabled by a micro-calorimeter array located in the focal plane of thin-foil X-ray optics; hard X-ray imaging spectrometers covering 5-80 keV, located in the focal plane of multilayer-coated, focusing hard X-ray mirrors; a wide-field imaging spectrometer sensitive over 0.4-12 keV, with an X-ray CCD camera in the focal plane of a soft X-ray telescope; and a non-focusing Compton-camera type soft gamma-ray detector, sensitive in the 40-600 keV band. The simultaneous broad bandpass, coupled with high spectral resolution, will enable the pursuit of a wide variety of important science themes.Comment: 22 pages, 17 figures, Proceedings of the SPIE Astronomical Instrumentation "Space Telescopes and Instrumentation 2012: Ultraviolet to Gamma Ray

The Quiescent Intracluster Medium in the Core of the Perseus Cluster

Clusters of galaxies are the most massive gravitationally-bound objects in the Universe and are still forming. They are thus important probes of cosmological parameters and a host of astrophysical processes. Knowledge of the dynamics of the pervasive hot gas, which dominates in mass over stars in a cluster, is a crucial missing ingredient. It can enable new insights into mechanical energy injection by the central supermassive black hole and the use of hydrostatic equilibrium for the determination of cluster masses. X-rays from the core of the Perseus cluster are emitted by the 50 million K diffuse hot plasma filling its gravitational potential well. The Active Galactic Nucleus of the central galaxy NGC1275 is pumping jetted energy into the surrounding intracluster medium, creating buoyant bubbles filled with relativistic plasma. These likely induce motions in the intracluster medium and heat the inner gas preventing runaway radiative cooling; a process known as Active Galactic Nucleus Feedback. Here we report on Hitomi X-ray observations of the Perseus cluster core, which reveal a remarkably quiescent atmosphere where the gas has a line-of-sight velocity dispersion of 164+/-10 km/s in a region 30-60 kpc from the central nucleus. A gradient in the line-of-sight velocity of 150+/-70 km/s is found across the 60 kpc image of the cluster core. Turbulent pressure support in the gas is 4% or less of the thermodynamic pressure, with large scale shear at most doubling that estimate. We infer that total cluster masses determined from hydrostatic equilibrium in the central regions need little correction for turbulent pressure.Comment: 31 pages, 11 Figs, published in Nature July