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 prognosis.

Connectome analysis of male world-class gymnasts using probabilistic multishell, multitissue constrained spherical deconvolution tracking.

In athletes, long-term intensive training has been shown to increase unparalleled athletic ability and might induce brain plasticity. We evaluated the structural connectome of world-class gymnasts (WCGs), as mapped by diffusion-weighted magnetic resonance imaging probabilistic tractography and a multishell, multitissue constrained spherical deconvolution method to increase the precision of tractography at the tissue interfaces. The connectome was mapped in 10 Japanese male WCGs and in 10 age-matched male controls. Network-based statistic identified subnetworks with increased connectivity density in WCGs, involving the sensorimotor, default mode, attentional, visual, and limbic areas. It also revealed a significant association between the structural connectivity of some brain structures with functions closely related to the gymnastic skills and the D-score, which is used as an index of the gymnasts' specific physical abilities for each apparatus. Furthermore, graph theory analysis demonstrated the characteristics of brain anatomical topology in the WCGs. They displayed significantly increased global connectivity strength with decreased characteristic path length at the global level and higher nodal strength and degree in the sensorimotor, default mode, attention, and limbic/subcortical areas at the local level as compared with controls. Together, these findings extend the current understanding of neural mechanisms that distinguish WCGs from controls and suggest brain anatomical network plasticity in WCGs resulting from long-term intensive training. Future studies should assess the contribution of genetic or early-life environmental factors in the brain network organization of WCGs. Furthermore, the indices of brain topology (i.e., connection density and graph theory indices) could become markers for the objective evaluation of gymnastic performance.

Regional brain gray matter volume in world-class artistic gymnasts.

The relationship between long-term intensive training and brain plasticity in gymnasts has recently been reported. However, the relationship between abilities in different gymnastic events and brain structural changes has not been explored. This study aimed to evaluate the correlation between world-class gymnasts (WCGs)' specific abilities in different gymnastics events and their gray matter (GM) volume. Ten right-handed Japanese male WCGs and 10 right-handed gender- and age-matched controls with no history of gymnastic training participated in this study. Whole brain three-dimensional T1-weighted images (magnetization-prepared rapid gradient-echo sequence) with 0.90 mm3 voxels were obtained using a 3 T-MRI scanner from each subject. Volume-based morphometry (VolBM) was used to compare GM volume differences between WCGs and controls. We then explored the correlation between specific gymnastic abilities using different gymnastic apparatuses, and GM volume. Significantly higher GM volumes (false discovery rate-corrected p < 0.05) in the inferior parietal lobule, middle temporal gyrus, precentral gyrus, rostral middle frontal gyrus, and superior frontal gyrus were demonstrated in WCGs, compared with controls using VolBM. Moreover, significant positive correlations were observed between brain regions and the difficulty scores for each gymnastic event, for example, rings and inferior parietal lobule and parallel bars and rostral middle frontal gyrus. These results may reflect the neural basis of an outstanding gymnastic ability resulting from brain plasticity in areas associated with spatial perception, vision, working memory, and motor control.

Functional MRI and Structural Connectome Analysis of Language Networks in Japanese-English Bilinguals.

We aimed to clarify the mechanisms of neural plasticity involved in language. We hypothesized that alterations which occur in bilinguals could reflect the mechanisms of acquisition of a second language and simulate neural plasticity related to language. We compared spatial characteristics of story listening-related hemodynamic modulations and subcortical fiber networks between monolinguals and bilinguals. Participants were Japanese monolinguals and Japanese-English bilinguals whose first language was Japanese. We divided bilinguals into early and late bilinguals depending on whether the age of acquisition was before after 7 years of age. We applied intergroup analysis to investigate the following: (1) blood oxygen level-dependent response (BOLD) responses during story listening by block-based fMRI; (2) number of fibers (NOFs) between specific edges by DTI. Both bilingual samples showed larger BOLD responses (BRs) in the right putamen and bilateral superior temporal gyri compared to the Japanese monolinguals in fMRI. Late bilinguals demonstrated bigger BRs in the right anterior temporal lobe and left medial parietal lobe than early bilinguals. Early bilinguals showed a higher NOFs between the right putamen and precentral gyrus than monolinguals and late bilinguals in DTI. Late bilinguals showed a lower NOFs between the left superior temporal gyrus and supramarginal gyrus than monolinguals and early bilinguals. Early bilinguals reinforce the subcortical fiber network between the right putamen and precentral gyrus, and activate the right putamen to gain alternative language function. We conclude that these key cerebral regions and subcortical fiber networks could contribute to the neural plasticity of language.

Mixed gangliocytoma-pituitary adenoma containing GH and GHRH co-secreting adenoma cells.

SUMMARY: A 67-year-old woman with a past history of type 2 diabetes mellitus presented with worsening glycemic control. She had some acromegaly symptoms and magnetic resonance imaging demonstrated a pituitary tumor. Endocrinological examination found the resting growth hormone (GH) level within the normal range, but elevated insulin-like growth factor 1 level. A 75 g oral glucose tolerance test showed inadequate suppression of nadir GH levels. Acromegaly due to GH-secreting pituitary tumor was diagnosed. The patient underwent endoscopic transsphenoidal surgery resulting in gross total removal of the tumor and recovered well postoperatively. Histological examination of the tumor showed coexistence of relatively large gangliocytoma cells and pituitary adenoma cells, suggesting mixed gangliocytoma-pituitary adenoma. In addition, colocalization of GH and GH-releasing hormone (GHRH) in pituitary adenoma cells was revealed, so the adenomatous components were more likely to produce GHRH in our mixed gangliocytoma-pituitary adenoma case. Mixed gangliocytoma-pituitary adenoma is very rare, and the present unique case demonstrated only the adenomatous components associated with GHRH production. LEARNING POINTS: Sellar gangliocytoma coexisting with pituitary adenoma is recognized as a mixed gangliocytoma-pituitary adenoma and is very rare. A proposed developmental mechanism of growth hormone (GH)-secreting mixed gangliocytoma-pituitary adenoma involves GH-releasing hormone (GHRH) produced by the gangliocytic components promoting the growth of tumor including GH-secreting adenomatous components. Since our present case indicated that the adenomatous components of mixed gangliocytoma-pituitary adenoma could secrete both GH and GHRH simultaneously, progression of GH-secreting mixed gangliocytoma and pituitary adenoma may involve exposure to spontaneously produced GHRH due to the adenomatous components.

Shunt Malfunction and Calcification of Abdominal Fascia Tissue Resulting in Obstruction of Abdominal Catheter.

BACKGROUND: Experiencing a ventriculoperitoneal (VP) shunt complication is a major obstacle in the management of hydrocephalus. Degradation of a shunt catheter associated with surrounding tissue calcification could be 1 reason for a difference in facture rates. Furthermore, tissue reactions around cerebrospinal fluid shunts may be a sign of bacterial shunt infection, which is not uncommon. CASE DESCRIPTION: A 31-year-old man was living with a ventriculoperitoneal shunt since childhood. Consequently, his cerebrospinal fluid absorption was supposed to be modified by the shunt. Shunt malfunction later occurred concomitant with symptoms of headache and repeated vomiting. He had undergone shunt revision a year before presentation, but examination revealed that a new, extremely rare calcified lesion had formed in the aponeurosis of the abdomen, compressing the shunt tube. We removed it and replaced the shunt tube, thus relieving his symptoms. CONCLUSIONS: We treated a rare case of shunt dysfunction caused by calcification of the aponeurosis coinciding with significant weight gain over the course of a year. To the best of our knowledge, this is the first report to describe a case of shunt malfunction caused by calcification of the aponeurosis.

Background Risk Factors Associated with Shunt Intervention for Possible Idiopathic Normal Pressure Hydrocephalus: A Nationwide Hospital-Based Survey in Japan.

BACKGROUND: Patients with idiopathic normal-pressure hydrocephalus (iNPH) are typically older adults with multiple comorbidities that are associated with a reduction in the efficacy of iNPH treatment via cerebrospinal fluid (CSF) shunt placement. OBJECTIVE: The present study aimed to investigate the effectiveness of CSF shunt for iNPH using data from a nationwide epidemiological survey in Japan. METHODS: We examined 1,423 patients (581 women) aged ≥60 years (median age [25%-75%]: 77 [73-80] years) who were diagnosed with iNPH following a hospital visit in 2012. Patients who experienced an improvement of at least one modified Rankin Scale (mRS) grade after the CSF shunt were classified as "improvement" while the remaining patients were classified as "non-improvement." The efficacy of the shunt intervention (n = 842) was analyzed using a binomial logistic regression analysis. RESULTS: An analysis of risk factors associated with shunt placement in patients with mRS grade 2 revealed an association between comorbid chronic ischemic lesions (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.11-4.67; p = 0.025) and cervical spondylosis (OR, 3.62; 95% CI, 1.15-11.34; p = 0.027). Patients with mRS grade 3 at study entry had an association with comorbid Alzheimer's disease (OR, 3.02; 95% CI, 1.44-6.31; p = 0.003). CONCLUSIONS: The results presented here showed that any age-related risk is minimal and should not be cause for rejection of surgical treatment options. Clinical decisions regarding CSF shunt should be individualized to each patient, with adequate consideration of the relative risks and benefits, including maximizing a healthy life expectancy.

Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated. OBJECTIVE: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. METHODS: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. RESULTS: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. CONCLUSIONS: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A Comparison of Small-Lumen Abdominal Catheters to Gravitational Add-On Valves in a Single Center.

BACKGROUND: Treating idiopathic normal pressure hydrocephalus (iNPH) with lumboperitoneal shunts (LPSs) may cause cerebrospinal fluid (CSF) overdrainage. OBJECTIVE: To investigate whether LPSs, including gravitational "add-on" and programmable pressure valves (PPVs/+GVs), reduce complications and improve outcomes. METHODS: We compared PPVs/+small lumen abdominal catheters (SLs) to PPVs/+GVs using different opening pressures for supine and standing positions. We analyzed 115 patients with iNPH in 2 consequent cohorts: 48 patients receiving LPSs with PPVs/+SLs and 67 patients receiving LPSs with PPVs/+GVs. The modified Rankin Scale (mRS), Japan iNPH grading scale, Mini Mental State Examination, Frontal Assessment Battery, and CSF biomarkers were evaluated. RESULTS: Comparisons of postoperative clinical factors in 64 patients in the PPV/+SL and PPV/+GV groups using 1:1 propensity score matching revealed differences in the mean (±standard deviation) postoperative mRS (2.65 ± 1.07 vs 2.16 ± 1.02, P = .049) and gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Thus, outcomes improved in the LPS group with the GV. Serious and nonserious adverse event rates for the PPV/+SL and PPV/+GV groups were 22.9% and 19.4% (P = .647) and 38% and 17.9% (P = .018), respectively, indicating higher rates of subdural collections for the PPV/+SL group. CONCLUSION: This is the first study to examine LPS treatment for iNPH using a GV in tandem with a PPV. Our results suggest that the CSF shunt flow volume is restricted in the standing position and maintained in the supine position, thus improving iNPH symptoms. This may reduce intracranial CSF hypotension-related complications.

Genetic studies of myelomeningocele.

INTRODUCTION: Myelomeningocele is one of the major congenital malformations involving the central nervous system. It is caused by a disruption of the neural tube closure, which is completed at 3-4 weeks of gestation. DISCUSSION: Multidisciplinary approach is necessary to treat and support this malformation which is a huge burden to the patient, family, and the society. This is a characteristic anomaly that it is known that taking folic acid during the periconceptional period, it is possible to reduce the risk of having a neural tube defect (NTD). Although folate fortification had dramatically reduced the incidence, it was not possible to diminish the risk. To date, many studies have been conducted focusing on candidate genes related to folate and glucose metabolism. We will describe a brief review of genetic etiology of candidate genes of metabolic pathways of folate and glucose, animal models of NTDs, and finally recent studies of microRNA.

Bystander killing effect of tymidine kinase gene-transduced adult bone marrow stromal cells with ganciclovir on malignant glioma cells.

Transduction of the suicide gene of Herpes simplex virus thymidine kinase (Hsv-tk) into glioma cells or neural stem cells combined with pro-drug ganciclovir (GCV) treatment has been effective to treat experimental glioma in the rat through the bystander effect. Bone marrow stromal cells (MSCs) in the adult bone marrow have tropism for brain tumors and act as tumor stromal cells. Whether adult MSCs expressing Hsv-tk can also act as effector cells of the bystander killing effect on murine glioma cells was investigated. In vitro study of co-culture between 9L/LacZ (9L) glioma cells and Hsv-tk-transduced MSCs (MSCs/tk(+)) followed by GCV administration in the culture medium resulted in apparent nuclear morphological changes in the 9L glioma cells surrounding the MSCs/tk(+). 9L glioma cell survival in the presence of MSCs/tk(+) and GCV treatment was quantitatively measured and showed significant decrease of 9L glioma cell proliferation with higher MSCs/tk(+) ratio and GCV concentration. Intracerebral co-inoculation experiments in Fisher rats used 9L glioma cells and either MSCs/tk(+) or Hsv-tk-non-transduced MSCs (MSCs/tk(-)) followed by intraperitoneal injection of GCV (100 mg/kg, daily for 7 days). The animals co-inoculated with 9L glioma cells and MSCs/tk(+) showed significant retardation of tumor growth and prolongation of survival time compared with the animals with 9L glioma cells and MSCs/tk(-). Quantitative findings were established of the novel effects of adult MSCs/tk(+) as effector cells of the bystander killing effect on glioma cells.

Malignant transformation 20 years after partial removal of intracranial epidermoid cyst--case report.

A 74-year-old woman presented with malignant progression of remnant epidermoid cyst manifesting as sudden onset of right ptosis and double vision. She had right oculomotor nerve paresis. She had a history of surgery for right cerebellopontine angle epidermoid cyst 20 years previously. T(1)-weighted magnetic resonance (MR) imaging demonstrated a hypointense mass lesion in the right cerebellopontine angle and basal cistern, and an isointense mass in the right paraclinoid region which was strongly enhanced. Diffusion-weighted MR imaging showed hyperintense areas in the right cerebellopontine angle, ambient cistern, and basal cistern, and the paraclinoid mass as hypointense. Surgery was performed using Dolenc's approach. Histological examination revealed that the paraclinoid tumor adjacent to the epidermoid tumor remnant was malignant transformation of epidermoid cyst into squamous cell carcinoma. She was treated with 46 Gy linac radiotherapy. She has been without tumor recurrence for 17 months. Malignant change of epidermoid cyst is extremely rare, but rapid progress of the symptoms suggests malignant transformation. MR imaging with gadolinium is useful for diagnosis.

Novel antitumor effect of carboplatin delivered by intracerebral microinfusion in a rat malignant glioma model.

Carboplatin loaded osmotic mini-pumps were implanted in 24 9L malignant glioma-bearing rats to investigate the implications of direct intracerebral microinfusion. Carboplatin using 0.1 mg/ml (low dose group) or 1.0 mg/ml (high dose group) with eight rats in each group, or 5% D-glucose (control group) in eight rats were infused at 1 microl/hr for 7 days. The tumor volume was serially measured by magnetic resonance (MR) imaging with gadolinium as the enhanced area, and the survival periods and histological findings were also examined. Separately, to examine the effects of intracerebral carboplatin infusion on vascular permeability, tumor-bearing rats received intravenous administration of 2% Evans blue at 21 days after infusion. The high dose group showed transient increase of enhanced volume at 21 days associated with mass effect, and significantly decreased tumor volume at 28 and 35 days compared with the control and low dose groups. The high dose group showed significant longer survival time than the control and low dose groups. Histological examination of the high dose group at 21 days showed the central tumor necrotic area around the infusion site and Evans blue leakage into the surrounding enhanced rim and the necrotic core. Therefore, leakage of plasma fluid into the necrotic area was considered to be the cause of apparent transient swelling. The present study demonstrated quantitatively using MR imaging that intracerebral carboplatin microinfusion significantly inhibited the rapid growth of experimental rat glioma but that the high dose required carries the risk of transient swelling of the target tumor.

Interstitial continuous infusion therapy in a malignant glioma model in rats.

PURPOSE: Local direct delivery of chemotherapeutic agents for the treatment of brain tumors is an area of focus in the development of new therapeutic paradigms. These techniques need improvement, especially in terms of drug retention in brain tissue. MATERIALS AND METHODS: In this study, we used a rat glioma model to examine carboplatin distribution, as measured by platinum penetration, after delivery via interstitial continuous (i.c.) infusion. We also examined rat survival times in response to carboplatin and oxaliplatin. I.C. infusion, a modified version of convection-enhanced delivery (CED) for local drug delivery, uses low volume (1 microl per hour) continuous infusion directly into the tumor. RESULTS: I.C. infusion produced a nearly 360-fold higher concentration of platinum in tumor tissue and significantly prolonged rodent survival time compared to intraperitoneal (i.p.) infusion. CONCLUSIONS: We showed i.c. infusion allows for circumvention of the blood-brain barrier, focused drug distribution, and sustained drug delivery. This method could be a promising strategy for treating brain tumors.