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1.  Scholarly Context Not Found: One in Five Articles Suffers from Reference Rot 
PLoS ONE  2014;9(12):e115253.
The emergence of the web has fundamentally affected most aspects of information communication, including scholarly communication. The immediacy that characterizes publishing information to the web, as well as accessing it, allows for a dramatic increase in the speed of dissemination of scholarly knowledge. But, the transition from a paper-based to a web-based scholarly communication system also poses challenges. In this paper, we focus on reference rot, the combination of link rot and content drift to which references to web resources included in Science, Technology, and Medicine (STM) articles are subject. We investigate the extent to which reference rot impacts the ability to revisit the web context that surrounds STM articles some time after their publication. We do so on the basis of a vast collection of articles from three corpora that span publication years 1997 to 2012. For over one million references to web resources extracted from over 3.5 million articles, we determine whether the HTTP URI is still responsive on the live web and whether web archives contain an archived snapshot representative of the state the referenced resource had at the time it was referenced. We observe that the fraction of articles containing references to web resources is growing steadily over time. We find one out of five STM articles suffering from reference rot, meaning it is impossible to revisit the web context that surrounds them some time after their publication. When only considering STM articles that contain references to web resources, this fraction increases to seven out of ten. We suggest that, in order to safeguard the long-term integrity of the web-based scholarly record, robust solutions to combat the reference rot problem are required. In conclusion, we provide a brief insight into the directions that are explored with this regard in the context of the Hiberlink project.
doi:10.1371/journal.pone.0115253
PMCID: PMC4277367  PMID: 25541969
2.  The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial 
Neuro-Oncology  2013;15(10):1420-1428.
Background
Fatigue, cognitive deficits, and depression are frequently reported but often undertreated symptoms that can profoundly affect daily life in patients with primary brain tumors (PBTs). To evaluate the effects of the psychostimulant modafinil on fatigue, depression, health-related quality of life (HRQOL), and cognitive functioning in PBT patients, we performed a multicenter, double-blind placebo-controlled crossover trial.
Methods
Patients randomly received either 6 weeks of treatment with modafinil (up to 400 mg/day) or 6 weeks with placebo. After a 1-week washout period, the opposite treatment was provided. Assessments took place at baseline and immediately after the first and second condition. Patients completed self-report questionnaires on fatigue (Checklist Individual Strength [CIS]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), HRQOL (Short-Form Health Survey [SF-36]), and self-perceived cognitive functioning (Medical Outcomes Study [MOS]). They also underwent comprehensive neurocognitive testing.
Results
In total, 37 patients participated. Relative to baseline, patients reported lower fatigue severity (CIS) and better motivation (CIS) in both the modafinil (P = .010 and P = .021, respectively) and the placebo condition (P < .001 and P = .027, respectively). The same held for physical health (SF-36 Physical Component Summary score; P = .001 and P = .008, respectively), working memory (P = .040 and P = .043), and information processing capacity (P = .036 and P = .040). No improvement in depressive symptoms was found in either condition.
Conclusions
Modafinil did not exceed the effects of placebo with respect to symptom management. Patient accrual was slow, and relatively many patients dropped out during the trial, due mostly to side effects. Other, preferably nonpharmacologic intervention studies should be considered to improve symptom management of PBT patients.
doi:10.1093/neuonc/not102
PMCID: PMC3779045  PMID: 23925452
brain tumor; cognitive functioning; fatigue; HRQOL; modafinil; mood
3.  Phenotypic Characterization of 3 Families With Autosomal Dominant Retinitis Pigmentosa Due to Mutations in KLHL7 
Archives of ophthalmology  2011;129(11):1475-1482.
Objective
To characterize the visual phenotype caused by mutations in the BTB-Kelch protein, KLHL7, responsible for the RP42 form of autosomal dominant retinitis pigmentosa (RP).
Methods
Comprehensive ophthalmic testing included visual acuity, static visual field, kinetic visual field, dark adaptometry, full-field electroretinography, spectral-domain optical coherence tomography, and fundus photography. Longitudinal visual function data (range, 15–27 years) were available for some of the affected individuals.
Results
We report a phenotypic assessment of 3 unrelated families, each harboring different KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). The fundi showed classic signs of RP. Best-corrected visual acuity was 20/50 or better in at least one eye up to age 65 years Static and kinetic visual fields showed concentric constriction to central 10° to 20° by age 65 years; 2 patients with Goldmann perimetry exhibited bilateral visual field retention in the far periphery. Both rod and cone full-field electroretinographic amplitudes were substantially lower than normal, with a decline rate of 3% per year in cone 31-Hz flicker response. Rod and cone activation and inactivation variables were abnormal. Spectral-domain optical coherence tomography indicated retention of foveal inner segment-outer segment junction through age 65 years.
Conclusions
Mutations in KLHL7 are associated with a late-onset form of autosomal dominant retinal degeneration that preferentially affects the rod photoreceptors. Full-field electroretinographic findings, including recovery kinetics, are consistent with those observed in other forms of autosomal dominant RP.
Clinical Relevance
The phenotypes are similar among patients with 3 types of KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). Strong retention of foveal function and bilateral concentric constriction of visual fields with far periphery sparing may guide mutation screening in autosomal dominant RP.
doi:10.1001/archophthalmol.2011.307
PMCID: PMC4106140  PMID: 22084217
4.  Changes in MEG resting-state networks are related to cognitive decline in type 1 diabetes mellitus patients 
NeuroImage : Clinical  2014;5:69-76.
Objective
Integrity of resting-state functional brain networks (RSNs) is important for proper cognitive functioning. In type 1 diabetes mellitus (T1DM) cognitive decrements are commonly observed, possibly due to alterations in RSNs, which may vary according to microvascular complication status. Thus, we tested the hypothesis that functional connectivity in RSNs differs according to clinical status and correlates with cognition in T1DM patients, using an unbiased approach with high spatio-temporal resolution functional network.
Methods
Resting-state magnetoencephalographic (MEG) data for T1DM patients with (n = 42) and without (n = 41) microvascular complications and 33 healthy participants were recorded. MEG time-series at source level were reconstructed using a recently developed atlas-based beamformer. Functional connectivity within classical frequency bands, estimated by the phase lag index (PLI), was calculated within eight commonly found RSNs. Neuropsychological tests were used to assess cognitive performance, and the relation with RSNs was evaluated.
Results
Significant differences in terms of RSN functional connectivity between the three groups were observed in the lower alpha band, in the default-mode (DMN), executive control (ECN) and sensorimotor (SMN) RSNs. T1DM patients with microvascular complications showed the weakest functional connectivity in these networks relative to the other groups. For DMN, functional connectivity was higher in patients without microangiopathy relative to controls (all p < 0.05). General cognitive performance for both patient groups was worse compared with healthy controls. Lower DMN alpha band functional connectivity correlated with poorer general cognitive ability in patients with microvascular complications.
Discussion
Altered RSN functional connectivity was found in T1DM patients depending on clinical status. Lower DMN functional connectivity was related to poorer cognitive functioning. These results indicate that functional connectivity may play a key role in T1DM-related cognitive dysfunction.
Highlights
•MEG RSN functional connectivity was estimated among T1DM+ and T1DM− patients and controls.•Lower alpha band in DMN, ECN and SMN significantly differed among groups.•Functional connectivity may play a key role in T1DM-related cognitive dysfunction.
doi:10.1016/j.nicl.2014.06.001
PMCID: PMC4081980  PMID: 25003029
Resting-state networks; Magnetoencephalography; Functional connectivity; Phase Lag Index (PLI); Oscillations; Type 1 diabetes mellitus
5.  Internet-based guided self-help for glioma patients with depressive symptoms: design of a randomized controlled trial 
BMC Neurology  2014;14:81.
Background
Among glioma patients, depression is estimated to be more prevalent than in both the general population and the cancer patient population. This can have negative consequences for both patients and their primary informal caregivers (e.g., a spouse, family member or close friend). At present, there is no evidence from randomized controlled trials for the effectiveness of psychological treatment for depression in glioma patients. Furthermore, the possibility of delivering mental health care through the internet has not yet been explored in this population. Therefore, a randomized controlled trial is warranted to evaluate the effects of an internet-based, guided self-help intervention for depressive symptoms in glioma patients.
Methods/design
The intervention is based on problem-solving therapy. An existing 5-week course is adapted for use by adult glioma patients with mild to moderate depressive symptoms (Center for Epidemiology Studies Depression Scale score ≥12). Sample size calculations yield 126 glioma patients to be included, who are randomly assigned to either the intervention group or a waiting list control group. In addition, we aim to include 63 patients with haematological cancer in a non-central nervous system malignancy control group. Assessments take place at baseline, after 6 and 12 weeks, and after 6 and 12 months. Primary outcome measure is the change in depressive symptoms. Secondary outcome measures include health-related quality of life, fatigue, costs and patient satisfaction. In addition, all patients are asked to assign a primary informal caregiver, who does not participate in the intervention but who is asked to complete similar assessments. Their mood, health-related quality of life and fatigue is evaluated as well.
Discussion
This is the first study to evaluate the effects of problem-solving therapy delivered through the internet as treatment for depressive symptoms in glioma patients. If proven effective, this treatment will contribute to the mental health care of glioma patients in clinical practice.
Trial registration
Netherlands Trial Register NTR3223
doi:10.1186/1471-2377-14-81
PMCID: PMC3989775  PMID: 24721108
Glioma; Brain tumor; Depression; Quality of life; Internet-based treatment; Informal caregiver
6.  Differential impact of subclinical carotid artery disease on cerebral structure and functioning in type 1 diabetes patients with versus those without proliferative retinopathy 
Background
Type 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.
Methods
In 51 asymptomatic T1DM patients with, 53 without proliferative retinopathy and 51 controls, right common carotid artery ultrasound was used to assess intima media thickness (cIMT) and distensibility (cD). Neuropsychological tests for cognitive functions, and magnetic resonance imagining for white matter integrity and functional connectivity, i.e. neuronal communication, were used.
Results
After correction for confounders, cIMT was borderline significantly increased in all T1DM patients (P = 0.071), whereas cD was not statistically significantly altered (P = 0.45). Patients with proliferative retinopathy showed the largest increase in cIMT and decrease in cD. In all participants, after adjustment for confounders, increased cIMT was related to decreased white matter integrity (β = −0.198 P = 0.041) and decreased functional connectivity in visual areas (β = −0.195 P = 0.046). For cognition, there was a significant interaction between cIMT and the presence of proliferative retinopathy after adjustment for confounding factors (all P < 0.05). Increased cIMT was associated with lower general cognitive ability (β = −0.334; P = 0.018), information processing speed (β = −0.361; P = 0.010) and attention (β = −0.394; P = 0.005) scores in patients without, but not in patients with proliferative retinopathy.
Conclusions
These findings suggest that subclinical macroangiopathy may be a factor in the development of diabetes-related cognitive changes in uncomplicated T1DM, whereas in patients with advanced T1DM, proliferative retinopathy may rather be the driving force of cerebral compromise.
doi:10.1186/1475-2840-13-58
PMCID: PMC3995631  PMID: 24620788
Type 1 diabetes; Cognition; Subclinical macroangiopathy; Microangiopathy; Neuroimaging; Cognition
7.  Levetiracetam improves verbal memory in high-grade glioma patients 
Neuro-Oncology  2012;15(2):216-223.
Background
Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of older and newer AEDs on cognitive performance in postoperative HGG patients.
Methods
We selected HGG patients from 3 separate cohorts for use of older, newer, or no AEDs, as they represented distinct treatment eras and provided the opportunity to compare older and newer AEDs. In all 3 cohorts, patients were included within 6 weeks following neurosurgery before the start of postoperative treatment. Cognitive functioning was evaluated by an extensive neuropsychological assessment, executed in 6 cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed).
Results
One hundred seventeen patients met the inclusion criteria; 44 patients used no AED, 35 were on monotherapy with a newer AED (all levetiracetam), and 38 were on monotherapy with an older AED (valproic acid or phenytoin). Patients on older and newer AEDs performed equally well as patients not on an AED, and patients on levetiracetam performed even better on verbal memory tests than patients not on an AED. Post-hoc analyses revealed that within the group using older AEDs, patients on valproic acid performed better than patients on phenytoin.
Conclusions
Neither levetiracetam nor valproic acid was associated with additional cognitive deficits in HGG patients. Both AEDs even appeared to have a beneficial effect on verbal memory in these patients.
doi:10.1093/neuonc/nos288
PMCID: PMC3548582  PMID: 23233537
high-grade glioma; cognitive functioning; anti-epileptic drugs; epilepsy; primary brain tumor
8.  Neurocognitive functioning in adult WHO grade II gliomas: impact of old and new treatment modalities 
Neuro-Oncology  2012;14(Suppl 4):iv17-iv24.
In the treatment of patients with low-grade glioma, there still is controversy on how surgical intervention, radiation therapy, and chemotherapy contribute to an ameliorated progression-free survival, overall survival, and treatment-related neurotoxicity. With the ongoing changes in treatment options for these patients, neurocognitive functioning is an increasingly important outcome measure, because neurocognitive impairments can have a large impact on self-care, social and professional functioning, and consequently, health-related quality of life. Many factors contribute to neurocognitive outcome, such as direct and indirect tumor effects, seizures, medication, and oncological treatment. Although the role of radiotherapy has been studied extensively, the adverse effects on neurocognitive function of other treatment-related factors remain elusive. This holds for both resective surgery, in which the use of intraoperative stimulation mapping has a high potential benefit concerning survival and patient functioning, and the use of chemotherapy that might have some interesting new applications, such as the facilitation of total resection for initially primary or recurrent diffuse low-grade glioma tumors. This article will discuss these treatment options in patients with low-grade glioma and their potential effects on neurocognitive functioning.
doi:10.1093/neuonc/nos161
PMCID: PMC3480241  PMID: 23095826
chemotherapy, cognition; low-grade gliomas; radiotherapy; surgery
9.  Resting-State Brain Networks in Type 1 Diabetic Patients With and Without Microangiopathy and Their Relation to Cognitive Functions and Disease Variables 
Diabetes  2012;61(7):1814-1821.
Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA+: n = 49) and without (MA−: n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA− patients showed increased connectivity in networks involved in motor and visual processes, whereas MA+ patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.
doi:10.2337/db11-1358
PMCID: PMC3379683  PMID: 22438575
10.  MEG Network Differences between Low- and High-Grade Glioma Related to Epilepsy and Cognition 
PLoS ONE  2012;7(11):e50122.
Objective
To reveal possible differences in whole brain topology of epileptic glioma patients, being low-grade glioma (LGG) and high-grade glioma (HGG) patients. We studied functional networks in these patients and compared them to those in epilepsy patients with non-glial lesions (NGL) and healthy controls. Finally, we related network characteristics to seizure frequency and cognitive performance within patient groups.
Methods
We constructed functional networks from pre-surgical resting-state magnetoencephalography (MEG) recordings of 13 LGG patients, 12 HGG patients, 10 NGL patients, and 36 healthy controls. Normalized clustering coefficient and average shortest path length as well as modular structure and network synchronizability were computed for each group. Cognitive performance was assessed in a subset of 11 LGG and 10 HGG patients.
Results
LGG patients showed decreased network synchronizability and decreased global integration compared to healthy controls in the theta frequency range (4–8 Hz), similar to NGL patients. HGG patients’ networks did not significantly differ from those in controls. Network characteristics correlated with clinical presentation regarding seizure frequency in LGG patients, and with poorer cognitive performance in both LGG and HGG glioma patients.
Conclusion
Lesion histology partly determines differences in functional networks in glioma patients suffering from epilepsy. We suggest that differences between LGG and HGG patients’ networks are explained by differences in plasticity, guided by the particular lesional growth pattern. Interestingly, decreased synchronizability and decreased global integration in the theta band seem to make LGG and NGL patients more prone to the occurrence of seizures and cognitive decline.
doi:10.1371/journal.pone.0050122
PMCID: PMC3498183  PMID: 23166829
11.  Relationships among Multifocal Electroretinogram Amplitude, Visual Field Sensitivity, and SD-OCT Receptor Layer Thicknesses in Patients with Retinitis Pigmentosa 
In patients with retinitis pigmentosa, preserved cone photoreceptor function measured by multifocal electroretinogram amplitude and visual field sensitivity correlate well with the remaining thickness of the photoreceptor layer.
Purpose.
To compare local functional measures, the multifocal electroretinogram (mfERG) and visual field sensitivity, with a local structural measure, spectral domain (SD) optical coherence tomography (OCT), of receptor damage in patients with retinitis pigmentosa (RP).
Methods.
MfERGs, visual fields, and SD-OCT scans were obtained from 10 patients with RP, ranging in age from 23 to 59 years. Average amplitudes, average linear sensitivities, and average layer thicknesses were measured from within the central 3° and from three concentric annuli located between 3° and 8°, 8° and 15°, and 15° and 24°. A computer program aided manual segmentation and calculated OCT thickness in the scans.
Results.
Within each patient with RP, mfERG amplitude for each circle/annulus was highly correlated with corresponding layer thicknesses in the outer retina (r = 0.88 to 0.99), but not at all correlated with thickness of the inner nuclear layer or total retina. Across all ring eccentricities, relative mfERG amplitude and relative visual field sensitivity were correlated with relative SD-OCT outer retinal thickness.
Conclusions.
In patients with RP, preserved cone photoreceptor function measured by mfERG amplitude and visual field sensitivity correlate well with the remaining thickness of the photoreceptor layer. All three measures show comparable relative loss beyond 3° eccentricity. In the fovea, SD-OCT outer retina thickness showed less relative loss than either mfERG or visual field sensitivity.
doi:10.1167/iovs.11-8410
PMCID: PMC3317422  PMID: 22247460
12.  Resistin in idiopathic inflammatory myopathies 
Arthritis Research & Therapy  2012;14(3):R111.
Introduction
The purpose of this study was to evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity.
Methods
Serum resistin levels were determined in 42 patients with inflammatory myopathies and 27 healthy controls. The association among resistin levels, inflammation, global disease activity and muscle strength was examined. The expression of resistin in muscle tissues from patients with inflammatory myopathies and healthy controls was evaluated. Gene expression and protein release from resistin-stimulated muscle and mononuclear cells were assessed.
Results
In patients with inflammatory myopathies, the serum levels of resistin were significantly higher than those observed in controls (8.53 ± 6.84 vs. 4.54 ± 1.08 ng/ml, P < 0.0001) and correlated with C-reactive protein (CRP) levels (r = 0.328, P = 0.044) and myositis disease activity assessment visual analogue scales (MYOACT) (r = 0.382, P = 0.026). Stronger association was observed between the levels of serum resistin and CRP levels (r = 0.717, P = 0.037) as well as MYOACT (r = 0.798, P = 0.007), and there was a trend towards correlation between serum resistin and myoglobin levels (r = 0.650, P = 0.067) in anti-Jo-1 positive patients. Furthermore, in patients with dermatomyositis, serum resistin levels significantly correlated with MYOACT (r = 0.667, P = 0.001), creatine kinase (r = 0.739, P = 0.001) and myoglobin levels (r = 0.791, P = 0.0003) and showed a trend towards correlation with CRP levels (r = 0.447, P = 0.067). Resistin expression in muscle tissue was significantly higher in patients with inflammatory myopathies compared to controls, and resistin induced the expression of interleukins (IL)-1β and IL-6 and monocyte chemoattractant protein (MCP)-1 in mononuclear cells but not in myocytes.
Conclusions
The results of this study indicate that higher levels of serum resistin are associated with inflammation, higher global disease activity index and muscle injury in patients with myositis-specific anti-Jo-1 antibody and patients with dermatomyositis. Furthermore, up-regulation of resistin in muscle tissue and resistin-induced synthesis of pro-inflammatory cytokines in mononuclear cells suggest a potential role for resistin in the pathogenesis of inflammatory myopathies.
doi:10.1186/ar3836
PMCID: PMC3446487  PMID: 22577940
13.  ApoER2 Function in the Establishment and Maintenance of Retinal Synaptic Connectivity 
The cellular and molecular mechanisms responsible for the development of inner retinal circuitry are poorly understood. Reelin and apolipoprotein E (apoE), ligands of apoE receptor 2 (ApoER2), are involved in retinal development and degeneration, respectively. Here we describe the function of ApoER2 in the developing and adult retina. ApoER2 expression was highest during postnatal inner retinal synaptic development and was considerably lower in the mature retina. Both during development and in the adult ApoER2 was expressed by A-II amacrine cells. ApoER2 knockout (KO) mice had rod bipolar morphogenic defects, altered A-II amacrine dendritic development, and impaired rod-driven retinal responses. The presence of an intact ApoER2 NPxY motif, necessary for binding disabled-1 (Dab1) and transducing the Reelin signal, was also necessary for development of the rod bipolar pathway while the alternatively-spliced exon19 was not. Mice deficient in another Reelin receptor, very low-density lipoprotein receptor (VLDLR), had normal rod bipolar morphology but altered A-II amacrine dendritic development. VLDLR KO mice also had reductions in oscillatory potentials and delayed synaptic response intervals. Interestingly, age-related reductions in rod and cone function were observed in both ApoER2 and VLDLR KOs. These results support a pivotal role for ApoER2 in the establishment and maintenance of normal retinal synaptic connectivity.
doi:10.1523/JNEUROSCI.3135-11.2011
PMCID: PMC3224795  PMID: 21976526
ApoER2; VLDLR; Reelin; Retinal Development; A-II Amacrine; Rod Bipolar Cell
14.  Cognition and resective surgery for diffuse infiltrative glioma: an overview 
Journal of Neuro-Oncology  2012;108(2):309-318.
Compared to classical oncological outcome measures such as time to progression and survival, the importance of cognitive functioning in patients with diffuse infiltrative brain tumors has only recently been recognized. Apart from the relatively low incidence and the invariably fatal outcome of gliomas, the general assumption that cognitive assessment is time-consuming and burdensome contributes to this notion. Our understanding of the effects of brain surgery on cognition, for instance, is largely based on studies in surgical patients with refractory epilepsy, with only a limited number of studies in surgical patients with gliomas. The impact of other factors affecting cognition in glioma patients such as direct tumor effects, radiotherapy and chemotherapy, and medical treatment, including anti-epileptic drugs and steroids, have been studied more extensively. The purpose of this paper is to provide an overview of cognition in patients with diffuse infiltrative gliomas and the impact of resective surgery as well as other tumor and treatment-related factors.
doi:10.1007/s11060-012-0811-x
PMCID: PMC3351615  PMID: 22362370
Glioma; Cognitive function; Neurosurgery; Radiotherapy; Epilepsy; Medical treatment
15.  Symptoms and problems in the end-of-life phase of high-grade glioma patients 
Neuro-Oncology  2010;12(11):1162-1166.
Despite multimodal treatment, it is not possible to cure high-grade glioma (HGG) patients. Therefore, the aim of treatment is not only to prolong life, but also to prevent deterioration of health-related quality of life as much as possible. When the patient's condition declines and no further tumor treatment seems realistic, patients in the Netherlands are often referred to a primary care physician for end-of-life care. This end-of-life phase has not been studied adequately yet. The purpose of this study was to explore specific problems and needs experienced in the end-of-life phase of patients with HGG. We retrospectively examined the files of 55 patients who received treatment in our outpatient clinic and died between January 2005 and August 2008. The clinical nurse specialist in neuro-oncology maintained contact on a regular basis with (relatives of) HGG patients once tumor treatment for recurrence was no longer given. She systematically asked for signs and symptoms. The majority of the patients experienced loss of consciousness and difficulty with swallowing, often arising in the week before death. Seizures occurred in nearly half of the patients in the end-of-life phase and more specifically in one-third of the patients in the week before dying. Other common symptoms reported in the end-of-life phase are progressive neurological deficits, incontinence, progressive cognitive deficits, and headache. Our study demonstrates that HGG patients, unlike the general cancer population, have specific symptoms in the end-of-life phase. Further research is needed in order to develop specific palliative care guidelines for these patients.
doi:10.1093/neuonc/nop045
PMCID: PMC3098016  PMID: 20511193
end-of-life; high-grade glioma
16.  Functional Brain Connectivity and Neurocognitive Functioning in Patients With Long-Standing Type 1 Diabetes With and Without Microvascular Complications 
Diabetes  2009;58(10):2335-2343.
OBJECTIVE
Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography.
RESEARCH DESIGN AND METHODS
Fluctuations in magnetic field at scalp for Δ, θ, lower and upper α, β, and lower and upper γ frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined.
RESULTS
Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention.
CONCLUSIONS
Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning.
doi:10.2337/db09-0425
PMCID: PMC2750229  PMID: 19584309
17.  Epilepsy is related to theta band brain connectivity and network topology in brain tumor patients 
BMC Neuroscience  2010;11:103.
Background
Both epilepsy patients and brain tumor patients show altered functional connectivity and less optimal brain network topology when compared to healthy controls, particularly in the theta band. Furthermore, the duration and characteristics of epilepsy may also influence functional interactions in brain networks. However, the specific features of connectivity and networks in tumor-related epilepsy have not been investigated yet. We hypothesize that epilepsy characteristics are related to (theta band) connectivity and network architecture in operated glioma patients suffering from epileptic seizures. Included patients participated in a clinical study investigating the effect of levetiracetam monotherapy on seizure frequency in glioma patients, and were assessed at two time points: directly after neurosurgery (t1), and six months later (t2). At these time points, magnetoencephalography (MEG) was recorded and information regarding clinical status and epilepsy history was collected. Functional connectivity was calculated in six frequency bands, as were a number of network measures such as normalized clustering coefficient and path length.
Results
At the two time points, MEG registrations were performed in respectively 17 and 12 patients. No changes in connectivity or network topology occurred over time. Increased theta band connectivity at t1 and t2 was related to a higher total number of seizures. Furthermore, higher number of seizures was related to a less optimal, more random brain network topology. Other factors were not significantly related to functional connectivity or network topology.
Conclusions
These results indicate that (pathologically) increased theta band connectivity is related to a higher number of epileptic seizures in brain tumor patients, suggesting that theta band connectivity changes are a hallmark of tumor-related epilepsy. Furthermore, a more random brain network topology is related to greater vulnerability to seizures. Thus, functional connectivity and brain network architecture may prove to be important parameters of tumor-related epilepsy.
doi:10.1186/1471-2202-11-103
PMCID: PMC2936439  PMID: 20731854
18.  Health-related quality of life of long-term high-grade glioma survivors 
Neuro-Oncology  2009;11(1):51-58.
The objective of this study was to compare the health-related quality of life (HRQOL) of long-term to short-term high-grade glioma (HGG) survivors, determine the prognostic value of HRQOL for overall survival, and determine the effect of tumor recurrence on HRQOL for long-term survivors. Following baseline assessment (after surgery, before radiotherapy), self-perceived HRQOL (using the Medical Outcomes Study Short Form 36 [SF-36]) and brain tumor–specific symptoms (using the 20-item Brain Cancer Module) were assessed every 4 months until 16 months after histological diagnosis. Kaplan-Meier survival analysis and the Cox proportional hazards model were performed to estimate overall survival of patients with impaired scores on the aggregated SF-36 higher-order summary scores measuring physical functioning on a physical component scale and on a mental component scale (MCS). Sixteen patients with a short-term survival (baseline and 4-month follow-up) and 16 with a long-term survival (follow-up until 16 months after diagnosis) were selected out of 68 initially recruited HGG patients. At baseline, the short-term and long-term survivors did not differ in their HRQOL. Between baseline and the 4-month follow-up, HRQOL of short-term survivors deteriorated, whereas the long-term survivors improved to a level comparable to healthy controls. Patients with impaired mental functioning (MCS) at baseline had a shorter median survival than patients with normal functioning. After accounting for differences in patient and tumor characteristics, however, mental functioning was not independently related to poorer overall survival. Not surprisingly, in the group of long-term survivors, the five patients with recurrence had a more compromised HRQOL at the 16-month follow-up compared to the 11 patients without recurrence. We concluded that baseline HRQOL is not related to duration of survival and that long-term survivors show improvement of HRQOL to a level comparable to that of the healthy.
doi:10.1215/15228517-2008-049
PMCID: PMC2718959  PMID: 18617599
health-related quality of life; high-grade glioma survivors
19.  The Lesioned Brain: Still a Small-World? 
The intra-arterial amobarbital procedure (IAP or Wada test) is used to determine language lateralization and contralateral memory functioning in patients eligible for neurosurgery because of pharmaco-resistant epilepsy. During unilateral sedation, functioning of the contralateral hemisphere is assessed by means of neuropsychological tests. We use the IAP as a reversible model for the effect of lesions on brain network topology. Three artifact-free epochs (4096 samples) were selected from each electroencephalogram record before and after amobarbital injection. Functional connectivity was assessed by means of the synchronization likelihood. The resulting functional connectivity matrices were constructed for all six epochs per patient in four frequency bands, and weighted network analysis was performed. The clustering coefficient, average path length, small-world index, and edge weight correlation were calculated. Recordings of 33 patients were available. Network topology changed significantly after amobarbital injection: clustering decreased in all frequency bands, while path length decreased in the theta and lower alpha band, indicating a shift toward a more random network topology. Likewise, the edge weight correlation decreased after injection of amobarbital in the theta and beta bands. Network characteristics after injection of amobarbital were correlated with memory score: higher theta band small-world index and increased upper alpha path length were related to better memory score. The whole-brain network topology in patients eligible for epilepsy surgery becomes more random and less optimally organized after selective sedation of one hemisphere, as has been reported in studies with brain tumor patients. Furthermore, memory functioning after injection seems related to network topology, indicating that functional performance is related to topological network properties of the brain.
doi:10.3389/fnhum.2010.00174
PMCID: PMC2991225  PMID: 21120140
small-world networks; Wada test; functional connectivity; brain network; graph theory
20.  Letters To The Editor 
Neuro-Oncology  2008;10(6):1172.
doi:10.1215/15228517-2008-057
PMCID: PMC2719005  PMID: 18676358
21.  Synchronized brain activity and neurocognitive function in patients with low-grade glioma: A magnetoencephalography study 
Neuro-Oncology  2008;10(5):734-744.
We investigated the mechanisms underlying neurocognitive dysfunction in patients with low-grade glioma (LGG) by relating functional connectivity revealed by magnetoencephalography to neurocognitive function. We administered a battery of standardized neurocognitive tests measuring six neurocognitive domains to a group of 17 LGG patients and 17 healthy controls, matched for age, sex, and educational level. Magnetoencephalography recordings were conducted during an eyes-closed “resting state,” and synchronization likelihood (a measure of statistical correlation between signals) was computed from the delta to gamma frequency bands to assess functional connectivity between different brain areas. We found that, compared with healthy controls, LGG patients performed more poorly in psychomotor function, attention, information processing, and working memory. LGG patients also had significantly higher long-distance synchronization scores in the delta, theta, and lower gamma frequency bands than did controls. In contrast, patients displayed a decline in synchronization likelihood in the lower alpha frequency band. Within the delta, theta, and lower and upper gamma bands, increasing short-and long-distance connectivity was associated with poorer neurocognitive functioning. In summary, LGG patients showed a complex overall pattern of differences in functional resting-state connectivity compared with healthy controls. The significant correlations between neurocognitive performance and functional connectivity in various frequencies and across multiple brain areas suggest that the observed neurocognitive deficits in these patients can possibly be attributed to differences in functional connectivity due to tumor and/or treatment.
doi:10.1215/15228517-2008-034
PMCID: PMC2666250  PMID: 18650489
low-grade glioma; magnetoencephalography; neurocognition; resting-state functional connectivity
22.  Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings 
Journal of Neuro-Oncology  2009;97(1):89-94.
The aim of this study was to evaluate cognitive functioning in newly-diagnosed glioblastoma multiforme (GBM) patients during treatment with radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ). Cognitive assessment took place following surgery, but prior to the start of RT (baseline), after 6 weeks of RT and concomitant TMZ (1st follow-up), and after three cycles of adjuvant TMZ (2nd follow-up). Standardized cognitive summary measures and delta scores for six cognitive domains were calculated at the individual level. Cognitive functioning of progression-free GBM patients was compared to that of matched healthy controls. Analyses were performed on a group of 13 GBM patients that were progression-free during follow-up. The results showed that the majority of patients had deficits in multiple cognitive domains at baseline. Between baseline and 1st follow-up, four patients improved in one cognitive domain, four patients deteriorated in one domain, one patient improved in one domain and deteriorated in another, and four patients remained stable in all six domains. Between 1st and 2nd follow-up, the majority of patients (11) remained stable in all six cognitive domains, whereas one patient declined in one domain, and one patient showed a deterioration in two domains. Overall, between baseline and 2nd follow-up, three patients improved in one cognitive domain, two patients deteriorated in two domains, one patient improved in one domain and deteriorated in another, and seven patients remained stable in all six cognitive domains. In conclusion, preceding treatment, the majority of GBM patients show clear-cut deficits in cognitive functioning. In the course of the first 6 months of their disease, however, progression-free GBM patients undergoing radiotherapy plus concomitant and adjuvant temozolomide treatment do not deteriorate in cognitive functioning.
doi:10.1007/s11060-009-9993-2
PMCID: PMC2814037  PMID: 19718545
Cognitive functioning; Glioblastoma multiforme; Radiotherapy; Temozolomide
23.  Disturbed functional brain networks and neurocognitive function in low-grade glioma patients: a graph theoretical analysis of resting-state MEG 
Background
To understand neurophysiological mechanisms underlying cognitive dysfunction in low-grade glioma (LGG) patients by evaluating the spatial structure of 'resting-state' brain networks with graph theory.
Methods
Standardized tests measuring 6 neurocognitive domains were administered in 17 LGG patients and 17 healthy controls. Magnetoencephalography (MEG) recordings were conducted during eyes-closed 'resting state'. The phase lag index (PLI) was computed in seven frequency bands to assess functional connectivity between brain areas. Spatial patterns were characterized with graph theoretical measures such as clustering coefficient (local connectivity), path length (global integration), network small world-ness (ratio of clustering coefficient/path length) and degree correlation (the extent to which connected nodes have similar degrees).
Results
Compared to healthy controls, patients performed poorer on psychomotor functioning, attention, information processing, and working memory. Patients displayed higher short- and long-distance synchronization and clustering coefficient in the theta band, whereas a lower clustering coefficient and small world-ness were observed in the beta band. A lower degree correlation was found in the upper gamma band. LGG patients with higher clustering coefficient, longer path length, and lower degree correlations in delta and lower alpha band were characterized by poorer neurocognitive performance.
Conclusion
LGG patients display higher short- and long-distance synchronization within the theta band. Network analysis revealed changes (in particularly the theta, beta, and upper gamma band) suggesting disturbed network architecture. Moreover, correlations between network characteristics and neurocognitive performance were found, Widespread changes in the strength and spatial organization of brain networks may be responsible for cognitive dysfunction in glioma patients.
doi:10.1186/1753-4631-3-9
PMCID: PMC2745411  PMID: 19698149
25.  The size of the treatment effect: do patients and proxies agree? 
BMC Neurology  2009;9:12.
Background
This study examined whether MS patients and proxy respondents agreed on change in disease impact, which was induced by treatment. This may be of interest in situations when patients suffer from limitations that interfere with reliable self-assessment, such as cognitive impairment.
Methods
MS patients and proxies completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after intravenous steroid treatment. Analyses focused on patient-proxy agreement between MSIS-29 change scores. Transition ratings were used to measure the patient's judgement of change and whether this change was reflected in the MSIS-29 change of patients and proxies. Receiver operating characteristic (ROC) analyses were also performed to examine the diagnostic properties of the MSIS-29 when completed by patients and proxies.
Results
42 patients and proxy respondents completed the MSIS-29 at baseline and follow-up. Patient-proxy differences between change scores on the physical and psychological MSIS-29 subscale were quite small, although large variability was found. The direction of mean change was in concordance with the transition ratings of the patients. Results of the ROC analyses of the MSIS-29 were similar when completed by patients (physical scale: AUC = 0.79, 95% CI: 0.65 – 0.93 and 0.66, 95% CI: 0.48 – 0.84 for the psychological scale) and proxies (physical scale: 0.80, 95% CI: 0.72 – 0.96 and 0.71, 95% CI: 0.56 – 0.87 for the psychological scale)
Conclusion
Although the results need to be further explored in larger samples, these results do point towards possible use of proxy respondents to assess patient perceived treatment change at the group level.
doi:10.1186/1471-2377-9-12
PMCID: PMC2667429  PMID: 19317921

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