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1.  Levetiracetam improves verbal memory in high-grade glioma patients 
Neuro-Oncology  2012;15(2):216-223.
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.
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).
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.
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.
PMCID: PMC3548582  PMID: 23233537
high-grade glioma; cognitive functioning; anti-epileptic drugs; epilepsy; primary brain tumor
2.  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.
PMCID: PMC3480241  PMID: 23095826
chemotherapy, cognition; low-grade gliomas; radiotherapy; surgery
3.  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.
PMCID: PMC3379683  PMID: 22438575
4.  MEG Network Differences between Low- and High-Grade Glioma Related to Epilepsy and Cognition 
PLoS ONE  2012;7(11):e50122.
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.
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.
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.
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.
PMCID: PMC3498183  PMID: 23166829
5.  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.
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).
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.
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.
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.
PMCID: PMC3317422  PMID: 22247460
6.  Resistin in idiopathic inflammatory myopathies 
Arthritis Research & Therapy  2012;14(3):R111.
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.
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.
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.
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.
PMCID: PMC3446487  PMID: 22577940
7.  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.
PMCID: PMC3224795  PMID: 21976526
ApoER2; VLDLR; Reelin; Retinal Development; A-II Amacrine; Rod Bipolar Cell
8.  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.
PMCID: PMC3351615  PMID: 22362370
Glioma; Cognitive function; Neurosurgery; Radiotherapy; Epilepsy; Medical treatment
9.  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.
PMCID: PMC3098016  PMID: 20511193
end-of-life; high-grade glioma
10.  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.
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.
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.
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.
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.
PMCID: PMC2750229  PMID: 19584309
11.  Epilepsy is related to theta band brain connectivity and network topology in brain tumor patients 
BMC Neuroscience  2010;11:103.
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.
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.
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.
PMCID: PMC2936439  PMID: 20731854
12.  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.
PMCID: PMC2718959  PMID: 18617599
health-related quality of life; high-grade glioma survivors
13.  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.
PMCID: PMC2991225  PMID: 21120140
small-world networks; Wada test; functional connectivity; brain network; graph theory
14.  Letters To The Editor 
Neuro-Oncology  2008;10(6):1172.
PMCID: PMC2719005  PMID: 18676358
15.  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.
PMCID: PMC2666250  PMID: 18650489
low-grade glioma; magnetoencephalography; neurocognition; resting-state functional connectivity
16.  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.
PMCID: PMC2814037  PMID: 19718545
Cognitive functioning; Glioblastoma multiforme; Radiotherapy; Temozolomide
17.  Disturbed functional brain networks and neurocognitive function in low-grade glioma patients: a graph theoretical analysis of resting-state MEG 
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.
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).
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.
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.
PMCID: PMC2745411  PMID: 19698149
19.  The size of the treatment effect: do patients and proxies agree? 
BMC Neurology  2009;9:12.
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.
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.
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)
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.
PMCID: PMC2667429  PMID: 19317921
20.  Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice 
The Journal of Clinical Investigation  2008;118(8):2908-2916.
Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.
PMCID: PMC2483685  PMID: 18654668
21.  Longitudinal proxy measurements in multiple sclerosis: patient-proxy agreement on the impact of MS on daily life over a period of two years 
BMC Neurology  2008;8:2.
The use of self-report measurements in clinical settings is increasing. However, in patients with limitations that interfere with reliable self-assessment such as cognitive impairment or mood disturbances, as may be the case in multiple sclerosis (MS), data collection might be problematic. In these situations, information obtained from proxy respondents (e.g. partners) may replace self-ratings. The aim of this study was to examine the value of proxy ratings at separate points in time and to assess patient-proxy agreement on possible changes in disease impact of MS.
Fifty-six MS patients and their partners completed the Multiple Sclerosis Impact Scale (MSIS-29) at baseline and follow-up, two years later. Patient-proxy agreement was assessed at both time points by calculating intraclass correlation coefficients (ICCs), exact and global agreement and the mean directional differences between groups. Agreement of change over time was assessed by calculating ICCs between change scores. In parallel, global ratings of both patients and proxy respondents of the extent to which the patient had improved or deteriorated over the past two years were collected to validate possible changes on the MSIS-29.
At both time points, agreement on the physical scale was higher than agreement on the psychological scale (ICCs at baseline were 0.81 for the physical scale and 0.72 for the psychological scale; at follow-up, the ICC values were 0.86 and 0.65 respectively). At follow-up, statistically significant mean differences between patients and proxies were noted for the physical scale (-4.8 ± 12.7, p = 0.006) and the psychological scale (-8.9 ± 18.8, p = 0.001). Agreement between change scores on the MSIS-29 was fair (ICC < 0.60). Our analyses suggest that the validity of measuring changes over time might be better for proxy respondents compared to patients.
Proxy respondents could act as a reliable source of information in cross-sectional studies. Moreover, results suggested that agreement on change over time might be better for proxy respondents compared to patients. Although this remarkable finding should be interpreted cautiously because of several limitations of the study, it does plead for further investigation of this important topic.
PMCID: PMC2270863  PMID: 18307788
22.  The course of neurocognitive functioning in high-grade glioma patients1 
Neuro-Oncology  2007;9(1):53-62.
We evaluated the course of neurocognitive functioning in newly diagnosed high-grade glioma patients and specifically the effect of tumor recurrence. Following baseline assessment (after surgery and before radiotherapy), neurocognitive functioning was evaluated at 8 and 16 months. Neurocognitive summary measures were calculated to detect possible deficits in the domains of (1) information processing, (2) psychomotor function, (3) attention, (4) verbal memory, (5) working memory, and (6) executive functioning. Repeated-measures analyses of covariance were used to evaluate changes over time. Thirty-six patients were tested at baseline only. Follow-up data were obtained for 32 patients: 14 had a follow-up at 8 months, and 18 had an additional follow-up at 16 months. Between baseline and eight months, patients deteriorated in information-processing capacity, psychomotor speed, and attentional functioning. Further deterioration was observed between 8 and 16 months. Of 32 patients, 15 suffered from tumor recurrence before the eight-month follow-up. Compared with recurrence-free patients, not only did patients with recurrence have lower information-processing capacity, psychomotor speed, and executive functioning, but they also exhibited a more pronounced deterioration between baseline and eight-month follow-up. This difference could be attributed to the use of antiepileptic drugs in the patient group with recurrence. This study showed a marked decline in neurocognitive functioning in HGG patients in the course of their disease. Patients with tumor progression performed worse on neurocognitive tests than did patients without progression, which could be attributed to the use of antiepileptic drugs. The possibility of deleterious effects is important to consider when prescribing antiepileptic drug treatment.
PMCID: PMC1828106  PMID: 17018697
high-grade glioma; neurocognitive functioning; neuropsychological assessment; tumor recurrence; prospective study
23.  Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4 
Molecular Vision  2007;13:258-272.
Autosomal dominant Stargardt disease-3 (STGD3) is caused by mutations in elongase of very long chain fatty acids-4 (ELOVL4). The goal of this study was to generate and characterize heterozygous and homozygous knockin-mice that carry a human STGD3 pathogenic mutation in the mouse Elovl4 gene.
Recombinant Stgd3-knockin mice were generated using a DNA construct which introduced a pathogenic five-base pair deletion and two point mutations in exon 6 of the Elovl4 gene. Stgd3-mouse genotypes were confirmed by Southern blot analysis and expression of wild-type (wt) and mutated Elovl4 mRNAs assayed by nuclease protection assay. The retinal phenotype of heterozygous Stgd3 mice was characterized by morphological studies, elecroretinographic (ERG) analysis and assay of lipofuscin accumulation. Homozygous Stgd3 mice were examined for both retinal and gross morphology. They were also analyzed for skin morphology and skin barrier function, and for epidermal lipid content using high performance liquid chromatography (HPLC) combined with mass spectrometry (MS).
The Stgd3 allele codes for a truncated mouse Elovl4 protein, which also contains the same aberrant 8-amino acid C-terminus encoded by the human pathogenic STGD3 allele. Heterozygous Stgd3 mice expressed equal amounts of both wt and mutant Elovl4 mRNAs in the retina, showed no significant changes in retinal morphology, but did show accumulation of lipofuscin and reduced visual function. Homozygous Stgd3 mice were born with an expected Mendelian frequency, without any initial gross anatomical or behavioral abnormalities. By 6-12 h postpartum, they became dehydrated and died. A skin permeability assay detected a defect in epidermal barrier function. Homozygous mutant epidermis expressed a normal content of mutated Elovl4 mRNA and contained all four epidermal cellular layers. HPLC/MS analysis of epidermal lipids revealed the presence of all barrier lipids with the exception of the complete absence of acylceramides, the critical lipids for barrier function of the skin.
The generated Stgd3-knockin mice are a genetic model of human STGD3 and reproduce features of the human disease: accumulation of lipofuscin and reduced visual functions. Homozygous Stgd3 mice showed a complete absence of acylceramides from the epidermis. Their absence suggests a role for Elovl4 in acylceramide synthesis, and in particular, a role in the synthesis of the unique very long chain C30-C40 fatty acids present in skin acylceramides.
PMCID: PMC2633486  PMID: 17356513
24.  Impact of a First-year Primary Care Experience on Residency Choice 
We designed a retrospective cohort study of first-year medical students to assess the impact of a community-based primary care course, Introduction to Primary Care (IPC), on residency choice. In the group that took IPC (n = 282), 48.2% entered generalist residencies (internal medicine, pediatrics, family medicine, or medicine/pediatrics), compared to 38.2% in the group that wanted IPC (n = 398) and 39.6% in the group that did not want IPC (n = 245). Controlling for gender, students who took IPC had a 40% higher odds of selecting a generalist residency than those who wanted to take IPC (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.04 to 1.95). There was no difference between those who wanted IPC and those who did not (OR, 1.08; CI, 0.78 to 1.52). The community-based primary care experience was positively associated with students' selection of generalist residencies.
PMCID: PMC1495307  PMID: 11903766
career choice; community-based training
25.  Benefits and Costs to Community-Based Physicians Teaching Primary Care to Medical Students 
The purpose of this study was to determine the benefits and costs to community-based primary care physicians teaching medical students in their offices. Survey data were collected from 185 preceptors between 1990 and 1996. Respondents reported increases in their enjoyment of the practice of medicine (82%), time spent reviewing clinical medicine (66%), desire to keep up with recent developments in medicine (49%), and patients' perception of their stature (44%). However, 61% reported a decrease in the number of patients seen when a student was present. We conclude that despite the costs associated with teaching medical students in their offices, preceptors derived many benefits.
PMCID: PMC1496982  PMID: 9686716
physician satisfaction; benefits of teaching; costs of teaching

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