Wilma Van De Berg | Vrije Universiteit Amsterdam (original) (raw)

Papers by Wilma Van De Berg

Brain, 2011

There are many indications that neurogenesis is impaired in Parkinson's disease, which might be d... more There are many indications that neurogenesis is impaired in Parkinson's disease, which might be due to a lack of dopamine in the subventricular zone. An impairment in neurogenesis may have negative consequences for the development of new therapeutic approaches in Parkinson's disease, as neural stem cells are a potential source for endogenous repair. In this study, we examined the subventricular zone of 10 patients with Parkinson's disease and 10 age-and sex-matched controls for proliferation and neural stem cell numbers. We also included five cases with incidental Lewy body disease, which showed Parkinson's disease pathology but no clinical symptoms and thus did not receive dopaminergic treatment. We quantified the neural stem cell number and proliferative capacity in the subventricular zone of these three donor groups. We found subventricular neural stem cells in each donor, with a high variation in number. We did not observe significant differences in neural stem cell number or in proliferation between the groups. Additionally, we were able to culture neural stem cells from post-mortem brain of several patients with Parkinson's disease, confirming the presence of viable neural stem cells in these brains. We have also examined the subventricular zone of a chronic, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model, and again found no effect of dopaminergic denervation on precursor proliferation. Lastly, we investigated the proliferation capacity of two different human neural stem cell lines in response to dopamine. Both cell lines did not respond with a change in proliferation to treatment with dopamine agonists and an antagonist. In summary, the adult neural stem cell pool in the subventricular zone was not clearly affected in the human parkinsonian brain or a Parkinson's disease mouse model. Furthermore, we did not find evidence that dopamine has a direct effect on human neural stem cell proliferation in vitro. Thus, we conclude that the number of adult neural stem cells is probably not diminished in the parkinsonian brain and that dopamine depletion most likely has no effect on human neural stem cells.

Additional file 1 Supplementary Figure 1. When clustering all donors with a complete dataset (n =... more Additional file 1 Supplementary Figure 1. When clustering all donors with a complete dataset (n = 164) based on clinical features and pathological stages, four clusters of donors can be distinguished, namely 1) a small cluster with high AD-type pathology, 2) a cluster with LP donors (except for 2 non-LP donors) with an early disease onset, a young age at death and relatively little AD-type pathology, 3) a cluster with almost all non-LP donors, and 4) a cluster with LP donors (except for 1 non-LP donor) with a late age at onset and a late age at death. Supplementary Figure 2. When clustering only the LP donors with a complete dataset (n = 98), Braak α-synuclein stages and neocortical LP are most closely related to Braak NFT stage and dementia.

$Research paper thumbnail of Demyelination, inflammation and axonal loss explain different patterns of fractional anisotropy abnormalities in MS cortical normal appering gray matter and lesions$

Multiple Sclerosis Journal, 2018

Objective: To define the histopathological substrates of diffusivity abnormalities in cortical no... more Objective: To define the histopathological substrates of diffusivity abnormalities in cortical normal-appearing gray matter (cNAGM) and cortical lesions (CLs) of patients with multiple sclerosis (PwMS) by combining postmortem diffusion tensor (DT) MRI and histopathology.Background: In PwMS, a higher fractional anisotropy (FA) has been found in CLs vs cNAGM and is clinically relevant. However, its pathological substrates have yet to be elucidated.Design/Methods: Brain 3DT1 and DT postmortem in situ 3T MRI were obtained from 16 PwMS and 10 non-neurological controls (nNC). At subsequent autopsy, 110 tissue blocks (54 from PwMS, 56 from nNC) were dissected from 6 standardized cortical regions. Tissue regions were matched to 3DT1 and co-registered to DT sequence to obtain regional FA. Cortical density of myelin and microglia, axon number and orientation, number and size of neurons and glial cells were evaluated. Histopathological correlates of diffusivity alterations were assessed throug...

Scientific Reports

The aim of the current study was to assess the structural centrality and microstructural integrit... more The aim of the current study was to assess the structural centrality and microstructural integrity of the cortical hubs of the salience network, the anterior insular cortex (AIC) subregions and anterior cingulate cortex (ACC), and their relationship to cognitive and affective impairment in PD. MRI of 53 PD patients and 15 age-matched controls included 3D-T1 for anatomical registration, and diffusion tensor imaging for probabilistic tractography. Network topological measures of eigenvector and betweenness centrality were calculated for ventral (vAI) and dorsal (dAI) AIC. Microstructural tract integrity between vAI, dAI and the ACC was quantified with fractional anisotrophy (FA) and mean diffusivity (MD). Structural integrity and connectivity were related to cognitive and affective scores. The dAI had significantly higher eigenvector centrality in PD than controls (p

Acta Neuropathologica Communications, Mar 26, 2020

The clinical diagnosis in patients with parkinsonian disorders can be challenging, and a definite... more The clinical diagnosis in patients with parkinsonian disorders can be challenging, and a definite diagnosis requires neuropathological confirmation. The aim of this study was to examine whether a clinical diagnosis of Parkinson’s disease (PD) and atypical parkinsonian disorders predict the presence of Lewy pathology (LP) and concomitant neuropathological lesions.We included 293 donors with a history of parkinsonism without dementia at disease onset, collected by the Netherlands Brain Bank (NBB) from 1989 to 2015. We retrospectively categorized donors according the International Parkinson and Movement Disorder Society clinical diagnostic criteria for PD (MDS-PD criteria) as ‘not PD’, ‘probable PD’ or ‘established PD’. We compared the final clinical diagnosis to presence of neuropathological lesions as defined by BrainNet Europe and National Institute on Aging – Alzheimer's Association guidelines.LP was present in 150 out of 176 donors (85%) with a clinical diagnosis of PD, in 8 out of 101 donors (8%) with atypical parkinsonian disorders and in 4 out of 16 donors (25%) without a definite clinical diagnosis. Independent from age at death, stages of amyloid-β, but not neurofibrillary tau or neuritic plaques, were higher in donors with LP compared to other types of pathology (p = 0.009). The MDS-PD criteria at a certainty level of ‘probable PD’ predicted presence of LP with a diagnostic accuracy of 89.3%. Among donors with LP, ‘established PD’ donors showed similar Braak α-synuclein stages and stages of amyloid-β, neurofibrillary tau and neuritic plaques compared to ‘not PD’ or ‘probable PD’ donors.In conclusion, both a clinical diagnosis of PD as well as MDS-PD criteria accurately predicted presence of LP in NBB donors. LP was associated with more widespread amyloid-β pathology, suggesting a link between amyloid-β accumulation and LP formation.

Neurotoxicity Research

Encephalopathy due to perinatal asphyxia (PA) is a major cause of neonatal morbidity and mortalit... more Encephalopathy due to perinatal asphyxia (PA) is a major cause of neonatal morbidity and mortality in the period around birth. Preterm infants are especially at risk for cognitive, attention and motor impairments. Therapy for this subgroup is limited to supportive care, and new targets are thus urgently needed. Post-asphyxic excitotoxicity is partially mediated by excessive nitric oxide (NO) release. The aims of this study were to determine the timing and distribution of nitric oxide (NO) production after global PA in brain areas involved in motor regulation and coordination. This study focused on the rat striatum and cerebellum, as these areas also affect cognition or attention, in addition to their central role in motor control. NO/peroxynitrite levels were determined empirically with a fluorescent marker on postnatal days P5, P8 and P12. The distributions of neuronal NO synthase (nNOS), cyclic guanosine monophosphate (cGMP), astroglia and caspase-3 were determined with immunohis-tochemistry. Apoptosis was additionally assessed by measuring caspase-3-like activity from P2-P15. On P5 and P8, increased intensity of NO-associated fluorescence and cGMP immunoreactivity after PA was apparent in the striatum, but not in the cerebellum. No changes in nNOS immunoreactivity or astrocytes were observed. Modest changes in caspase-3-activity were observed between groups, but the overall time course of apoptosis over the first 11 days of life was similar between PA and controls. Altogether, these data suggest that PA increases NO/ peroxynitrite levels during the first week after birth within the striatum, but not within the cerebellum, without marked astrogliosis. Therapeutic benefits of interventions that reduce endogenous NO production would likely be greater during this time frame.

Neuroscience, 2006

Chronic or repeated stress during human fetal brain development has been associated with various ... more Chronic or repeated stress during human fetal brain development has been associated with various learning, behavioral, and/or mood disorders, including depression in later life. The mechanisms accounting for these effects of prenatal stress are not fully understood. The aim of this study was to investigate the effects of prenatal stress on early postnatal brain development, a disturbance of which may contribute to this increased vulnerability to psychopathology. We studied the effects of prenatal stress on fetal growth, stress-induced corticosterone secretion, brain cell proliferation, caspase-3-like activity and brain-derived neurotrophic factor protein content in newborn Fischer 344 rats. In addition to a slight reduction in birth weight, prenatal stress was associated with elevated corticosterone levels (33.8%) after 1 h of maternal deprivation on postnatal day 1, whereas by postnatal day 8 this pattern was reversed (؊46.5%). Further, prenatal stress resulted in an approximately 50% decrease in brain cell proliferation just after birth in both genders with a concomitant increase in caspase-3-like activity within the hippocampus at postnatal day 1 (36.1%) and at postnatal day 5 (females only; 20.1%). Finally, brainderived neurotrophic factor protein content was reduced in both the olfactory bulbs (؊24.6%) and hippocampus (؊28.2%) of prenatally stressed male offspring at postnatal days 1 and 5, respectively. These detrimental central changes observed may partly explain the increased susceptibility of prenatally stressed subjects to mood disorders including depression in later life.

Glia, 2002

We investigated developmental apoptosis in the white matter of the cervical spinal cord at postna... more We investigated developmental apoptosis in the white matter of the cervical spinal cord at postnatal days 2, 5, and 8. Apoptotic cells were labeled using TUNEL and caspase-3 immunostaining. Apoptotic cells were diffusely distributed throughout the white matter of the spinal cord. The total amount of apoptotic cells in the cervical spinal cord white matter was related to postnatal age, with the lowest at P2 (mean 7.9, SD 5.6) and the highest at P8 (mean 109, SD 21.4). Using double immunostaining for ED-1 and O4, apoptotic cells were identified as microglia and oligodendrocytes. GLIA 37:89-91, 2002.

Neuroscience, 2003

Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters within the striatum... more Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters within the striatum. The striatum plays an important role in motor control, sensorimotor integration and learning. In the present study we investigated whether perinatal asphyxia leads to motor deficits related to striatal damage, and in particular to the loss of GABAergic neurons. Perinatal asphyxia was induced in time-pregnant Wistar rats on the day of delivery by placing the uterus horns, containing the pups, in a 37°C water bath for 20 min. Three motor performance tasks (open field, grip test and walking pattern) were performed at 3 and 6 weeks of age. Antibodies against calbindin and parvalbumin were used to stain GABAergic striatal projection neurons and interneurons, respectively. The motor tests revealed subtle effects of perinatal asphyxia, i.e. small decrease in motor activity. Analysis of the walking pattern revealed an increase in stride width at 6 weeks of age after perinatal asphyxia. Furthermore, a substantial loss of calbindin-immunoreactive (؊22%) and parvalbumin-immunoreactive (؊43%) cells was found in the striatum following perinatal asphyxia at two months of age. GABA A receptor autoradiography revealed no changes in GABA binding activity within the striatum, globus pallidus or substantia nigra. We conclude that perinatal asphyxia resulted in a loss of GABAergic projection neurons and interneurons in the striatum without alteration of GABA A receptor affinity. Despite a considerable loss of striatal neurons, only minor deficits in motor performance were found after perinatal asphyxia.

European Journal of Neurology, 2014

The cerebrospinal fluid (CSF) concentration of α-synuclein may reflect the aggregation of α-synuc... more The cerebrospinal fluid (CSF) concentration of α-synuclein may reflect the aggregation of α-synuclein in brain tissue that neuropathologically characterizes Parkinson&amp;amp;amp;#39;s disease (PD). Although most studies in large cohorts report reduced CSF α-synuclein levels in PD, the available data to date are not consistent due to variation in group sizes, pre-analytical confounding factors and assay characteristics. Furthermore, it remains unclear whether CSF α-synuclein concentrations correlate with measures of disease severity. Acknowledging the methodological issues that emerged from previous studies, we evaluated whether CSF α-synuclein levels differ between patients with PD and controls, and relate to disease duration or severity. α-Synuclein levels were measured in CSF samples of 53 well-characterized patients with PD and 50 healthy controls employing a recently developed time-resolved Förster&amp;amp;amp;#39;s resonance energy transfer assay. In addition, we studied the relationship of CSF α-synuclein levels with disease duration, clinical measures of disease severity and the striatal dopaminergic deficit as measured by dopamine transporter binding and single photon emission computed tomography. In patients with PD, we observed a decrease in mean CSF α-synuclein levels that was unrelated to disease duration or measures of disease severity. Using total protein normalized α-synuclein, a sensitivity and specificity of 70% and 74% could be reached for distinguishing between patients with PD and controls. CSF α-synuclein levels are reduced in patients with PD compared with healthy controls. However, sensitivity and specificity indicate that α-synuclein will not suffice as a single biomarker. CSF α-synuclein levels do not correlate with measures of disease severity, including striatal dopaminergic deficit.

Parkinsonism & Related Disorders, 2009

Introduction: Dopamine dysregulation syndrome (DDS) and impulse control disorders (ICDs) in Parki... more Introduction: Dopamine dysregulation syndrome (DDS) and impulse control disorders (ICDs) in Parkinson's disease (PD) are connected with reward system pathology. The D2 dopamine receptor (DRD2) has been profoundly implicated in reward mechanism in the brain and the DRD2 gene has been referred to as reward gene. Aim: The aim of this study was the evaluation of the relationship between TaqI A polymorphism of DRD2 gene and DDS/ICDs in PD. Patients and Methods: 94 subjects with idiopathic PD were examined-26 subjects (19 men) 42-77 years old with coexisting DDS and ICDs (Group I) and 68 subjects (46 men) 39-79 years old without these disorders (Group II). The presence of psychiatric problems was diagnosed by structured clinical interview: DDS (criteria by Giovannoni et al.) and ICDs-punding (criteria by Evans et al.), pathological gambling (DSM-IV), pathological hypersexuality (criteria by Voon et al.). The A1 and A2 alleles were determined by PCR. Results: In Group I-19 (73.1%) patients were homozygotes A2/A2 of DRD2 gene, 7 (26.9%) patients were heterozygotes A1/A2. Among PD patients without DDS/ICDs (Group II) genotype distribution for each variant DRD2 gene was as follows: A2/A2-45 (66.2%), A1/A2-21 (30.9%) and A1/A1-2 (2.9%). The genotype frequency distribution of DRD2 did not show significant differences in examined groups. Conclusion: The present study suggests that TaqI A polymorphism is not related to the development of DDS/ICDs in PD.

Journal of Chemical …, 2000

Deficits in cognitive function have been related to quantitative changes in synaptic population, ... more Deficits in cognitive function have been related to quantitative changes in synaptic population, particularly in the cerebral cortex. Here, we used an established model of perinatal asphyxia that induces morphological changes, i.e. neuron loss in the cerebral cortex and striatum, as well as behavioural deficits. We hypothesized that perinatal asphyxia may lead to a neurodegenerative process resulting in cognitive impairment and altered presynaptic bouton numbers in adult rats. We studied cognitive performance at 18 months and presynaptic bouton numbers at 22 months following perinatal asphyxia. Data of the spatial Morris water escape task did not reveal clear memory or learning deficits in aged asphyctic rats compared to aged control rats. However, a memory impairment in aged rats versus young rats was observed, which was more pronounced in asphyctic rats. We found an increase in presynaptic bouton density in the parietal cortex, whereas no changes were found in striatum and frontal cortex in asphyctic rats. An increase of striatal volume was observed in asphyctic rats, leading to an increase in presynaptic bouton numbers in this area. These findings stress the issue that volume measurements have to be taken into account when determining presynaptic bouton density. Furthermore, perinatal asphyxia led to region-specific changes in presynaptic bouton numbers and it worsened the age-related cognitive impairment. These results suggest that perinatal asphyxia induced neuronal loss, which is compensated for by an increase in presynaptic bouton numbers.

Movement disorders : official journal of the Movement Disorder Society, 2011

There may be a relationship between cognitive impairment and visual hallucinations (VHs) in patie... more There may be a relationship between cognitive impairment and visual hallucinations (VHs) in patients with Parkinson's disease (PD). The objective of this study was to compare the cognitive profile of hallucinating vs. nonhallucinating patients with Parkinson's disease dementia (PDD).

There is a cholinergic deficit in Parkinson disease (PD) and in dementia with Lewy bodies (DLB) t... more There is a cholinergic deficit in Parkinson disease (PD) and in dementia with Lewy bodies (DLB) that plays a role in a variety of clinical symptoms, including visual hallucinations (VH). The aim of this study was to assess cholinergic neuronal loss and PD and Alzheimer disease pathology in the pedunculopontine nucleus pars compacta (PPNc) of PD and DLB patients with VH. Postmortem brainstem tissue samples of 9 clinically diagnosed and pathologically confirmed PD patients with VH, 9 DLB patients with VH, and 9 age-and sex-matched nondemented controls were obtained from the Netherlands Brain Bank. Using a morphometric approach, we estimated the density of cholinergic neurons in the PPNc and determined the local load of >-synucleinYimmunoreactive Lewy pathology, neurofibrillary tangles, and A-amyloid plaques. Cholinergic cell density in the PPNc was significantly lower in PD compared with DLB patients with VH (j39%, p G 0.001) and controls (j41%, p G 0.001). Alpha-synuclein load was higher in PD, whereas A-amyloid plaque pathology was more pronounced in DLB patients. The mean cell density in DLB patients was not significantly reduced compared with that in controls. These results may indicate different patterns of degeneration of cholinergic output structures in PD and DLB.

Neuropathology and applied neurobiology, Jan 24, 2018

The insular cortex consists of a heterogenous cytoarchitecture and diverse connections and is tho... more The insular cortex consists of a heterogenous cytoarchitecture and diverse connections and is thought to integrate autonomic, cognitive, emotional and interoceptive functions to guide behaviour. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), it reveals α-synuclein pathology in advanced stages. The aim of this study is to assess the insular cortex cellular and subregional vulnerability to α-synuclein pathology in well-characterized PD and DLB subjects. We analysed postmortem insular tissue from 24 donors with incidental Lewy body disease, PD, PD with dementia (PDD), DLB and age-matched controls. The load and distribution of α-synuclein pathology and tyrosine hydroxylase (TH) cells were studied throughout the insular subregions. The selective involvement of von Economo neurons (VENs) in the anterior insula and astroglia was assessed in all groups. A decreasing gradient of α-synuclein pathology load from the anterior periallocortical agranular towards the intermed...

Cognitive deficits in Alzheimer’s disease, specifically amnestic (memory dominant) deficits, are ... more Cognitive deficits in Alzheimer’s disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-β and phosphorylated-tau pathology at autopsy. To better understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimer’s disease, we utilized a combined post-mortem in-situ MRI and histopathology approach. A total of 19 Alzheimer’s disease (10 amnestic and 9 non-amnestic) and 9 non-neurological control donors underwent 3T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed fo...