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Wolf N.I.,VU University Amsterdam | Salomons G.S.,VU University Amsterdam | Rodenburg R.J.,Radboud University Nijmegen | Pouwels P.J.W.,Neuroscience Campus Amsterdam | And 8 more authors.
Annals of Neurology | Year: 2014

Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl-tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination. Ann Neurol 2014;76:134-139 © 2014 American Neurological Association.


Schomaker J.,VU University Amsterdam | Berendse H.W.,VU University Amsterdam | Foncke E.M.J.,VU University Amsterdam | van der Werf Y.D.,Neuroscience Campus Amsterdam | And 4 more authors.
Neuropsychologia | Year: 2014

Parkinson[U+05F3]s disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic cells, resulting in dopamine depletion. This depletion is counteracted through dopamine replacement therapy (DRT). Dopamine has been suggested to affect novelty processing and memory, which suggests that these processes are also implicated in PD and that DRT could affect them. Objective: To investigate word learning and novelty processing in patients with PD as indexed by the P2 and P3 event-related potential components, and the role of DRT in these processes. Methods: 21 patients with PD and 21 matched healthy controls were included. Patients with PD were tested on and off DRT in two sessions in a counterbalanced design, and healthy controls were tested twice without intervention. Electroencephalogram (EEG) was measured while participants performed a word learning Von Restorff task. Results: Healthy controls showed the typical Von Restorff effect, with better memory for words that were presented in novel fonts, than for words presented in standard font. Surprisingly, this effect was reversed in the patients with PD. In line with the behavioral findings, the P3 was larger for novel than for standard font words in healthy controls, but not in patients with PD. For both groups the P2 and P3 event-related components were larger for recalled versus forgotten words. DRT did not affect these processes. Conclusions: Learning of novel information is compromised in patients with PD. Likewise, the P2 and P3 components that predict successful memory encoding are reduced in PD patients. This was true both on and off DRT, suggesting that these findings reflect abnormalities in learning and memory in PD that are not resolved by dopaminergic medication. © 2014 Elsevier Ltd.


Remijnse P.L.,VU University Amsterdam | van den Heuvel O.A.,VU University Amsterdam | Nielen M.M.A.,VU University Amsterdam | Vriend C.,VU University Amsterdam | And 6 more authors.
PLoS ONE | Year: 2013

Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD. © 2013 Remijnse et al.


Van Rooden S.,Leiden University | Goos J.D.C.,Neuroscience Campus Amsterdam | Van Opstal A.M.,Leiden University | Versluis M.J.,Leiden University | And 9 more authors.
Radiology | Year: 2014

Purpose: To assess the prevalence and number of cortical microinfarcts in patients with Alzheimer disease (AD) by using a 7-T magnetic resonance (MR) imaging system, to assess the independent association of cortical microinfarcts with cognitive dysfunction, and to investigate potential confounding effects of the coexisting presence of cerebral amyloid angiopathy (CAA). Materials and Methods: The local institutional review board approved this study. In all cases, informed consent was obtained. High-spatialresolution fluid-attenuated inversion recovery and T2*-weighted images were acquired in 14 AD patients and 18 control subjects to assess the presence of microinfarcts and microbleeds. Presence of CAA was assessed according to the Boston criteria. Image analysis was performed independently by two reviewers. Mann-Whitney U test was performed to assess differences in number of microinfarcts between groups. Negative binomial regression models were used to assess the association between diagnosis of AD and diagnosis of CAA and number of microinfarcts, between diagnosis of AD and number of microbleeds and number of microinfarcts, and between cognitive function and number of microinfarcts, all corrected for age and sex. Results: Interobserver agreement was excellent for detecting microinfarcts (k = 0.91) (P < .001). Patients with AD demonstrated higher number (P = .005) of microinfarcts (mean, 7.2) compared with control subjects (mean, 1.8). Negative binomial regression models showed an independent association between AD and number of microinfarcts (P = .006) and a trend for CAA and microinfarcts (P = .052). A negative correlation was found between cognitive function and the number of microinfarcts (P = .009). Conclusion: Patients with AD show more microinfarcts than do control subjects, the number of microinfarcts correlates with global cognitive performance, and the presence of microinfarcts was mainly AD rather than CAA related. © RSNA, 2013.


Vriend C.,VUmc | Vriend C.,VU University Amsterdam | Raijmakers P.,VU University Amsterdam | Veltman D.J.,VUmc | And 8 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

Background Depression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD. Methods In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non-demented PD patients (median Hoehn and Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [123I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT). Results Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients. Conclusions These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatalthalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression.


Geytenbeek J.J.M.,VU University Amsterdam | Vermeulen R.J.,Neuroscience Campus Amsterdam | Vermeulen R.J.,VU University Amsterdam | Becher J.G.,VU University Amsterdam | And 2 more authors.
Developmental Medicine and Child Neurology | Year: 2015

Aim: To assess spoken language comprehension in non-speaking children with severe cerebral palsy (CP) and to explore possible associations with motor type and disability. Method: Eighty-seven non-speaking children (44 males, 43 females, mean age 6y 8mo, SD 2y 1mo) with spastic (54%) or dyskinetic (46%) CP (Gross Motor Function Classification System [GMFCS] levels IV [39%] and V [61%]) underwent spoken language comprehension assessment with the computer-based instrument for low motor language testing (C-BiLLT), a new and validated diagnostic instrument. A multiple linear regression model was used to investigate which variables explained the variation in C-BiLLT scores. Associations between spoken language comprehension abilities (expressed in z-score or age-equivalent score) and motor type of CP, GMFCS and Manual Ability Classification System (MACS) levels, gestational age, and epilepsy were analysed with Fisher's exact test. A p-value <0.05 was considered statistically significant. Results: Chronological age, motor type, and GMFCS classification explained 33% (R=0.577, R2=0.33) of the variance in spoken language comprehension. Of the children aged younger than 6 years 6 months, 52.4% of the children with dyskinetic CP attained comprehension scores within the average range (z-score ≥-1.6) as opposed to none of the children with spastic CP. Of the children aged older than 6 years 6 months, 32% of the children with dyskinetic CP reached the highest achievable age-equivalent score compared to 4% of the children with spastic CP. No significant difference in disability was found between CP-related variables (MACS levels, gestational age, epilepsy), with the exception of GMFCS which showed a significant difference in children aged younger than 6 years 6 months (p=0.043). Interpretation: Despite communication disabilities in children with severe CP, particularly in dyskinetic CP, spoken language comprehension may show no or only moderate delay. These findings emphasize the importance of introducing alternative and/or augmentative communication devices from early childhood. © 2014 Mac Keith Press.


Vriend C.,VU University Amsterdam | Boedhoe P.S.W.,VU University Amsterdam | Rutten S.,VU University Amsterdam | Berendse H.W.,Neuroscience Campus Amsterdam | And 4 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2016

Background: Up to 50% of all patients with Parkinson's disease (PD) suffer from anxiety symptoms, a much higher percentage than in the general population. This suggests that PD associated pathological alterations partly underlie these symptoms, although empirical evidence is limited. Methods: Here we investigated the association between anxiety symptoms measured with the Beck Anxiety Inventory (BAI) and hippocampal and amygdalar volume in 110 early-stage patients with PD. Measures of anxiety in PD are often obscured by overlap with the somatic symptoms. We therefore also used a subscale of the BAI, established by our recent factor analysis, that reflects 'psychological' anxiety symptoms and is independent of the severity of PD-related motor and autonomic symptoms. We used FreeSurfer and voxel-based morphometry for the volumetric analyses. Results: Both software packages showed a negative correlation between the 'psychological' subscale of the BAI, but not total BAI and volume of the left amygdala, independent of the severity of motor symptoms, autonomic dysfunction and dopaminergic or anxiolytic medication status. Conclusions: These results confirm studies in non-PD samples showing lower left amygdalar volume in anxious patients. The results also indicate that the 'psychological' BAI subscale is a better reflection of neural correlates of anxiety in PD. Whether the left amygdalar volume decrease constitutes a premorbid trait, a PD-associated neurobiological susceptibility to anxiety or arises as a consequence of chronic anxiety symptoms remains to be determined by future prospective longitudinal studies. Nonetheless, we speculate that the Parkinson pathology is responsible for the reduction in amygdalar volume and the concomitant development of anxiety symptoms. © 2016, BMJ Publishing Group. All rights reserved.


Vriend C.,VU University Amsterdam | Gerrits N.J.H.M.,VU University Amsterdam | Berendse H.W.,Neuroscience Campus Amsterdam | Berendse H.W.,VU University Amsterdam | And 4 more authors.
Neurobiology of Aging | Year: 2015

Behavioral impairments in response inhibition and initiation are common in Parkinson's disease (PD) and are associated with reduced impulse control. No prior study, however, has investigated the functional correlates of response inhibition in de novo PD. Twenty-one de novo PD patients and 37 matched healthy controls performed a stop-signal task during functional magnetic resonance imaging. The results showed that PD patients, compared with healthy controls, were slower on response initiation but not inhibition. Task-related activation of the response inhibition network, including the inferior frontal gyrus, was reduced in PD patients, and the activity in the inferior frontal gyrus correlated negatively with motor symptom severity. These findings show that de novo PD patients exhibit functional deficits in the response inhibition network, which are partly related to disease pathology and already evident before commencing dopamine replacement therapy. This study provides insights into the neural underpinnings of impulse control deficits, relevant for the study of the neural vulnerability factors involved in the development of impulse control disorders in PD. © 2015 Elsevier Inc.


Jochemsen H.M.,University Utrecht | Muller M.,University Utrecht | Muller M.,VU University Amsterdam | Visseren F.L.,University Utrecht | And 5 more authors.
JAMA Neurology | Year: 2013

IMPORTANCE Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life, whereas studies in older populations have shown a relation between low BP and more brain atrophy. Yet, prospective evidence is limited, and the relation remains unclear in patients with manifest arterial disease. OBJECTIVE To examine the associations of baseline BP and change in BP over time with progression of brain atrophy. DESIGN The Secondary Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) Study is a prospective cohort study with baseline measurements in 2001-2005 and follow-up measurements in 2006-2009. The mean follow-up time was 3.9 years. SETTING University Medical Center Utrecht, the Netherlands. PARTICIPANTS A total of 663 patients (mean [SD] age, 57 [9] years; 81%male) with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysm were included. MAIN OUTCOMES AND MEASURES Using automated segmentation at baseline and follow-up, change in brain parenchymal fraction, cortical gray matter fraction, and ventricular fraction (%ICV) were quantified as indicators of progression of global, cortical, and subcortical brain atrophy. RESULTS Multivariable adjusted regression analysis showed that patients with lower baseline diastolic BP (DBP) or mean arterial pressure had more progression of subcortical atrophy. The mean differences in the change in ventricular fraction between low and high DBP was 0.07% (95%CI, 0.01-0.14) and between low and high mean arterial pressure was 0.05%(95%CI, 0.00-0.10). Furthermore, in patients with higher baseline BP (DBP, mean arterial pressure, or systolic BP), those with declining BP levels over time had less progression of subcortical atrophy compared with those with rising BP levels. CONCLUSIONS AND RELEVANCE In patients with manifest arterial disease, low baseline DBP was associated with more progression of subcortical atrophy, irrespective of the BP course during follow-up. Furthermore, in patients with higher baseline BP, declining BP levels over time were associated with less progression of subcortical atrophy. This could imply that BP lowering is beneficial in patients with higher BP levels, but caution should be taken with further BP lowering in patients who already have a low DBP.


van Mierlo T.J.,VU University Amsterdam | Chung C.,VU University Amsterdam | Foncke E.M.,VU University Amsterdam | Berendse H.W.,VU University Amsterdam | van den Heuvel O.A.,Neuroscience Campus Amsterdam
Movement Disorders | Year: 2015

Depression and anxiety are common in Parkinson's disease (PD), and are among the non-motor symptoms that interfere with quality of life dramatically. Motor, cognitive, and affective features overlap in PD, hampering diagnosis. To shed more light on the contribution of structural brain changes to the presence of PD-related depressive symptoms, we conducted a Voxel-Based Morphometry (VBM) study. We hypothesized that depressive symptoms in PD are related to regional gray matter (GM) volume loss within the limbic circuit. We analyzed the T1-weigthed magnetic resonance imaging (MRI) images of 67 PD patients with a mean disease duration of 2.95 (±3.39) years. Scores on the Beck Depression Inventory (BDI) and GM probability maps were analyzed by regression analysis to study the association between GM volume and severity of depressive symptoms. Results are reported at both the uncorrected and the family-wise error (FWE) corrected level for multiple comparisons. The BDI scores correlated negatively with bilateral hippocampus and right amygdala volume and positively with the volume of the anterior cingulate cortex. These findings confirm the hypothesized involvement of the limbic circuit in PD-related depressive symptoms. We speculate that non-dopaminergic changes are essential in the pathophysiology of depressive symptoms in PD, because our findings suggest the involvement of extra-striatal brain regions. © 2015 International Parkinson and Movement Disorder Society.

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