Publications by authors named "Huub A M Middelkoop"

45 Publications

Cross-cohort generalizability of deep and conventional machine learning for MRI-based diagnosis and prediction of Alzheimer's disease.

Neuroimage Clin 2021 4;31:102712. Epub 2021 Jun 4.

Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924-0.955) and CNN (0.933; 95%CI: 0.918-0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p<0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855-0.932) and CNN (0.876; 95%CI: 0.836-0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p=0.01). Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice.
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http://dx.doi.org/10.1016/j.nicl.2021.102712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203808PMC
September 2021

Preoperative Electroencephalography-Based Machine Learning Predicts Cognitive Deterioration after Subthalamic Deep Brain Stimulation.

Mov Disord 2021 Jun 3. Epub 2021 Jun 3.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Subthalamic deep brain stimulation (STN DBS) may relieve refractory motor complications in Parkinson's disease (PD) patients. Despite careful screening, it remains difficult to determine severity of alpha-synucleinopathy involvement which influences the risk of postoperative complications including cognitive deterioration. Quantitative electroencephalography (qEEG) reflects cognitive dysfunction in PD and may provide biomarkers of postoperative cognitive decline.

Objective: To develop an automated machine learning model based on preoperative EEG data to predict cognitive deterioration 1 year after STN DBS.

Methods: Sixty DBS candidates were included; 42 patients had available preoperative EEGs to compute a fully automated machine learning model. Movement Disorder Society criteria classified patients as cognitively stable or deteriorated at 1-year follow-up. A total of 16,674 EEG-features were extracted per patient; a Boruta algorithm selected EEG-features to reflect representative neurophysiological signatures for each class. A random forest classifier with 10-fold cross-validation with Bayesian optimization provided class-differentiation.

Results: Tweny-five patients were classified as cognitively stable and 17 patients demonstrated cognitive decline. The model differentiated classes with a mean (SD) accuracy of 0.88 (0.05), with a positive predictive value of 91.4% (95% CI 82.9, 95.9) and negative predictive value of 85.0% (95% CI 81.9, 91.4). Predicted probabilities between classes were highly differential (hazard ratio 11.14 [95% CI 7.25, 17.12]); the risk of cognitive decline in patients with high probabilities of being prognosticated as cognitively stable (>0.5) was very limited.

Conclusions: Preoperative EEGs can predict cognitive deterioration after STN DBS with high accuracy. Cortical neurophysiological alterations may indicate future cognitive decline and can be used as biomarkers during the DBS screening. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28661DOI Listing
June 2021

Vigilance: discussion of related concepts and proposal for a definition.

Sleep Med 2021 07 4;83:175-181. Epub 2021 May 4.

Department of Neurology and Clinical Neurophysiology, Leiden University Medical Center, the Netherlands.

We reviewed current definitions of vigilance to propose a definition, applicable in sleep medicine. As previous definitions contained terms such as attention, alertness, and arousal, we addressed these concepts too. We defined alertness as a quantitative measure of the mind state governing sensitivity to stimuli. Arousal comprises a stimulus-induced upward change in alertness, irrespective of the subsequent duration of the increased level of alertness. Vigilance is defined as the capability to be sensitive to potential changes in one's environment, ie the capability to reach a level of alertness above a threshold for a certain period of time rather than the state of alertness itself. It has quantitative and temporal dimensions. Attention adds direction towards a stimulus to alertness, requiring cognitive control: it involves being prepared to process stimuli coming from an expected direction. Sustained attention corresponds to a state in which some level of attention is purposefully maintained, adding a time factor to the definition of attention. Vigilance differs from sustained attention in that the latter in addition implies a direction to which attention is cognitively directed as well as a specification of duration. Attempts to measure vigilance, however, are often in fact measurements of sustained attention.
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http://dx.doi.org/10.1016/j.sleep.2021.04.038DOI Listing
July 2021

Mortality in patients with systemic lupus erythematosus and neuropsychiatric involvement: A retrospective analysis from a tertiary referral center in the Netherlands.

Lupus 2020 Dec 20;29(14):1892-1901. Epub 2020 Oct 20.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Objective: We aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018.

Methods: Patients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.

Results: 351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6-8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2-6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5-2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.

Conclusion: Mortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients.
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http://dx.doi.org/10.1177/0961203320963815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684795PMC
December 2020

Effect of deep brain stimulation on caregivers of patients with Parkinson's disease: A systematic review.

Parkinsonism Relat Disord 2020 12 1;81:20-27. Epub 2020 Oct 1.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: Caregivers of patients with Parkinson's Disease (PD) often provide important support in the pre- and postoperative phase of Deep Brain Stimulation (DBS). DBS-associated changes of patient-functioning may affect caregiver wellbeing and impact the support system. Factors influencing caregiver-wellbeing under these circumstances are incompletely known.

Objective: to systematically review studies of sufficient methodological quality on the impact of DBS on caregivers of PD patients.

Methods: using PRISMA guidelines, major databases were searched up to May 2020. Five subcategories were identified: Caregiver burden, Caregiver cognitive and psychiatric functioning, Caregiver Quality of Life (QoL), Marital Satisfaction/Conflicts, and Caregiver Satisfaction. Quality was assessed using an in-house checklist.

Results: 293 studies were identified; 12 were ultimately included. Caregiver burden, psychiatric and cognitive functioning and QoL remained relatively unchanged. Results on marital satisfaction/conflicts were contrasting: an increase in marital conflicts despite improved relationship quality scores DBS. Caregiver satisfaction with surgery was low with 50-58% of caregivers being disappointed with DBS outcomes. Concerning caregiver related factors: a higher preoperative caregiver QoL, younger age, lower scores on psychiatric rating scales, and more favourable preoperative relationship quality scores, were associated with better caregiver wellbeing. A favourable patient-profile includes younger age and age-at-onset, shorter disease duration, lower medication requirements, and lower scores on psychiatric rating scales.

Conclusion: Although most patient- and caregiver-related subdomains remained unchanged after DBS, dissatisfaction among caregivers and marital problems may constitute a large risk for a well-functioning patient-caregiver dyad. Early recognition of potential problem situations may improve post-DBS care for both patients and caregivers.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.038DOI Listing
December 2020

The Association Between Biomarkers and Neuropsychiatric Symptoms Across the Alzheimer's Disease Spectrum.

Am J Geriatr Psychiatry 2020 07 20;28(7):735-744. Epub 2020 Feb 20.

Department of Psychiatry and Neuropsychology (LCPB, IHGBR, SK, FRJV, PA), Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.

Objective: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms.

Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses.

Results: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning.

Conclusion: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.
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http://dx.doi.org/10.1016/j.jagp.2020.01.012DOI Listing
July 2020

Cognitive functioning as a predictor of employment status in relapsing-remitting multiple sclerosis: a 2-year longitudinal study.

Neurol Sci 2019 Dec 19;40(12):2555-2564. Epub 2019 Jul 19.

Department of Psychology, Health, Medical and Neuropsychology Unit, Leiden University, PO Box 9555, 2300 RB, Leiden, The Netherlands.

Background: Cognitive functioning has been linked to employment outcomes in multiple sclerosis (MS) in cross-sectional studies. Longitudinal studies are however lacking and previous studies did not extensively examine executive functioning.

Objectives: We examined whether baseline cognitive functioning predicts a change in employment status after 2 years, while taking into account mood, fatigue and disability level.

Methods: A total of 124 patients with relapsing-remitting MS (pwMS) and 60 healthy controls were included. They underwent neurological and neuropsychological examinations and completed online questionnaires. PwMS were divided into a stable and deteriorated employment status group (SES and DES), based on employment status 2 years after baseline. We first examined baseline differences between the SES and DES groups in cognitive functioning, mood, fatigue and disability level. A logistic regression analysis was performed, with change in employment status (SES/DES) as dependent variable.

Results: The DES group included 22% pwMS. Group differences were found in complex attention, executive functioning, self-reported cognitive functioning, fatigue and physical disability. More physical disability (OR = 1.90, p = 0.01) and lower executive functioning (OR = 0.30, p = 0.03) were retained as independent predictors of DES (R = 0.22, p ≤ 0.001).

Conclusions: Baseline physical disability and executive functioning, but none of the other variables, moderately predicted a deterioration in employment status 2 years later.

Trial Registration: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. This study is registered at the Dutch CCMO register (https://www.toetsingonline.nl).
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http://dx.doi.org/10.1007/s10072-019-03999-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848242PMC
December 2019

Visual Object Perception in Premanifest and Early Manifest Huntington's Disease.

Arch Clin Neuropsychol 2019 Nov;34(8):1320-1328

Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands.

Objective: In Huntington's disease (HD), a hereditary neurodegenerative disorder, cognitive impairment in early disease stages mainly involves executive dysfunction. However, visual cognitive deficits have additionally been reported and are of clinical relevance given their influence on daily life and overall cognitive performance. This study aimed to assess visual perceptual skills in HD gene carriers.

Methods: Subtasks of the Visual Object and Space Perception battery and Groningen Intelligence Test were administered in 62 participants (18 healthy controls, 22 participants with a genetic confirmation of HD without symptoms, i.e., premanifest HD, and 22 participants with a genetic confirmation of HD with symptoms, i.e., manifest HD). Group differences in task performance were measured using analysis of covariance with and without correction for age. Receiver Operating Characteristics (ROC) analysis was performed to examine which task best discriminated between groups and cut-off scores were provided.

Results: Manifest HD performed significantly worse compared to both controls and premanifest HD on all visual perceptional tasks. Premanifest HD did not differ in task performance from controls. Besides the Shape Detection, all tasks were robust in discriminating between groups. The Animal Silhouettes test was most accurate in discriminating manifest HD from premanifest HD (AUC = 0.90, SE = 0.048, p < .001).

Conclusion: Visual perceptual deficits are present in early manifest HD, especially an impaired recognition of animals and objects from sketched silhouettes, and not in premanifest HD. This suggests that decline in visual processing only occurs in clinical disease stages. The visual cognitive battery, especially the Silhouettes tasks used in this study is sensitive in discriminating manifest HD from premanifest HD and controls.
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http://dx.doi.org/10.1093/arclin/acz002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227804PMC
November 2019

Early Magnetic Resonance Imaging and Cognitive Markers of Hereditary Cerebral Amyloid Angiopathy.

Stroke 2016 12 10;47(12):3041-3044. Epub 2016 Nov 10.

From the C.J. Gorter Center for High-Field MRI (S.v.R., A.M.v.O., A.G.W., J.v.d.G., M.A.v.B.), Department of Radiology (S.v.R., A.M.v.O., G.L., A.G.W., J.v.d.G., M.A.v.B.), and Department of Neurology (G.M.T., M.J.H.W., H.A.M.M.), Leiden University Medical Center, The Netherlands; and Department of Neurology, Massachusetts General Hospital, Boston (S.M.G.).

Background And Purpose: Early markers for cerebral amyloid angiopathy are largely unknown. We aimed to identify which magnetic resonance imaging (MRI) (performed at 7 and 3T) and cognitive markers are an early sign in (pre) symptomatic subjects with hereditary cerebral hemorrhage with amyloidosis-Dutch type.

Methods: Twenty-seven DNA-proven Dutch-type mutation carriers (15 symptomatic and 12 presymptomatic) (mean age of 45.9 years) and 33 controls (mean age of 45.6 years) were included. 7T and 3T MRI was performed, cerebral amyloid angiopathy and small-vessel disease type MRI markers were estimated, and cognitive performance was assessed. Univariate general linear modeling analysis was used to assess the association between MRI markers and cognitive performance on the one hand and on the other, mutation status, adjusted for age, sex, and education.

Results: In symptomatic patients, all established cerebral amyloid angiopathy MRI markers (microbleeds, intracerebral hemorrhages, subarachnoid hemorrhages, superficial siderosis, microinfarcts, volume of white matter hyperintensities, and dilated perivascular spaces in centrum semiovale) were increased compared with controls (P<0.05). In presymptomatic subjects, the prevalence of microinfarcts and median volume of white matter hyperintensities were increased in comparison to controls (P<0.05). Symptomatic patients performed worse on all cognitive domains, whereas presymptomatic subjects did not show differences in comparison with controls (P<0.05).

Conclusions: White matter hyperintensities and microinfarcts are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages.
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http://dx.doi.org/10.1161/STROKEAHA.116.014418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127744PMC
December 2016

The [email protected] study: a 3-year prospective observational study on factors involved with work participation in patients with relapsing-remitting Multiple Sclerosis.

BMC Neurol 2015 Aug 12;15:134. Epub 2015 Aug 12.

Department of Neurology, St. Elisabeth-TweeSteden Hospital, PO Box 90151, Tilburg, 5000 LC, The Netherlands.

Background: Multiple Sclerosis (MS) is the most common cause of neurological disability in young and middle-aged adults. At this stage in life most people are in the midst of their working career. The majority of MS patients are unable to retain employment within 10 years from disease onset. Leading up to unemployment, many may experience a reduction in hours or work responsibilities and increased time missed from work. The [email protected] study examines various factors that may influence work participation in relapsing-remitting MS patients, including disease-related factors, the working environment and personal factors.

Methods/design: The [email protected] study is a multicenter, 3-year prospective observational study on work participation in patients with relapsing-remitting MS. We aim to include 350 patients through 15-18 MS outpatient clinics in the Netherlands. Eligible participants are 18 years and older, and either currently employed or within three years since their last employment. At baseline and after 1, 2 and 3 years, the participants are asked to complete online questionnaires (including questions on work participation, work problems and accommodations, cognitive and physical ability, anxiety, depression, psychosocial stress, quality of life, fatigue, empathy, personality traits and coping strategies) and undergo cognitive and neurological examinations. After six months, patients are requested to only complete online questionnaires. Patient perspectives on maintaining and improving work participation and reasons to stop working are gathered through semi-structured interviews in a sub-group of patients.

Discussion: Prospective studies with long-term follow-up on work participation in MS are rare, or take into account a limited number of factors. The [email protected] study provides a 3-year follow-up on various factors that may influence work participation in patients with relapsing-remitting MS. We aim to identify factors that relate to job loss and to provide information about preventative measures for physicians, psychologists and other professionals working in the field of occupational health.
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http://dx.doi.org/10.1186/s12883-015-0375-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531500PMC
August 2015

Association between changes in brain microstructure and cognition in older subjects at increased risk for vascular disease.

BMC Neurol 2015 Aug 7;15:133. Epub 2015 Aug 7.

Department of Radiology, C3-Q, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.

Background: The purpose of this study is to investigate whether changes in brain microstructure, detected by magnetization transfer imaging, are associated with cognition in older subjects at increased risk for vascular disease.

Methods: One hundred ninety three nondemented subjects (105 men, mean age 77 ± 3 years) from the Prospective Study of Pravastatin in the Elderly at Risk were included. To assess cross-sectional associations between magnetization transfer ratio (MTR) peak height and cognitive test scores, general linear model multivariate analysis was performed. Models were adjusted for age, sex, education level, vascular risk factors, individual white matter lesion volume, and brain atrophy. A repeated measures general linear model was used to investigate whether MTR peak height relates to cognitive test performance at baseline and 3.3-year follow-up.

Results: Cross-sectionally, MTR peak height was associated with performance on the STROOP test (unstandardized β = -0.27, p = 0.045), delayed Picture Word Learning (PWL) test (β = 0.48, p = 0.007), and the Letter Digit Coding test (β = 1.1, p = 0.006). Repeated measures general linear model analysis showed that individuals with low MTR peak height at baseline performed worse on the STROOP test compared to subjects with intermediate MTR peak height (mean time to complete the test at baseline and follow-up, lower versus middle tertile of MTR peak height: 61.6 versus 52.7 s, p = 0.019) or compared to subjects with high MTR peak height (p = 0.046). Similarly, low MTR peak height was associated with worse performance on the immediate (lower versus middle tertile, p = 0.023; lower versus higher tertile, p = 0.032) and delayed PWL test (lower versus middle, p = 0.004; lower versus higher, p = 0.012) at baseline and follow-up testing.

Conclusions: MTR peak height is associated with cognitive function in older subjects at increased risk for vascular disease.
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http://dx.doi.org/10.1186/s12883-015-0396-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545822PMC
August 2015

Cortical phase changes measured using 7-T MRI in subjects with subjective cognitive impairment, and their association with cognitive function.

NMR Biomed 2016 09 19;29(9):1289-94. Epub 2014 Dec 19.

C. J. Gorter Center for High-Field MRI, Leiden University Medical Center, Leiden, the Netherlands.

Studies have suggested that, in subjects with subjective cognitive impairment (SCI), Alzheimer's disease (AD)-like changes may occur in the brain. Recently, an in vivo study has indicated the potential of ultra-high-field MRI to visualize amyloid-beta (Aβ)-associated changes in the cortex in patients with AD, manifested by a phase shift on T2 *-weighted MRI scans. The main aim of this study was to investigate whether cortical phase shifts on T2 *-weighted images at 7 T in subjects with SCI can be detected, possibly implicating the deposition of Aβ plaques and associated iron. Cognitive tests and T2 *-weighted scans using a 7-T MRI system were performed in 28 patients with AD, 18 subjects with SCI and 27 healthy controls (HCs). Cortical phase shifts were measured. Univariate general linear modeling and linear regression analysis were used to assess the association between diagnosis and cortical phase shift, and between cortical phase shift and the different neuropsychological tests, adjusted for age and gender. The phase shift (mean, 1.19; range, 1.00-1.35) of the entire cortex in AD was higher than in both SCI (mean, 0.85; range, 0.73-0.99; p < 0.001) and HC (mean, 0.94; range, 0.79-1.10; p < 0.001). No AD-like changes, e.g. increased cortical phase shifts, were found in subjects with SCI compared with HCs. In SCI, a significant association was found between memory function (Wechsler Memory Scale, WMS) and cortical phase shift (β = -0.544, p = 0.007). The major finding of this study is that, in subjects with SCI, an increased cortical phase shift measured at high field is associated with a poorer memory performance, although, as a group, subjects with SCI do not show an increased phase shift compared with HCs. This increased cortical phase shift related to memory performance may contribute to the understanding of SCI as it is still unclear whether SCI is a sign of pre-clinical AD. Copyright © 2014 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/nbm.3248DOI Listing
September 2016

A pilot study on factors involved with work participation in the early stages of multiple sclerosis.

PLoS One 2014 25;9(8):e105673. Epub 2014 Aug 25.

St. Elisabeth Hospital, Department of Neurology, Tilburg, The Netherlands; University of Humanistic Studies, Utrecht, The Netherlands.

Background: Up to 30% of recently diagnosed MS patients lose their jobs in the first four years after diagnosis. Taking into account the personal and socio-economic importance of sustaining employment, it is of the utmost importance to examine factors involved with work participation.

Objective: To investigate differences in self-reported functioning in recently diagnosed MS patients with and without a paid job.

Methods: Self-reports of physical and cognitive functioning, depression, anxiety and fatigue were gathered from 44 relapsing-remitting MS patients diagnosed within 3 years.

Results: Patients with a paid job (57%) reported better physical functioning (p<0.001), better memory functioning (p = 0.01) and a lower physical impact of fatigue (p = 0.018) than patients without a paid job. Physical functioning was the main predictor of employment status in a logistic regression model. In those with a paid job better memory functioning (r = 0.54, p = 0.005) and a lower social impact of fatigue (r =  -0.46, p = 0.029) correlated with an increased number of working hours.

Conclusion: Better physical functioning is the primary factor involved with increased work participation in early MS. Better self-reported memory functioning and less social fatigue were associated with increased working hours. These findings highlight the importance of battling these symptoms in the early stages of MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105673PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143284PMC
November 2015

Nonlinguistic cognitive impairment in poststroke aphasia: a prospective study.

Neurorehabil Neural Repair 2014 Mar-Apr;28(3):273-81. Epub 2013 Nov 8.

1Erasmus MC University Medical Center, Rotterdam, Netherlands.

Background And Objectives: Information on cognitive impairment in aphasic patients is limited. Our aim was to investigate the prevalence and course of nonlinguistic cognitive impairments in the first year after stroke and their association with aphasia and functional outcome.

Methods: We included 147 patients with acute aphasia. At 3 months and 1 year, we assessed cognition with a nonlinguistic cognitive examination including abstract reasoning, visual memory, visual perception and construction, and executive functioning. We assessed language with a verbal communication rating (Aphasia Severity Rating Scale), the ScreeLing (a linguistic-level screening test), and the Token Test. We evaluated functional outcome with the modified Rankin scale and registered the use of antidepressants.

Results: In total, 107 (88%) patients had impairments in at least one nonlinguistic cognitive domain at 3 months and 91 (80%) at 1 year. The most frequently observed impairment concerned visual memory (83% at 3 months; 78% at 1 year) and the least frequent visual perception and construction (19% at 3 months; 14% at 1 year). There was improvement on all cognitive domains including language, except for abstract reasoning. Patients with persisting aphasia had lower cognitive domain scores, worse functional outcome, and were more often depressed than patients who had recovered from aphasia.

Conclusions: Standard nonlinguistic cognitive examination is recommended in aphasic stroke patients. Nonlinguistic cognitive impairments are common and associated with poor functional outcome and depression, especially in patients with persisting aphasia.
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http://dx.doi.org/10.1177/1545968313508467DOI Listing
September 2014

Longitudinal pilot-study of Sustained Attention to Response Task and P300 in manifest and pre-manifest Huntington's disease.

J Neuropsychol 2015 Mar 24;9(1):10-20. Epub 2013 Oct 24.

Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Earlier research has found cross-sectional attentional control deficits in manifest Huntington's disease (HD) using neuropsychological testing combined with simultaneous P300 registration. In the current pilot-study, we investigate attentional control in pre-manifest and manifest HD over a 3-year follow-up period.

Method: Five manifest HD (MHD), 9 pre-manifest HD (PMHD), and 12 control subjects were included. Sustained Attention to Response task (SART) and P300 registration resulted in number of errors, reaction time (RT), and P300 amplitude and latency. RT change patterns surrounding No-go trials were also investigated. Within-subject differences were tested using paired-samples t-tests and between-group results with ANCOVA on delta scores (follow-up--baseline scores).

Results: Manifest HD made more errors and were slower than controls and PMHD. Longitudinally, MHD showed an overall RT increase and a specific slowing on trials preceding a correct No-go trial (within-group effects). The latter was also seen in PMHD. P300 latency prolongation was found for controls on No-go and for MHD on Go trials. On specific trials surrounding both correct and incorrect No-go trials, MHD became significantly slower over time than controls and PMHD (between-group effects).

Conclusions: Over 3-years, MHD subjects became slower on the SART and showed a prolongation of P300 latency on specific SART trials. Specific slowing of performance over time was also seen in PMHD, suggestive of compensatory mechanisms in this group.
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http://dx.doi.org/10.1111/jnp.12031DOI Listing
March 2015

Increased functional connectivity and brain atrophy in elderly with subjective memory complaints.

Brain Connect 2013 21;3(4):353-62. Epub 2013 Jun 21.

Institute of Psychology, Leiden University, Leiden, The Netherlands.

Subjective memory complaints (SMC) are common among elderly. Although subtle changes in memory functioning can hardly be determined using neuropsychological evaluation, neuroimaging studies indicate regionally smaller brain structures in elderly with SMC. Imaging of resting-state functional connectivity is sensitive to detect changes in neurodegenerative diseases, but is currently underexplored in SMC. Here, we investigate resting-state functional connectivity and brain structure in SMC. We analyzed magnetic resonance imaging data of 25 elderly with SMC and 29 age-matched controls (mean age of 71 years). Voxel-based morphometry and volume measurements of subcortical structures were employed on the structural scans using FSL. The dual regression method was used to analyze voxel-wise functional connectivity in relation to eight well-characterized resting-state networks. Group differences were studied with two-sample t-tests (p<0.05, Family-Wise Error corrected). In addition to gray matter volume reductions (hippocampus, anterior cingulate cortex (ACC), medial prefrontal cortex, cuneus, precuneus, and precentral gyrus), elderly with SMC showed increased functional connectivity in the default mode network (hippocampus, thalamus, posterior cingulate cortex (PCC), cuneus, precuneus, and superior temporal gyrus) and the medial visual network (ACC, PCC, cuneus, and precuneus). This study is the first which demonstrates that, in addition to smaller regional brain volumes, increases in functional connectivity are present in elderly with SMC. This suggests that self-reported SMC is a reflection of objective alterations in brain function. Furthermore, our results indicate that functional imaging, in addition to structural imaging, can be a useful tool to objectively determine a difference in brain integrity in SMC.
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http://dx.doi.org/10.1089/brain.2013.0144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749691PMC
March 2014

A review of cognition in Huntington's disease.

Front Biosci (Schol Ed) 2013 Jan 1;5:1-18. Epub 2013 Jan 1.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

With the prospect of potential treatments for Huntington's disease (HD), non-invasive markers of disease progression are needed. Cognitive impairment has long been recognised as one of the core symptoms of HD. The first aim of this review is to provide insight into the onset and nature of cognitive loss in the progressing stages of HD. The second aim is to provide an overview of the cognitive functions that have been examined in an attempt to identify those areas that have the most potential to yield a cognitive biomarker. Literature, consisting of 110 studies, since the implementation of genetic testing until the beginning of 2011 has been included in this review. The clinical features of premanifest HD include deficits in psychomotor speed, negative emotion recognition and to some extent in executive functioning. The clinical profile of manifest HD includes impairment in memory, psychomotor speed, negative emotion recognition and executive functioning. Furthermore, potential candidate biomarkers should be most expected from such domains as working memory, psychomotor speed, recognition of negative emotions, attentional and visuospatial executive functions.
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http://dx.doi.org/10.2741/s355DOI Listing
January 2013

Cognition in Huntington's disease in manifest, premanifest and converting gene carriers over ten years.

J Huntingtons Dis 2013 ;2(2):137-47

Leiden University Medical Center, Department of Neurology, Leiden, The Netherlands.

Background: Cognitive decline in Huntington's disease (HD) remains an area of inconsistencies, especially far from disease onset.

Objective: To clarify the course of cognition in premanifest HD.

Methods: Twenty-six premanifest HD, 19 manifest HD, and 87 control subjects were followed for ten years, using an extensive cognitive battery. Differences in baseline levels and change over time, on four factors (motor speed, global cognition, executive functioning (EF), and memory) were examined, using multilevel regression analyses. Converters were additionally analysed as a separate group. Also, the influence of motor speed and predicted years to disease onset on the cognitive factors was studied.

Results: Manifest HD subjects showed lower baseline scores compared to controls on the motor speed (p=0.002), memory (p<0.001) and EF (p<0.001). They additionally deteriorated over the ten-year follow-up on memory (p=0.01). Converters deteriorated on EF (p=0.04). Further analyses of premanifest subjects 'far from and close to predicted onset' revealed lower baseline scores for the 'close' group on EF, as compared to controls (p=0.001). They also deteriorated on memory (p=0.01). Motor speed substantially mediated the results of the three cognitive factors; when added as covariate to the model several baseline and slope differences for the cognitive factors ceased to be significant.

Conclusions: Memory and EF are highly sensitive for ascertaining deterioration in premanifest HD gene carriers, especially in subjects close to onset. Lack of deterioration for the subjects further away from onset suggests that both domains are largely unaffected in those far from onset. Also, motor influence on cognition is substantial and should be taken into account in cognitive HD research.
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http://dx.doi.org/10.3233/JHD-130059DOI Listing
October 2014

Cerebral atrophy in elderly with subjective memory complaints.

J Magn Reson Imaging 2013 Aug 13;38(2):358-64. Epub 2012 Dec 13.

Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To evaluate ventricular shape differences along the complete surface of the lateral and third ventricles of persons with subjective memory complaints (MC).

Materials And Methods: We included 28 controls and 21 persons with MC. FLAIR, T2, and PD-weighted brain MRI scans were acquired at 1.5 Tesla, followed by semi-automated segmentation of the lateral and third ventricles, and local shape difference analysis based on growing and adaptive meshes. Ventricular meshes were used to highlight local areas with significant differences between controls and persons with MC, determined by permutation tests with a predefined threshold (P = 0.01).

Results: Compared with control subjects, relevant differences were found in the shape of the ventricular surface adjacent to the thalamus and corona radiata in persons with MC. Before correction for multiple comparisons, relevant differences were also found in the shape of the ventricular surface adjacent to the corpus callosum, hippocampus, and amydala.

Conclusion: Our findings suggest the presence of localized structural brain differences in patients with subjective memory complaints in the thalamus and the corona radiata.
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http://dx.doi.org/10.1002/jmri.23977DOI Listing
August 2013

Structural brain changes in migraine.

JAMA 2012 Nov;308(18):1889-97

Department of Radiology, Leiden University Medical Center, the Netherlands.

Context: A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)-measured ischemic lesions in the brain.

Objective: To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline.

Design, Setting, And Participants: In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective population-based observational study of Dutch participants with migraine and an age- and sex-matched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43-72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44-71 years), and 69% were women. MAIN OUTCOME MEASURES Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured.

Results: Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0-4.1; P = .04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in the migraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0-59.5; P = .05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P = .07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores (-3.7 in the migraine group vs 1.4 in the control group; 95% CI, -4.4 to 0.2; adjusted P = .07).

Conclusions: In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.
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http://dx.doi.org/10.1001/jama.2012.14276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633206PMC
November 2012

Prospective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy.

J Rheumatol 2012 Nov 15;39(11):2118-26. Epub 2012 Sep 15.

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Objective: To describe clinical phenotypes in neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods: Data were prospectively collected in the Leiden NPSLE referral clinic, where patients suspected of having NPSLE are assessed in a standardized multidisciplinary manner. In consensus meetings, all medical specialists agreed on therapeutic strategy based on the suspected pathogenetic mechanism of NPSLE in the individual patient. An algorithm illustrates the process of decision-making during the consensus meeting. Clinical phenotypes are described, classified by pathogenetic mechanism.

Results: One hundred consecutive patients were evaluated, of whom 71 had SLE (29 patients did not fulfill ≥ 4 American College of Rheumatology criteria) and 46 had NPSLE. Primary NPSLE was diagnosed in 38 patients (53%) and could be differentiated in 21 patients (55%) with inflammatory NPSLE who were advised on immunosuppressive therapy, 12 patients (32%) with ischemic NPSLE who were advised on anticoagulant therapy, and 5 patients (13%) with undefined NPSLE who were advised symptomatic treatment only. Cognitive dysfunction and higher level of disease activity were associated with inflammatory NPSLE. Although presence of immunoglobulin G anticardiolipin antibodies and abnormalities on magnetic resonance imaging (MRI) were associated with ischemic NPSLE, abnormalities on MRI lacked specificity to distinguish phenotypes. A history of renal disease and use of corticosteroids were associated with secondary NPSLE.

Conclusion: We describe multidisciplinary consensus as a standard for diagnosing and defining phenotypes in NPSLE. These phenotypes show specific characteristics, which can be used to support diagnosis and guide therapeutic decisions. Clinical phenotyping and selection of patients becomes increasingly important when advances in experimental science lead to new targets for therapy in NPSLE.
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http://dx.doi.org/10.3899/jrheum.120545DOI Listing
November 2012

Sustained attention to response task (SART) shows impaired vigilance in a spectrum of disorders of excessive daytime sleepiness.

J Sleep Res 2012 Aug 19;21(4):390-5. Epub 2011 Nov 19.

Leiden University Medical Centre, Department of Neurology and Clinical Neurophysiology, Leiden, The Netherlands.

The sustained attention to response task comprises withholding key presses to one in nine of 225 target stimuli; it proved to be a sensitive measure of vigilance in a small group of narcoleptics. We studied sustained attention to response task results in 96 patients from a tertiary narcolepsy referral centre. Diagnoses according to ICSD-2 criteria were narcolepsy with (n=42) and without cataplexy (n=5), idiopathic hypersomnia without long sleep time (n=37), and obstructive sleep apnoea syndrome (n=12). The sustained attention to response task was administered prior to each of five multiple sleep latency test sessions. Analysis concerned error rates, mean reaction time, reaction time variability and post-error slowing, as well as the correlation of sustained attention to response task results with mean latency of the multiple sleep latency test and possible time of day influences. Median sustained attention to response task error scores ranged from 8.4 to 11.1, and mean reaction times from 332 to 366ms. Sustained attention to response task error score and mean reaction time did not differ significantly between patient groups. Sustained attention to response task error score did not correlate with multiple sleep latency test sleep latency. Reaction time was more variable as the error score was higher. Sustained attention to response task error score was highest for the first session. We conclude that a high sustained attention to response task error rate reflects vigilance impairment in excessive daytime sleepiness irrespective of its cause. The sustained attention to response task and the multiple sleep latency test reflect different aspects of sleep/wakefulness and are complementary.
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http://dx.doi.org/10.1111/j.1365-2869.2011.00979.xDOI Listing
August 2012

Electromyographic activity in the EEG in Alzheimer's disease: noise or signal?

Int J Alzheimers Dis 2011 Mar 29;2011:547024. Epub 2011 Mar 29.

Neuropsychology, Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Many efforts have been directed at negating the influence of electromyographic (EMG) activity on the EEG, especially in elderly demented patients. We wondered whether these "artifacts" might reflect cognitive and behavioural aspects of dementia. In this pilot study, 11 patients with probable Alzheimer's disease (AD), 13 with amnestic mild cognitive impairment (MCI) and 13 controls underwent EEG registration. As EMG measures, we used frontal and temporal 50-70 Hz activity. We found that the EEGs of AD patients displayed more theta activity, less alpha reactivity, and more frontal EMG than controls. Interestingly, increased EMG activity indicated more cognitive impairment and more depressive complaints. EEG variables on the whole distinguished better between groups than EMG variables, but an EMG variable was best for the distinction between MCI and controls. Our results suggest that EMG activity in the EEG could be more than noise; it differs systematically between groups and may reflect different cerebral functions than the EEG.
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http://dx.doi.org/10.4061/2011/547024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089836PMC
March 2011

Shape abnormalities of the striatum in Alzheimer's disease.

J Alzheimers Dis 2011 ;23(1):49-59

Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Postmortem studies show pathological changes in the striatum in Alzheimer's disease (AD). Here, we examine the surface of the striatum in AD and assess whether changes of the surface are associated with impaired cognitive functioning. The shape of the striatum (n. accumbens, caudate nucleus, and putamen) was compared between 35 AD patients and 35 individuals without cognitive impairment. The striatum was automatically segmented from 3D T1 magnetic resonance images and automatic shape modeling tools (Growing Adaptive Meshes) were applied for morphometrical analysis. Repeated permutation tests were used to identify locations of consistent shape deformities of the striatal surface in AD. Linear regression models, corrected for age, gender, educational level, head size, and total brain parenchymal volume were used to assess the relation between cognitive performance and local surface deformities. In AD patients, differences of shape were observed on the medial head of the caudate nucleus and on the ventral lateral putamen, but not on the accumbens. The head of the caudate nucleus and ventral lateral putamen are characterized by extensive connections with the orbitofrontal and medial temporal cortices. Severity of cognitive impairment was associated with the degree of deformity of the surfaces of the accumbens, rostral medial caudate nucleus, and ventral lateral putamen. These findings provide evidence for the hypothesis that in AD primarily associative and limbic cerebral networks are affected.
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http://dx.doi.org/10.3233/JAD-2010-101026DOI Listing
May 2011

Increased psychopathology and maladaptive personality traits, but normal cognitive functioning, in patients after long-term cure of acromegaly.

J Clin Endocrinol Metab 2010 Dec 15;95(12):E392-402. Epub 2010 Sep 15.

Department of Endocrinology and Metabolic Diseases C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Objective: Active acromegaly is associated with psychopathology, personality changes, and cognitive dysfunction. It is unknown whether, and to what extent, these effects are present after long-term cure of acromegaly.

Aim: The aim of the study was to assess psychopathology, personality traits, and cognitive function in patients after long-term cure of acromegaly.

Design: This was a cross-sectional study.

Patients And Methods: We studied 68 patients after long-term cure (13±1 yr) of acromegaly and 68 matched controls. We compared these data with 60 patients treated for nonfunctioning pituitary macroadenomas (NFMAs) and 60 matched controls. Psychopathology was assessed using the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form, and personality was assessed by the Dimensional Assessment of Personality Pathology short-form (DAPPs). Cognitive function was assessed by 11 tests.

Results: Compared with matched controls, patients cured from acromegaly scored significantly worse on virtually all psychopathology questionnaires and on several subscales of the DAPPs. Compared with NFMA patients, patients cured from acromegaly scored worse on negative affect (P=0.050) and somatic arousal (P=0.009) and seven of 18 subscales of the DAPPs (P<0.05). Cognitive function in patients cured from acromegaly did not differ from matched controls or patients treated for NFMA.

Conclusion: Patients with long-term cure of acromegaly show a higher prevalence of psychopathology and maladaptive personality traits but not cognitive dysfunction, compared with matched controls and patients treated for NFMA. These results suggest irreversible effects of previous GH excess, rather than effects of pituitary adenomas per se and/or their treatment, on the central nervous system.
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http://dx.doi.org/10.1210/jc.2010-1253DOI Listing
December 2010

Increased prevalence of psychopathology and maladaptive personality traits after long-term cure of Cushing's disease.

J Clin Endocrinol Metab 2010 Oct 21;95(10):E129-41. Epub 2010 Jul 21.

Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Context And Objective: Psychopathology and maladaptive personality traits are often observed during the active phase of Cushing's disease (CD). We hypothesized that patients with long-term cure of CD show persistent psychopathology and maladaptive personality traits.

Design: Four questionnaires on frequently occurring psychopathology in somatic illnesses were used, including the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form. Personality was assessed using the Dimensional Assessment of Personality Pathology short-form (DAPPs).

Patients And Control Subjects: We included 51 patients cured of CD (16% men, 53 ± 13 yr) and 51 matched controls. In addition, we included 55 patients treated for nonfunctioning pituitary macroadenomas (55% men, 62 ± 10 yr), and 55 matched controls.

Results: Mean duration of remission was 11 yr (range 1-32 yr). Compared with matched controls, patients cured from CD scored significantly worse on virtually all questionnaires. Compared with nonfunctioning pituitary macroadenoma patients, patients treated for CD scored worse on apathy (P < 0.001), irritability (P < 0.001), anxiety (P < 0.001), negative affect and lack of positive affect (P < 0.001 on both scales), somatic arousal (P < 0.001), and 11 of 18 subscales of the Dimensional Assessment of Personality Pathology short-form (P < 0.05).

Conclusions: Patients with long-term cured CD show an increased prevalence of psychopathology and maladaptive personality traits. These observations suggest irreversible effects of previous glucocorticoid excess on the central nervous system rather than an effect of pituitary tumors and/or their treatment in general. This may also be of relevance for patients treated with high doses of exogenous glucocorticoids.
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http://dx.doi.org/10.1210/jc.2010-0512DOI Listing
October 2010

Subtle cognitive impairments in patients with long-term cure of Cushing's disease.

J Clin Endocrinol Metab 2010 Jun 6;95(6):2699-714. Epub 2010 Apr 6.

Department of Endocrinology and Metabolism, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Context And Objective: Active Cushing's disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushing's disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushing's disease.

Design: Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning.

Patients And Control Subjects: We included 74 patients cured of Cushing's disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education.

Results: Compared with NFMA patients, patients cured from Cushing's disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushing's disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushing's disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushing's disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients.

Conclusions: Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushing's disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.
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http://dx.doi.org/10.1210/jc.2009-2032DOI Listing
June 2010

Magnetization transfer imaging in 'premanifest' Huntington's disease.

J Neurol 2010 Mar 13;257(3):426-32. Epub 2009 Oct 13.

Department of Neurology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.

To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in 'premanifest' carriers of the Huntington's disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity.
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http://dx.doi.org/10.1007/s00415-009-5339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837878PMC
March 2010

Basal ganglia volume and clinical correlates in 'preclinical' Huntington's disease.

J Neurol 2008 Nov 8;255(11):1785-91. Epub 2008 Dec 8.

Dept. of Neurology, Leiden University Medical Center, 9600, 2300 RC Leiden, The Netherlands.

Objective: To establish differences in basal ganglia and thalamic volume between preclinical carriers and non-carriers of the Huntington's disease (HD) gene and to link the volume to motor, cognitive and behavioural characteristics in carriers.

Methods: Sixteen HD gene carriers without overt clinical motor signs and 14 non-gene carriers underwent clinical evaluation and a MRI scan. Volumes of the caudate nucleus, putamen, gobus pallidus and thalamus were measured using T1-weighted MR images. Motor, cognitive and behavioural functioning was assessed using the Unified Huntington's Disease Rating Scale (UHDRS), cognitive testing and the Beck Depression Inventory (BDI-II).

Results: Volumes of the caudate nucleus, putamen and globus pallidus were significantly smaller in carriers than in non-carriers while no differences between groups were found on clinical evaluation. In gene carriers smaller globus pallidus volume was associated with more motor abnormalities. A smaller putamen volume correlated significantly with worse psychomotor function on the Symbol Digit Modalities Task and the Trail Making Test B.

Conclusions: In line with previous research we demonstrated that basal ganglia abnormalities precede overt disease manifestation of HD. Besides we showed that smaller basal ganglia volumes are related to subtle motor abnormalities and worse psychomotor performance in gene carriers without clinical diagnosis. Motor and psychomotor measures may be suitable clinical markers in future neuroprotective trials when combined with volumetric imaging.
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http://dx.doi.org/10.1007/s00415-008-0050-4DOI Listing
November 2008
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