Publications by authors named "Pauline Aalten"

74 Publications

The Associations of Common Psychological Problems With Mental Disorders Among College Students.

Front Psychiatry 2021 27;12:573637. Epub 2021 Sep 27.

Department of Clinical, Neuro and Developmental Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Psychological problems like procrastination, perfectionism, low self-esteem, test anxiety and stress are common among college students. There are evidence-based interventions available for these problems that not only have direct effects on these problems, but also indirect effects on mental disorders such as depression and anxiety disorders. Targeting these psychological problems may offer new opportunities to prevent and treat mental disorders in a way that is less stigmatizing to students. In this study we examined the association of five psychological problems with five common mental disorders (panic, generalized anxiety, bipolar, major depressive, and substance use disorder) in a sample of 2,449 students from two Dutch universities. Psychological problems were measured with one item for each problem and mental disorders were measured with the Composite International Diagnostic Interview Screening Scales. Associations were examined with Poisson regression models as relative risks (RR) of the disorders as a function of the psychological problems. The population attributable fraction (PAF) indicates by what percentage the prevalence of the mental disorder would be reduced if the psychological problem was addressed successfully by an intervention. Especially generalized anxiety disorder was strongly associated with psychological problems (strong associations with stress and low self-esteem and moderately with test anxiety). The group with three or more psychological problems had a strongly increased risk for generalized anxiety (RR = 11.25; 95% CI: 7.51-16.85), and a moderately increase risk for major depression (RR = 3.22; 95% CI: 2.63-3.95), panic disorder (RR = 3.19; 95% CI: 1.96-5.20) and bipolar disorder (RR = 3.66; 95% CI: 2.40-5.58). The PAFs for having any of the psychological problems (one or more) were considerable, especially for generalized anxiety (60.8%), but also for panic disorder (35.1%), bipolar disorder (30.6%) and major depression (34.0%). We conclude that common psychological problems are associated with mental disorders and with each other. After adjustment, psychological problems are associated with different patterns of mental disorders. If the impact of the psychological problems could be taken away, the prevalence of several mental disorders would be reduced considerably. The psychological problems may provide a promising target to indirectly prevent and intervene in psychopathology in hard to reach college students with mental disorders.
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http://dx.doi.org/10.3389/fpsyt.2021.573637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502858PMC
September 2021

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

Imaging markers associated with the development of post-stroke depression and apathy: Results of the Cognition and Affect after Stroke - a Prospective Evaluation of Risks study.

Eur Stroke J 2020 Mar 16;5(1):78-84. Epub 2019 Oct 16.

Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, The Netherlands.

Introduction: It has been suggested that the development of post-stroke apathy (PSA) and depression (PSD) may be more strongly associated with generalised brain pathology, rather than the stroke lesion itself. The present study aimed to investigate associations between imaging markers of lesion-related and generalised brain pathology and the development of PSA and PSD during a one-year follow-up.

Patients And Methods: In a prospective cohort study, 188 stroke patients received 3-Tesla MRI at baseline (three months post-stroke) for evaluation of lesion-related, vascular, and degenerative brain pathology. Presence of lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces was summed to provide a measure of total cerebral small vessel disease (cSVD) burden (range 0-4). The Mini International Neuropsychiatric Interview and Apathy Evaluation Scale were administered at baseline and repeated at 6- and 12-month follow-up to define presence of PSD and PSA, respectively.

Results: Population-averaged logistic regression models showed that global brain atrophy and severe cSVD burden (score 3-4) were significantly associated with the odds of having PSA (OR 5.33, 95% CI 1.99-14.25 and 3.04, 95% CI 1.20-7.69, respectively), independent of stroke lesion volume and co-morbid PSD. Medium cSVD burden (score 2) was significantly associated with the odds of having PSD (OR 2.92, 95% CI 1.09-7.78), independent of stroke lesion volume, co-morbid PSA, and pre-stroke depression. No associations were found with lesion-related markers.

Conclusions: The results suggest that generalised degenerative and vascular brain pathology, rather than lesion-related pathology, is an important predictor for the development of PSA, and less strongly for PSD.
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http://dx.doi.org/10.1177/2396987319883445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092734PMC
March 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

Determinants of Cross-Sectional and Longitudinal Health-Related Quality of Life in Memory Clinic Patients Without Dementia.

J Geriatr Psychiatry Neurol 2020 09 23;33(5):256-264. Epub 2019 Oct 23.

Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.

Objective: To identify determinants within 3 different domains (ie, somatic comorbidities, cognitive functioning, and neuropsychiatric symptoms [NPS]) of health-related quality of life (HRQoL) over time in memory clinic patients without dementia.

Methods: This longitudinal multicenter cohort study with a 3-year observation period recruited 315 individuals (age: 69.8 ± 8.6, 64.4% males, Mini-Mental State Examination score 26.9 ± 2.6). A multivariable explanatory model was built using linear mixed effects models (forward selection per domain) to select determinants for self-perceived HRQoL over time, as measured by the EuroQoL-5D visual analogue scale (EQ VAS).

Results: Mean HRQoL at study entry was 69.4 ± 15.6. The presence of agitation, appetite and eating abnormalities, and eyes/ears/nose (ie, sensory impairment) comorbidities were associated with a change in HRQoL over time. Agitation was most strongly associated with HRQoL over time.

Conclusions: The association of somatic comorbidities and NPS in memory clinic patients with course of HRQoL shows that these should receive more awareness, detection, and monitoring by clinicians.
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http://dx.doi.org/10.1177/0891988719882104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361660PMC
September 2020

Affective symptoms and AT(N) biomarkers in mild cognitive impairment and Alzheimer's disease: A systematic literature review.

Neurosci Biobehav Rev 2019 12 13;107:346-359. Epub 2019 Sep 13.

Alzheimer Center Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands. Electronic address:

Introduction: Alzheimer's disease (AD) biomarkers such as amyloid, p-tau and neuronal injury markers have been associated with affective symptoms in cognitively impaired individuals, but results are conflicting.

Methods: CINAHL, Embase, PsycINFO and PubMed were searched for studies evaluating AD biomarkers with affective symptoms in mild cognitive impairment and AD dementia. Studies were classified according to AT(N) research criteria.

Result: Forty-five abstracts fulfilled eligibility criteria, including in total 8,293 patients (41 cross-sectional studies and 7 longitudinal studies). Depression and night-time behaviour disturbances were not related to AT(N) markers. Apathy was associated with A markers (PET, not CSF). Mixed findings were reported for the association between apathy and T(N) markers; anxiety and AT(N) markers; and between agitation and irritability and A markers. Agitation and irritability were not associated with T(N) markers.

Discussion: Whereas some AD biomarkers showed to be associated with affective symptoms in AD, most evidence was inconsistent. This is likely due to differences in study design or heterogeneity in affective symptoms. Directions for future research are given.
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http://dx.doi.org/10.1016/j.neubiorev.2019.09.014DOI Listing
December 2019

Trajectories and Determinants of Quality of Life in Dementia with Lewy Bodies and Alzheimer's Disease.

J Alzheimers Dis 2019 ;70(2):389-397

Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking.

Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer's disease (AD) and controls.

Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0-100) and the health-related Visual Analogue Scale (VAS, 0-100). Twenty-nine DLB patients (age 69±6), 68 AD patients (age 70±6), and 41 controls (age 70±5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD).

Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: β±SE = -7.6±2.8, controls: β±SE = -7.9±3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (β±SE = 2.9±1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS β±SE = -1.8±0.3, EQ5D-utility β±SE = -3.7±0.4; DAD: VAS = 0.1±0.0, EQ5D-utility β±SE = 0.1±0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model.

Conclusion: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL.
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http://dx.doi.org/10.3233/JAD-190041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839497PMC
October 2020

A survey on the prevalence of apathy in elderly people referred to specialized memory centers.

Int J Geriatr Psychiatry 2019 10 8;34(10):1369-1377. Epub 2019 May 8.

Université Côte d'Azur, CoBTeK lab, Centre Hospitalier Universitaire de Nice, CMRR, Nice, France.

Background: Apathy is a pervasive neuropsychiatric syndrome in people with neurocognitive and psychiatric disorders. The diagnostic criteria for apathy (DCA) have been revised in 2018.

Objectives: Employing the 2018 DCA, in the present study, we investigated in groups of elderly subjects suffering from different neuropsychiatric disorders (a) the apathy prevalence; (b) the most commonly affected apathy dimensions (behavior/cognition, emotion, and social interaction); (c) the sensitivity and specificity of those dimensions for apathy diagnosis; and (d) the concurrent validity of 2018 DCA compared with the 2009 DCA.

Methods: This multicenter survey included 166 subjects. Each center checked the presence of apathy in subjects belonging to the following DSM-5 diagnoses: mild neurocognitive disorders (mild NCDs); major NCDs; affective disorders (Aff D); and subjective cognitive decline (SCD).

Results: The frequency of apathy varied significantly based on the diagnostic groups (0% of subjects with apathy in the SCD group; 25% in the mild NCD group; 77% in the major NCD group; and 57% in the Aff. D group). All subjects with apathy fulfilled the criteria for the behavior/cognition dimension, 73.1% fulfilled the criteria for the emotion dimension, and 97.4% fulfilled the criteria for the social interaction dimension. Behavior/cognition showed the highest sensitivity, the copresence of emotion and social interaction the highest specificity. The concordance between the 2009 and the 2018 DCA indicated an almost perfect agreement.

Conclusions: These results are consistent with previous reports and confirm that the social interaction dimension added to the 2018 DCA is present in most of subjects with apathy referred to specialized memory centers.
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http://dx.doi.org/10.1002/gps.5125DOI Listing
October 2019

Apolipoprotein E and affective symptoms in mild cognitive impairment and Alzheimer's disease dementia: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2019 01 1;96:302-315. Epub 2018 Dec 1.

Alzheimer Center Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address:

Objective: APOE status has been associated to affective symptoms in cognitively impaired subjects, with conflicting results.

Methods: Databases CINAHL, Embase, PsychINFO and PubMed were searched for studies evaluating APOE genotype with affective symptoms in MCI and AD dementia. Symptoms were meta-analyzed separately and possible sources of heterogeneity were examined.

Results: Fifty-three abstracts fulfilled the eligibility criteria. No association was found between the individual symptoms and APOE ε4 carriership or zygosity. For depression and anxiety, only pooled unadjusted estimates showed positive associations with between-study heterogeneity, which could be explained by variation in study design, setting and way of symptom assessment.

Conclusions: There is no evidence that APOE ε4 carriership or zygosity is associated with the presence of depression, anxiety, apathy, agitation, irritability or sleep disturbances in cognitively impaired subjects. Future research should shift its focus from this single polymorphism to a more integrated view of other biological factors.
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http://dx.doi.org/10.1016/j.neubiorev.2018.11.020DOI Listing
January 2019

Personality traits and course of symptoms of depression and apathy after stroke: Results of the CASPER study.

J Psychosom Res 2018 08 21;111:69-75. Epub 2018 May 21.

Alzheimer Center Limburg and School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. Electronic address:

Objective: Post-stroke depression (PSD) and post-stroke apathy (PSA) are both associated with adverse outcome after stroke. This study aimed to examine whether personality traits predict the course of PSD and PSA.

Methods: In this prospective cohort study, 240 stroke patients completed the NEO Five Factor Inventory, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months post-stroke. Neuropsychiatric assessment was repeated at 6- and 12-month follow-up after initial testing.

Results: Linear mixed models showed that high neuroticism scores were associated with higher depression levels at baseline, and this association remained stable at follow-up. High extraversion scores and high conscientiousness scores were associated with lower apathy levels at baseline. For neuroticism, a significant interaction with time was found, with higher neuroticism scores at baseline being associated with an increase in apathy scores from 6-month to 12-month follow-up. Prospective analyses showed that high extraversion predicted low apathy levels at 6-month and 12-month follow-up independent of its relations with baseline depression and apathy. High neuroticism predicted high apathy levels at 12-month follow-up, whereas high agreeableness and high openness predicted high apathy levels and low apathy levels, respectively, at 6-month follow-up. None of the personality traits predicted depression scores at follow-up.

Conclusion: Personality traits are associated with the development and sustainability of PSD and PSA. The traits associated with PSD and PSA were different, providing support for the independence of these constructs. The findings highlight the importance to take personality traits into account as a potential vulnerability factor for PSD and PSA.
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http://dx.doi.org/10.1016/j.jpsychores.2018.05.010DOI Listing
August 2018

Correction to: Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline.

Alzheimers Res Ther 2018 06 20;10(1):56. Epub 2018 Jun 20.

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.

Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.
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http://dx.doi.org/10.1186/s13195-018-0391-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011342PMC
June 2018

Shades of white: diffusion properties of T1- and FLAIR-defined white matter signal abnormalities differ in stages from cognitively normal to dementia.

Neurobiol Aging 2018 08 5;68:48-58. Epub 2018 Apr 5.

Alzheimer Center Limburg, School for Mental Health and Neuroscience (MHeNS), Maastricht University Medical Centre, Maastricht, The Netherlands; Faculty of Psychology and Neuroscience, Department of Cognitive Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital/Harvard Medical School, Boston, MA.

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the "diseased" but the NAWM is a potentially sensitive indicator for cognitive brain health status.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.03.029DOI Listing
August 2018

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease.

Alzheimers Dement 2018 07 28;14(7):913-924. Epub 2018 Mar 28.

Department of Nuclear Medicine, Technische Universitaet München, Munich, Germany.

Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.

Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.

Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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http://dx.doi.org/10.1016/j.jalz.2018.02.009DOI Listing
July 2018

Co-occurrence of depressive symptoms and executive dysfunction after stroke: associations with brain pathology and prognosis.

J Neurol Neurosurg Psychiatry 2018 08 8;89(8):859-865. Epub 2018 Feb 8.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.

Objective: To examine, first, whether the co-occurrence of executive dysfunction (ED) and poststroke depression (PSD) shows different associations with neuroimaging markers and the course of depression and executive function, and second, whether it is associated with a different course on other cognitive domains and quality of life.

Methods: The present study included 245 stroke patients (35.9% female, mean age 67.5 years (SD=11.9). All patients completed neuropsychological and neuropsychiatric assessment 3 months poststroke, which were repeated at 6-month and 12-month follow-up. A subset (n=186) received 3-Tesla brain MRI at baseline to evaluate lesion-related imaging markers, white matter hyperintensity volume, global brain atrophy and total cerebral small vessel disease burden.

Results: Patients with 'depression-executive dysfunction syndrome' (DES) showed higher white matter hyperintensity volumes compared with all other groups and more frequently showed left-sided lesions compared with ED only and PSD only. They also had more frequently old infarcts and higher total cerebral small vessel disease burden compared with PSD only and patients with neither ED nor PSD, and more global brain atrophy compared with PSD only. Longitudinal analyses showed that patients with DES had a more chronic course of depressive symptoms relative to PSD only, and a stable pattern of worse cognitive performance similar to patients with ED only.

Conclusions: The co-occurrence of ED and PSD is associated with a worse prognosis of depression, persistent cognitive impairment and a higher amount of vascular and degenerative brain pathology. Future studies are needed to examine whether these patients represent a more severe subtype within the PSD spectrum.

Clinical Trial Registration: NCT02585349;Results.
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http://dx.doi.org/10.1136/jnnp-2017-317548DOI Listing
August 2018

Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline.

Alzheimers Res Ther 2017 12 29;9(1):101. Epub 2017 Dec 29.

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.

Background: Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia.

Methods: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics.

Results: MTA and t-tau were elevated in the Aβ - WMH+, Aβ + WMH-, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline.

Conclusions: In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.
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http://dx.doi.org/10.1186/s13195-017-0328-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747152PMC
December 2017

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.

JAMA Psychiatry 2018 01;75(1):84-95

Center for Neuroscience and Cell Biology, Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Portugal.

Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.

Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.

Design, Setting, And Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.

Main Outcomes And Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.

Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.

Conclusions And Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786156PMC
January 2018

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

J Alzheimers Dis 2018 ;61(1):309-320

Department of Internal Medicine and Cardiovascular Research Institute, Maastricht University Medical Centre +, Maastricht, the Netherlands.

Background: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).

Objective: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.

Methods: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.

Results: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).

Conclusion: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.
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http://dx.doi.org/10.3233/JAD-170522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734123PMC
July 2018

Baseline Vascular Cognitive Impairment Predicts the Course of Apathetic Symptoms After Stroke: The CASPER Study.

Am J Geriatr Psychiatry 2018 03 28;26(3):291-300. Epub 2017 Sep 28.

Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience (MHeNs), Alzheimer Center Limburg, Maastricht, The Netherlands. Electronic address:

Objective: To examine the influence of vascular cognitive impairment (VCI) on the course of poststroke depression (PSD) and poststroke apathy (PSA).

Methods: Included were 250 stroke patients who underwent neuropsychological and neuropsychiatric assessment 3 months after stroke (baseline) and at a 6- and 12-month follow-up after baseline. Linear mixed models tested the influence of VCI in at least one cognitive domain (any VCI) or multidomain VCI (VCI in multiple cognitive domains) at baseline and domain-specific VCI at baseline on levels of depression and apathy over time, with random effects for intercept and slope.

Results: Almost half of the patients showed any VCI at baseline, and any VCI was associated with increasing apathy levels from baseline to the 12-month follow-up. Patients with multidomain VCI had higher apathy scores at the 6- and 12-month follow-up compared with patients with VCI in a single cognitive domain. Domain-specific analyses showed that impaired executive function and slowed information processing speed went together with increasing apathy levels from baseline to 6- and 12-month follow-up. None of the cognitive variables predicted the course of depressive symptoms.

Conclusion: Baseline VCI is associated with increasing apathy levels from baseline to the chronic stroke phase, whereas no association was found between baseline VCI and the course of depressive symptoms. Health professionals should be aware that apathy might be absent early after stroke but may evolve over time in patients with VCI.
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http://dx.doi.org/10.1016/j.jagp.2017.09.022DOI Listing
March 2018

Temporal Associations between Fatigue, Depression, and Apathy after Stroke: Results of the Cognition and Affect after Stroke, a Prospective Evaluation of Risks Study.

Cerebrovasc Dis 2017 26;44(5-6):330-337. Epub 2017 Oct 26.

Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience (MHeNs), Alzheimer Center Limburg, Maastricht, the Netherlands.

Background: Poststroke fatigue (PSF) is a form of pathological fatigue that can develop after stroke and has a negative impact on functional outcome. PSF is associated with poststroke depression (PSD), which in turn shows similarities with poststroke apathy (PSA). This study aimed at disentangling the temporal associations between PSF and PSD and between PSF and PSA.

Methods: A total of 250 stroke patients were included, of which 243 completed the Fatigue Severity Scale, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months poststroke, with follow-up measurements at 6 and 12 months after initial testing. Linear mixed models and linear regressions were performed to evaluate the temporal associations between PSF and PSD, and between PSF and PSA.

Results: PSF was present in 119 patients (49%), of whom 62 patients also had PSD (26%), and 21 patients (9%) also had PSA. At baseline, PSF patients showed higher depression levels, which remained stable at follow-up. PSD patients had higher fatigue levels compared with no-PSD patients at baseline, which remained stable at follow-up. No association between apathy and fatigue was found at baseline and no interaction with time was found. Change in fatigue from baseline to 12-month follow-up was associated with change in depression and with change in apathy.

Conclusions: Bidirectional associations were found between PSF and PSD. In treatment and rehabilitation programs, early focus on the presence of PSD and PSF is important, since these conditions tend to persist. As there are currently more treatment options for PSD, attention for PSD is important and might also have a beneficial effect on PSF.
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http://dx.doi.org/10.1159/000481577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804825PMC
March 2019

Imaging Markers of Post-Stroke Depression and Apathy: a Systematic Review and Meta-Analysis.

Neuropsychol Rev 2017 Sep 22;27(3):202-219. Epub 2017 Aug 22.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Center Limburg, Maastricht University, Dr. Tanslaan 12, PO Box 616 (DRT 12), 6200 MD, Maastricht, The Netherlands.

Several brain imaging markers have been studied in the development of post-stroke depression (PSD) and post-stroke apathy (PSA), but inconsistent associations have been reported. This systematic review and meta-analysis aims to provide a comprehensive and up-to-date evaluation of imaging markers associated with PSD and PSA. Databases (Medline, Embase, PsycINFO, CINAHL, and Cochrane Database of Systematic Reviews) were searched from inception to July 21, 2016. Observational studies describing imaging markers of PSD and PSA were included. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to examine the association between PSD or PSA and stroke lesion laterality, type, and location, also stratified by study phase (acute, post-acute, chronic). Other imaging markers were reviewed qualitatively. The search retrieved 4502 studies, of which 149 studies were included in the review and 86 studies in the meta-analyses. PSD in the post-acute stroke phase was significantly associated with frontal (OR 1.72, 95% CI 1.34-2.19) and basal ganglia lesions (OR 2.25, 95% CI 1.33-3.84). Hemorrhagic stroke related to higher odds for PSA in the acute phase (OR 2.58, 95% CI 1.18-5.65), whereas ischemic stroke related to higher odds for PSA in the post-acute phase (OR 0.20, 95% CI 0.06-0.69). Frequency of PSD and PSA is modestly associated with stroke type and location and is dependent on stroke phase. These findings have to be taken into consideration for stroke rehabilitation programs, as this could prevent stroke patients from developing PSD and PSA, resulting in better clinical outcome.
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http://dx.doi.org/10.1007/s11065-017-9356-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613051PMC
September 2017

The clinical course and interrelations of dementia related symptoms.

Int Psychogeriatr 2018 06 13;30(6):859-866. Epub 2017 Mar 13.

Department of Geriatric Medicine,Radboud Institute for Health Sciences,Radboud University Medical Center,Reinier Postlaan 4,6525 GC,Nijmegen,the Netherlands.

ABSTRACTBackground:Dementia is a neurodegenerative syndrome that interferes with multiple aspects of life, including cognition, daily functioning, and behavior. Despite the large heterogeneity in symptom development, these three domains are seldom studied simultaneously. This study investigates how trajectories of these domains are interrelated within individuals over time, and how they in turn are related to dementia severity and quality of life (QoL).

Methods: We used data from a longitudinal clinical cohort study, including 331 dementia patients. Cognitive status was measured using the Mini-Mental State Examination, daily functioning was measured with the disability assessment for dementia and neuropsychiatric symptoms (NPS) were scored using the neuropsychiatric inventory. We investigated the relationships in the time course of the various dementia domains using random effects multilevel models and parallel-process growth models.

Results: Changes in cognition and daily functioning were highly correlated over time (r = 0.85, p < 0.01), as were changes in NPS and functioning (r = -0.60, p < 0.01), while changes in cognition and NPS were not (r = -0.20, p = 0.06). All three domains were strongly associated with dementia severity over time (p < 0.01). Decreased functioning and increased NPS were both associated with decreased QoL (β = 2.97, p < 0.01 and β = -2.41, p < 0.01, respectively), while cognition was not (β = 0.01, p = 0.93).

Conclusion: This study demonstrates the heterogeneity of dementia progression between individuals and between different dementia domains within individuals. To improve our understanding of dementia progression, future research should embrace a broader perspective encompassing multiple outcome measures along with the patient's profile, including neurological factors as well as physical, social, and psychiatric health.
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http://dx.doi.org/10.1017/S1041610217000321DOI Listing
June 2018

Gait Speed and Grip Strength Reflect Cognitive Impairment and Are Modestly Related to Incident Cognitive Decline in Memory Clinic Patients With Subjective Cognitive Decline and Mild Cognitive Impairment: Findings From the 4C Study.

J Gerontol A Biol Sci Med Sci 2017 Jun;72(6):846-854

Alzheimer Center, Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, The Netherlands.

Background: Prospective studies in the general population show that slow gait speed is associated with cognitive decline and clinical progression to dementia. However, longitudinal studies in memory clinic populations are mostly lacking. We aimed to study the association between gait speed and grip strength and cognitive functioning at baseline and cognitive decline over time in memory clinic patients with subjective cognitive decline and mild cognitive impairment.

Methods: We included 309 patients (age 70 ± 9 years, 108 [35%] women, Mini-Mental State Examination 27 ± 3 points). Baseline gait speed was assessed over 15 feet, grip strength with a hydraulic hand dynamometer. Cognitive functioning was assessed annually with a comprehensive test battery during 3 years.

Results: Age- and gender-adjusted linear mixed models showed that slower gait speed was related to worse baseline attention, memory, information processing speed, and verbal fluency. Longitudinally, gait speed was related to decline in information processing speed and executive functioning. Weaker grip strength was related to worse baseline information processing speed and executive functioning but there were no longitudinal associations. Cox proportional hazards models revealed no significant associations with clinical progression.

Conclusions: Our findings suggest that markers of physical performance are related to current cognitive status and modestly related to cognitive decline but are seemingly not useful as an early marker of incident clinical progression.
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http://dx.doi.org/10.1093/gerona/glx003DOI Listing
June 2017

Diagnostic impact of [F]flutemetamol PET in early-onset dementia.

Alzheimers Res Ther 2017 Jan 17;9(1). Epub 2017 Jan 17.

Alzheimer Center & Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Background: Early-onset dementia patients often present with atypical clinical symptoms, hampering an accurate clinical diagnosis. The purpose of the present study was to assess the diagnostic impact of the amyloid-positron emission tomography (PET) imaging agent [F]flutemetamol in early-onset dementia patients, in terms of change in (confidence in) diagnosis and patient management plan.

Methods: This prospective bi-center study included 211 patients suspected of early-onset dementia who visited a tertiary memory clinic. Patients were eligible with Mini Mental State Examination ≥ 18 and age at diagnosis ≤ 70 years and in whom the diagnostic confidence was <90% after routine diagnostic work-up. All patients underwent [F]flutemetamol PET, which was interpreted as amyloid-negative or amyloid-positive based on visual rating. Before and after disclosing the PET results, we assessed the diagnostic confidence (using a visual analog scale of 0-100%) and clinical diagnosis. The impact of [F]flutemetamol PET on the patient management plan was also evaluated.

Results: [F]flutemetamol PET scans were positive in 133 out of 211 (63%) patients, of whom 110 out of 144 (76%) patients had a pre-PET Alzheimer's disease (AD) diagnosis and 23 out of 67 (34%) patients had a non-AD diagnosis. After disclosure of PET results, 41/211 (19%) diagnoses changed. Overall, diagnostic confidence increased from 69 ± 12% to 88 ± 15% after disclosing PET results (P < 0.001; in 87% of patients). In 79 (37%) patients, PET results led to a change in patient management and predominantly the initiation of AD medication when PET showed evidence for amyloid pathology.

Conclusions: [F]flutemetamol PET changed clinical diagnosis, increased overall diagnostic confidence, and altered the patient management plan. Our results suggest that amyloid PET may have added value over the standardized diagnostic work-up in early-onset dementia patients with uncertain clinical diagnosis. This study provides evidence for the recommendations put forward in the appropriate use criteria for amyloid PET in clinical practice.

Trial Registration: Nederlands Trial Register NTR3743 . Registered 7 December 2012.
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http://dx.doi.org/10.1186/s13195-016-0228-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240413PMC
January 2017

A profile of The Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment and Dementia Study (The 4C study): two complementary longitudinal, clinical cohorts in the Netherlands.

BMC Neurol 2016 Nov 25;16(1):242. Epub 2016 Nov 25.

Radboud Institute of Health Sciences, Department of Geriatric Medicine & Radboudumc Alzheimer Centre, Radboud University Medical Center, PO Box 9109, (House post 925), 6500 HB, Nijmegen, The Netherlands.

Background: Heterogeneous disease trajectories of mild cognitive impairment (MCI) and dementia are frequently encountered in clinical practice, but there is still insufficient knowledge to understand the reasons and mechanisms causing this heterogeneity. In addition to correlates of the disorder, patient characteristics such as their health status, social environment, comorbidities and frailty may contribute to variability in trajectories over time. The current paper outlines the study design and the study population of and provides an overview of the data collected in the Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment (4C-MCI cohort, n = 315) and Dementia (4C-Dementia cohort, n = 331) Study.

Methods: The two complementary longitudinal cohorts part of the 4C study began enrolment in March 2010. Participants were prospectively recruited from three collaborating Dutch Alzheimer Centers, with three annual follow-up assessments after baseline. Extensive neuropsychological assessments, and detailed profiling of comorbidities, health and frailty at each follow up were the key features of the 4C study. As such, the 4C study was designed to study if and how patients' comorbidities and frailty are associated with the course of MCI and dementia measured with a comprehensive and multidimensional set of outcomes including cognition, daily functioning, quality of life, behavioral disturbances, caregiver burden, institutionalization and death and whether the effects of medical health and frailty differ between MCI and dementia stages of cognitive disorders.

Conclusion: Sampled in a clinical setting, the 4C study complements population-based studies on neurodegenerative disorders in terms of the type of assessment (e.g. comorbidity, frailty, and functional status were repeatedly assessed). The 4C study complements available clinical cohorts of MCI and dementia patients, because the exclusion criteria were kept to a minimum, to obtain a sample that is representative for the average patient visiting a memory clinic.
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http://dx.doi.org/10.1186/s12883-016-0750-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123233PMC
November 2016

The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients.

J Alzheimers Dis 2017 ;55(2):679-689

Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.

Background: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown.

Objective: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients.

Methods: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments.

Results: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%.

Conclusion: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.
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http://dx.doi.org/10.3233/JAD-160126DOI Listing
February 2018

White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β.

J Alzheimers Dis 2017 ;55(1):333-342

Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, The Netherlands.

Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.
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http://dx.doi.org/10.3233/JAD-160474DOI Listing
February 2018

The Cognition and Affect after Stroke - a Prospective Evaluation of Risks (CASPER) study: rationale and design.

BMC Neurol 2016 May 12;16:65. Epub 2016 May 12.

Alzheimer Center Limburg and School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.

Background: Cognitive impairment and neuropsychiatric syndromes, like depression and apathy, are frequent residual consequences of stroke. These have a large impact on quality of life and long-term prognosis. Several factors are involved in the development of these residual syndromes, although their exact role and their interrelationships remain still rather unclear. The Cognition and Affect after Stroke: a Prospective Evaluation of Risks (CASPER) study has been primarily designed to examine whether stroke-specific (e.g. lesion location, volume, type, severity), cerebrovascular and neurodegenerative (e.g. white matter changes, atrophy, microbleeds, perivascular spaces), inflammatory, endothelial, and (epi)genetic markers are associated with cognitive impairment, post-stroke depression, and post-stroke apathy, and whether they predict their course over 12 months. The secondary aims are to investigate how the above-mentioned markers interact with each other, and to determine if patients with apathy and depression after stroke differ in pathogenesis, course, and outcome (e.g. functional outcome, neurocognitive performance, quality of life).

Methods/design: CASPER is a 1-year prospective clinical cohort follow-up study in 250 stroke patients recruited at the neurological in- and outpatient services at Maastricht University Medical Center (MUMC+, Maastricht, The Netherlands), and Zuyderland Medical Center (Sittard and Heerlen, The Netherlands). At baseline (3 months post-stroke), a neuropsychological assessment, neuropsychiatric interview, blood sample, and brain magnetic resonance imaging (MRI) scan are conducted. Assessment of neuropsychiatric and neurocognitive status are repeated 6 and 12 months later.

Discussion: The CASPER study investigates stroke-specific, vascular, neurodegenerative, inflammatory, and genetic markers of the development of vascular cognitive impairment, depression, and apathy after stroke. This creates the possibility to study not only the contribution of these individual markers but also their joint contribution, which differentiates this study from earlier stroke cohorts who lacked long-term follow-up data, a large sample size, an extensive MRI protocol, and markers from the blood. The knowledge we derive from this study might help in identifying markers that are associated with, or can predict the onset, maintenance, and progression of vascular cognitive impairment, depression, and apathy after stroke, and could provide new insights into possibilities for treatment and rehabilitation that result in better functional outcome after stroke.

Trial Registration: ClinicalTrials.gov NCT02585349.
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http://dx.doi.org/10.1186/s12883-016-0588-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866410PMC
May 2016

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort.

J Alzheimers Dis 2016 03;52(3):875-85

Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands.

Background: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup.

Objective: This study aims to investigate the added prognostic value of AD CSF biomarkers.

Methods: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information.

Results: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment.

Conclusion: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.
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http://dx.doi.org/10.3233/JAD-151120DOI Listing
March 2016

The Role of Information and Communication Technologies in Clinical Trials with Patients with Alzheimer's Disease and Related Disorders.

Front Aging Neurosci 2015 9;7:110. Epub 2015 Jun 9.

CoBTeK Cognition Behaviour Technology EA 7276, Research Center Edmond and Lily Safra, University of Nice Sophia Antipolis , Nice , France.

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http://dx.doi.org/10.3389/fnagi.2015.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460798PMC
June 2015
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