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Featured researches published by Everard Vijverberg.


Journal of Alzheimer's Disease | 2016

Diagnostic Accuracy of MRI and Additional [ 18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes

Everard Vijverberg; Mike P. Wattjes; Annemiek Dols; Welmoed A. Krudop; Christiane Möller; Anne Peters; Cora J. Kerssens; Flora Gossink; Niels D. Prins; Max L. Stek; Philip Scheltens; Bart N.M. van Berckel; Frederik Barkhof; Yolande A.L. Pijnenburg

BACKGROUND Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown. OBJECTIVE To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes. METHODS Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging. RESULTS 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52-85%) with a specificity of 93% (95% CI 86-97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66-100%) with a specificity of 68% (95% CI 56-79%). The sensitivity of combined neuroimaging was 96% (95% CI 85-100%) with a specificity of 73% (95% CI 63-81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis. CONCLUSION A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.


Dementia and Geriatric Cognitive Disorders | 2016

Diagnostic Accuracy of the Frontotemporal Dementia Consensus Criteria in the Late-Onset Frontal Lobe Syndrome.

Everard Vijverberg; Annemiek Dols; Welmoed A. Krudop; Anne Peters; Cora J. Kerssens; Bart N.M. van Berckel; Mike P. Wattjes; Frederik Barkhof; Flora Gossink; Niels D. Prins; Max L. Stek; Philip Scheltens; Yolande A.L. Pijnenburg

Background/Aims: We aimed to prospectively assess the diagnostic accuracy of the revised criteria for behavioural variant frontotemporal dementia (bvFTD) among subjects presenting with a frontal lobe syndrome in middle-late adulthood. Methods: Patients were included based on a predominant behavioural clinical presentation, a Frontal Behavioural Inventory (FBI) score of ≥11 and/or a Stereotypy Rating Inventory (SRI) score of ≥10. At baseline, the fulfilment of the international consensus criteria for behavioural variant FTD (FTDC) was systematically recorded. The 2-year follow-up consensus diagnosis was used as the gold standard to calculate sensitivity and specificity of the FTDC criteria for possible and probable bvFTD. Results: Two-year follow-up data were available for 116 patients (85%). Two-year follow-up consensus diagnoses consisted of probable/definite bvFTD (n = 27), other dementia (n = 30), psychiatric disorders (n = 46) and other neurological disorders (n = 13). Sensitivity for possible bvFTD was 85% (95% CI 70-95%) at a specificity of 27% (95% CI 19-37%). Sensitivity for probable bvFTD was 85% (95% CI 69-95%), whereas their specificity was 82% (95% CI 73-89%). Conclusions: We found a good diagnostic accuracy for FTDC probable bvFTD. However, the specificity for FTDC possible bvFTD was low. Our results reflect the symptomatic overlap between bvFTD, other neurological conditions and psychiatric disorders, and the relevance of adding neuroimaging to the diagnostic process.


Neurology | 2018

Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum

Lieke H.H. Meeter; Everard Vijverberg; Marta Del Campo; Annemieke Rozemuller; Laura Donker Kaat; Frank Jan de Jong; Wiesje M. van der Flier; Charlotte E. Teunissen; John C. van Swieten; Yolande A.L. Pijnenburg

Objective To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort. Methods CSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS). Results NfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau). Conclusion NfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo. Classification of evidence This study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.


Neuropsychiatric Disease and Treatment | 2017

Psychosis in behavioral variant frontotemporal dementia

Flora Gossink; Everard Vijverberg; Welmoed A. Krudop; Philip Scheltens; Max L. Stek; Yolande A.L. Pijnenburg; Annemiek Dols

Background Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer’s disease. However, for behavioral variant of frontotemporal dementia (bvFTD), studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD. Methods In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale) was used in patients with probable and definite bvFTD (n=22) and with a primary psychiatric disorder (n=35) in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years. Results In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5%) and formal thought disorders (81.8%). “Difficulty in abstract thinking” and “stereotypical thinking” (formal thought disorders) differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, “anxiety”, “guilt feelings,” and “tension” explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P<0.001). Conclusion Delusions, hallucinatory behavior, and suspiciousness were present in one-fifth of bvFTD patients, whereas negative psychotic symptoms such as social and emotional withdrawal, blunted affect, and formal thought disorders were more frequently present. This suggests that negative psychotic symptoms and formal thought disorders have an important role in the psychiatric misdiagnosis in bvFTD; misdiagnosis in bvFTD might be reduced by systematically exploring the broad spectrum of psychiatric symptoms.


Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring | 2017

Cerebrospinal fluid biomarker examination as a tool to discriminate behavioral variant frontotemporal dementia from primary psychiatric disorders

Everard Vijverberg; Annemiek Dols; Welmoed A. Krudop; Marta Del Campo Milan; Cora J. Kerssens; Flora Gossink; Niels D. Prins; Max L. Stek; Philip Scheltens; Charlotte E. Teunissen; Yolande A.L. Pijnenburg

To prospectively determine the diagnostic value of cerebrospinal fluid (CSF) levels total‐tau (tau) to amyloid‐β1–42 ratio (Aβ1–42) ratio (tau/Aβ1–42 ratio), phosphorylated‐tau (p‐tau) to tau ratio (p‐tau/tau ratio), neurofilament light chain (NfL) and YKL40 in the late‐onset frontal lobe syndrome, in particular for the differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) versus primary psychiatric disorders (PSY).


The Journal of Clinical Psychiatry | 2017

The Diagnostic Challenge of the Late-Onset Frontal Lobe Syndrome: Clinical Predictors for Primary Psychiatric Disorders Versus Behavioral Variant Frontotemporal Dementia

Everard Vijverberg; Flora Gossink; Welmoed A. Krudop; Sietske A.M. Sikkes; Cora J. Kerssens; Niels D. Prins; Max L. Stek; Philip Scheltens; Yolande A.L. Pijnenburg; Annemiek Dols

OBJECTIVE Primary psychiatric disorders (PsD) can present with symptomatology identical to that of behavioral variant frontotemporal dementia (bvFTD). To date, clinical guidelines do not provide a solution for this diagnostic challenge. The aim of our study was to prospectively determine which demographic, clinical, neuropsychological, neuroimaging, and cerebrospinal fluid biomarkers are important in distinguishing PsD from bvFTD. METHODS Patients with late-onset behavioral disturbances (aged 45-75 years, 73% male) were included based on their scores on the Frontal Behavioral Inventory and the Stereotypy Rating Inventory and followed for 2 years from April 2011 to June 2015. Odds ratios (ORs) were calculated with backward stepwise logistic regression analyses to investigate the association between baseline clinical and demographic variables and the 2-year follow-up diagnosis of PsD (n = 46) (DSM-IV) versus probable/definite bvFTD (n = 27) (International Behavioral Variant FTD Criteria Consortium criteria). We separately measured the association between additional investigations and the 2-year follow-up diagnosis. Finally, we combined the selected variables to measure the predictive value of both clinical and additional investigations in a single model. RESULTS Male gender (OR = 5.9; 95% CI, 1.3-26.0), less stereotypy (OR = 0.08; 95% CI, 0.02-0.34), and more depressive symptoms (OR = 1.13; 95% CI, 1.04-1.24) explained 49% of the variance predicting PsD versus bvFTD (χ²₃ = 29.4, P < .001) and correctly classified 82.1% of the cases. Neuroimaging (OR = 0.02; 95% CI, 0.002-0.123) explained 55% of the variance (χ²₁ = 37.5, P < .001) and, in combination with clinical variables, 66.1% of the variance (χ²₃ = 44.06, P < .001). CONCLUSIONS The present study demonstrated that PsD can be distinguished from probable/definite bvFTD with a thorough clinical evaluation by a psychiatrist and neurologist along with use of validated questionnaires for depression and stereotypy; these measures are even more effective in combination with neuroimaging.


Journal of Psychiatric Research | 2018

Disease trajectories in behavioural variant frontotemporal dementia, primary psychiatric and other neurodegenerative disorders presenting with behavioural change

Lianne M. Reus; Everard Vijverberg; Betty M. Tijms; Mara ten Kate; Flora Gossink; Welmoed A. Krudop; Marta Del Campo; Charlotte E. Teunissen; Frederik Barkhof; Wiesje M. van der Flier; Pieter Jelle Visser; Annemiek Dols; Yolande A.L. Pijnenburg

Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-up = 3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (n = 34), other neurodegenerative (n = 28) and primary psychiatric disorders (n = 43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning.


Journal of Neuropsychiatry and Clinical Neurosciences | 2018

Neuropsychiatry in Clinical Practice: The Challenge Of Diagnosing Behavioral Variant Frontotemporal Dementia

Flora Gossink; Everard Vijverberg; Yol; e Pijnenburg; Annemiek Dols

The behavioral variant of Frontotemporal dementia (bvFTD) is an insidious neurodegenerative disease associated with progressive degeneration of the frontal lobes, anterior temporal lobes, or both [1]. Alterations in social cognition represent the core symptoms of bvFTD resulting in emotional disengagement and socially inappropriate responses or activities [2,3]. As is apparent in revised consortium criteria, additional neuropsychiatric symptoms including apathy and stereotypical and impulsive behavior are prominent in the clinical presentation [4]. Consequently, both neurodegenerative diseases and primary psychiatric disorders are crucial in the challenging differential diagnosis. The differentiation between bvFTD and Alzheimer’s disease (AD) has become easier by the use of biomarkers that are able to identify underlying AD pathology, such as the amyloid-β (Aβ) and tau [1,5]. However, to distinguish bvFTD from psychiatric disorders can still be difficult, particularly since biomarkers for bvFTD are less robust [6]. Previous studies indicated that as a result of symptomatic overlap between bvFTD and psychiatric disorders, bvFTD patients are clinically often mistaken for psychiatric patients and vice versa [7-10]. The current clinical criteria for bvFTD require that “if behavioral disturbance is better accounted for by a psychiatric diagnosis, a diagnosis of bvFTD has to be excluded” [4]. Despite clinical overlap, bvFTD patients do not often fulfill formal criteria for a psychiatric diagnosis, suggesting that it is valuable to apply formal criteria for psychiatric disorders [11]. Careful clinical phenotyping of overlapping symptoms can help to distinguish bvFTD from psychiatric disorders in clinical practice (Figure 1) [12,13]. Figure 1 Overlap and differentiation between bvFTD and psychiatric disorders in clinical practice. The value of different symptom rating scales and clinical tools has been proven useful in clinical practice in case of suspected bvFTD when a psychiatric disorder is also probable (Figure 2) [11,14,15]. Figure 2 Clinical hallmarks and supportive measuring instruments in the differential diagnosis bvFTD and psychiatric disorders. According to current criteria, the diagnostic certainty of bvFTD increases when Frontotemporal abnormalities are found on neuroimaging. In a large cohort of patients with late-onset behavioral changes, MRI had a sensitivity of 70% and a specificity of 93% for a bvFTD diagnosis [4]. The additional [18F]FDG-PET, when the MRI was inconclusive, had a sensitivity of 90% at the cost of a lower specificity (68%) [16]. [18F]FDG-PET is mainly useful when Frontotemporal hypo-metabolism is absent to exclude bvFTD diagnosis. The interpretation of neuroimaging results should especially be taken with caution in cases with a psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation and in cases with a genetic background where both MRI and [18F]FDG-PET can show a specific abnormalities [16-18]. Genetic screening especially for C9orf72 repeat expansion is emphasized [19,20]. particularly in cases with a remarkable (prolonged) disease course. In clinical practice, bvFTD has a broad differential diagnosis including both neurodegenerative diseases and primary psychiatric disorders. The current criteria for bvFTD have clearly improved diagnostics but differentiating bvFTD from psychiatric disorders remains difficult. The challenge for the next decade is finding specific biomarkers for bvFTD on the one hand, and optimizing the neuropsychiatric diagnosis of bvFTD on the other hand. To this end, patient care for suspected bvFTD patients would be largely improved in a setting where neurologists and psychiatrists work hand in hand, ideally applying a consensus set of clinical rating scales next to their clinical expertise.


The Journal of Clinical Psychiatry | 2017

Cognitive Deficits in Patients With Neuropsychiatric Symptoms: A Comparative Study Between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders

Everard Vijverberg; Sigfried Schouws; Paul D. Meesters; Esmée Verwijk; Hannie C. Comijs; Ted Koene; Charlotte Schreuder; Aartjan T.F. Beekman; Philip Scheltens; Max L. Stek; Yolande A.L. Pijnenburg; Annemieke Dols

OBJECTIVE To compare neuropsychological profiles in behavioral variant frontotemporal dementia (bvFTD) with its most common primary psychiatric differential diagnoses, major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia, in older patients with active symptoms. METHODS We included patients from different cohorts with MDD (DSM-IV-TR: 296.20-296.23, 296.30-296.33; n = 42; mean ± SD age, 72.0 ± 8.0 years; female = 57.1%) included from 2002 to 2007, noneuthymic BD (DSM-IV-TR: 296.00-296.06, 296.40-296.46, 296.50-296.56, 296.60-296.66, 296.7; DSM-IV-TR: 296.89; DSM-IV-TR: 296.80; n = 41; age, 71.7 ± 8.8 years; female = 53.7%) included from 2011 to 2015, nonremitted schizophrenia (DSM-IV-TR: 295.10, 295.20, 295.30, 295.60, 295.90; n = 47; age, 67.5 ± 7.1 years; female = 66%) included from 2006 to 2008, or probable/definite bvFTD (n = 173; age, 62.6 ± 8.0 years; female = 39.9%) (Frontotemporal Dementia Consensus criteria) included from 2000 to 2015 and healthy controls (n = 78; age, 71.9 ± 8.0 years; female = 71.8%) included from 2005 to 2007. Neuropsychological tests concerned the domains of attention and working memory, verbal memory, verbal fluency, and executive functioning. Analyses of variance were performed with age, gender, and education level as covariates. Post hoc Bonferroni tests were used to detail group differences. RESULTS Compared to the healthy controls, both the bvFTD and primary psychiatric disorder groups showed significant impairment on all cognitive domains. Executive function was more disturbed in all primary psychiatric disorders compared to bvFTD (P < .001). Attention and working memory were significantly better in the bvFTD and schizophrenia groups compared to the MDD and BD groups (P < .001). For verbal memory, the bvFTD group scored significantly higher compared to patients with schizophrenia, BD, or MDD (P < .001). Patients with bvFTD had significantly lower scores on verbal fluency, especially due to Animal Naming, in comparison with the BD group (P < .001); however, these scores were not significantly different from those of MDD or schizophrenia patients. CONCLUSIONS Cognitive deficits in bvFTD are less severe than in primary psychiatric disorders with active symptoms. This indicates that in the differential diagnosis of bvFTD, disturbances on tests for cognitive performance do not rule out primary psychiatric diagnoses.


Neurobiology of Aging | 2017

Gray matter network differences between behavioral variant frontotemporal dementia and Alzheimer's disease

Everard Vijverberg; Betty M. Tijms; J. Dopp; Y.J. Hong; Charlotte E. Teunissen; Frederik Barkhof; P. Scheltens; Yolande A.L. Pijnenburg

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Flora Gossink

VU University Medical Center

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Annemiek Dols

VU University Medical Center

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Max L. Stek

VU University Amsterdam

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Welmoed A. Krudop

VU University Medical Center

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Frederik Barkhof

VU University Medical Center

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Niels D. Prins

Erasmus University Rotterdam

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