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Authors: Wilkinson, David | Fox, Nick C. | Barkhof, Frederik | Phul, Ravinder | Lemming, Ole | Scheltens, Philip | for the Study 10112 investigators

Article Type: Research Article

Abstract: The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimer's disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1 : 1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary …efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (−0.04 mL/year [(95% CI: −2.60, 2.52), p = 0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes. Show more

Keywords: Acetyl cholinesterase inhibitors, behavior, cognition, memantine, MRI, placebo, total brain atrophy

DOI: 10.3233/JAD-2011-111616

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 459-469, 2012

Authors: Möller, Christiane | Dieleman, Nikki | van der Flier, Wiesje M. | Versteeg, Adriaan | Pijnenburg, Yolande | Scheltens, Philip | Barkhof, Frederik | Vrenken, Hugo

Article Type: Research Article

Abstract: Background: The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. Objective: We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer's disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. Methods: For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of hippocampus, amygdala, thalamus, caudate …nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1-weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. Results: Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. Conclusion: Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD. Show more

Keywords: Alzheimer's disease, atrophy, basal ganglia, frontotemporal dementia

DOI: 10.3233/JAD-141230

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 635-647, 2015

Authors: Ketter, Nzeera | Brashear, H. Robert | Bogert, Jennifer | Di, Jianing | Miaux, Yves | Gass, Achim | Purcell, Derk D. | Barkhof, Frederik | Arrighi, H. Michael

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). Objectives: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ 4 allele carriers or noncarriers). Methods: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ 4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. Results: In the Final …Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ 4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. Conclusion: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study. Show more

Keywords: Alzheimer’s disease, bapineuzumab, brain amyloid-related imaging abnormality, magnetic resonance imaging Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302)

DOI: 10.3233/JAD-160216

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 557-573, 2017

Authors: van Rossum, Ineke A. | Visser, Pieter Jelle | Knol, Dirk L. | van der Flier, Wiesje M. | Teunissen, Charlotte E. | Barkhof, Frederik | Blankenstein, Marinus A. | Scheltens, Philip

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and …lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42 , APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, clinical progression, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2011-111694

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 319-327, 2012

Authors: van der Vlies, Annelies E. | Staekenborg, Salka S. | Admiraal-Behloul, Faiza | Prins, Niels D. | Barkhof, Frederik | Vrenken, Hugo | Reiber, Johan H.C. | Scheltens, Philip | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Aim: To assess the associations of global atrophy and white matter hyperintensities (WMH) with neuropsychological function in early and late onset Alzheimer's disease (AD). Methods: We included 107 patients with sporadic AD (21 early onset and 86 late onset) from our memory clinic. Tests for (working) memory, language, executive function, mental speed, and attention were administered. Global atrophy and global and lobar WMH were measured using 1 Tesla MRI. Linear regression analyses with terms for MRI measures, neuropsychological test results, age, gender, education, and the interaction between separate brain measures and age of onset were performed. Results: Global atrophy was …associated with more severely impaired global cognition, working memory, mental speed, and executive function (p < 0.05). Significant interactions between global atrophy and age at onset showed that these associations were mostly attributable to patients with early onset AD. By contrast, an association between global atrophy and memory was found, which was specifically attributable to late onset AD patients. No associations between global WMH and cognitive function were found. Subsequently we analyzed regional WMH and found that temporal WMH was associated with impaired memory, and frontal WMH was associated with slower mental speed. Conclusion: Cortical atrophy, a key feature of AD, is linked to a wide range of cognitive functions, specifically in early onset AD patients. For WMH, there were no interactions with age at onset, but we found specific associations between temporal WMH and memory and frontal WMH and mental speed. Show more

Keywords: Age of onset, Alzheimer's disease, cognition, magnetic resonance imaging

DOI: 10.3233/JAD-121291

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 169-178, 2013

Authors: Prins, Niels D. | van der Flier, Wiesje M. | Brashear, H. Robert | Knol, Dirk L. | van de Pol, Laura A. | Barkhof, Frederik | Scheltens, Philip

Article Type: Research Article

Abstract: We studied the predictive value of cognitive performance, vascular risk factors, apolipoprotein E (APOE) genotype, and structural brain changes on MRI, on progression to dementia in post hoc analyses of 426 placebo patients (mean age 71 years; 55% women) with mild cognitive impairment (MCI) who participated in a previously published large multi-center clinical trial (Gal-Int-11). The ADAS-cog/MCI test, the New York University Paragraph Recall Test, and the Digit Symbol Coding Test were available at baseline, as were vascular risk factors and APOE genotype. Medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH) and lacunes were assessed on MRI. Over two …years of follow-up, 81 patients (19%) converted to dementia, while 345 patients (81%) remained stable. Results of Cox proportional-hazards regression analysis showed that higher age, worse cognitive test performance, presence of an APOE ε4 allele, and higher MTA scores on MRI increased the risk of progression to dementia in univariate analyses. Vascular risk factors, and WMH and lacunes on MRI, were not associated with progression to dementia. Lower performance on the ADAS-cog/MCI test (HR 1.08 per point increase; 95% CI 1.06–1.10) and Delayed recall test (HR 0.76 per point increase; 95% CI 0.68–0.85), as well as higher MTA scores on MRI (HR 1.33 per point increase; 95% CI 1.00–1.77) were independent predictors of progression to dementia in a step-wise Cox proportional-hazards model with age and gender forced into the model. We conclude that global cognitive function, episodic memory performance, and MTA on MRI independently predict progression to dementia in patients with MCI. Show more

Keywords: Alzheimer's disease, apolipoprotein E, brain infarction, clinical trial, dementia, hippocampus, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-122233

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 79-85, 2013

Authors: Duits, Flora H. | Hernandez-Guillamon, Mar | Montaner, Joan | Goos, Jereon D.C. | Montañola, Alex | Wattjes, Mike P. | Barkhof, Frederik | Scheltens, Philip | Teunissen, Charlotte E. | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer’s disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral micro-bleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β1 - 42 (Aβ42 ), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and TIMP1 …and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p  <  0.05), and higher CSF MMP10 levels compared to controls (p  <  0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p  <  0.05), and CSF MMP10 with tau (St.B 0.38, p  <  0.001) and p-tau (St.B 0.40, p  <  0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebrospinal fluid, matrix metalloproteinases, microbleeds, tissue inhibitors of matrix metalloproteinases

DOI: 10.3233/JAD-143186

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 711-720, 2015

Authors: Rhodius-Meester, Hanneke F.M. | Koikkalainen, Juha | Mattila, Jussi | Teunissen, Charlotte E. | Barkhof, Frederik | Lemstra, Afina W. | Scheltens, Philip | Lötjönen, Jyrki | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: Recent criteria allow biomarkers to provide evidence of Alzheimer’s disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients. Objective: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis. Methods: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on …individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure. Results: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86). Conclusion: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice. Show more

Keywords: KeywordsAlzheimer’s disease, clinical decision support system, diagnostic test assessment, mild cognitive impairment, prognosis

DOI: 10.3233/JAD-150548

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 261-270, 2016

Authors: Groot, Colin | Tolboom, Nelleke | Ikonomovic, Milos D. | Lammertsma, Adriaan A. | Boon, Baayla D.C. | Barkhof, Frederik | Scheltens, Philip | Klunk, William E. | Rozemuller, Annemieke J.M. | Ossenkoppele, Rik | van Berckel, Bart N.M.

Article Type: Short Communication

Abstract: This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11 C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND ) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does not detect the …atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11 C]PiB-PET to detect atypical forms of amyloid pathology. Show more

Keywords: Amyloid, case study, histology, positron emission tomography

DOI: 10.3233/JAD-180316

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 71-77, 2018

Authors: Reimand, Juhan | Groot, Colin | Teunissen, Charlotte E. | Windhorst, Albert D. | Boellaard, Ronald | Barkhof, Frederik | Nazarenko, Sergei | van der Flier, Wiesje M. | van Berckel, Bart N.M. | Scheltens, Philip | Ossenkoppele, Rik | Bouwman, Femke

Article Type: Research Article

Abstract: Background: Amyloid-β positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer’s disease. Objective: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. Methods: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. Results: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD���= 3.8). CSF …analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n  = 53, 74%), followed by incongruent MRI (n  = 16, 22%), unusual clinical presentation (n  = 11, 15%) and young age (n  = 8, 11%). An amyloid-β PET scan was rarely (n  = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n  = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n  = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. Conclusion: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography, tau proteins

DOI: 10.3233/JAD-190836

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 559-569, 2020