Authors: van der Flier, Wiesje M. | Scheltens, Philip
Article Type: Review Article
Abstract: The Alzheimer center of the VU University Medical Center opened in 2000 and was initiated to combine both patient care and research. Together, to date, all patients forming the Amsterdam Dementia Cohort number almost 6,000 individuals. In this cohort profile, we provide an overview of the results produced based on the Amsterdam Dementia Cohort. We describe the main results over the years in each of these research lines: 1) early diagnosis, 2) heterogeneity, and 3) vascular factors. Among the most important research efforts that have also impacted patients’ lives and/or the research field, we count the development of novel, easy …to use diagnostic measures such as visual rating scales for MRI and the Amsterdam IADL Questionnaire, insight in different subgroups of AD, and findings on incidence and clinical sequelae of microbleeds. Finally, we describe in the outlook how our research endeavors have improved the lives of our patients. Show more
Keywords: Alzheimer’s disease, Amsterdam Dementia Cohort, dementia, diagnosis, heterogeneity, mild cognitive impairment, prognosis, vascular factors
DOI: 10.3233/JAD-170850
Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1091-1111, 2018
Authors: Yakhia, Maja | König, Alexandra | van der Flier, Wiesje M. | Friedman, Leah | Robert, Philippe H. | David, Renaud
Article Type: Research Article
Abstract: Background: Individuals with mild cognitive impairment (MCI) may exhibit changes in motor activity in conducting their activities of daily living. Depression, one of the most frequent neuropsychiatric symptoms, might affect motor activity in MCI. Objective: To assess motor activity in MCI subjects carrying out short functional activity tasks using ambulatory actigraphy. Secondly, we sought to investigate the influence of depressive symptoms on motor activity. Methods: 20 MCI and 14 healthy subjects carried out a 30-minute standardized scenario while wearing a chest actigraph. The protocol consisted of directed activities (execution of motor tasks), semi-directed activities (execution of Instrumental Activities of Daily …Living, IADL), and undirected ‘free’ activities. Several common assessment scales (GDS, MADRS, and NPI) were used to diagnose depression. Results: MCI subjects had significantly reduced mean motor activity while carrying out directed and semi-directed activities, compared to healthy control subjects. No difference was found in motor activity between MCI subjects with or without depression. Conclusion: Actigraphic measurement of motor activity during the evaluation of IADLs and motor tasks is a potential objective tool in detecting early changes in MCI. Depressive symptoms seem not to be associated with motor activity in MCI subjects. Show more
Keywords: Actigraphy, depressive symptoms, mild cognitive impairment, motor activity
DOI: 10.3233/JAD-131691
Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 869-875, 2014
Authors: Barnes, Josephine | Bartlett, Jonathan W. | Wolk, David A. | van der Flier, Wiesje M. | Frost, Chris
Article Type: Research Article
Abstract: Health-care professionals, patients, and families seek as much information as possible about prognosis for patients with Alzheimer’s disease (AD); however, we do not yet have a robust understanding of how demographic factors predict prognosis. We evaluated associations between age at presentation, age of onset, and symptom length with cognitive decline as measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum-of-boxes (CDR-SOB) in a large dataset of AD patients. Age at presentation was associated with post-presentation decline in MMSE (p < 0.001), with younger patients showing faster decline. There was little evidence of an association with change in …CDR-SOB. Symptom length, rather than age, was the strongest predictor of MMSE and CDR-SOB at presentation, with increasing symptom length associated with worse outcomes. The evidence that younger AD patients have a more aggressive disease course implies that early diagnosis is essential. Show more
Keywords: Age factors, age of onset, Alzheimer’s disease, cognition, cognitive decline
DOI: 10.3233/JAD-170841
Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 631-642, 2018
Authors: van Harten, Argonde C. | Mulders, Joyce | Scheltens, Philip | van der Flier, Wiesje M. | Oudejans, Cees B.M.
Article Type: Research Article
Abstract: Background and Objective: The need to find a better reflection of Alzheimer’s disease (AD) pathophysiology led us to investigate differential expression of microRNA (miRNA) in cerebrospinal fluid (CSF) of AD patients compared to matched controls, using a genome-wide data-driven approach. Methods: From the Amsterdam Dementia Cohort, we selected 19 AD patients with CSF indicative of AD pathophysiology and 19 age and gender-matched controls without CSF evidence of AD (67 ± 6 years old, 20 [53%] female). We measured 754 miRNA in CSF using qRT-PCR (Taqman Array MicroRNA cards A and B, v3.0) according to the Megaplex Taqman protocol. Hierarchical cluster …analysis was performed and groups were compared using Linear Models for Microarray Data, a modified t -test. We performed validation analysis using qRT-PCR single assays. Results: 144 ± 66 miRNA could be detected using Megaplex array analysis (19% ). Mean Ct (average 32.4 ± 0.5) was correlated to age (r = 0.52, p = 0.001). Five miRNA were differentially expressed in CSF of AD patients. None of these could be replicated. After stratification by age, seven miRNA showed differential expression in late-onset AD, of which lower abundance of let-7a was replicated (log10RQ −1.46, p < 0.05). In early-onset AD, twelve miRNA were differentially expressed of which lower abundance of miRNA-532-3p remained borderline significant (log10RQ −1.27, p = 0.05). Conclusion: Although we could not consistently separate AD patients and controls in the whole group, we have found indications miRNA in CSF are able to reflect aging and perhaps also heterogeneity in AD. Further investigation requires optimizing RNA input, while maintaining strict age matching. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, microRNAs
DOI: 10.3233/JAD-140075
Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 243-252, 2015
Authors: Kester, Maartje I. | Blankenstein, Marinus A. | Bouwman, Femke H. | van Elk, Evert J. | Scheltens, Philip | van der Flier, Wiesje M.
Article Type: Research Article
Abstract: The object of this study was to elucidate the effect of age in the relationship between APOE genotype and CSF biomarkers amyloid-β1–42 (Aβ42 ), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) in AD and controls. 302 AD patients and 174 controls were categorized into APOE ε4 carriers and non-carriers, and into younger and older (⩾65years). In controls, older age and APOE ε4 were independently associated with lower Aβ42 and higher tau and ptau-181 levels (p < 0.05). For tau and ptau-181, there were also interactions (p < 0.10): older carriers had higher levels than older non-carriers, without …effect for younger controls. In AD, APOE ε4 genotype had a main effect on Aβ42 , but there was also an interaction: older carriers had lower Aβ42 than older non-carriers, without effect for younger AD patients (p < 0.05). For tau and ptau-181, there were only interactions: older carriers had higher levels than older non-carriers, while younger AD patients showed the opposite (p ⩽ 0.05). Association between CSF biomarkers and APOE genotype were modified by age in both controls and AD patients. This suggests that cognitively healthy APOE ε4 carriers are more prone to develop AD pathology with aging. For AD patients, this provides support for the existence of subtypes within the disease. Show more
Keywords: Aging, Alzheimer's disease, APOE genotype, biomarkers, cerebrospinal fluid
DOI: 10.3233/JAD-2009-0999
Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 601-607, 2009
Authors: Koedam, Esther L.G.E. | Lauffer, Vivian | van der Vlies, Annelies E. | van der Flier, Wiesje M. | Scheltens, Philip | Pijnenburg, Yolande A.L.
Article Type: Research Article
Abstract: Alzheimer's disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files …of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD (⩾ 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 ± 5 years and 74 ± 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p < 0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia. Show more
Keywords: Alzheimer's disease, clinical presentation, dementia, early onset
DOI: 10.3233/JAD-2010-1337
Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1401-1408, 2010
Authors: Mulder, Sandra D. | Hack, C. Erik | van der Flier, Wiesje M. | Scheltens, Philip | Blankenstein, Marinus A. | Veerhuis, Robert
Article Type: Research Article
Abstract: Serum amyloid P (SAP) and C-reactive protein (CRP) are proteins involved in innate immunity. The expression of SAP and CRP is increased in Alzheimer's disease (AD) brain tissue, compared to healthy controls. Although both proteins are found in cerebrospinal fluid (CSF), their origin is unclear. We investigated if increased local production of SAP and CRP in AD brain results in higher levels in CSF with the use of index values. To study this, SAP, CRP, and albumin levels were determined in CSF and serum samples of 30 control (65 ± 11 years; 57% female) and 140 AD subjects (65 ± …9 years; 53% female). To correct for inter-individual differences in protein diffusion from blood to CSF, quotients (Q = CSF/serum) of SAP, CRP, and albumin and index values (Qprotein /Qalb ) were calculated. The results showed no significant differences in SAP and CRP index values between control and AD subjects, although eight percent of individual AD patients showed evidence of intrathecal SAP or CRP production using the Reiber hyperbolic model. Interestingly, the SAP index value was much lower than expected, based on its molecular size. In conclusion, these data suggest that local production of SAP and CRP in the AD brain does not substantially contribute to the CSF levels. Show more
Keywords: Alzheimer's disease, C-reactive protein, index value, serum amyloid p
DOI: 10.3233/JAD-2010-100888
Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1073-1079, 2010
Authors: Kester, Maartje I. | van der Flier, Wiesje M. | Mandic, Gorana | Blankenstein, Marinus A. | Scheltens, Philip | Muller, Majon
Article Type: Research Article
Abstract: We examined the impact of hypertension on cerebrospinal fluid (CSF) biomarkers amyloid-β1-42 (Aβ42 ), total tau (tau), and phosphorylated tau at threonine 181 (ptau-181), and assessed the modifying role of APOE genotype in this relation in 546 patients (mean age 65 ± 10, 47% female) from our memory-clinic. Of these patients 150 had subjective complaints, 140 were diagnosed with mild cognitive impairment, and 256 with Alzheimer's disease. Linear regression analyses adjusted for age, gender, and diagnosis showed that the association of hypertension with tau and ptau-181 was modified by APOE genotype (p-values for interaction p< 0.05). In APOE ε4 homozygotes …(n=74), and to a lesser extent in APOE ε4 heterozygotes, hypertension was associated with higher tau and ptau-181 levels; β (95%CI) were 188 (11; 364) pg/mL and 22 (3; 42) pg/mL for the APOE ε4 homozygotes. Hypertension was not associated with Aβ42 levels, and APOE genotype did not modify this relation. Our findings suggest that hypertension is directly related to tau pathology in APOE ε4 homozygous carriers. Show more
Keywords: Alzheimer's disease, APOE genotype, CSF biomarkers, hypertension
DOI: 10.3233/JAD-2010-091198
Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1083-1090, 2010
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: Willemse, Eline A.J. | Durieux-Lu, Sisi | van der Flier, Wiesje M. | Pijnenburg, Yolande A.L. | de Jonge, Robert | Teunissen, Charlotte E.
Article Type: Research Article
Abstract: Progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF) are increasingly studied as potential markers for neurodegenerative disorders. We aimed to 1) characterize two commercially available PGRN ELISAs on several assay validation parameters, 2) assess the stability of PGRN in serum and CSF under pre-analytical conditions, and 3) compare stability in the two assays. Intra- and inter-assay variation, inter-lot variation, linearity, lower limit of detection, and kit correlations were assessed for the Adipogen and R&D PGRN ELISA kits. Blood and serum samples were experimentally exposed to ≤9 freeze/thaw cycles, delayed processing for ≤24 h at room temperature and 4°C, and to …temperature stability tests for ≤3 weeks at –20°C, 4°C, room temperature, and 37°C. Both commercial PGRN ELISA kits showed acceptable ranges for intra- and inter-assay variation, where the R&D kit performed more accurate than the Adipogen kit, especially for inter-assay variation (intra-assay serum: 6.7 and 8.3%, respectively; inter-assay serum: 9.2 and 21.0%; intra-assay CSF: 3.6 and 12.0%; inter-assay CSF: 16.0 and 44.5%). Absolute serum PGRN concentrations were 1.9-fold higher in Adipogen than R&D (p < 0.001) and strongly correlated between both kits (ρ = 0.86, p < 0.0001) and CSF PGRN levels were on the borderline of detection in both kits. PGRN was typically stable under all pre-analytical conditions addressed, although two weeks at 37°C resulted in decreased PGRN concentrations in CSF, only when using the Adipogen kit. These results support further examination of PGRN as a potential marker in neurodegenerative diseases, since PGRN is stable in serum and CSF and can be measured using ELISA kits from several providers. Show more
Keywords: Cerebrospinal fluid, human progranulin protein, ELISA, method comparison, pre-analytical variation, protein stability, serum
DOI: 10.3233/JAD-160061
Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 107-116, 2016