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.
Objective
We investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with ...subjective cognitive decline (SCD).
Methods
We included 248 subjects with SCD (61 ± 9 years, 42% female, Mini‐Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models.
Results
Fifty‐seven (23%) subjects were CSF‐amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF‐amyloid status (plasma ratio: area under the curve AUC = 77%, 95% confidence interval CI = 69–84%; plasma Abeta42: AUC = 66%, 95% CI: 58–74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77–89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4–2.3).
Interpretation
Plasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656–666
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of ...Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
For many years, blood-based biomarkers for Alzheimer's disease seemed unattainable, but recent results have shown that they could become a reality. Convincing data generated with new high-sensitivity ...assays have emerged with remarkable consistency across different cohorts, but also independent of the precise analytical method used. Concentrations in blood of amyloid and phosphorylated tau proteins associate with the corresponding concentrations in CSF and with amyloid-PET or tau-PET scans. Moreover, other blood-based biomarkers of neurodegeneration, such as neurofilament light chain and glial fibrillary acidic protein, appear to provide information on disease progression and potential for monitoring treatment effects. Now the question emerges of when and how we can bring these biomarkers to clinical practice. This step would pave the way for blood-based biomarkers to support the diagnosis of, and development of treatments for, Alzheimer's disease and other dementias.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have ...reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods ...Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD PCA-AD, Lewy body disease PCA-LBD, corticobasal degeneration PCA-CBD, prion disease PCA-prion) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's ...disease (AD). Recently, the ratio of T1‐weighted by T2‐weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content (i.e., a lower T1‐w/T2‐w ratio value). We selected structural T1‐w and T2‐w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1‐w/T2‐w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1‐w/T2‐w ratios than NC, and regionally in 31 anatomical areas (p < .0005; d = 0.21 to 0.48), predominantly in the inferior parietal lobule, angular gyrus, anterior cingulate, and precuneus. Regional higher T1‐w/T2‐w values were associated with higher CSF tau concentrations (p < .0005; r = .16 to .22) and worse MMSE scores (p < .0005; r = −.16 to −.21). These higher T1‐w/T2‐w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1‐w/T2‐w values.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Introduction Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working ...group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed. Methods Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly. Results Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors. Discussion Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Brain microbleeds are small dot-like lesions appearing as hyposignals on gradient echo magnetic resonance sequences. In Alzheimer's disease, brain microbleeds are of special interest as they may play ...a crucial role in the pathophysiology. They may be a missing link between two important theories on the neuropathogenesis of Alzheimer's disease-the amyloid cascade hypothesis and the vascular hypothesis. Moreover, they may affect the clinical course of the disease and may have therapeutic consequences. The aim of this article is to review available data to understand the meaning of brain microbleeds in clinical terms and underlying pathology in the context of Alzheimer's disease. We also review the available evidence and highlight the pitfalls of our current knowledge on brain microbleeds in the setting of clinical trials design.
Abstract The interrelationships between pathological processes and emerging clinical phenotypes in Alzheimer's disease (AD) are important yet complicated to study, because the brain is a complex ...network where local disruptions can have widespread effects. Recently, properties in brain networks obtained with neuroimaging techniques have been studied in AD with tools from graph theory. However, the interpretation of graph alterations remains unclear, because the definition of connectivity depends on the imaging modality used. Here we examined which graph properties have been consistently reported to be disturbed in AD studies, using a heuristically defined “graph space” to investigate which theoretical models can best explain graph alterations in AD. Findings from structural and functional graphs point to a loss of highly connected areas in AD. However, studies showed considerable variability in reported group differences of most graph properties. This suggests that brain graphs might not be isometric, which complicates the interpretation of graph measurements. We highlight confounding factors such as differences in graph construction methods and provide recommendations for future research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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