Publications by authors named "Charlotte Teunissen"

335 Publications

Alzheimer's disease.

Lancet 2021 Mar 2. Epub 2021 Mar 2.

Alzheimer Centre Amsterdam, Amsterdam University Medical Centers, Amsterdam, Netherlands; Department of Epidemiology and Datascience, Amsterdam University Medical Centers, Amsterdam, Netherlands.

In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.
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http://dx.doi.org/10.1016/S0140-6736(20)32205-4DOI Listing
March 2021

Ultrasensitive immunoassay allows measurement of serum neurofilament heavy in multiple sclerosis.

Mult Scler Relat Disord 2021 Feb 10;50:102840. Epub 2021 Feb 10.

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Department of Clinical Neurosciences, Neurology Unit, Geneva University Hospital, Geneva, Switzerland.

Background: Neurofilament heavy (NfH) is a promising biomarker for neuro-axonal damage in Multiple Sclerosis (MS). We compared the performance of high-sensitivity serum-NfH immunoassays, with as aim to investigate the value of serum-NfH as biomarker for MS.

Methods: We measured serum-NfH in 76 MS patients with Simoa (one commercial, one in-house) or Luminex assays. Serum-NfH measured by the immunoassay with greatest sensitivity was related to clinical and radiological outcomes with age and sex-adjusted linear regression analysis, and to biological outcomes cerebrospinal fluid (CSF)-NfH, serum neurofilament light (NfL) and CSF-NfL with Spearman's correlation analysis.

Results: With the commercial Simoa assay, we obtained 100% serum-NfH detectability (in-house Simoa: 70%, Luminex: 61%), with lowest coefficient of variation (CV) between duplicates of 11%CV (in-house Simoa: 22%CV, Luminex: 30%CV). Serum-NfH quantified with the commercial Simoa assay was associated with disease duration (standardized beta (sβ) = 0.28, p = 0.034), T2 lesion volume (sβ = 0.23, p = 0.041), and tended to associate with black hole count (sβ = 0.21, p = 0.084) but not with Expanded Disease Disability Score (EDSS) or normalized brain volume (all: p>0.10). Furthermore, serum-NfH showed correlations with CSF-NfH (rho = 0.27, p = 0.018) and serum-NfL (rho=0.44, p < 0.001), but not with CSF-NfL.

Conclusions: Serum-NfH can be quantified with high-sensitivity technology. Cross-sectionally, we observed some weak correlations of serum-NfH with MS disease burden parameters, suggesting there might be some utility for serum-NfH as biomarker for MS disease burden.
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http://dx.doi.org/10.1016/j.msard.2021.102840DOI Listing
February 2021

Lumbar puncture patient video increases knowledge and reduces uncertainty: An RCT.

Alzheimers Dement (N Y) 2021 14;7(1):e12127. Epub 2021 Feb 14.

Department of Neurology, Alzheimer Center, Neuroscience Campus Amsterdam VU University Medical Center Amsterdam UMC Amsterdam the Netherlands.

Background: Patients often perceive a lumbar puncture (LP) as an invasive procedure. We aimed to evaluate the impact of a 3-minute educational animation-video explaining the LP procedure, on patients' knowledge, uncertainty, anxiety, and post-LP complications.

Methods: We included 203 newly referred memory clinic patients, who were randomly assigned to one of three conditions: (1) home viewing of the video, (2) clinic viewing of the video, or (3) control condition (care as usual). Participants completed questionnaires measuring knowledge as information recall, uncertainty, anxiety, and post-LP complications, the latter when patients underwent an LP procedure (n = 145).

Results: Viewing the video increased information recall for both home (< .001), and clinic viewers (< .001) compared to controls. Levels of uncertainty decreased after viewing (.044), particularly for clinic viewers. Viewing the video or not did not affect anxiety and post-LP complications.

Discussion: Preparing individuals for an LP by means of an educational video can help to increase knowledge about the procedure and reduce feelings of uncertainty.
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http://dx.doi.org/10.1002/trc2.12127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882513PMC
February 2021

Neuronal and glial CSF biomarkers in multiple sclerosis: a systematic review and meta-analysis.

Rev Neurosci 2021 Feb 16. Epub 2021 Feb 16.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.
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http://dx.doi.org/10.1515/revneuro-2020-0145DOI Listing
February 2021

Onset of Preclinical Alzheimer Disease in Monozygotic Twins.

Ann Neurol 2021 Feb 14. Epub 2021 Feb 14.

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

Objective: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.

Methods: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aβ) aggregation as measured by the Aβ1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta-secretase 1, Aβ1-40, and Aβ1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.

Results: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aβ1-38 in one twin correlated with Aβ1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in Aβ production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD.

Interpretation: Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26048DOI Listing
February 2021

Concatenating plasma p-tau to Alzheimer's disease.

Brain 2021 Feb;144(1):14-17

Neurochemistry laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers (AUMC), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, The Netherlands.

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http://dx.doi.org/10.1093/brain/awaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880662PMC
February 2021

Biomarker Testing: Piercing the Fog of Alzheimer's and Related Dementia.

Biomed Hub 2020 Sep-Dec;5(3):19-40. Epub 2020 Nov 23.

National and Kapodistrian University of Athens Medical School, Athens, Greece.

Alzheimer's disease (AD) and related dementia is one of the growing threats to the sustainability of health and care systems in developed countries, and efforts to find therapies have had scant success. The main reasons for this are lack of efficient therapy, which is linked to too late discovery of the disease itself. With this in mind, biomarkers are recognised as an element which can bring a major contribution to research, helping elucidate the disease and the search for treatments. They are also playing an increasing role in early detection and timely diagnosis, which are considered the principal hopes of effective management in the absence of an effective drug. The current arsenal of biomarkers could already, if more widely deployed, provide an effective minimum service to patients and health systems. A concerted action by policy makers and stakeholders could drive progress in access to AD biomarker testing to provide an optimum service in the medium term. This paper discusses how to improve the use of and access to biomarker testing in the detection and diagnosis of AD and other diseases featuring dementia, and how EU healthcare systems could benefit. It outlines the challenges, lists the achievements to date, and highlights the actions needed to allow biomarker testing to deliver more fully on their potential in AD.
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http://dx.doi.org/10.1159/000511233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841748PMC
November 2020

Targeting hippocampal hyperactivity with real-time fMRI neurofeedback: protocol of a single-blind randomized controlled trial in mild cognitive impairment.

BMC Psychiatry 2021 Feb 9;21(1):87. Epub 2021 Feb 9.

University Hospital of Old Age Psychiatry and Psychotherapy, Bern University, Bern, Switzerland.

Background: Several fMRI studies found hyperactivity in the hippocampus during pattern separation tasks in patients with Mild Cognitive Impairment (MCI; a prodromal stage of Alzheimer's disease). This was associated with memory deficits, subsequent cognitive decline, and faster clinical progression. A reduction of hippocampal hyperactivity with an antiepileptic drug improved memory performance. Pharmacological interventions, however, entail the risk of side effects. An alternative approach may be real-time fMRI neurofeedback, during which individuals learn to control region-specific brain activity. In the current project we aim to test the potential of neurofeedback to reduce hippocampal hyperactivity and thereby improve memory performance.

Methods: In a single-blind parallel-group study, we will randomize n = 84 individuals (n = 42 patients with MCI, n = 42 healthy elderly volunteers) to one of two groups receiving feedback from either the hippocampus or a functionally independent region. Percent signal change of the hemodynamic response within the respective target region will be displayed to the participant with a thermometer icon. We hypothesize that only feedback from the hippocampus will decrease hippocampal hyperactivity during pattern separation and thereby improve memory performance.

Discussion: Results of this study will reveal whether real-time fMRI neurofeedback is able to reduce hippocampal hyperactivity and thereby improve memory performance. In addition, the results of this study may identify predictors of successful neurofeedback as well as the most successful regulation strategies.

Trial Registration: The study has been registered with clinicaltrials.gov on the 16th of July 2019 (trial identifier: NCT04020744 ).
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http://dx.doi.org/10.1186/s12888-021-03091-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871643PMC
February 2021

Cerebrospinal fluid N-224 tau helps discriminate Alzheimer's disease from subjective cognitive decline and other dementias.

Alzheimers Res Ther 2021 02 8;13(1):38. Epub 2021 Feb 8.

Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

Background: Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer's disease (AD). However, the T-tau assay measures only the mid-region of the protein, while tau in CSF is instead composed of a series of fragments. One fragment species in particular, N-224, shows increased levels in AD compared to controls. In this multicentre study, we performed a clinical validation of the N-224 assay in cohorts including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, non-AD dementias and controls.

Methods: Cohorts consisted of 30 SCD and 30 probable AD from the Amsterdam Dementia Cohort (cohort 1) and 539 controls, 195 SCD, 232 MCI, 137 AD and 253 non-AD from the Swedish BioFINDER study (cohort 2). All samples had AD core biomarkers (Aβ42, T-tau, P-tau181) measurements. N-224 was measured with an in-house ultrasensitive Simoa assay.

Results: N-224 levels were significantly higher in AD compared to SCD (cohort 1: p = 0.003) and in AD compared to all other diagnostic groups in cohort 2 (control, SCD, MCI and non-AD, p < 0.0001). Within the non-AD group, N-224 showed significantly lower concentrations compared to AD in Parkinson's disease (PD, p < 0.0001), Parkinson's disease dementia (PDD, p = 0.004), progressive supranuclear palsy (PSP, < 0.0001), multiple system atrophy (MSA, p = 0.002) and parkinsonisms not otherwise specified (NOS, p = 0.007). In cohort 1, higher concentrations of N-224 were associated to lower Mini-Mental State Examination (MMSE) scores (R = 0.318, β = 0.564, p ≤ 0.0001) and could accurately identify a pathological (< 24) MMSE score (p < 0.0001, AUC = 0.824).

Conclusions: N-224 tau can distinguish AD subjects from SCD and can discriminate subgroups of non-AD dementias from AD. Therefore, N-224 may be a useful addition to the tau biomarker toolbox for the study of tau species in CSF and for better understanding disease pathogenesis.
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http://dx.doi.org/10.1186/s13195-020-00756-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871566PMC
February 2021

α-Synuclein evokes NLRP3 inflammasome-mediated IL-1β secretion from primary human microglia.

Glia 2021 Jan 28. Epub 2021 Jan 28.

Amsterdam UMC, Vrije Universiteit Amsterdam, Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Synucleinopathies such as Parkinson's disease (PD) are hallmarked by α-synuclein (α-syn) pathology and neuroinflammation. This neuroinflammation involves activated microglia with increased secretion of interleukin-1β (IL-1β). The main driver of IL-1β secretion from microglia is the NLRP3 inflammasome. A critical link between microglial NLRP3 inflammasome activation and the progression of both α-syn pathology and dopaminergic neurodegeneration has been identified in various PD models in vivo. α-Syn is known to activate the microglial NLRP3 inflammasome in murine models, but its relationship to this inflammasome in human microglia has not been established. In this study, IL-1β secretion from primary mouse microglia induced by α-syn fibrils was dependent on NLRP3 inflammasome assembly and caspase-1 activity, as previously reported. We show that exposure of primary human microglia to α-syn fibrils also resulted in significant IL-1β secretion that was dependent on inflammasome assembly and involved the recruitment of caspase-1 protein to inflammasome scaffolds as visualized with superresolution microscopy. While canonical IL-1β secretion was clearly dependent on caspase-1 enzymatic activity, this activity was less clearly involved for α-syn-induced IL-1β secretion from human microglia. This work presents similarities between primary human and mouse microglia in the mechanisms of activation of the NLRP3 inflammasome by α-syn, but also highlights evidence to suggest that there may be a difference in the requirement for caspase-1 activity in IL-1β output. The data represent a novel characterization of PD-related NLRP3 inflammasome activation in primary human microglia and further implicate this mechanism in the pathology underlying PD.
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http://dx.doi.org/10.1002/glia.23970DOI Listing
January 2021

Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.

Brain 2020 12;143(12):3776-3792

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

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
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http://dx.doi.org/10.1093/brain/awaa325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805814PMC
December 2020

Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer's disease.

Transl Psychiatry 2021 01 11;11(1):27. Epub 2021 Jan 11.

Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia.

Glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein, can be measured in blood samples, and has been associated with Alzheimer's disease (AD). However, plasma GFAP has not been investigated in cognitively normal older adults at risk of AD, based on brain amyloid-β (Aβ) load. Cross-sectional analyses were carried out for plasma GFAP and plasma Aβ1-42/Aβ1-40 ratio, a blood-based marker associated with brain Aβ load, in participants (65-90 years) categorised into low (Aβ-, n = 63) and high (Aβ+, n = 33) brain Aβ load groups via Aβ positron emission tomography. Plasma GFAP, Aβ1-42, and Aβ1-40 were measured using the Single molecule array (Simoa) platform. Plasma GFAP levels were significantly higher (p < 0.00001), and plasma Aβ1-42/Aβ1-40 ratios were significantly lower (p < 0.005), in Aβ+ participants compared to Aβ- participants, adjusted for covariates age, sex, and apolipoprotein E-ε4 carriage. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished Aβ+ from Aβ- (area under the curve, AUC = 0.78), but was outperformed when plasma GFAP was added to the base model (AUC = 0.91) and further improved with plasma Aβ1-42/Aβ1-40 ratio (AUC = 0.92). The current findings demonstrate that plasma GFAP levels are elevated in cognitively normal older adults at risk of AD. These observations suggest that astrocytic damage or activation begins from the pre-symptomatic stage of AD and is associated with brain Aβ load. Observations from the present study highlight the potential of plasma GFAP to contribute to a diagnostic blood biomarker panel (along with plasma Aβ1-42/Aβ1-40 ratios) for cognitively normal older adults at risk of AD.
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http://dx.doi.org/10.1038/s41398-020-01137-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801513PMC
January 2021

Biomarker testing in MCI patients-deciding who to test.

Alzheimers Res Ther 2021 01 7;13(1):14. Epub 2021 Jan 7.

Department of Epidemiology and Data Sciences, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

Background: We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value.

Methods: MCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45-55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell's C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation.

Results: The optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell's C = 0.60, Brier = 0.198 (Harrell's C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell's C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance.

Interpretation: CSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy.
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http://dx.doi.org/10.1186/s13195-020-00763-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792312PMC
January 2021

Four subgroups based on tau levels in Alzheimer's disease observed in two independent cohorts.

Alzheimers Res Ther 2021 01 4;13(1). Epub 2021 Jan 4.

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

Background: As Alzheimer's disease (AD) pathology presents decades before dementia manifests, unbiased biomarker cut-points may more closely reflect presence of pathology than clinically defined cut-points. Currently, unbiased cerebrospinal fluid (CSF) tau cut-points are lacking.

Methods: We investigated CSF t-tau and p-tau cut-points across the clinical spectrum using Gaussian mixture modelling, in two independent cohorts (Amsterdam Dementia Cohort and ADNI).

Results: Individuals with normal cognition (NC) (total n = 1111), mild cognitive impairment (MCI) (total n = 1213) and Alzheimer's disease dementia (AD) (total n = 1524) were included. In both cohorts, four CSF t- and p-tau distributions and three corresponding cut-points were identified. Increasingly high tau subgroups were characterized by steeper MMSE decline and higher progression risk to AD (cohort/platform-dependent HR, t-tau 1.9-21.3; p-tau 2.2-9.5).

Limitations: The number of subjects in some subgroups and subanalyses was small, especially in the highest tau subgroup and in tau PET analyses.

Conclusions: In two independent cohorts, t-tau and p-tau levels showed four subgroups. Increasingly high tau subgroups were associated with faster clinical decline, suggesting our approach may aid in more precise prognoses.
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http://dx.doi.org/10.1186/s13195-020-00713-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780683PMC
January 2021

LDL cholesterol and uridine levels in blood are potential nutritional biomarkers for clinical progression in Alzheimer's disease: The NUDAD project.

Alzheimers Dement (Amst) 2020 30;12(1):e12120. Epub 2020 Dec 30.

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam the Netherlands.

Introduction: We examined associations between nutritional biomarkers and clinical progression in individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD)-type dementia.

Methods: We included 528 individuals (64 ± 8 years, 46% F, follow-up 2.1 ± 0.87 years) with SCD (n = 204), MCI (n = 130), and AD (n = 194). Baseline levels of cholesterol, triglycerides, glucose, homocysteine, folate, vitamin A, B12, E and uridine were measured in blood and S-adenosylmethionine and S-adenosylhomocysteine in cerebrospinal fluid. We determined associations between nutritional biomarkers and clinical progression using Cox proportional hazard models.

Results: Twenty-two (11%) patients with SCD, 45 (35%) patients with MCI, and 100 (52%) patients with AD showed clinical progression. In SCD, higher levels of low-density lipoprotein (LDL) cholesterol were associated with progression (hazard ratio [HR] [95% confidence interval (CI)] 1.88 [1.04 to 3.41]). In AD, lower uridine levels were associated with progression (0.79 [0.63 to 0.99]).

Discussion: Our findings suggest that LDL cholesterol and uridine play a-stage-dependent-role in the clinical progression of AD.
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http://dx.doi.org/10.1002/dad2.12120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772937PMC
December 2020

Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF.

Cells 2020 Dec 29;10(1). Epub 2020 Dec 29.

Neurochemistry Department, Clinical Chemistry, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands.

Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy ( = 27), DLB ( = 48), and AD ( = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain.
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http://dx.doi.org/10.3390/cells10010038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824459PMC
December 2020

Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer's disease in individuals with subjective cognitive decline.

Alzheimers Res Ther 2020 12 24;12(1):169. Epub 2020 Dec 24.

Competence Center for Biospectroscopy, Center for Protein Diagnostics (PRODI), Ruhr-University Bochum, Bochum, Germany.

Background: We evaluated Aβ misfolding in combination with Aβ ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD) in individuals with subjective cognitive decline (SCD).

Methods: Baseline plasma samples (n = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 ± 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 cm reflected normal Aβ folding; readouts at ≤ 1646 cm reflected low and at < 1644 cm high misfolding. We used Cox proportional hazard models to quantify Aβ misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and APOEε4 status. Additionally, plasma Aβ data measured by SIMOA were statistically analyzed and compared.

Results: All 22 patients who converted to MCI or AD-dementia within 6 years exhibited Aβ misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2-157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0-110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86-1.00; 6-year follow-up) for Aβ misfolding in an age, sex, and APOEε4 model. A similar model with plasma Aβ ratio yielded an AUC of 0.92 (95% CI, 0.82-1.00). The AUC increased to 0.99 (95% CI, 0.99-1.00) after inclusion of both Aβ misfolding and the Aβ ratio.

Conclusions: A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings.
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http://dx.doi.org/10.1186/s13195-020-00738-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761044PMC
December 2020

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis.

Alzheimers Res Ther 2020 12 5;12(1):162. Epub 2020 Dec 5.

Laboratory for Molecular Neurobiomarker Research, Department of Neurosciences, KU Leuven, box 7003, Herestraat 49, 3000, Leuven, Belgium.

Background: Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.

Methods: In this prospective cross-sectional study, we quantified plasma Aβ/Aβ ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ/Aβ to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer's disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms.

Results: ELISA and SIMOA plasma Aβ/Aβ detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72-0.84; SIMOA: AUC 0.79, 95% CI 0.73-0.85), and both increased the performance of a basic demographic model including only age and APOE-ε4 genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ/Aβ correlated similarly with amyloid-PET for both platforms (Spearman ρ = - 0.32, p <  0.0001), yet correlations with CSF Aβ/t-tau were stronger for ELISA (ρ = 0.41, p = 0.002) than for SIMOA (ρ = 0.29, p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ and Aβ measured by SIMOA consistently underestimating those measured by ELISA.

Conclusions: ELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ/Aβ, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment.

Trial Registration: EudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE ).
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http://dx.doi.org/10.1186/s13195-020-00728-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719262PMC
December 2020

Plasma p-tau217: from 'new kid' to most promising candidate for Alzheimer's disease blood test.

Brain 2020 12;143(11):3170-3172

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1093/brain/awaa329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719020PMC
December 2020

Nutritional Status Is Associated With Clinical Progression in Alzheimer's Disease: The NUDAD Project.

J Am Med Dir Assoc 2020 Nov 15. Epub 2020 Nov 15.

Faculty of Science, Department of Health Sciences, Vrije Universiteit Amsterdam and the Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Objective: In cognitively normal adults, nutritional parameters are related to cognitive decline and incidence of dementia. Studies on the role of nutrition in predementia stages subjective cognitive decline and mild cognitive impairment, and mild stages of Alzheimer's disease (AD) dementia in a clinical setting are lacking. In the absence of a curative treatment, this evidence is important for targeting nutritional factors to potentially prevent or delay further cognitive decline. Our aim is to investigate associations of nutritional parameters with clinical progression in patients ranging from those who are cognitively normal to those who have AD dementia.

Design: Longitudinal.

Setting And Participants: Memory clinic, 551 patients (219 with subjective cognitive decline, 135 with mild cognitive impairment, and 197 with AD dementia), mean age 64 ± 8 years.

Measurements: We assessed body mass index, fat-free mass, Mini-Nutritional Assessment, and dietary intake with the Dutch Healthy Diet food frequency questionnaire and the 238-item healthy life in an urban setting (HELIUS) food frequency questionnaire at baseline. Cox proportional hazard models were used to evaluate associations of nutritional parameters with clinical progression. Additional analyses were restricted to patients who were amyloid positive.

Results: We observed clinical progression in 170 patients (31%) over 2.2 ± 0.9 years. Poorer Mini-Nutritional Assessment score [hazard ratio (95% confidence interval) 1.39 (1.18-1.64)], lower body mass index [1.15 (0.96-1.38)], lower fat-free mass [1.40 (0.93-2.10)], and a less healthy dietary pattern [1.22 (1.01-1.48)] were associated with a higher risk of clinical progression. Similar effect sizes were found in patients who were amyloid positive.

Conclusions And Implications: Poorer nutritional status and a less healthy dietary pattern are associated with a higher risk of clinical progression. This study provides support for investigating whether improving nutritional status can alter the clinical trajectory of AD.
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http://dx.doi.org/10.1016/j.jamda.2020.10.020DOI Listing
November 2020

Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.

Transl Psychiatry 2020 11 22;10(1):403. Epub 2020 Nov 22.

Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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http://dx.doi.org/10.1038/s41398-020-01074-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680793PMC
November 2020

CSF Biomarkers Reflecting Protein Pathology and Axonal Degeneration Are Associated with Memory, Attentional, and Executive Functioning in Early-Stage Parkinson's Disease.

Int J Mol Sci 2020 Nov 12;21(22). Epub 2020 Nov 12.

Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

In early-stage Parkinson's disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament light chain, amyloid-β, and tau are associated with cognitive performance in early-stage PD patients. CSF levels of total-α-synuclein and phosphorylated-α-synuclein, neurofilament light chain, amyloid-β, and total-tau and phosphorylated-tau were measured in 26 PD patients (disease duration ≤5 years and Hoehn and Yahr stage 1-2.5). Multivariable linear regression models, adjusted for age, gender, and educational level, were used to assess the relationship between CSF biomarker levels and memory, attention, executive and visuospatial function, and language performance scores. In 26 early-stage PD patients, attention and memory were the most commonly affected domains. A higher CSF phosphorylated-α-synuclein/total-α-synuclein ratio was associated with better executive functioning (sβ = 0.40). Higher CSF neurofilament light was associated with worse memory (sβ = -0.59), attentional (sβ = -0.32), and executive functioning (sβ = -0.35). Reduced CSF amyloid-β levels were associated with poorer attentional functioning (sβ = 0.35). Higher CSF phosphorylated-tau was associated with worse language functioning (sβ = -0.33). Thus, CSF biomarker levels, in particular neurofilament light, were related to the most commonly affected cognitive domains in early-stage PD. This indicates that CSF biomarker levels may identify early-stage PD patients who are at an increased risk of developing cognitive impairment.
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http://dx.doi.org/10.3390/ijms21228519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697681PMC
November 2020

Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
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http://dx.doi.org/10.1101/2020.10.29.20211920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654872PMC
November 2020

Decline in cognitively complex everyday activities accelerates along the Alzheimer's disease continuum.

Alzheimers Res Ther 2020 10 29;12(1):138. Epub 2020 Oct 29.

Department of Neurology, Amsterdam Neuroscience, Alzheimer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.

Background: Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD.

Methods: In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized.

Results: The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p < .001) and nearly two SD units per year in stage 4+ (1.93 [- 2.19, - 1.67], p < .001). Overall, results were similar between community-based and memory clinic study cohorts.

Conclusions: Our results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results imply that incremental changes in function are a meaningful measure for early disease monitoring. Combined with the low-cost assessment, this advocates the use of these functional questionnaires for capturing the effects of early AD-related cognitive decline on daily life.
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http://dx.doi.org/10.1186/s13195-020-00706-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597034PMC
October 2020

Amyloid-β PET and CSF in an autopsy-confirmed cohort.

Ann Clin Transl Neurol 2020 11 20;7(11):2150-2160. Epub 2020 Oct 20.

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

Objective: Accumulation of amyloid-β is among the earliest changes in Alzheimer's disease (AD). Amyloid-β positron emission tomography (PET) and Aβ in cerebrospinal fluid (CSF) both assess amyloid-β pathology in-vivo, but 10-20% of cases show discordant (CSF+/PET- or CSF-/PET+) results. The neuropathological correspondence with amyloid-β CSF/PET discordance is unknown.

Methods: We included 21 patients from our tertiary memory clinic who had undergone both CSF Aβ analysis and amyloid-β PET, and had neuropathological data available. Amyloid-β PET and CSF results were compared with neuropathological ABC scores (comprising of Thal (A), Braak (B), and CERAD (C) stage, all ranging from 0 [low] to 3 [high]) and neuropathological diagnosis.

Results: Neuropathological diagnosis was AD in 11 (52%) patients. Amyloid-β PET was positive in all A3, C2, and C3 cases and in one of the two A2 cases. CSF Aβ was positive in 92% of ≥A2 and 90% of ≥C2 cases. PET and CSF were discordant in three of 21 (14%) cases: CSF+/PET- in a patient with granulomatosis with polyangiitis (A0B0C0), CSF+/PET- in a patient with FTLD-TDP type B (A2B1C1), and CSF-/PET+ in a patient with AD (A3B3C3). Two CSF+/PET+ cases had a non-AD neuropathological diagnosis, that is FTLD-TDP type E (A3B1C1) and adult-onset leukoencephalopathy with axonal spheroids (A1B1C0).

Interpretation: Our study demonstrates neuropathological underpinnings of amyloid-β CSF/PET discordance. Furthermore, amyloid-β biomarker positivity on both PET and CSF did not invariably result in an AD diagnosis at autopsy, illustrating the importance of considering relevant comorbidities when evaluating amyloid-β biomarker results.
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http://dx.doi.org/10.1002/acn3.51195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664271PMC
November 2020

Metabolic Age Based on the BBMRI-NL H-NMR Metabolomics Repository as Biomarker of Age-related Disease.

Circ Genom Precis Med 2020 10 14;13(5):541-547. Epub 2020 Aug 14.

Department of Molecular Epidemiology (E.B.v.d.A., J.J.H.B.W., M.B., H.E.D.S., J.D., D.C., H.M., I.M., L.M.'t.H., P.E.S.).

Background: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status.

Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts.

Results: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data.

Conclusions: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.
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http://dx.doi.org/10.1161/CIRCGEN.119.002610DOI Listing
October 2020

Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab.

Neurol Neuroimmunol Neuroinflamm 2021 01 13;8(1). Epub 2020 Oct 13.

From the Department of Neurology (A.A.T., Z.Y.G.L., E.E.M.S., B.A.J., Z.L.E.K., J.K.), Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam; Department of Clinical Chemistry (C.E.T.), Neurochemistry Laboratory and Biobank, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam; Department of Ophthalmology (A.P.), Neuro-ophthalmology Expertise Center, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Diagnostic and Interventional Neuroradiology (M.P.W.), Hanover Medical School, Hanover, Germany; Department of Radiology and Nuclear Medicine (M.P.W., F.B.), Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam, the Netherlands; Department of Neuroinflammation (F.B.), Queen Square MS Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London; and National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (F.B.), London, United Kingdom.

Objective: To describe the disease course of carryover progressive multifocal leukoencephalopathy (PML) after switching from natalizumab to ocrelizumab in 2 patients with relapsing-remitting MS.

Methods: Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (NfL) levels and B-cells.

Results: PML was diagnosed 78 days (case 1) and 97 days (case 2) after discontinuation of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite B-cell depletion caused by ocrelizumab. NfL levels increased in both patients during PML-IRIS. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine, followed by methylprednisolone, and both patients continued therapy with ocrelizumab when B-cells started to repopulate.

Conclusions: The clinical course of carryover PML was mild in both patients, suggesting that B-cell depletion possibly did not aggravate PML-IRIS in these 2 patients.
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http://dx.doi.org/10.1212/NXI.0000000000000904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577542PMC
January 2021

Plasma NfL and GFAP as biomarkers of spinal cord degeneration in adrenoleukodystrophy.

Ann Clin Transl Neurol 2020 11 13;7(11):2127-2136. Epub 2020 Oct 13.

Department of Paediatric Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Objective: To explore the potential of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of spinal cord degeneration in adrenoleukodystrophy, as objective treatment-outcome parameters are needed.

Methods: Plasma NfL and GFAP levels were measured in 45 male and 47 female ALD patients and compared to a reference cohort of 73 healthy controls. For male patients, cerebrospinal fluid (CSF) samples (n = 33) and 1-year (n = 39) and 2-year (n = 18) follow-up data were also collected. Severity of myelopathy was assessed with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up-and-go.

Results: NfL and GFAP levels were higher in male (P < 0.001, effect size (partial ƞ ) NfL = 0.49, GFAP = 0.13) and female (P < 0.001, effect size NfL = 0.19, GFAP = 0.23) patients compared to controls; levels were higher in both symptomatic and asymptomatic patients. In male patients, NfL levels were associated with all three clinical parameters of severity of myelopathy (EDSS, SSPROM, and timed up-and go), while GFAP in male and NfL and GFAP in female patients were not. Changes in clinical parameters during follow-up did not correlate with (changes in) NfL or GFAP levels. Plasma and CSF NfL were strongly correlated (r = 0.60, P < 0.001), but plasma and CSF GFAP were not (r = 0.005, P = 0.98).

Interpretation: Our study illustrates the potential of plasma NfL as biomarker of spinal cord degeneration in adrenoleukodystrophy, which was superior to plasma GFAP in our cohort.
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http://dx.doi.org/10.1002/acn3.51188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664277PMC
November 2020

Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease.

J Int Neuropsychol Soc 2020 Oct 13:1-13. Epub 2020 Oct 13.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Objective: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging - Alzheimer's Association (NIA-AA) research framework.

Method: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models.

Results: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = -.58, p < .001). Word List Delayed Recall (β = -.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = -1.13, p < .001) and 4 (β = -2.23, p < .001).

Conclusions: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.
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http://dx.doi.org/10.1017/S1355617720000934DOI Listing
October 2020