Publications by authors named "Philip Scheltens"

779 Publications

Tau PET correlates with different Alzheimer's disease-related features compared to CSF and plasma p-tau biomarkers.

EMBO Mol Med 2021 Jul 13:e14398. Epub 2021 Jul 13.

Clinical Memory Research Unit, Lund University, Lund, Sweden.

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([ F]RO948 in BioFINDER-2, [ F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.
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http://dx.doi.org/10.15252/emmm.202114398DOI Listing
July 2021

The natural history of primary progressive aphasia: beyond aphasia.

J Neurol 2021 Jul 3. Epub 2021 Jul 3.

Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands.

Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes.

Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1-6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed.

Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4).

Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.
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http://dx.doi.org/10.1007/s00415-021-10689-1DOI Listing
July 2021

[18F]Flortaucipir PET Across Various Mutations in Presymptomatic and Symptomatic Carriers.

Neurology 2021 Jul 1. Epub 2021 Jul 1.

Department of Neurology, Alzheimer Center, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Objective: To assess the [F]flortaucipir binding distribution across mutations in presymptomatic and symptomatic carriers.

Methods: We compared regional [F]flortaucipir binding potential(BP) derived from a 130-minute dynamic [F]flortaucipir PET scan, in nine (pre)symptomatic mutation carriers(4 with P301L[1 symptomatic], 2 with R406W[1 symptomatic]; 1 presymptomatic L315R, 1 presymptomatic S320F and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 Alzheimer's disease patients.

Results: [F]flortaucipir BP images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal and frontal lobe. Elevated medial temporal lobe BP was observed in a presymptomatic R406W carrier. The single symptomatic and one of the three presymptomatic P301L carriers showed elevated [F]flortaucipir BP in the insula, parietal and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BP with at neuropathological examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BP compared to controls. The BP values of the S320F presymptomatic mutation carrier fell within the range of controls.

Conclusion: Presymptomatic mutation carriers already showed subtle elevated tau binding, whereas symptomatic mutation carriers showed a more marked increase in [F]flortaucipir BP. Tau deposition was most pronounced in R406W (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [F]flortaucipir may serve as an early biomarker for mutation carriers in mutations that cause 3R/4R tauopathies.
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http://dx.doi.org/10.1212/WNL.0000000000012448DOI Listing
July 2021

The plasma peptides of Alzheimer's disease.

Clin Proteomics 2021 Jun 28;18(1):17. Epub 2021 Jun 28.

Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON, Canada.

Background: A practical strategy to discover proteins specific to Alzheimer's dementia (AD) may be to compare the plasma peptides and proteins from patients with dementia to normal controls and patients with neurological conditions like multiple sclerosis or other diseases. The aim was a proof of principle for a method to discover proteins and/or peptides of plasma that show greater observation frequency and/or precursor intensity in AD. The endogenous tryptic peptides of Alzheimer's were compared to normals, multiple sclerosis, ovarian cancer, breast cancer, female normal, sepsis, ICU Control, heart attack, along with their institution-matched controls, and normal samples collected directly onto ice.

Methods: Endogenous tryptic peptides were extracted from blinded, individual AD and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC-ESI-MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins identified using the X!TANDEM algorithm. Observation frequency of the identified proteins was counted using SEQUEST algorithm. The proteins with apparently increased observation frequency in AD versus AD Control were revealed graphically and subsequently tested by Chi Square analysis. The proteins specific to AD plasma by Chi Square with FDR correction were analyzed by the STRING algorithm. The average protein or peptide log precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system.

Results: Peptides and/or phosphopeptides of common plasma proteins such as complement C2, C7, and C1QBP among others showed increased observation frequency by Chi Square and/or precursor intensity in AD. Cellular gene symbols with large Chi Square values (χ2 ≥ 25, p ≤ 0.001) from tryptic peptides included KIF12, DISC1, OR8B12, ZC3H12A, TNF, TBC1D8B, GALNT3, EME2, CD1B, BAG1, CPSF2, MMP15, DNAJC2, PHACTR4, OR8B3, GCK, EXOSC7, HMGA1 and NT5C3A among others. Similarly, increased frequency of tryptic phosphopeptides were observed from MOK, SMIM19, NXNL1, SLC24A2, Nbla10317, AHRR, C10orf90, MAEA, SRSF8, TBATA, TNIK, UBE2G1, PDE4C, PCGF2, KIR3DP1, TJP2, CPNE8, and NGF amongst others. STRING analysis showed an increase in cytoplasmic proteins and proteins associated with alternate splicing, exocytosis of luminal proteins, and proteins involved in the regulation of the cell cycle, mitochondrial functions or metabolism and apoptosis. Increases in mean precursor intensity of peptides from common plasma proteins such as DISC1, EXOSC5, UBE2G1, SMIM19, NXNL1, PANO, EIF4G1, KIR3DP1, MED25, MGRN1, OR8B3, MGC24039, POLR1A, SYTL4, RNF111, IREB2, ANKMY2, SGKL, SLC25A5, CHMP3 among others were associated with AD. Tryptic peptides from the highly conserved C-terminus of DISC1 within the sequence MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFR and ARQCGLDSR showed a higher frequency and highest intensity in AD compared to all other disease and controls.

Conclusion: Proteins apparently expressed in the brain that were directly related to Alzheimer's including Nerve Growth Factor (NFG), Sphingomyelin Phosphodiesterase, Disrupted in Schizophrenia 1 (DISC1), the cell death regulator retinitis pigmentosa (NXNl1) that governs the loss of nerve cells in the retina and the cell death regulator ZC3H12A showed much higher observation frequency in AD plasma vs the matched control. There was a striking agreement between the proteins known to be mutated or dis-regulated in the brains of AD patients with the proteins observed in the plasma of AD patients from endogenous peptides including NBN, BAG1, NOX1, PDCD5, SGK3, UBE2G1, SMPD3 neuronal proteins associated with synapse function such as KSYTL4, VTI1B and brain specific proteins such as TBATA.
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http://dx.doi.org/10.1186/s12014-021-09320-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240224PMC
June 2021

Differential trajectories of hypometabolism across cognitively-defined Alzheimer's disease subgroups.

Neuroimage Clin 2021 Jun 12;31:102725. Epub 2021 Jun 12.

Department of Medicine, University of Washington, Seattle, WA, USA.

Disentangling biologically distinct subgroups of Alzheimer's disease (AD) may facilitate a deeper understanding of the neurobiology underlying clinical heterogeneity. We employed longitudinal [F]FDG-PET standardized uptake value ratios (SUVRs) to map hypometabolism across cognitively-defined AD subgroups. Participants were 384 amyloid-positive individuals with an AD dementia diagnosis from ADNI who had a total of 1028 FDG-scans (mean time between first and last scan: 1.6 ± 1.8 years). These participants were categorized into subgroups on the basis of substantial impairment at time of dementia diagnosis in a specific cognitive domain relative to the average across domains. This approach resulted in groups of AD-Memory (n = 135), AD-Executive (n = 8), AD-Language (n = 22), AD-Visuospatial (n = 44), AD-Multiple Domains (n = 15) and AD-No Domains (for whom no domain showed substantial relative impairment; n = 160). Voxelwise contrasts against controls revealed that all AD-subgroups showed progressive hypometabolism compared to controls across temporoparietal regions at time of AD diagnosis. Voxelwise and regions-of-interest (ROI)-based linear mixed model analyses revealed there were also subgroup-specific hypometabolism patterns and trajectories. The AD-Memory group had more pronounced hypometabolism compared to all other groups in the medial temporal lobe and posterior cingulate, and faster decline in metabolism in the medial temporal lobe compared to AD-Visuospatial. The AD-Language group had pronounced lateral temporal hypometabolism compared to all other groups, and the pattern of metabolism was also more asymmetrical (left < right) than all other groups. The AD-Visuospatial group had faster decline in metabolism in parietal regions compared to all other groups, as well as faster decline in the precuneus compared to AD-Memory and AD-No Domains. Taken together, in addition to a common pattern, cognitively-defined subgroups of people with AD dementia show subgroup-specific hypometabolism patterns, as well as differences in trajectories of metabolism over time. These findings provide support to the notion that cognitively-defined subgroups are biologically distinct.
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http://dx.doi.org/10.1016/j.nicl.2021.102725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238088PMC
June 2021

SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network.

Cell Rep 2021 Jun;35(11):109259

UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UK. Electronic address:

Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons. We find that truncating mutation results in SORL1 haploinsufficiency and enlarged endosomes in human neurons. Analysis of isogenic SORL1 wild-type, heterozygous, and homozygous null neurons demonstrates that, whereas SORL1 haploinsufficiency results in endosome dysfunction, complete loss of SORL1 leads to additional defects in lysosome function and autophagy. Neuronal endolysosomal dysfunction caused by loss of SORL1 is relieved by extracellular antisense oligonucleotide-mediated reduction of APP protein, demonstrating that PSEN1, APP, and SORL1 act in a common pathway regulating the endolysosome system, which becomes dysfunctional in AD.
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http://dx.doi.org/10.1016/j.celrep.2021.109259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220253PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease.

Alzheimers Res Ther 2021 05 27;13(1):106. Epub 2021 May 27.

Alzheimer Center, Department of Neurology, Amsterdam UMC, Amsterdam, The Netherlands.

Background: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.

Methods: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau), Aβ, Aβ, neurogranin, and neurofilament light chain].

Results: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.

Conclusions And Relevance: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.

Trial Registration: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.
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http://dx.doi.org/10.1186/s13195-021-00843-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157623PMC
May 2021

Clinical Phenotypes of Behavioral Variant Frontotemporal Dementia by Age at Onset.

J Alzheimers Dis 2021 ;82(1):381-390

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

Background: Behavioral variant frontotemporal dementia (bvFTD) is generally considered a young-onset dementia, although age at onset is highly variable. While several studies indicate clinical differences regarding age at onset, no biomarker validated cohort studies with updated clinical criteria have been performed.

Objective: We aimed to examine behavior, cognition, and mortality over the full age spectrum in a cohort of bvFTD patients with neuroimaging, genetic, or histopathological confirmation and exclusion of positive Alzheimer's disease biomarkers or severe cerebrovascular damage.

Methods: In total, 315 patients with a clinical diagnosis of probable or definite bvFTD were included from the Amsterdam Dementia Cohort and grouped into quartiles by age-at-diagnosis. Neuropsychiatric symptoms and cognitive functioning were assessed with the neuropsychiatric inventory, the geriatric depression scale and a neuropsychological test battery. Data on mortality was obtained from the Dutch municipal register. Associations between age-at-diagnosis and clinical features and mortality risk were examined.

Results: Age-at-diagnosis ranged from 26 to 85 years and established quartiles with mean ages of 52±6, 61±2, 66±2, and 74±3 years. In the total sample, 44.4%exceeded an age of 65 years at time of diagnosis. Earlier age-at-diagnosis was associated with more severe behavioral symptoms, while later age-at-diagnosis was associated with more severe memory impairment. Unexpectedly, mortality risk was not associated with age-at-diagnosis.

Conclusion: In bvFTD, symptom profile is associated with age-at-diagnosis. This should be taken into account with regard to diagnostics, patient management, and trial design. Additionally, based on our sample, the prevalence of late-onset bvFTD is higher than generally thought.
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http://dx.doi.org/10.3233/JAD-210179DOI Listing
January 2021

Kinetics and 28-day test-retest repeatability and reproducibility of [C]UCB-J PET brain imaging.

J Cereb Blood Flow Metab 2021 Jun 8;41(6):1338-1350. Epub 2020 Oct 8.

Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands.

[C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K) and volume of distribution (V) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_V and 2T4k_V described the [C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V, DVR and SRTM BP were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [C]UCB-J kinetics can be well described by a 1T2k_V model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V, DVR and BP was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [C]UCB-J PET.
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http://dx.doi.org/10.1177/0271678X20964248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138337PMC
June 2021

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

Alzheimers Dement 2021 May 14. Epub 2021 May 14.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.

Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.

Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.

Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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http://dx.doi.org/10.1002/alz.12330DOI Listing
May 2021

Comparing CSF amyloid-beta biomarker ratios for two automated immunoassays, Elecsys and Lumipulse, with amyloid PET status.

Alzheimers Dement (Amst) 2021 1;13(1):e12182. Epub 2021 May 1.

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

Introduction: We evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aβ)-ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aβ alone.

Methods: We selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer's disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aβ, phosphorylated tau (p-tau), and total tau (t-tau) were measured with Elecsys and Lumipulse assays, and Aβ with Lumipulse. CSF cut-points were defined using receiver operating characteristic (ROC) for amyloid PET positivity.

Results: For both Elecsys and Lumipulse the p-tau/Aβ, Aβ/Aβ, and t-tau/Aβ ratios showed similarly good concordance with amyloid PET (Elecsys: 93,90,90%; Lumipulse: 94,92,90%) and were higher than Aβ alone (Elecsys 85%; Lumipulse 84%).

Discussion: Biomarker ratios p-tau/Aβ, Aβ/Aβ, t-tau/Aβ on two automated platforms show similar optimal concordance with amyloid PET in a memory clinic cohort.
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http://dx.doi.org/10.1002/dad2.12182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088096PMC
May 2021

Highly specific and ultrasensitive plasma test detects Abeta(1-42) and Abeta(1-40) in Alzheimer's disease.

Sci Rep 2021 May 6;11(1):9736. Epub 2021 May 6.

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

Plasma biomarkers that reflect specific amyloid beta (Abeta) proteoforms provide an insight in the treatment effects of Alzheimer's disease (AD) therapies. Our aim was to develop and validate ready-to-use Simoa 'Amyblood' assays that measure full length Abeta and Abeta and compare their performance with two commercial assays. Linearity, intra- and inter-assay %CV were compared between Amyblood, Quanterix Simoa triplex, and Euroimmun ELISA. Sensitivity and selectivity were assessed for Amyblood and the Quanterix triplex. Clinical performance was assessed in CSF biomarker confirmed AD (n = 43, 68 ± 6 years) and controls (n = 42, 62 ± 5 years). Prototype and Amyblood showed similar calibrator curves and differentiation (20 AD vs 20 controls, p < 0.001). Amyblood, Quanterix triplex, and ELISA showed similar linearity (96%-122%) and intra-assay %CVs (≤ 3.1%). A minor non-specific signal was measured with Amyblood of + 2.4 pg/mL Abeta when incubated with 60 pg/mL Abeta. A substantial non-specific signal of + 24.7 pg/mL Abeta was obtained when 40 pg/mL Abeta was measured with the Quanterix triplex. Selectivity for Abeta at physiological Abeta and Abeta concentrations was 125% for Amyblood and 163% for Quanterix. Amyblood and Quanterix ratios (p < 0.001) and ELISA Abeta concentration (p = 0.025) could differentiate AD from controls. We successfully developed and upscaled a prototype to the Amyblood assays with similar technical and clinical performance as the Quanterix triplex and ELISA, but better specificity and selectivity than the Quanterix triplex assay. These results suggest leverage of this specific assay for monitoring treatment response in trials.
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http://dx.doi.org/10.1038/s41598-021-89004-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102604PMC
May 2021

Early life involvement in C9orf72 repeat expansion carriers.

J Neurol Neurosurg Psychiatry 2021 Apr 27. Epub 2021 Apr 27.

Alzheimer Center, Department of Neurology, Location VU University Medical Center, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

Objectives: The chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72-associated disease is sometimes hard to define, we hypothesise that C9orf72 may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72. Second, we aimed to describe distinctive characteristics of C9orf72 during disease course.

Methods: Out of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72 bvFTD patients and 23 C9orf72 negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses.

Results: Education, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having 'fixed behavioural patterns in daily life' and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers.

Conclusion: This is the first study thoroughly exploring biographies of bvFTD patients with C9orf72, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72 exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72 -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.
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http://dx.doi.org/10.1136/jnnp-2020-325994DOI Listing
April 2021

Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups.

Neuroimage Clin 2021 3;30:102660. Epub 2021 Apr 3.

Department of Neurology & Alzheimer Center, Amsterdam University Medical Center - Location VU University Medical Center, Amsterdam, The Netherlands; Lund University, Clinical Memory Research Unit, Lund, Sweden. Electronic address:

The clinical presentation of Alzheimer's disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences.
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http://dx.doi.org/10.1016/j.nicl.2021.102660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186562PMC
April 2021

The bvFTD phenocopy syndrome: a case study supported by repeated MRI, [F]FDG-PET and pathological assessment.

Neurocase 2021 Apr 21;27(2):181-189. Epub 2021 Apr 21.

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

A clinical syndrome with neuropsychiatric features of bvFTD without neuroimaging abnormalities and a lack of decline is a phenocopy of bvFTD (phFTD). Growing evidence suggests that psychological, psychiatric and environmental factors underlie phFTD. We describe a patient diagnosed with bvFTD prior to the revision of the diagnostic guidelines of FTD. Repeated neuroimaging was normal and there was no FTD pathology at autopsy, rejecting the diagnosis. We hypothesize on etiological factors that on hindsight might have played a role. This case report contributes to the understanding of phFTD and adds to the sparse literature of the postmortem assessment of phFTD.
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http://dx.doi.org/10.1080/13554794.2021.1905855DOI Listing
April 2021

Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer's disease.

J Neurol Neurosurg Psychiatry 2021 Apr 13. Epub 2021 Apr 13.

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

Objective: The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.

Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [F]flortaucipir or [F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).

Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05).

Conclusions: Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.
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http://dx.doi.org/10.1136/jnnp-2020-325497DOI Listing
April 2021

The predictive value of normal EEGs in dementia due to Alzheimer's disease.

Ann Clin Transl Neurol 2021 05 9;8(5):1038-1048. Epub 2021 Apr 9.

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

Objective: To determine differences in clinical presentation and disease progression between patients with dementia due to AD with visually normal and abnormal EEG recordings. We hypothesized that patients with normal electroencephalographs (EEGs) are a representation of the heterogeneity of AD. We expected this group to have a phenotype with relatively predominant hippocampal atrophy, memory deficits, and a slower disease progression.

Methods: Patients were included based on diagnosis of dementia due to AD, positive amyloid and tau cerebrospinal fluid (CSF) biomarkers, and the availability of EEG recordings. Patients were categorized in groups of normal (N = 208) and abnormal (N = 336) EEG recordings based on visual assessment by experienced neurophysiologists. At baseline demographics, cognitive, MRI, and CSF measures were compared between groups. Cognitive data from follow-up visits were assessed by linear mixed-effects models (LMMs), and corrected for baseline value, sex, age, and educational level, to compare cognitive deterioration over time between groups.

Results: About 1 in 4.5 patients with AD dementia had a visually normal EEG and this group showed better overall cognitive performance compared to the abnormal group, where memory was the most prominent affected domain. The normal group showed less global and parietal but similar medial temporal atrophy. Follow-up data showed a slower deterioration on all tested cognitive domains in the normal EEG group.

Interpretation: Patients with dementia due to AD and visually normal EEG recordings showed a milder clinical presentation and had a milder disease progression compared to patients with an abnormal EEG. These results provide evidence of clinical and biological heterogeneity within AD dementia.
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http://dx.doi.org/10.1002/acn3.51339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108419PMC
May 2021

White matter microstructure disruption in early stage amyloid pathology.

Alzheimers Dement (Amst) 2021 1;13(1):e12124. Epub 2021 Apr 1.

Dept. of Biological Psychology VU University Amsterdam Amsterdam The Netherlands.

Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort.

Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF-AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract-level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden.

Results: Regression analyses showed a non-linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC.

Discussion: Early amyloid deposition is associated with changes in WM microstructure. The non-linear relationship might reflect multiple stages of axonal damage.
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http://dx.doi.org/10.1002/dad2.12124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015832PMC
April 2021

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.

Alzheimers Dement 2021 Jul 3;17(7):1189-1204. Epub 2021 Apr 3.

Department of Radiology and Nuclear Medicine, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Background: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.

Materials And Methods: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R  = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.

Results: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001).

Discussion: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
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http://dx.doi.org/10.1002/alz.12292DOI Listing
July 2021

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 Mar 31. Epub 2021 Mar 31.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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http://dx.doi.org/10.1002/alz.12322DOI Listing
March 2021

Alzheimer's disease.

Lancet 2021 Apr 2;397(10284):1577-1590. 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
April 2021

Visual assessment of [F]flutemetamol PET images can detect early amyloid pathology and grade its extent.

Eur J Nucl Med Mol Imaging 2021 07 22;48(7):2169-2182. Epub 2021 Feb 22.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Purpose: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR.

Methods: [F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density.

Results: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERAD-based classification (i.e., any region mCERAD > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aβ plaque was observed in all FP cases. Regional VR was also associated with regional plaque density.

Conclusion: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.
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http://dx.doi.org/10.1007/s00259-020-05174-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175297PMC
July 2021

Dutch Brain Research Registry for study participant recruitment: Design and first results.

Alzheimers Dement (N Y) 2021 14;7(1):e12132. Epub 2021 Feb 14.

Department of Neurology Alzheimer Center Amsterdam Amsterdam Neuroscience Amsterdam University Medical Center Amsterdam the Netherlands.

Introduction: The Dutch Brain Research Registry aims to facilitate online recruitment of participants for brain disease studies.

Methods: Registrants were primarily recruited through an online social media campaign. The registration process included a short questionnaire, which was subsequently used in the prescreening process to match participants to studies.

Results: In the first 18 months, 17,218 registrants signed up (58±11 years old, 78% female). Out of 34,696 study invitations that were sent, 36% were accepted by registrants, of which 50% to 84% were finally enrolled, resulting in 10,661 participants in 28 studies. Compared to non-participants, study participants were more often older, male, more highly educated, retired or unemployed, non-smoking, healthier, and more often had a family member with dementia.

Discussion: The Dutch Brain Research Registry facilitates effective matching of participants to brain disease studies. Participant factors related to study enrollment may reflect facilitators or barriers for participation, which is useful for improving recruitment strategies.
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http://dx.doi.org/10.1002/trc2.12132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882519PMC
February 2021

Onset of Preclinical Alzheimer Disease in Monozygotic Twins.

Ann Neurol 2021 05 4;89(5):987-1000. Epub 2021 Mar 4.

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;89:987-1000.
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http://dx.doi.org/10.1002/ana.26048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251701PMC
May 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

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

Alzheimers Res Ther 2021 02 5;13(1):35. Epub 2021 Feb 5.

Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

Background: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([F]flortaucipir PET), synaptic density (synaptic vesicle 2A [C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease.

Methods: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [F]flortaucipir PET, dynamic 60-min [C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [F]flortaucipir- and [C]UCB-J-specific binding (binding potential, BP) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [F]flortaucipir BP, [C]UCB-J BP and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models.

Results: Across subjects, higher regional [F]flortaucipir uptake was associated with lower [C]UCB-J uptake. Within subjects, the association between [C]UCB-J and [F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [F]flortaucipir and lower [C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe.

Conclusions: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.
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http://dx.doi.org/10.1186/s13195-021-00772-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866464PMC
February 2021

Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline.

JAMA Netw Open 2021 01 4;4(1):e2031654. Epub 2021 Jan 4.

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

Importance: Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging.

Objective: To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology.

Design, Setting, And Participants: This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020.

Exposures: Age, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques).

Main Outcomes And Measures: In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology.

Results: Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: β, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: β, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline.

Conclusions And Relevance: While we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.31654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811180PMC
January 2021