Publications by authors named "Wiesje M van der Flier"

459 Publications

Short Digital Spatial Memory Test Detects Impairment in Alzheimer's Disease and Mild Cognitive Impairment.

Brain Sci 2021 Oct 14;11(10). Epub 2021 Oct 14.

Helmholtz Institute, Experimental Psychology, Utrecht University, 3584 CS Utrecht, The Netherlands.

Background: Impairment in navigation abilities and object location memory are often seen in early-stage Alzheimer's Disease (AD), yet these constructs are not included in standard neuropsychological assessment. We investigated the differential ability of a short digital spatial memory test in mild AD dementia and mild cognitive impairment (MCI).

Methods: 21 patients with AD dementia (66.9 ± 6.9; 47% female), 22 patients with MCI (69.6 ± 8.3; 46% female) and 21 patients with subjective cognitive decline (SCD) (62.2 ± 8.9; 48% female) from the Amsterdam Dementia Cohort performed the Object Location Memory Test (OLMT), consisting of a visual perception and memory trial, and the Virtual Tübingen (VT) test, consisting of a scene recognition, route continuation, route ordering and distance comparison task. The correlations with other cognitive domains were examined.

Results: Patients with mild AD dementia (Z: -2.51 ± 1.15) and MCI (Z: -1.81 ± 0.92) performed worse than participants with SCD (Z: 0.0 ± 1.0) on the OLMT. Scene recognition and route continuation were equally impaired in patients with AD dementia (Z: -1.14 ± 0.73; Z: -1.44 ± 1.13) and MCI (Z: -1.37 ± 1.25; Z: -1.21 ± 1.07). Route ordering was only impaired in patients with MCI (Z: -0.82 ± 0.78). Weak to moderate correlations were found between route continuation and memory (r(64) = 0.40, < 0.01), and between route ordering and attention (r(64) = 0.33, < 0.01), but not for the OLMT.

Conclusion: A short digital spatial memory test battery was able to detect object location memory and navigation impairment in patients with mild AD dementia and MCI, highlighting the value of incorporating such a test battery in standard neuropsychological assessment.
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http://dx.doi.org/10.3390/brainsci11101350DOI Listing
October 2021

Dementia risk communication. A user manual for Brain Health Services-part 3 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):170. Epub 2021 Oct 11.

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

Growing evidence suggests dementia incidence can be reduced through prevention programs targeting risk factors. To accelerate the implementation of such prevention programs, a new generation of brain health services (BHS) is envisioned, involving risk profiling, risk communication, risk reduction, and cognitive enhancement. The purpose of risk communication is to enable individuals at risk to make informed decisions and take action to protect themselves and is thus a crucial step in tailored prevention strategies of the dementia incidence. However, communicating about dementia risk is complex and challenging.In this paper, we provide an overview of (i) perspectives on communicating dementia risk from an ethical, clinical, and societal viewpoint; (ii) insights gained from memory clinical practice; (iii) available evidence on the impact of disclosing APOE and Alzheimer's disease biomarker test results gathered from clinical trials and observational studies; (iv) the value of established registries in light of BHS; and (v) practical recommendations regarding effective strategies for communicating about dementia risk.In addition, we identify challenges, i.e., the current lack of evidence on what to tell on an individual level-the actual risk-and on how to optimally communicate about dementia risk, especially concerning worried yet cognitively unimpaired individuals. Ideally, dementia risk communication strategies should maximize the desired impact of risk information on individuals' understanding of their health/disease status and risk perception and minimize potential harms. More research is thus warranted on the impact of dementia risk communication, to (1) evaluate the merits of different approaches to risk communication on outcomes in the cognitive, affective and behavioral domains, (2) develop an evidence-based, harmonized dementia risk communication protocol, and (3) develop e-tools to support and promote adherence to this protocol in BHSs.Based on the research reviewed, we recommend that dementia risk communication should be precise; include the use of absolute risks, visual displays, and time frames; based on a process of shared decision-making; and address the inherent uncertainty that comes with any probability.
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http://dx.doi.org/10.1186/s13195-021-00840-5DOI Listing
October 2021

Brain Health Services: organization, structure, and challenges for implementation. A user manual for Brain Health Services-part 1 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):168. Epub 2021 Oct 11.

Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.

Dementia has a devastating impact on the quality of life of patients and families and comes with a huge cost to society. Dementia prevention is considered a public health priority by the World Health Organization. Delaying the onset of dementia by treating associated risk factors will bring huge individual and societal benefit. Empirical evidence suggests that, in higher-income countries, dementia incidence is decreasing as a result of healthier lifestyles. This observation supports the notion that preventing dementia is possible and that a certain degree of prevention is already in action. Further reduction of dementia incidence through deliberate prevention plans is needed to counteract its growing prevalence due to increasing life expectancy.An increasing number of individuals with normal cognitive performance seek help in the current memory clinics asking an evaluation of their dementia risk, preventive interventions, or interventions to ameliorate their cognitive performance. Consistent evidence suggests that some of these individuals are indeed at increased risk of dementia. This new health demand asks for a shift of target population, from patients with cognitive impairment to worried but cognitively unimpaired individuals. However, current memory clinics do not have the programs and protocols in place to deal with this new population.We envision the development of new services, henceforth called Brain Health Services, devoted to respond to demands from cognitively unimpaired individuals concerned about their risk of dementia. The missions of Brain Health Services will be (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction, and (iv) cognitive enhancement. In this paper, we present the organizational and structural challenges associated with the set-up of Brain Health Services.
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http://dx.doi.org/10.1186/s13195-021-00827-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507194PMC
October 2021

BDNF-Met polymorphism and amyloid-beta in relation to cognitive decline in cognitively normal elderly: the SCIENCe project.

Neurobiol Aging 2021 Sep 4;108:146-154. Epub 2021 Sep 4.

Alzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Department of Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

Brain-derived neurotrophic factor (BNDF) plays a role in synapse integrity. We investigated in 398 cognitively normal adults (60±8years, 41% female, MMSE=28±1) the joint association of the Val66Met polymorphism of the BDNF gene (Met+/-) and plasma BDNF levels and abnormal cerebrospinal fluid (CSF) amyloid-beta status (A+/-) with cognitive decline and dementia risk. Age-, sex- and education-adjusted linear mixed models showed that compared to Met-A-, Met+A+ showed steeper decline on tests of global cognition, memory, language, attention and executive functioning, while Met-A+ showed steeper decline on a smaller number of tests. There were no associations between Met+A- and cognitive decline. Cox models showed that compared to Met-A-, Met+A+ participants were at increased risk of dementia (HR=8.8, 95%CI: 2.8-27.9), as were Met-A+ participants (HR=6.5, 95%CI: 2.2-19.5). Lower plasma BDNF was associated with an increased risk of progression to dementia in the A+ participants. Our results imply that Met-carriage on top of amyloid-beta pathology might increase rate of cognitive decline to dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.08.018DOI Listing
September 2021

Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.

Neurology 2021 06;96(22):e2673-e2684

From the Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC (R.J.J., S.A.M.S., W.M.V.d.F., P.S., P.J.V., B.M.T.), and Clinical Developmental Psychology & Clinical Neuropsychology (S.A.M.S.), VU University; Alzheimer Center Limburg, School for Mental Health and Neuroscience (P.J.V.), Maastricht University, the Netherlands; and Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics (P.J.V.), Karolinska Institutet, Stockholm, Sweden.

Objective: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.

Methods: Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, ε4 status, CSF total tau levels) on the variability in effect sizes.

Results: Individual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).

Conclusions: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.
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http://dx.doi.org/10.1212/WNL.0000000000012022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205463PMC
June 2021

The Cognitive Online Self-Test Amsterdam (COST-A): Establishing norm scores in a community-dwelling population.

Alzheimers Dement (Amst) 2021 14;13(1):e12234. Epub 2021 Sep 14.

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

Background: Heightened public awareness about Alzheimer's disease and dementia increases the need for at-home cognitive self-testing. We offered Cognitive Online Self-Test Amsterdam (COST-A) to independent groups of cognitively normal adults and investigated the robustness of a norm-score formula and cutoff.

Methods: Three thousand eighty-eight participants (mean age ± standard deviation = 61 ± 12 years, 70% female) completed COST-A and evaluated it. Demographically adjusted norm scores were the difference between expected COST-A scores, based on age, gender, and education, and actual scores. We applied the resulting norm-score formula to two independent cohorts.

Results: Participants evaluated COST-A to be of adequate difficulty and duration. Our norm-score formula was shown to be robust: ≈8% of participants in two cognitively normal cohorts had abnormal scores. A cutoff of -1.5 standard deviations proved optimal for distinguishing normal from impaired cognition.

Conclusion: With robust norm scores, COST-A is a promising new tool for research and clinical practice, providing low cost and minimally invasive remote assessment of cognitive functioning.
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http://dx.doi.org/10.1002/dad2.12234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438682PMC
September 2021

Risk of dementia in ε4 carriers is mitigated by a polygenic risk score.

Alzheimers Dement (Amst) 2021 14;13(1):e12229. Epub 2021 Sep 14.

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

Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia.

Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The was not included in the PRS and was analyzed separately.

Results: The PRS and ε4 were associated with amyloid-positive ATN profiles, and ε4 additionally with isolated increased tau (A-T+N-). A high PRS and ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers.

Discussion: Genetic variants beyond are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.
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http://dx.doi.org/10.1002/dad2.12229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438688PMC
September 2021

Sex and Cardiovascular Function in Relation to Vascular Brain Injury in Patients with Cognitive Complaints.

J Alzheimers Dis 2021 Sep 10. Epub 2021 Sep 10.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function.

Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function.

Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker).

Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05).

Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.
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http://dx.doi.org/10.3233/JAD-210360DOI Listing
September 2021

Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions.

Transl Psychiatry 2021 09 2;11(1):451. Epub 2021 Sep 2.

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

Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10, rs117204439: OR = 4.9, P = 6.0 × 10) and replication analysis (P < 1.1 × 10). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 GC repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 GC. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.
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http://dx.doi.org/10.1038/s41398-021-01577-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413318PMC
September 2021

Identifying relevant outcomes in the progression of Alzheimer's disease; what do patients and care partners want to know about prognosis?

Alzheimers Dement (N Y) 2021 20;7(1):e12189. Epub 2021 Aug 20.

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

Background: Prognostic studies in the context of Alzheimer's disease (AD) mainly predicted time to dementia. However, it is questionable whether onset of dementia is the most relevant outcome along the AD disease trajectory from the perspective of patients and their care partners. Therefore, we aimed to identify the most relevant outcomes from the viewpoint of patients and care partners.

Methods: We used a two-step, mixed-methods approach. As a first step we conducted four focus groups in the Netherlands to elicit a comprehensive list of outcomes considered important by patients ( = 12) and care partners ( = 14) in the prognosis of AD. The focus groups resulted in a list of 59 items, divided into five categories. Next, in an online European survey, we asked participants ( = 232; 99 patients, 133 care partners) to rate the importance of all 59 items (5-point Likert scale). As participants were likely to rate a large number of outcomes as "important" (4) or "very important" (5), we subsequently asked them to select the three items they considered most important.

Results: The top-10 lists of items most frequently mentioned as "most important" by patients and care partners were merged into one core outcome list, comprising 13 items. Both patients and care partners selected outcomes from the category "cognition" most often, followed by items in the categories "functioning and dependency" and "physical health." No items from the category "behavior and neuropsychiatry" and "social environment" ended up in our core list of relevant outcomes.

Conclusion: We identified a core list of outcomes relevant to patients and care partner, and found that prognostic information related to cognitive decline, dependency, and physical health are considered most relevant by both patients and their care partners.
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http://dx.doi.org/10.1002/trc2.12189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377775PMC
August 2021

A Cystatin C Cleavage ELISA Assay as a Quality Control Tool for Determining Sub-Optimal Storage Conditions of Cerebrospinal Fluid Samples in Alzheimer's Disease Research.

J Alzheimers Dis 2021 ;83(3):1367-1377

Department of Clinical Chemistry, Neurochemistry Laboratory, Amsterdam Neuroscience, Amsterdam University Medical Center, VU University, Amsterdam, the Netherlands.

Background: An N-terminal octapeptide cleavage of the cystatin C protein was discovered by mass spectrometry when cerebrospinal fluid (CSF) was stored at -20°C for 3 months, which did not occur when CSF was stored at -80°C.

Objective: The aim was to develop an immunoassay as quality assessment tool to detect this -20°C cleavage of cystatin C in CSF and support Alzheimer's disease research.

Methods: A specific monoclonal antibody and a double indirect sandwich ELISA were developed: one assay quantifies the octapeptide uncleaved protein specifically and the other quantifies the total cystatin C present in the biological fluid (both cleaved and uncleaved forms). The ratio of these concentrations was calculated to assess the extent of cleavage of cystatin C. The novel ELISA was validated and applied in a short-term (up to 4 weeks) and mid-term (up to one year) stability study of CSF stored at 4°C, -20°C, -80°C, and liquid nitrogen. Impact of freeze-thaw cycles, adsorption, and protease inhibitors were tested.

Results: The ratio of truncated protein was modified following -20°C storage and seemed to reach a plateau after 6 months. The ratio was impacted neither by freeze-thaw cycles nor adsorption. The -20°C specific cleavage was found to be protease related.

Conclusion: Using this novel double indirect sandwich ELISA, absolute levels of the total and uncleaved cystatin C and the ratio of truncated cystatin C can be measured. This assay is an easily applicable tool which can be used to confirm that CSF biospecimen are fit-for-purpose for Alzheimer's disease research.
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http://dx.doi.org/10.3233/JAD-210741DOI Listing
January 2021

Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations.

Neurology 2021 Sep 19;97(13):e1276-e1287. Epub 2021 Aug 19.

From the Departments of Neurology (W.S.E., E.v.d.B., J.M.P.), Biostatistics (S.J.B.), and Psychiatry (M.C.), Erasmus MC, University Medical Center, Rotterdam; Department of Neurology, Alzheimer Center Amsterdam (E.H.S., A.E.L., Y.A.L.P., P.S., W.M.v.d.F., R.O.), Neurochemistry Laboratory, Department of Clinical Chemistry (C.E.T.), and Department of Radiology and Nuclear Medicine (B.N.M.v.B.), Amsterdam University Medical Centers, the Netherlands; and Clinical Memory Research Unit (R.O.), Lund University, Malmö, Sweden.

Background And Objectives: To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid-positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.

Methods: In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up).

Results: We included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = -0.18 to -0.11, false discovery rate [FDR]-adjusted < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = -0.32 to 0.36, all FDR-adjusted > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = -0.13 to 0.44, all FDR-adjusted > 0.05).

Discussion: NPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.
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http://dx.doi.org/10.1212/WNL.0000000000012598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480405PMC
September 2021

Comparing a Single Clinician Versus a Multidisciplinary Consensus Conference Approach for Dementia Diagnostics.

J Alzheimers Dis 2021 ;83(2):741-751

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Evidence-based recommendations on the optimal evaluation approach for dementia diagnostics are limited. This impedes a harmonized workup across clinics and nations.

Objective: To evaluate the diagnostic performance of a multidisciplinary consensus conference compared to a single clinician approach.

Methods: In this prospective study, we enrolled 457 patients with suspected cognitive decline, from two European memory clinics. A diagnostic evaluation was performed at baseline independently in two ways: 1) by a single clinician and 2) at a multidisciplinary consensus conference. A syndrome diagnosis and an etiological diagnosis was made. The confidence in the diagnosis was recorded using a visual analogue scale. An expert panel re-evaluation diagnosis served as reference for the baseline syndrome diagnosis and a 12-24-month follow-up diagnosis for the etiological diagnosis.

Results: 439 patients completed the study. We observed 12.5%discrepancy (k = 0.81) comparing the baseline syndrome diagnoses of the single clinician to the consensus conference, and 22.3%discrepancy (k = 0.68) for the baseline etiological diagnosis. The accuracy of the baseline etiological diagnosis was significantly higher at the consensus conference and was driven mainly by increased accuracy in the MCI group. Confidence in the etiological diagnosis at baseline was significantly higher at the consensus conference (p < 0.005), especially for the frontotemporal dementia diagnosis.

Conclusion: The multidisciplinary consensus conference performed better on diagnostic accuracy of disease etiology and increased clinicians' confidence. This highlights the importance of a multidisciplinary diagnostic evaluation approach for dementia diagnostics, especially when evaluating patients in the MCI stage.
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http://dx.doi.org/10.3233/JAD-210278DOI Listing
January 2021

Serum and cerebrospinal fluid Neutrophil gelatinase-associated lipocalin (NGAL) levels as biomarkers for the conversion from mild cognitive impairment to Alzheimer's disease dementia.

Neurobiol Aging 2021 Jul 10;107:1-10. Epub 2021 Jul 10.

Department of Neurology and Alzheimer Research Centre, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; Laboratory of Neurochemistry and Behavior, Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n=82), mild cognitive impairment (MCI) (n=98) and AD dementia (n=88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta, total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.07.001DOI Listing
July 2021

Plasma amyloid-β oligomerization assay as a pre-screening test for amyloid status.

Alzheimers Res Ther 2021 07 26;13(1):133. Epub 2021 Jul 26.

Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.

Objective: We assessed the performance of plasma amyloid oligomerization tendency (OAβ) as a marker for abnormal amyloid status. Additionally, we examined long-term storage effects on plasma OAβ.

Methods: We included 399 subjects regardless of clinical diagnosis from the Amsterdam Dementia Cohort and European Medical Information Framework for AD project (age, 63.8 ± 6.6; 44% female). Amyloid status was determined by visual read on positron emission tomography (PET; n = 206). Plasma OAβ was measured using the multimer detection system (MDS). Long-term storage effects on MDS-OAβ were assessed using general linear models. Associations between plasma MDS-OAβ and Aβ-PET status were assessed using logistic regression and receiver operating characteristics analyses. Correlations between plasma MDS-OAβ and CSF biomarker levels were evaluated using Pearson correlation analyses.

Results: MDS-OAβ was higher in individuals with abnormal amyloid, and it identified abnormal Aβ-PET with an area under the curve (AUC) of 0.74 (95% CI, 0.67-0.81), especially in samples with a storage duration < 4 years. Combining APOEe4 and age with plasma MDS-OAβ revealed an AUC of 81% for abnormal amyloid PET status (95% CI, 74-87%). Plasma MDS-OAβ correlated negatively with MMSE (r = - 0.29, p < .01) and CSF Aβ42 (r = - 0.20, p < 0.05) and positively with CSF Tau (r = 0.20, p = 0.01).

Conclusions: Plasma MDS-OAβ combined with APOEe4 and age accurately identifies brain amyloidosis in a large Aβ-confirmed population. Using plasma MDS-OAβ as a screener reduced the costs and number of PET scans needed to screen for amyloidosis, which is relevant for clinical trials. Additionally, plasma MDS-OAβ levels appeared affected by long-term storage duration, which could be of interest for others measuring plasma Aβ biomarkers.
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http://dx.doi.org/10.1186/s13195-021-00873-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311929PMC
July 2021

Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies.

J Alzheimers Dis 2021 ;83(1):269-279

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

Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.

Objective: We tested if genetic variants in part explain the heterogeneity in DLB.

Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.

Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.

Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.
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http://dx.doi.org/10.3233/JAD-210365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461715PMC
January 2021

Global Prevalence of Young-Onset Dementia: A Systematic Review and Meta-analysis.

JAMA Neurol 2021 Sep;78(9):1080-1090

Western Australian Centre for Health and Aging, University of Western Australia, Perth, Australia.

Importance: Reliable prevalence estimates are lacking for young-onset dementia (YOD), in which symptoms of dementia start before the age of 65 years. Such estimates are needed for policy makers to organize appropriate health care.

Objective: To determine the global prevalence of YOD.

Data Sources: The PubMed, Embase, CINAHL, and PsycInfo databases were systematically searched for population-based studies on the prevalence of YOD published between January 1, 1990, and March 31, 2020.

Study Selection: Studies containing data on the prevalence of dementia in individuals younger than 65 years were screened by 2 researchers for inclusion in a systematic review and meta-analysis.

Data Extraction And Synthesis: Prevalence estimates on 5-year age bands, from 30 to 34 years to 60 to 64 years, were extracted. Random-effects meta-analyses were conducted to pool prevalence estimates. Results were age standardized for the World Standard Population. Heterogeneity was assessed by subgroup analyses for sex, dementia subtype, study design, and economic status based on the World Bank classification and by meta-regression.

Main Outcomes And Measures: Prevalence estimates of YOD for 5-year age bands.

Results: A total of 95 unique studies were included in this systematic review, of which 74 with 2 760 379 unique patients were also included in 5-year age band meta-analyses. Studies were mostly conducted in Europe and in older groups in Asia, North America, and Oceania. Age-standardized prevalence estimates increased from 1.1 per 100 000 population in the group aged 30 to 34 years to 77.4 per 100 000 population in the group aged 60 to 64 years. This gives an overall global age-standardized prevalence of 119.0 per 100 000 population in the age range of 30 to 64 years, corresponding to 3.9 million people aged 30 to 64 years living with YOD in the world. Subgroup analyses showed prevalence between men and women to be similar (crude estimates for men, 216.5 per 100 000 population; for women, 293.1 per 100 000 population), whereas prevalence was lower in high-income countries (crude estimate, 663.9 per 100 000 population) compared with upper-middle-income (crude estimate, 1873.6 per 100 000 population) and lower-middle-income (crude estimate, 764.2 per 100 000 population) countries. Meta-regression showed that age range (P < .001), sample size (P < .001), and study methodology (P = .02) significantly influenced heterogeneity between studies.

Conclusions And Relevance: This systematic review and meta-analysis found an age-standardized prevalence of YOD of 119.0 per 100 000 population, although estimates of the prevalence in low-income countries and younger age ranges remain scarce. These results should help policy makers organize sufficient health care for this subgroup of individuals with dementia.

Study Registration: PROSPERO CRD42019119288.
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http://dx.doi.org/10.1001/jamaneurol.2021.2161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290331PMC
September 2021

Measuring Resilience and Resistance in Aging and Alzheimer Disease Using Residual Methods: A Systematic Review and Meta-analysis.

Neurology 2021 09 15;97(10):474-488. Epub 2021 Jul 15.

From the Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience (D.I.B., A.C.v.L., C.G., W.M.v.d.F., R.O.), and Department of Radiology and Nuclear Medicine (F.B.), Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands; Institutes of Neurology and Healthcare Engineering (F.B.), University College London, UK; Department of Epidemiology and Biostatistics (W.M.v.d.F.), VU University Medical Center, Amsterdam, the Netherlands; and Clinical Memory Research Unit (R.O.), Lund University, Sweden.

Background And Objective: There is a lack of consensus on how to optimally define and measure resistance and resilience in brain and cognitive aging. Residual methods use residuals from regression analysis to quantify the capacity to avoid (resistance) or cope (resilience) "better or worse than expected" given a certain level of risk or cerebral damage. We reviewed the rapidly growing literature on residual methods in the context of aging and Alzheimer disease (AD) and performed meta-analyses to investigate associations of residual method-based resilience and resistance measures with longitudinal cognitive and clinical outcomes.

Methods: A systematic literature search of PubMed and Web of Science databases (consulted until March 2020) and subsequent screening led to 54 studies fulfilling eligibility criteria, including 10 studies suitable for the meta-analyses.

Results: We identified articles using residual methods aimed at quantifying resistance (n = 33), cognitive resilience (n = 23), and brain resilience (n = 2). Critical examination of the literature revealed that there is considerable methodologic variability in how the residual measures were derived and validated. Despite methodologic differences across studies, meta-analytic assessments showed significant associations of levels of resistance (hazard ratio [HR] [95% confidence interval (CI)] 1.12 [1.07-1.17]; < 0.0001) and levels of resilience (HR [95% CI] 0.46 [0.32-0.68]; < 0.001) with risk of progression to dementia/AD. Resilience was also associated with rate of cognitive decline (β [95% CI] 0.05 [0.01-0.08]; < 0.01).

Discussion: This review and meta-analysis supports the usefulness of residual methods as appropriate measures of resilience and resistance, as they capture clinically meaningful information in aging and AD. More rigorous methodologic standardization is needed to increase comparability across studies and, ultimately, application in clinical practice.
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http://dx.doi.org/10.1212/WNL.0000000000012499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448552PMC
September 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

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

Neurology 2021 09 1;97(10):e1017-e1030. Epub 2021 Jul 1.

From the Department of Radiology & Nuclear Medicine (E.E.W., S.C.J.V., D.V., E.W., H.T., T.T., R.B., M.Y., F.B., A.D.W., B.N.M.v.B.) and Alzheimer Center Amsterdam, Department of Neurology (E.E.W., C.G., W.M.v.d.F., Y.A.L.P., P.S., R.O.), Amsterdam Neuroscience, and Department of Epidemiology and Biostatistics (W.M.v.d.F.), Vrije Universiteit Amsterdam, Amsterdam UMC; Department of Neurology, Alzheimer Center (J.M.P., E.L.v.d.E., L.A.A.G., J.C.v.S., H.S.), and Department of Radiology & Nuclear Medicine (D.M.E.v.A., D.A.K., M.S.), Erasmus MC University Medical Center, Rotterdam; Department of Pathology (A.J.M.R.), Amsterdam Neuroscience, Amsterdam UMC, location VUmc, the Netherlands; Institutes of Neurology & Healthcare Engineering (F.B.), UCL, London, UK; and Clinical Memory Research Unit (R.O.), Lund University, Sweden.

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 9 (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 patients with Alzheimer disease.

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 carrier and 1 of the 3 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 neuropathologic 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448551PMC
September 2021

Diagnostic Value of the CSF α-Synuclein Real-Time Quaking-Induced Conversion Assay at the Prodromal MCI Stage of Dementia With Lewy Bodies.

Neurology 2021 08 1;97(9):e930-e940. Epub 2021 Jul 1.

From IRCCS (M.R., S.B., C.Q., A.M., M.S.-M., C.Z., S.C., P.P.), Istituto delle Scienze Neurologiche di Bologna; Department of Experimental, Diagnostic and Specialty Medicine (S.B., P.P.) and Department of Biomedical and Neuromotor Sciences (L.S., S.C.), University of Bologna, Italy; Neurochemistry Laboratory, Department of Clinical Chemistry (C.E.T.), and Department of Neurology (M.v.d.B., W.M.V.d.F., A.W.L.), Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands; and LPVD (B.C.), Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT.

Objective: To investigate whether the CSF α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment (MCI) due to probable Lewy body (LB) disease.

Methods: We applied α-syn RT-QuIC to 289 CSF samples obtained from 2 independent cohorts, including 81 patients with probable MCI-LB (age 70.7 ± 6.6 years, 13.6% female, Mini-Mental State Examination [MMSE] score 26.1 ± 2.4), 120 with probable MCI due to Alzheimer disease (AD) (age 68.6 ± 7.4 years, 45.8% female, MMSE score 25.5 ± 2.8), and 30 with unspecified MCI (age 65.4 ± 9.3 years, 30.0% female, MMSE score 27.0 ± 3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathologic examination were used as controls.

Results: RT-QuIC identified patients with MCI-LB against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy and showed 98% specificity in neuropathologic controls. The accuracy of the test for MCI-LB was consistent between the 2 cohorts (97.3% vs 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed 1 core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB copathology.

Conclusions: These findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB.

Classification Of Evidence: This study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI-LB.
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http://dx.doi.org/10.1212/WNL.0000000000012438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408510PMC
August 2021

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

Neuroimage Clin 2021 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
September 2021

Contribution of Gut Microbiota to Immunological Changes in Alzheimer's Disease.

Front Immunol 2021 31;12:683068. Epub 2021 May 31.

Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, Netherlands.

Emerging evidence suggests that both central and peripheral immunological processes play an important role in the pathogenesis of Alzheimer's disease (AD), but regulatory mechanisms remain unknown. The gut microbiota and its key metabolites are known to affect neuroinflammation by modulating the activity of peripheral and brain-resident immune cells, yet an overview on how the gut microbiota contribute to immunological alterations in AD is lacking. In this review, we discuss current literature on microbiota composition in AD patients and relevant animal models. Next, we highlight how microbiota and their metabolites may contribute to peripheral and central immunological changes in AD. Finally, we offer a future perspective on the translation of these findings into clinical practice by targeting gut microbiota to modulate inflammation in AD. Since we find that gut microbiota alterations in AD can induce peripheral and central immunological changes the release of microbial metabolites, we propose that modulating their composition may alter ongoing inflammation and could therefore be a promising future strategy to fight progression of AD.
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http://dx.doi.org/10.3389/fimmu.2021.683068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200826PMC
May 2021

Cross-cohort generalizability of deep and conventional machine learning for MRI-based diagnosis and prediction of Alzheimer's disease.

Neuroimage Clin 2021 4;31:102712. Epub 2021 Jun 4.

Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924-0.955) and CNN (0.933; 95%CI: 0.918-0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p<0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855-0.932) and CNN (0.876; 95%CI: 0.836-0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p=0.01). Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice.
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http://dx.doi.org/10.1016/j.nicl.2021.102712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203808PMC
September 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

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293634PMC
September 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

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
July 2021

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

Alzheimers Dement 2021 07 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359976PMC
July 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354300PMC
April 2021
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