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Article ; Online: Distinct disease mechanisms may underlie cognitive decline related to hearing loss in different age groups.

van 't Hooft, Jochum J / Pelkmans, Wiesje / Tomassen, Jori / Smits, Cas / Legdeur, Nienke / den Braber, Anouk / Barkhof, Frederik / van Berckel, Bart / Yaqub, Maqsood / Scheltens, Philip / Pijnenburg, Yolande Al / Visser, Pieter Jelle / Tijms, Betty M

Journal of neurology, neurosurgery, and psychiatry

2023 Volume 94, Issue 4, Page(s) 314–320

Abstract: Background: Hearing loss in older adults is associated with increased dementia risk. Underlying mechanisms that connect hearing loss with dementia remain largely unclear.: Methods: We studied the association of hearing loss and biomarkers for ... ...

Abstract	Background: Hearing loss in older adults is associated with increased dementia risk. Underlying mechanisms that connect hearing loss with dementia remain largely unclear. Methods: We studied the association of hearing loss and biomarkers for dementia risk in two age groups with normal cognition: 65 participants from the European Medical Information Framework (EMIF)-Alzheimer's disease (AD) 90+ study (oldest-old; mean age 92.7 years, 56.9% female) and 60 participants from the EMIF-AD PreclinAD study (younger-old; mean age 74.4, 43.3% female). Hearing function was tested by the 'digits-in-noise test' and cognition by repeated neuropsychological evaluation. Regressions and generalised estimating equations were used to test the association of hearing function and PET-derived amyloid burden, and linear mixed models were used to test the association of hearing function and cognitive decline. In the oldest-old group, mediation analyses were performed to study whether cognitive decline is mediated through regional brain atrophy. Results: In oldest-old individuals, hearing function was not associated with amyloid pathology (p=0.7), whereas in the younger-old individuals hearing loss was associated with higher amyloid burden (p=0.0034). In oldest-old individuals, poorer hearing was associated with a steeper decline in memory, global cognition and language, and in the younger-old with steeper decline in language only. The hippocampus and nucleus accumbens mediated the effects of hearing loss on memory and global cognition in the oldest-old individuals. Conclusions: Hearing loss was associated with amyloid binding in younger-old individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.
MeSH term(s)	Humans ; Female ; Aged ; Aged, 80 and over ; Male ; Alzheimer Disease/pathology ; Cognitive Dysfunction/pathology ; Cognition ; Neuropsychological Tests ; Hearing Loss/complications ; Hearing Loss/epidemiology ; Amyloid beta-Peptides/metabolism
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2023-01-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3087-9
ISSN	1468-330X ; 0022-3050
ISSN (online)	1468-330X
ISSN	0022-3050
DOI	10.1136/jnnp-2022-329726
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Article ; Online: Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles.

Nature aging

2024 Volume 4, Issue 1, Page(s) 33–47

Abstract: Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, ...

Abstract	Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Proteomics
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Journal Article
ISSN	2662-8465
ISSN (online)	2662-8465
DOI	10.1038/s43587-023-00550-7
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Article ; Online: Plasma biomarkers predict amyloid pathology in cognitively normal monozygotic twins after 10 years.

den Braber, Anouk / Verberk, Inge M W / Tomassen, Jori / den Dulk, Ben / Stoops, Erik / Dage, Jeffrey L / Collij, Lyduine E / Barkhof, Frederik / Willemsen, Gonneke / Nivard, Michel G / van Berckel, Bart N M / Scheltens, Philip / Visser, Pieter Jelle / de Geus, Eco J C / Teunissen, Charlotte E

Brain communications

2023 Volume 5, Issue 1, Page(s) fcad024

Abstract: Blood-based biomarkers could prove useful to predict Alzheimer's disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics and the contribution of confounding to ...

Abstract	Blood-based biomarkers could prove useful to predict Alzheimer's disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics and the contribution of confounding to their association with Alzheimer's disease pathology. Here we assess the value of plasma amyloid-β
Language	English
Publishing date	2023-02-04
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcad024
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Article: Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes.

Reus, Lianne M / Boltz, Toni / Francia, Marcelo / Bot, Merel / Ramesh, Naren / Koromina, Maria / Pijnenburg, Yolande A L / den Braber, Anouk / van der Flier, Wiesje M / Visser, Pieter Jelle / van der Lee, Sven J / Tijms, Betty M / Teunissen, Charlotte E / Loohuis, Loes Olde / Ophoff, Roel A

bioRxiv : the preprint server for biology

2023

Abstract: Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological ... ...

Abstract	Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanisms
Language	English
Publishing date	2023-09-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.26.559021
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Article ; Online: The heritability of vocal tract structures estimated from structural MRI in a large cohort of Dutch twins.

Dediu, Dan / Jennings, Emily M / Van't Ent, Dennis / Moisik, Scott R / Di Pisa, Grazia / Schulze, Janna / de Geus, Eco J C / den Braber, Anouk / Dolan, Conor V / Boomsma, Dorret I

Human genetics

2022 Volume 141, Issue 12, Page(s) 1905–1923

Abstract: While language is expressed in multiple modalities, including sign, writing, or whistles, speech is arguably the most common. The human vocal tract is capable of producing the bewildering diversity of the 7000 or so currently spoken languages, but ... ...

Abstract	While language is expressed in multiple modalities, including sign, writing, or whistles, speech is arguably the most common. The human vocal tract is capable of producing the bewildering diversity of the 7000 or so currently spoken languages, but relatively little is known about its genetic bases, especially in what concerns normal variation. Here, we capitalize on five cohorts totaling 632 Dutch twins with structural magnetic resonance imaging (MRI) data. Two raters placed clearly defined (semi)landmarks on each MRI scan, from which we derived 146 measures capturing the dimensions and shape of various vocal tract structures, but also aspects of the head and face. We used Genetic Covariance Structure Modeling to estimate the additive genetic, common environmental or non-additive genetic, and unique environmental components, while controlling for various confounds and for any systematic differences between the two raters. We found high heritability, h
MeSH term(s)	Humans ; Language ; Magnetic Resonance Imaging ; Speech ; Phonetics ; Cohort Studies
Language	English
Publishing date	2022-07-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-022-02469-2
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Article ; Online: Abnormal cerebrospinal fluid levels of amyloid and tau are associated with cognitive decline over time in cognitively normal older adults: A monozygotic twin study.

Tomassen, Jori / den Braber, Anouk / van der Landen, Sophie M / Konijnenberg, Elles / Teunissen, Charlotte E / Vermunt, Lisa / de Geus, Eco J C / Boomsma, Dorret I / Scheltens, Philip / Tijms, Betty M / Visser, Pieter Jelle

Alzheimer's & dementia (New York, N. Y.)

2022 Volume 8, Issue 1, Page(s) e12346

Abstract: Introduction: The contribution of genetic and environmental factors to the relation between cerebrospinal fluid (CSF) biomarkers and cognitive decline in preclinical Alzheimer's disease remains unclear. We studied this in initially cognitively normal ... ...

Abstract	Introduction: The contribution of genetic and environmental factors to the relation between cerebrospinal fluid (CSF) biomarkers and cognitive decline in preclinical Alzheimer's disease remains unclear. We studied this in initially cognitively normal monozygotic twins. Methods: We included 122 cognitively normal monozygotic twins (51 pairs) with a follow-up of 4.3 ± 0.4 years. We first tested associations of baseline CSF Aβ1-42/1-40 ratio, total tau (t-tau), and 181-phosphorylated-tau (p-tau) status with subsequent cognitive decline using linear mixed models, and then performed twin specific analyses. Results: Baseline abnormal amyloid-β and tau CSF markers predicted steeper decline on memory ( Discussion: These results suggest that memory and language decline are early features of AD that are in part determined by the same genetic factors that influence amyloid-β and tau regulation.
Language	English
Publishing date	2022-09-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12346
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Article ; Online: The heritability of vocal tract structures estimated from structural MRI in a large cohort of Dutch twins

Dediu, Dan / Jennings, Emily M. / van’t Ent, Dennis / Moisik, Scott R. / Di Pisa, Grazia / Schulze, Janna / de Geus, Eco J. C. / den Braber, Anouk / Dolan, Conor V. / Boomsma, Dorret I.

Hum Genet. 2022 Dec., v. 141, no. 12, p. 1905-1923

2022 , Page(s) 1905–1923

Abstract	While language is expressed in multiple modalities, including sign, writing, or whistles, speech is arguably the most common. The human vocal tract is capable of producing the bewildering diversity of the 7000 or so currently spoken languages, but relatively little is known about its genetic bases, especially in what concerns normal variation. Here, we capitalize on five cohorts totaling 632 Dutch twins with structural magnetic resonance imaging (MRI) data. Two raters placed clearly defined (semi)landmarks on each MRI scan, from which we derived 146 measures capturing the dimensions and shape of various vocal tract structures, but also aspects of the head and face. We used Genetic Covariance Structure Modeling to estimate the additive genetic, common environmental or non-additive genetic, and unique environmental components, while controlling for various confounds and for any systematic differences between the two raters. We found high heritability, h², for aspects of the skull and face, the mandible, the anteroposterior (horizontal) dimension of the vocal tract, and the position of the hyoid bone. These findings extend the existing literature, and open new perspectives for understanding the complex interplay between genetics, environment, and culture that shape our vocal tracts, and which may help explain cross-linguistic differences in phonetics and phonology.
Keywords	face ; genetic covariance ; heritability ; humans ; magnetism ; skull ; speech
Language	English
Dates of publication	2022-12
Size	p. 1905-1923
Publishing place	Springer Berlin Heidelberg
Document type	Article ; Online
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-022-02469-2
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Article ; Online: Genetically identical twin-pair difference models support the amyloid cascade hypothesis.

Brain : a journal of neurology

2023 Volume 146, Issue 9, Page(s) 3735–3746

Abstract: The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot ... ...

Abstract	The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = -0.37, P = 0.03) and memory functioning (β = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.
MeSH term(s)	Humans ; Twins, Monozygotic/genetics ; tau Proteins/genetics ; tau Proteins/metabolism ; Cross-Sectional Studies ; Positron-Emission Tomography/methods ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid/metabolism ; Amyloidogenic Proteins ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/metabolism ; Amyloid beta-Peptides/metabolism
Chemical Substances	tau Proteins ; Amyloid ; Amyloidogenic Proteins ; Amyloid beta-Peptides
Language	English
Publishing date	2023-03-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awad077
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Article ; Online: Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

Moonen, Justine E F / Haan, Renée / Bos, Isabelle / Teunissen, Charlotte / van de Giessen, Elsmarieke / Tomassen, Jori / den Braber, Anouk / van der Landen, Sophie M / de Geus, Eco J C / Legdeur, Nienke / van Harten, Argonde C / Trieu, Calvin / de Boer, Casper / Kroeze, Lior / Barkhof, Frederik / Visser, Pieter Jelle / van der Flier, Wiesje M

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 3, Page(s) 1868–1880

Abstract: Introduction: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease.: Methods: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic ... ...

Abstract	Introduction: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. Methods: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aβ) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). Results: Thirty-nine percent had neither Aβ nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aβ only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. Discussion: In non-demented persons Aβ was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. Highlights: Amyloid beta (Aβ; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aβ should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.
MeSH term(s)	Humans ; Amyloid beta-Peptides ; Alzheimer Disease/pathology ; Cognitive Dysfunction/diagnostic imaging ; Cognition Disorders ; Cerebral Small Vessel Diseases/complications ; Cerebral Small Vessel Diseases/diagnostic imaging ; Magnetic Resonance Imaging ; Dementia, Vascular
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2023-12-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13607
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Article ; Online: Performance of a [

Coomans, Emma M / de Koning, Lotte A / Rikken, Roos M / Verfaillie, Sander C J / Visser, Denise / den Braber, Anouk / Tomassen, Jori / van de Beek, Marleen / Collij, Lyduine E / Lemstra, Afina W / Windhorst, Albert D / Barkhof, Frederik / Golla, Sandeep S V / Visser, Pieter Jelle / Scheltens, Philip / van der Flier, Wiesje M / Ossenkoppele, Rik / van Berckel, Bart N M / van de Giessen, Elsmarieke

Neurology

2023 Volume 101, Issue 19, Page(s) e1850–e1862

Abstract: Background and objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [: Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two ...

Abstract	Background and objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [ Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). Results: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = -0.52, CI -0.74 to -0.30, Discussion: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. Classification of evidence: This study provides Class II evidence that [
MeSH term(s)	Humans ; Female ; Aged ; Male ; Alzheimer Disease/metabolism ; Lewy Body Disease/complications ; Prospective Studies ; Reproducibility of Results ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography/methods ; Cognitive Dysfunction/complications ; Amyloid/metabolism
Chemical Substances	7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole (J09QS3Z3WB) ; tau Proteins ; Amyloid beta-Peptides ; Amyloid
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000207794
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