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Publications (75)
In Alzheimer’s disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperact...
In Alzheimer’s disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau 181 determined...
Background
Memory clinic patients typically present with Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) to varying degrees. Therefore, it is crucial to determine the etiology of cognitive deficits for facilitating patient‐centered treatment in memory clinics. Plasma biomarkers (ptau217, Glial Fibrillary Acidic Protein [GFAP], Neur...
Background
Lewy body pathology consisting of aggregated alpha‐Synuclein (a‐Syn) is the hallmark pathology in Parkinson’s disease, yet a‐Syn aggregates are also commonly observed post‐mortem as a co‐pathology in Alzheimer’s disease (AD) patients. Preclinical research has shown that a‐Syn can amplify Ab‐associated tau seeding and aggregation, hence a...
Background
Neuroimaging studies have revealed age and sex‐specific differences in Alzheimer’s disease (AD) trajectories. However, how age and sex modulate tau spreading remains unclear. Thus, we investigated how age and sex modulate the amyloid‐beta (Aß)‐induced accumulation and spreading of tau pathology from local epicenters across connected brai...
Background
The myelin sheath around axons is of fundamental importance for signal transduction. Myelin is reduced in white matter hyperintensities (WMH), which occur in both small vessel disease (SVD) and Alzheimer’s disease (AD), giving rise to the question to what extent myelin is reduced in these diseases. Here, we employed an advanced MRI based...
Background
In Alzheimer’s disease (AD), cortical tau aggregation is a strong predictor of cortical brain atrophy as shown by MRI and PET studies, particularly driving the degeneration of neuronal somata in the grey matter. However, tau’s physiological role is to stabilize microtubules within axons in the brain’s white matter (WM) pathways. Therefor...
Background
In Alzheimer’s disease, Aß triggers tau spreading which drives neurodegeneration and cognitive decline. However, the mechanistic link between Aß and tau remains unclear, which hinders therapeutic efforts to attenuate Aß‐related tau accumulation. Preclinical research could show that tau spreads across connected neurons in an activity‐depe...
Background
Memory clinic patients typically present with Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) to varying degrees. Therefore, it is crucial to determine the etiology of cognitive deficits for facilitating patient‐centered treatment in memory clinics. Plasma biomarkers (ptau217, Glial Fibrillary Acidic Protein [GFAP], Neur...
Background
Lewy body pathology consisting of aggregated alpha‐Synuclein (a‐Syn) is the hallmark pathology in Parkinson’s disease, yet a‐Syn aggregates are also commonly observed post‐mortem as a co‐pathology in Alzheimer’s disease (AD) patients. Preclinical research has shown that a‐Syn can amplify Ab‐associated tau seeding and aggregation, hence a...
Background
The myelin sheath around axons is of fundamental importance for signal transduction. Myelin is reduced in white matter hyperintensities (WMH), which occur in both small vessel disease (SVD) and Alzheimer’s disease (AD), giving rise to the question to what extent myelin is reduced in these diseases. Here, we employed an advanced MRI based...
Background
In Alzheimer’s disease, Aβ triggers tau spreading which drives neurodegeneration and cognitive decline. However, the mechanistic link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ‐related tau accumulation. Preclinical research could show that tau spreads across connected neurons in an activity‐depe...
Background
In Alzheimer’s disease (AD), cortical tau aggregation is a strong predictor of cortical brain atrophy as shown by MRI and PET studies, particularly driving the degeneration of neuronal somata in the grey matter. However, tau’s physiological role is to stabilize microtubules within axons in the brain’s white matter (WM) pathways. Therefor...
Background
Neuroimaging studies have revealed age and sex‐specific differences in Alzheimer’s disease (AD) trajectories. However, how age and sex modulate tau spreading remains unclear. Thus, we investigated how age and sex modulate the amyloid‐beta (Aβ)‐induced accumulation and spreading of tau pathology from local epicenters across connected brai...
BACKGROUND
White matter hyperintensities (WMHs) are established structural imaging markers of cerebral small vessel disease. The pathophysiologic condition of brain tissue varies over the core, the vicinity, and the subtypes of WMH and cannot be interpreted from conventional magnetic resonance imaging. We aim to improve our pathophysiologic underst...
Patients suffering from strokes are at increased risk of developing post-stroke dementia. Serum anti-NMDA receptor autoantibodies (NMDAR1-abs) have been associated with unfavorable post-stroke outcomes. However, their effect on specific cognitive domains remains unclear. We used data from the prospective multicenter DZNE—mechanisms after stroke (DE...
INTRODUCTION
While incident ischemic lesions (IILs) are not unusual on follow‐up magnetic resonance imaging (MRI) following stroke, their risk factors and prognostic significance remain unknown.
METHODS
In a prospective multicenter study of 503 acute stroke patients, we assessed IILs on registered MRI images at baseline and 6 months, analyzing ris...
White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables...
Background
Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4‐repeat (4R) tauopathies and its role in accelerating disease progression.
Objective
We tested whether microglial activation (1) progresses in similar spatial patterns as the...
Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and g...
BACKGROUND
Post-stroke cognitive impairment (PSCI) occurs in up to 50% of stroke survivors. Presence of pre-existing vascular brain injury, in particular the extent of white matter hyperintensities (WMH), is associated with worse cognitive outcome after stroke, but the role of WMH location in this association is unclear.
AIM
We determined if WMH i...
Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that les...
INTRODUCTION
White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid‐β1‐42 (Aβ42)‐positive status.
METHODS
Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) f...
In Alzheimer’s disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity...
Background
Recent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathob...
Background
In Alzheimer’s disease (AD), Amyloid‐beta deposition (Ab) is associated with tau spreading from epicenters to connected regions. Yet, Ab and tau accumulate in strikingly different patterns, and it is unclear how Abdrives tau spreading. We envision two mechanisms, i.e. i) that cortical Ab exerts remote effects and “pulls” tau out of conne...
Background
Targeting amyloid (Aß) may show highest clinical efficacy when preventing downstream tau spreading and subsequent neurodegeneration. Thus, it’s critical to establish Aß‐PET thresholds at which tau spreading is triggered, which may depend on ApoE4, i.e. a key genetic risk factor for Aß, tau and cognitive decline. Yet, ApoE4’s impact on Aß...
Background
Animal and in vitro studies of Alzheimer’s disease (AD) found that tau spreads trans‐synaptically in an activity‐dependent manner, suggesting that synapses are key routes for tau spread. Importantly, amyloid‐beta (Ab) induces synaptic remodeling and aberrant synaptic activity, which may accelerate trans‐synaptic tau spread. In AD patient...
Background
Myelin is the cholesterol‐rich layer ensheathing axons in the white matter (WM). The APOE ε4 allele has been associated with both reduced cholesterol transport to myelin layers in mice and with faster tau progression in individuals with AD. Here we asked the questions whether 1) APOE ε4 is associated with lower myelin and 2) any myelin d...
Background
State‐of‐the‐art preprocessing of MRI and PET data is crucial for Alzheimer’s disease (AD) neuroimaging research. Therefore, standardization and harmonization of neuroimaging preprocessing across sites is key to generate comparable and sharable datasets and to reduce potential bias introduced by different preprocessing strategies. Furthe...
Background
State‐of‐the‐art preprocessing of MRI and PET data is crucial for Alzheimer’s disease (AD) neuroimaging research. Therefore, standardization and harmonization of neuroimaging preprocessing across sites is key to generate comparable and sharable datasets and to reduce potential bias introduced by different preprocessing strategies. Furthe...
Background
Recent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathob...
Background
Animal and in vitro studies of Alzheimer’s disease (AD) found that tau spreads trans‐synaptically in an activity‐dependent manner, suggesting that synapses are key routes for tau spread. Importantly, amyloid‐beta (Ab) induces synaptic remodeling and aberrant synaptic activity, which may accelerate trans‐synaptic tau spread. In AD patient...
Background
Targeting amyloid (Aß) may show highest clinical efficacy when preventing downstream tau spreading and subsequent neurodegeneration. Thus, it’s critical to establish Aß‐PET thresholds at which tau spreading is triggered, which may depend on ApoE4, i.e. a key genetic risk factor for Aß, tau and cognitive decline. Yet, ApoE4’s impact on Aß...
Background
In Alzheimer’s disease (AD), Amyloid‐beta deposition (Ab) is associated with tau spreading from epicenters to connected regions. Yet, Ab and tau accumulate in strikingly different patterns, and it is unclear how Abdrives tau spreading. We envision two mechanisms, i.e. i) that cortical Ab exerts remote effects and “pulls” tau out of conne...
The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer’s disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation.
To address our objectives, we repurposed florbetapir-PE...
Importance
For the Alzheimer disease (AD) therapies to effectively attenuate clinical progression, it may be critical to intervene before the onset of amyloid-associated tau spreading, which drives neurodegeneration and cognitive decline. Time points at which amyloid-associated tau spreading accelerates may depend on individual risk factors, such a...
Introduction
The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as “unusual”, but this is largely based on expert opinion, because detailed quantitative information about WMH distribution f...
BACKGROUND
White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patient...
Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neur...
Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients wit...
Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) are the two main causes of age‐related cognitive decline and frequently co‐exist in memory clinic patients. White matter diffusion alterations have been described as key features of both diseases with different spatial patterns in AD and SVD. Biomarkers that capture and disentangle th...
Alzheimer’s disease (AD) is characterized by Aβ and tau accumulation, microglial activation, metabolic brain changes, neurodegeneration, and cognitive decline. Studies found both detrimental and protective effects of microglial activation on AD progression, hence neuroinflammation may be a double‐edged sword in AD, which is critical for clinical tr...
Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) are the two main causes of age‐related cognitive decline and frequently co‐exist in memory clinic patients. White matter diffusion alterations have been described as key features of both diseases with different spatial patterns in AD and SVD. Biomarkers that capture and disentangle th...
In Alzheimer’s disease (AD), the functional connectome plays a key role in the trans‐neuronal spreading of tau pathology, a key driver of cognitive decline. The functional connectome is comprised of segregated, but communicating networks which lose segregation with age, resulting in an overall more diffuse connectome. Prior neuroimaging studies hav...
In Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto‐parietal regions which typically harbor globally connected hub...
In Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto‐parietal regions which typically harbor globally connected hub...
4‐repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R‐tauopathies are progressive‐supranuclear‐palsy (PSP) and corticobasal‐syndrome (CBS) characterized by tau accumulation in subcortical nuclei as well as cortical neuronal dysfunction, as shown by PET‐assessed hyp...
Introduction:
Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study.
Methods:
Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the asso...
In Alzheimer’s disease (AD), the functional connectome plays a key role in the trans‐neuronal spreading of tau pathology, a key driver of cognitive decline. The functional connectome is comprised of segregated, but communicating networks which lose segregation with age, resulting in an overall more diffuse connectome. Prior neuroimaging studies hav...
4‐repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R‐tauopathies are progressive‐supranuclear‐palsy (PSP) and corticobasal‐syndrome (CBS) characterized by tau accumulation in subcortical nuclei as well as cortical neuronal dysfunction, as shown by PET‐assessed hyp...
Fibrillar tau progresses from initial epicenters of high tau accumulation to closely connected cortical regions during the course of Alzheimer’s disease (AD). Myelin ensheaths the interregional axonal connections, where ontogenetically late and thinly myelinated fibers are more susceptible to damage and may propel the propagation of fibrillar tau,...
Introduction:
Lower network segregation is associated with accelerated cognitive decline in Alzheimer's disease (AD), yet it is unclear whether less segregated brain networks facilitate connectivity-mediated tau spreading.
Methods:
We combined resting state functional magnetic resonance imaging (fMRI) with longitudinal tau positron emission tomo...
Background
Tau-PET is a prognostic marker for cognitive decline in Alzheimer’s disease, and the heterogeneity of tau-PET patterns matches cognitive symptom heterogeneity. Thus, tau-PET may allow precision-medicine prediction of individual tau-related cognitive trajectories, which can be important for determining patient-specific cognitive endpoints...
Purpose
To investigate if network thresholding and raw data harmonization improve consistency of diffusion MRI (dMRI)-based brain networks while also increasing precision and sensitivity to detect disease effects in multicentre datasets.
Methods
Brain networks were reconstructed from dMRI of five samples with cerebral small vessel disease (SVD; 62...
Background:
In Alzheimer's disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels-which differ substantially between white matter tr...
Purpose
Early after [ ¹⁸ F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [ ¹⁸ F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease...
Background
Microglial activation occurs early in Alzheimer’s disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Therefore, it is critical to investigate at which AD stages microglial activation could be protective or detrimental to evaluate microglia as a treatment target. To address t...
Our understanding of post‐stroke language function is largely based on older age groups, who show increasing age‐related brain pathology and neural reorganisation. To illustrate language outcomes in the young‐adult brain, we present the case of J., a 23 y.o. woman with chronic aphasia from a left‐hemisphere stroke affecting the temporal lobe. Diffu...
In Alzheimer’s disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/Bio...
Alzheimer’s disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and co-exist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer’s and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are...
Introduction:
It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes.
Methods:
In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular space...
We investigated if network thresholding and diffusion MRI (dMRI) harmonization improve a) cross-site consistency of network architecture and b) precision and sensitivity to detect network connections disrupted in cerebral small vessel disease (SVD). Brain networks were reconstructed from dMRI in five cohorts. Consistency of network architecture was...
In Alzheimer's disease (AD), pathologic tau gradually progresses from initially circumscribed predilection regions to closely connected cortical regions. The pattern of tau-deposition is of critical importance for the clinical expression of AD, but the factors that underlie region-dependent susceptibility and resistance to tau pathology remain elus...
Purpose
Early after [¹⁸F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [¹⁸F]PI-2620 tau-PET is able to discriminate 4-repeat tauopathies (4RTs) from disease controls and healthy controls. Here, we investigated whether ear...
Cerebral small vessel disease (SVD) is considered a disconnection syndrome, which can be quantified using structural brain network analysis obtained from diffusion MRI. Network analysis is a demanding analysis approach and the added benefit over simpler diffusion MRI analysis is largely unexplored in SVD. In this pre-registered study, we assessed t...
Background
Myelination of axons in the grey matter (GM) and axonal connections may modulate the spreading of brain pathologies such as pathologic tau. Here, we tested for the first time whether MRI‐assessed myelination in the GM and white matter (WM) is associated with tau‐PET assessed spreading of pathologic tau between connected brain regions. We...
Objectives
Acquisition-related differences in diffusion magnetic resonance imaging (dMRI) hamper pooling of multicentre data to achieve large sample sizes. A promising solution is to harmonize the raw diffusion signal using rotation invariant spherical harmonic (RISH) features, but this has not been tested in elderly subjects. Here we aimed to esta...
Our understanding of post-stroke language recovery and underlying neuroplasticity is largely based on older age groups, who have increasing brain pathology and potentially more bilateral language functioning. We present the case of A., a 23 y.o. woman with chronic aphasia from a left-hemisphere stroke. Deterministic tractography indicated that A.’s...
Objective: To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change and reproducibility of diffusion metrics.
Methods: We included 50 sporadic and 59 genetically defined...
In Alzheimer's disease (AD), the Braak staging scheme suggests a stereotypical tau spreading pattern that does, however, not capture interindividual variability in tau deposition. This complicates the prediction of tau spreading, which may become critical for defining individualized tau-PET readouts in clinical trials. Since tau is assumed to sprea...
