Biomarkers.

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. Therefore, tau's white-to-grey-matter translocation and aggregation in neurofibrillary tangles close to neuronal somata may induce WM degeneration through destabilization of axonal microtubule integrity.

Biomarkers.

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-dependent manner, and Aβ was shown to trigger neuronal hyperactivity and hyperconnectivity.

Biomarkers.

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-Syn co-pathology may contribute to the Ab-induced progression of tau pathology in AD. To address this, we combined a novel CSF-based RT-QuIC seed-amplification assay to determine a-Syn positivity, with PET-neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a-Syn co-pathology accelerates Ab-driven tau accumulation.

Biomarkers.

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 (ptau, Glial Fibrillary Acidic Protein [GFAP], Neurofilament light chain [NfL]) and fixel-based advanced diffusion MRI markers (fiber density, fiber-bundle cross-section) show potential towards disentangling AD- and SVD-related brain changes (Dewenter et al.

Biomarkers.

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 method to assess myelin independently from a major confounding factor, i.

Alzheimer's Imaging Consortium.

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], Neurofilament light chain [NfL]) and fixel-based advanced diffusion MRI markers (fiber density, fiber-bundle cross-section) show potential towards disentangling AD- and SVD-related brain changes (Dewenter et al.

Alzheimer's Imaging Consortium.

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 method to assess myelin independently from a major confounding factor, i.

Alzheimer's Imaging Consortium.

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 brain regions.

Alzheimer's Imaging Consortium.

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. Therefore, tau's white-to-grey-matter translocation and aggregation in neurofibrillary tangles close to neuronal somata may induce WM degeneration through destabilization of axonal microtubule integrity.

Alzheimer's Imaging Consortium.

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-Syn co-pathology may contribute to the Ab-induced progression of tau pathology in AD. To address this, we combined a novel CSF-based RT-QuIC seed-amplification assay to determine a-Syn positivity, with PET-neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a-Syn co-pathology accelerates Ab-driven tau accumulation.

Alzheimer's Imaging Consortium.

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-dependent manner, and Aß was shown to trigger neuronal hyperactivity and hyperconnectivity.

Heterogeneity and Penumbra of White Matter Hyperintensities in Small Vessel Diseases Determined by Quantitative MRI.

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 understanding of WMHs and the adjacently injured normal-appearing white matter in terms of microstructural and microvascular alterations using quantitative magnetic resonance imaging in patients with sporadic and genetic cerebral small vessel disease.

Risk factors and clinical significance of post-stroke incident ischemic lesions.

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 risk factors and clinical outcomes across 36 months.

Results: At 6 months, 78 patients (15.

Neuroinflammation Parallels 18F-PI-2620 Positron Emission Tomography Patterns in Primary 4-Repeat Tauopathies.

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 primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading.

Methods: We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET.

Strategic white matter hyperintensity locations associated with post-stroke cognitive impairment: A multicenter study in 1568 stroke patients.

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.

Aims: We determined if WMH in strategic white matter tracts explain cognitive performance after stroke.

Enhancing Cognitive Performance Prediction through White Matter Hyperintensity Connectivity Assessment: A Multicenter Lesion Network Mapping Analysis of 3,485 Memory Clinic Patients.

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 lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders.

Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner.

Purpose: 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.

Methods: To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aβ) PET tracers bind to WM myelin. We assessed 43 Aβ-biomarker negative (Aβ-) cognitively normal participants and 108 Aβ+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years.

Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts.

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 frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns.

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels.

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 as apolipoprotein E ε4 (ApoE4) carriership, which is linked to faster disease progression; however, the association of ApoE4 with amyloid-related tau spreading is unclear.

Objective: To assess if ApoE4 carriers show accelerated amyloid-related tau spreading and propose amyloid positron emission tomography (PET) thresholds at which tau spreading accelerates in ApoE4 carriers vs noncarriers.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

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 patients with ischemic stroke from different cohorts.