Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-ß pathology.

BACKGROUND: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid ß-peptide (Aß) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD. METHODS: A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aß1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score. RESULTS: CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aß pathology (A+) but no tau pathology or neurodegeneration (TN-), is present. CONCLUSIONS: Aß pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aß pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline.

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.

White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease.

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-ß1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease.

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Spatial Patterns of Longitudinal Gray Matter Change as Predictors of Concurrent Cognitive Decline in Amyloid Positive Healthy Subjects.

A substantial proportion of cognitively healthy elders (HC) show abnormally high amyloid-ß (Aß) deposition, a major pathology of Alzheimer's disease (AD). These subjects are at increased risk of Alzheimer's disease (AD) dementia, and biomarkers are needed to predict their cognitive deterioration. Here we used relevance vector regression (RVR), a pattern-recognition method, to predict concurrent cognitive decline on the basis of longitudinal gray matter (GM) changes, within two a priori, meta-analytically defined functional networks subserving episodic memory and executive function. Ninety-six HC subjects were assessed annually for three years with structural MRI and cognitive tests within the Alzheimer's Disease Neuroimaging Initiative. Presence of abnormal biomarker values of Aß (Aß+) were determined with cerebrospinal fluid and amyloid-PET (HC-Aß+, n=30; with n=66 for normal HC-Aß-). Using leave-one-out cross-validation, we found that in HC-Aß+ patterns of GM changes within both networks predicted decline in episodic memory (r=0.61, p<0.001; r=0.40, p=0.03), but not executive function. In HC-Aß-, GM changes within the executive function network predicted decline in executive function (r=0.44, p<0.001). Previously established region-of-interest (ROI)-based predictors such as changes in hippocampal volume, within an AD-signature multi-ROI, or total GM volume were not predictive of cognitive decline in any group or cognitive domain. RVR analyses unrestricted to the a priori networks yielded compatible results with the restricted case. In conclusion, RVR-derived patterns of subtle cortical GM changes are biomarker candidates of concurrent cognitive decline in aging and subjects at risk for AD.

Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury.

Emerging evidence supports a role for innate immunity and microglia in Alzheimer's disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs). We also determined the temporal sequence of changes in CSF sTREM2 and markers for amyloid deposition and neurodegeneration as well as cognitive performance. We included 218 participants consisting of 127 MC and 91 NC siblings from the Dominantly Inherited Alzheimer Network. We observed that CSF sTREM2 increased in MCs compared to NCs 5 years before the expected symptom onset and this difference remained significant until 5 years after the expected symptom onset. Changes in CSF sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. We propose that microglial activation occurs several years before the expected symptom onset, but after amyloidosis and neuronal injury have already occurred.

sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers.

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of-function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho-tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

Mapping 3-year changes in gray matter and metabolism in Aß-positive nondemented subjects.

Gray matter (GM) atrophy and brain glucose hypometabolism are already detected in the predementia stages of Alzheimer's disease (AD), but the regional and longitudinal associations between the two are not well understood. Here, we analyzed the patterns of longitudinal atrophy (magnetic resonance imaging [MRI]) and (18)F-Fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) metabolism decline in 40 cognitively healthy control (HC) and 52 mildly impaired (mild cognitive impairment [MCI]) subjects during 3 years. Based on cerebrospinal fluid and brain amyloid-PET, the subjects were divided into amyloid-beta (Aß)- and Aß+ subgroups. In voxel-based and region of interest analyses, we compared the 3-year rates of change in GM and glucose metabolism between Aß-subgroups, within each diagnostic group. In joint-independent component analyses, we assessed the patterns of covariation between longitudinal change in GM volume and glucose metabolism. MCI-Aß+ showed faster atrophy than MCI-Aß- within the temporal, medial temporal, and medial parietal lobes. HC-Aß+ showed faster atrophy within the precuneus than HC-Aß-. For FDG-PET metabolism, MCI-Aß+ exhibited faster decline than MCI-Aß- in temporoparietal regions, whereas no differences between HC subgroups were observed. Joint-independent component analysis showed that accelerated atrophy and metabolism decline correlated across distant brain regions for MCI-Aß+. In conclusion, abnormally increased levels of Aß in nondemented subjects were associated with accelerated decline in both GM and glucose metabolism, where both types of neurodegeneration progress in spatially divergent patterns.

Model-based optoacoustic image reconstruction of large three-dimensional tomographic datasets acquired with an array of directional detectors.

Image quality in 3-D optoacoustic (photoacoustic) tomography is greatly influenced by both the measurement system, in particular the number and spatial arrangement of ultrasound sensors, and the ability to account for the spatio-temporal response of the sensor element(s) in the reconstruction algorithm. Herein we present a reconstruction procedure based on the inversion of a time-domain forward model incorporating the spatial impulse response due to the shape of the transducer, which is subsequently applied in a tomographic system based on a translation-rotation scan of a linear detector array. The proposed method was also adapted to cope with the data-intensive requirements of high-resolution volumetric optoacoustic imaging. The processing of 2 · 10 (4) individual signals resulted in well-resolved images of both ~ 200 µm absorbers in phantoms and complex vascular structures in biological tissue. The results reported herein demonstrate that the introduced model-based methodology exhibits a better contrast and resolution than standard back-projection and model-based algorithms that assume point detectors. Moreover, the capability of handling large datasets anticipates that model-based methods incorporating the sensor properties can become standard practice in volumetric opto acoustic image formation.

Model-based optoacoustic imaging using focused detector scanning.

Optoacoustic (photoacoustic) mesoscopic and microscopic imaging is often implemented by linearly scanning a spherically focused ultrasound transducer. In this case, the resolution and sensitivity along the scan direction are limited by diffraction and therefore degrade rapidly for imaging depths away from the focal point. Partial restoration of the lost resolution can be achieved by using data-processing techniques, such as the virtual detector delay-and-sum method. However, these techniques are based on an approximate description of the detector properties, which limits the improvement in image quality they achieve. Herein we propose a reconstruction method based on an exact model of the optoacoustic generation and propagation that incorporates the spatial response of the sensor. The proposed method shows superior imaging performance over previously considered techniques.