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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 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-β1-42 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.

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.

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 (Aβ)- and Aβ+ subgroups. In voxel-based and region of interest analyses, we compared the 3-year rates of change in GM and glucose metabolism between Aβ-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-Aβ+ showed faster atrophy than MCI-Aβ- within the temporal, medial temporal, and medial parietal lobes. HC-Aβ+ showed faster atrophy within the precuneus than HC-Aβ-. For FDG-PET metabolism, MCI-Aβ+ exhibited faster decline than MCI-Aβ- 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-Aβ+. In conclusion, abnormally increased levels of Aβ in nondemented subjects were associated with accelerated decline in both GM and glucose metabolism, where both types of neurodegeneration progress in spatially divergent patterns.

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 β-peptide (Aβ) 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 Aβ1-42 (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 Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present. Conclusions: Aβ 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, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2. [ABSTRACT FROM AUTHOR]

Purpose: Optoacoustic imaging relies on the detection of ultrasonic waves induced by laser pulse excitations to map optical absorption in biological tissue. A tomographic geometry employing a conventional ultrasound linear detector array for volumetric optoacoustic imaging is reported. The geometry is based on a translate-rotate scanning motion of the detector array, and capitalizes on the geometrical characteristics of the transducer assembly to provide a large solid angular detection aperture. A system for three-dimensional whole-body optoacoustic tomography of small animals is implemented. Methods: The detection geometry was tested using a 128-element linear array (5.0/7.0 MHz, Acuson L7, Siemens), moved by steps with a rotation/translation stage assembly. Translation and rotation range of 13.5 mm and 180°, respectively, were implemented. Optoacoustic emissions were induced in tissue-mimicking phantoms and ex vivo mice using a pulsed laser operating in the near-IR spectral range at 760 nm. Volumetric images were formed using a filtered backprojection algorithm. Results: The resolution of the optoacoustic tomography system was measured to be better than 130 μm in-plane and 330 μm in elevation (full width half maximum), and to be homogenous along a 15 mm diameter cross section due to the translate-rotate scanning geometry. Whole-body volumetric optoacoustic images of mice were performed ex vivo, and imaged organs and blood vessels through the intact abdominal and head regions were correlated to the mouse anatomy. Conclusions: Overall, the feasibility of three-dimensional and high-resolution whole-body optoacoustic imaging of small animal using a conventional linear array was demonstrated. Furthermore, the scanning geometry may be used for other linear arrays and is therefore expected to be of great interest for optoacoustic tomography at macroscopic and mesoscopic scale. Specifically, conventional detector arrays with higher central frequencies may be investigated. [ABSTRACT FROM AUTHOR]