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Neuroinflammation is believed to be a key process in Alzheimer’s disease (AD) pathogenesis. Recently, the neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte ratios (LMR) have been proposed to be useful peripheral markers of inflammation. However, it is unclear how these inflammatory ratios relate to AD pathology, such as β-amyloid (Aβ) plaques and tau tangles. Using 18 F-florbetapir and 18 F-flortaucipir positron emission tomography (PET), we sought to determine how the NLR and LMR are associated with AD pathology both cross-sectionally and longitudinally. We further evaluated associations between the NLR and LMR and longitudinal cognitive decline. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we analyzed blood, PET, and cognitive data from 1544 subjects—405 cognitively normal, 838 with mild cognitive impairment (MCI), and 301 with AD. Associations between the NLR and LMR and Aβ and tau on PET were assessed using ordinary least-squares and mixed-effects regression models, while adjusting for age, sex, years of education, and apolipoprotein E ε2 or ε4 carrier status. Associations between the NLR and LMR and cognitive function, as measured by the AD Assessment Scale-Cognitive Subscale, 13-item version, were also assessed. MCI and AD subjects had higher NLR ( p  = 0.017, p  < 0.001, respectively) and lower LMR ( p  = 0.013, p  = 0.023). The NLR, but not the LMR, was significantly associated with Aβ ( p  = 0.028), suggesting that higher NLR was associated with greater Aβ deposition in the brain. Neither the NLR nor the LMR was associated with tau deposition ( p  > 0.05). A higher NLR was associated with greater longitudinal cognitive decline ( p  < 0.001). A higher ratio of peripheral neutrophils to lymphocytes, possibly reflecting an imbalance in innate versus adaptive immunity, is related to greater Aβ deposition and longitudinal cognitive decline. As the field moves toward blood-based biomarkers of AD, the altered balance of innate versus adaptive immunity could be a useful biomarker of underlying pathology and may also serve as a potential therapeutic target.

Background In sporadic Alzheimer’s disease (AD), brain amyloid-beta (Aβ) deposition is believed to be a consequence of impaired Aβ clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer 18 F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aβ levels. Methods In the present study, we use two PET tracers, 18 F-THK5351 and 11 C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. Results we observed that the ventricular CSF clearance measures were correlated (r = 0.66, p < 0.01), with reductions in AD of 18 and 27%, respectively. We also replicated a significant relationship between ventricular CSF clearance ( 18 F-THK5351) and brain Aβ load (r =  − 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. Conclusions Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aβ deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.

Choroid plexus (CP), best known for producing CSF, also regulate inflammation and clear metabolic waste to maintain brain homeostasis. CP dysfunction is implicated in Alzheimer’s Disease (AD), with MRI studies showing CP enlargement in AD. The basis for CP enlargement is unknown. We hypothesized that calcium deposition within CP, which increases with aging and in certain neurodegenerative conditions, might underlie pathologic CP enlargement and be linked to neurodegeneration. In 166 cognitively normal participants, we used multimodal imaging to examine CP structure (MRI-measured overall volume, CT-measured calcium volume), PET-measured Aβ, age, and APOE genotype as predictors of neurodegeneration, indexed as hippocampal volume. CP enlargement was associated with reduced hippocampal volume, particularly in APOE4 carriers. CP calcium was not independently associated with hippocampal volume. However, a significant interaction revealed APOE4 genotype-specific associations between CP calcium and neurodegeneration, with APOE4 carriers showing greater hippocampal volumes in association with greater CP calcium—opposite to our hypothesis. Results suggest that a factor other than calcium drives pathologic CP enlargement associated with neurodegeneration, with this factor especially important in APOE4 carriers. Candidate factors include lipids and inflammatory cells, which are known to accumulate in CP and be regulated by APOE. Our findings highlight CP as a critical locus for studying AD pathogenesis and the mechanisms by which APOE4 promotes AD.

Background Quantitative transport mapping (QTM) of blood velocity, based on the transport equation has been demonstrated higher accuracy and sensitivity of perfusion quantification than the traditional Kety’s method-based cerebral blood flow (CBF). This study aimed to investigate the associations between QTM velocity and cognitive function in Alzheimer’s disease (AD) using multiple post-labeling delay arterial spin labeling (ASL) MRI. Methods A total of 128 subjects (21 normal controls (NC), 80 patients with mild cognitive impairment (MCI), and 27 AD) were recruited prospectively. All participants underwent MRI examination and neuropsychological evaluation. QTM velocity and traditional CBF maps were computed from multiple delay ASL. Regional quantitative perfusion measurements were performed and compared to study group differences. We tested the hypothesis that cognition declines with reduced cerebral blood perfusion with consideration of age and gender effects. Results In cortical gray matter (GM) and the hippocampus, QTM velocity and CBF showed decreased values in the AD group compared to NC and MCI groups; QTM velocity, but not CBF, showed a significant difference between MCI and NC groups. QTM velocity and CBF showed values decreasing with age; QTM velocity, but not CBF, showed a significant gender difference between male and female. QTM velocity and CBF in the hippocampus were positively correlated with cognition, including global cognition, memory, executive function, and language function. Conclusion This study demonstrated an increased sensitivity of QTM velocity as compared with the traditional Kety’s method-based CBF. Specifically, we observed only in QTM velocity, reduced perfusion velocity in GM and the hippocampus in MCI compared with NC. Both QTM velocity and CBF demonstrated a reduction in AD vs. controls. Decreased QTM velocity and CBF in the hippocampus were correlated with poor cognitive measures. These findings suggest QTM velocity as potential biomarker for early AD blood perfusion alterations and it could provide an avenue for early intervention of AD.

In rodents, hypothalamic inflammation plays a critical role in aging and age-related diseases. Hypothalamic inflammation has not previously been assessed in vivo in humans. We used Positron Emission Tomography (PET) with a radiotracer sensitive to the translocator protein (TSPO) expressed by activated microglia, to assess correlations between age and regional brain TSPO in a group of healthy subjects (n = 43, 19 female, aged 23–78), focusing on hypothalamus. We found robust age-correlated TSPO expression in thalamus but not hypothalamus in the combined group of women and men. This pattern differs from what has been described in rodents. Prominent age-correlated TSPO expression in thalamus in humans, but in hypothalamus in rodents, could reflect evolutionary changes in size and function of thalamus versus hypothalamus, and may be relevant to the appropriateness of using rodents to model human aging. When examining TSPO PET results in women and men separately, we found that only women showed age-correlated hypothalamic TSPO expression. We suggest this novel result is relevant to understanding a stark sex difference in human aging: that only women undergo loss of fertility—menopause—at mid-life. Our finding of age-correlated hypothalamic inflammation in women could have implications for understanding and perhaps altering reproductive aging in women.

Our objective was to apply multi-compartment T2 relaxometry in cognitively normal individuals aged 20-80 years to study the effect of aging on the parenchymal CSF fraction (CSFF), a potential measure of the subvoxel CSF space. A total of 60 volunteers (age range, 22-80 years) were enrolled. Voxel-wise maps of short-T2 myelin water fraction (MWF), intermediate-T2 intra/extra-cellular water fraction (IEWF), and long-T2 CSFF were obtained using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) sequence and three-pool non-linear least squares fitting. Multiple linear regression analyses were performed to study the association between age and regional MWF, IEWF, and CSFF measurements, adjusting for sex and region of interest (ROI) volume. ROIs include the cerebral white matter (WM), cerebral cortex, and subcortical deep gray matter (GM). In each model, a quadratic term for age was tested using an ANOVA test. A Spearman's correlation between the normalized lateral ventricle volume, a measure of organ-level CSF space, and the regional CSFF, a measure of tissue-level CSF space, was computed. Regression analyses showed that there was a statistically significant quadratic relationship with age for CSFF in the cortex ( = 0.018), MWF in the cerebral WM ( = 0.033), deep GM ( = 0.017) and cortex ( = 0.029); and IEWF in the deep GM ( = 0.033). There was a statistically highly significant positive linear relationship between age and regional CSFF in the cerebral WM ( < 0.001) and deep GM ( < 0.001). In addition, there was a statistically significant negative linear association between IEWF and age in the cerebral WM ( = 0.017) and cortex ( < 0.001). In the univariate correlation analysis, the normalized lateral ventricle volume correlated with the regional CSFF measurement in the cerebral WM (ρ = 0.64, < 0.001), cortex (ρ = 0.62, < 0.001), and deep GM (ρ = 0.66, < 0.001). Our cross-sectional data demonstrate that brain tissue water in different compartments shows complex age-dependent patterns. Parenchymal CSFF, a measure of subvoxel CSF-like water in the brain tissue, is quadratically associated with age in the cerebral cortex and linearly associated with age in the cerebral deep GM and WM.

The choroid plexus (CP), a critical structure for cerebrospinal fluid (CSF) production, has been increasingly recognized for its involvement in Alzheimer's disease (AD). Accurate segmentation of CP from magnetic resonance imaging (MRI) remains challenging due to its irregular shape, variable MR signal, and proximity to the lateral ventricles. This study aimed to develop and evaluate a region-informed Gaussian Mixture Model (One-GMM) for automatic CP segmentation using anatomical priors derived from FreeSurfer (FS) software and compare it with manual, FS, and one previous GMM-based (Two-GMM) methods. T1-weighted (T1w) and T2-fluid-attenuated inversion recovery (FLAIR) MRI scans were acquired from 38 participants [19 cognitively normal (CN)], 11 with mild cognitive impairment (MCI), and 8 with AD. Manual segmentations served as ground truth. A GMM was applied within an anatomically constrained region combining the lateral ventricles and CP derived from FS reconstruction. The segmentation accuracy was assessed using the dice similarity coefficient (DSC), the 95th percentile Hausdorff distance (HD95), and volume difference percentage (VD%). Results were compared with those from FS and one previous GMM method-based segmentations across diagnostic groups. The region-informed One-GMM achieved significantly higher accuracy compared to FS and Two-GMM, with a mean DSC of 0.82 ± 0.05 for One-GMM versus 0.24 ± 0.11 for FS (   <  0.001), and 0.66 ± 0.10 for Two-GMM (  < 0.001), lower HD95 (One-GMM: 6.06 ± 10.32 mm vs. FS: 26.21 ± 7.32 mm vs. Two-GMM: 10.58 ± 6.47 mm), and comparable volume difference (One-GMM: 20.97 ± 9.53% vs. FS: 24.32 ± 28.13% vs. Two-GMM: 24.27 ± 22.10,  = 0.87). Segmentation accuracy of our proposed method was consistent across all diagnostic groups. Clinical analysis showed that there is no diagnostic group difference in CP volume obtained from manual, FS, Two-GMM, and our proposed One-GMM methods. In the whole cohort, there are also no age and sex effects of CP volume with all methods. Restricting to the CN group, CP volume from both manual (  = 0.03), Two-GMM (  < 0.01) and the proposed One-GMM (  = 0.05), methods show an aging effect, but not for the FS segmented CP volume (  = 0.22). A region-informed One-GMM method significantly improved CP segmentation accuracy over FS, providing a practical and accessible tool for CP quantification in AD and other research studies. Within this small cohort, no diagnostic group difference in CP volume was observed. An aging effect of CP volume was found within the CN group.

A defect sensing method based on electrical impedance spectroscopy is proposed to image cracks and reinforcing bars in concrete structures. The method utilizes the frequency-dependent behavior of thin insulating cracks: low-frequency electrical currents are blocked by insulating cracks, whereas high-frequency currents can pass through thin cracks to probe the conducting bars. From various frequency-dependent electrical impedance tomography (EIT) images, we can show its advantage in terms of detecting both thin cracks with their thickness and bars. We perform numerical simulations and phantom experiments to support the feasibility of the proposed method.

Background Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer’s disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1- 11 C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. Methods 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1- 11 C]-Butanol. Imaging with either [ 11 C]-PiB or [ 18 F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. Results LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. Conclusion The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Introduction Blood‐based biomarkers, most notably plasma phosphorylated tau (p‐tau)217, have transformed the diagnostic landscape of Alzheimer's disease (AD). Methods We applied an unsupervised machine learning approach to tau positron emission tomography (PET) imaging in 606 participants (age 73.95 ± 7.72; 309 female) to identify AD subtypes. Within each subtype, we evaluated plasma p‐tau217 levels, their association with regional tau PET uptake, differences between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, and relationships to cognitive performance. Results Four subtypes were identified: limbic, medial temporal lobe (MTL) sparing, posterior, and lateral temporal (l temporal). Plasma p‐tau217 was elevated in CI versus CU in limbic, posterior, and l temporal subtypes and strongly associated with tau deposition and cognitive performance. In the MTL‐sparing subtype, p‐tau217 showed a significant association with tau but no elevation in CI and no relationship to cognition. Discussion These findings indicate that p‐tau217's diagnostic utility varies across AD subtypes, reflecting distinct biological mechanisms not captured by current blood biomarkers. Highlights Plasma phosphorylated tau (p‐tau)217 differentiated cognitively unimpaired from impaired individuals in most subtypes, with the notable limitation of the medial temporal lobe (MTL)‐sparing group. P‐tau217 level was linked to regional tau accumulation as measured by tau positron emission tomography, across all subtypes. The MTL‐sparing subtype appeared to be unique, as p‐tau217 was not elevated in cognitively impaired individuals, and there was no clear relationship between p‐tau217 levels and cognitive performance.