Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid

Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology. 122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models. We find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants. The combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer's Disease-related episodic memory decline, suggesting utility in clinical trials

On the possibility of magneto-structural correlations: detailed studies of di-nickel carboxylate complexes

A series of water-bridged dinickel complexes of the general formula [Ni&lt;sub&gt;2&lt;/sub&gt;(μ&lt;sub&gt;2&lt;/sub&gt;-OH&lt;sub&gt;2&lt;/sub&gt;)(μ2- O&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu)&lt;sub&gt;2&lt;/sub&gt;(O&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu)2(L)(L0)] (L = HO&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu, L0 = HO&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu (1), pyridine (2), 3-methylpyridine (4); L = L0 = pyridine (3), 3-methylpyridine (5)) has been synthesized and structurally characterized by X-ray crystallography. The magnetic properties have been probed by magnetometry and EPR spectroscopy, and detailed measurements show that the axial zero-field splitting, D, of the nickel(ii) ions is on the same order as the isotropic exchange interaction, J, between the nickel sites. The isotropic exchange interaction can be related to the angle between the nickel centers and the bridging water molecule, while the magnitude of D can be related to the coordination sphere at the nickel sites

Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study

Background: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. Methods: We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. Findings: This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9−0.95) and its concentrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8–33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Interpretation: Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials. Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit

Cerebral Amyloid Angiopathy in Down Syndrome and Sporadic and Autosomal-Dominant Alzheimer\u27s Disease

Introduction—We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer\u27s disease (AD) (early-onset AD [EOAD]). Methods—Neuroimaging features of CAA, APOE, and cerebrospinal fluid-Aβ40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). Results—CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE-ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (p = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. Discussion—CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid-Aβ40 levels are not a useful biomarker for CAA in AD

Delineation of Diverse Macrophage Activation Programs in Response to Intracellular Parasites and Cytokines

Macrophages are a type of immune cell that engulf and digest microorganisms. Despite their role in protecting the host from infection, many pathogens have developed ways to hijack the macrophage and use the cell for their own survival and proliferation. This includes the parasites Trypanosoma cruzi and Leishmania mexicana. In order to gain further understanding of how these pathogens interact with the host macrophage, we compared macrophages that have been infected with these parasites to macrophages that have been stimulated in a number of different ways. Macrophages can be activated by a wide variety of stimuli, including common motifs found on pathogens (known as pathogen associated molecular patterns or PAMPs) and cytokines secreted by other immune cells. In this study, we have delineated the relationships between the macrophage activation programs elicited by a number of cytokines and PAMPs. Furthermore, we have placed the macrophage responses to T. cruzi and L. mexicana into the context of these activation programs, providing a better understanding of the interactions between these pathogens and macrophages

Magnetic Slow Relaxation in a Metal&#8211;Organic Framework Made of Chains of Ferromagnetically Coupled Single-Molecule Magnets

International audienceWe report the study of a Dy-based metal-organic framework (MOF) with unprecedented magnetic properties. The compound is made of nine-coordinated Dy-III magnetic building blocks (MBBs) with poor intrinsic single-molecule magnet behavior. However, the MOF architecture constrains the MBBs in a one-dimensional structure that induces a ferromagnetic coupling between them. Overall, the material shows a magnetic slow relaxation in absence of external static field and a hysteretic behavior at 0.5K. Low-temperature magnetic studies, diamagnetic doping, and ab initio calculations highlight the crucial role played by the Dy-Dy ferromagnetic interaction. Overall, we report an original magnetic object at the frontier between single-chain magnets and single-molecule magnets that host intrachain couplings that cancel quantum tunneling between the MBBs. This compound is evidence that a bottom-up approach through MOF design can induce spontaneous organization of MBBs able to produce remarkable molecular magnetic materials

APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls

BACKGROUND: The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE-by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC). METHODS: Cross-sectional study. HC from the Alzheimer's Disease Neuroimaging Initiative with available CSF (n = 274) and/or 3T-MRI (n = 168) and/or a FDG-PET analyses (n = 328) were selected. CSF amyloid-β1-42 (Aβ1-42), total-tau (t-tau) and phospho-tau (p-tau181p) levels were measured by Luminex assays. We analyzed the APOE-by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses. RESULTS: APOE4 carriers had lower CSF Aβ1-42 and higher CSF p-tau181p values than non-carriers, but there was no APOE-by-sex interaction on CSF biomarkers. The APOE-by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers. CONCLUSIONS: The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE-by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

\ua9 The Author(s) 2024.Up to 80% of Parkinson\u27s disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson\u27s disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson\u27s disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson\u27s disease and dementia with Lewy bodies/Parkinson\u27s disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson\u27s, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson\u27s Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies