Microglial activation and connectivity in Alzheimer disease and aging

OBJECTIVE Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. METHODS We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. RESULTS We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner. INTERPRETATION Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022

Associations between sex, body mass index and the individual microglial response in Alzheimer's disease

Background and objectives18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between beta-amyloid-accumulation and microglial activation in AD.Methods49 patients with AD (29 females, all A beta-positive) and 15 A beta-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and beta-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional A beta-PET on TSPO-PET was used to determine the A beta-plaque-dependent microglial response (slope) and the A beta-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI).ResultsIn AD, females showed higher mean cortical TSPO-PET z-scores (0.91 +/- 0.49;males 0.30 +/- 0.75;p = 0.002), while A beta-PET z-scores were similar. The A beta-plaque-independent microglial response was stronger in females with AD (+ 0.37 +/- 0.38;males with AD - 0.33 +/- 0.87;p = 0.006), pronounced at the prodromal stage. On the contrary, the A beta-plaque-dependent microglial response was not different between sexes. The A beta-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the A beta-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005).ConclusionWhile microglia response to fibrillar A beta is similar between sexes, women with AD show a stronger A beta-plaque-independent microglia response. This sex difference in A beta-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the A beta-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD

MOSAiC goes O2A - Arctic Expedition Data Flow from Observations to Archives

During the largest polar expedition in history starting in September 2019, the German research icebreaker Polarstern spends a whole year drifting with the ice through the Arctic Ocean. The MOSAiC expedition takes the closest look ever at the Arctic even throughout the polar winter to gain fundamental insights and most unique on-site data for a better understanding of global climate change. Hundreds of researchers from 20 countries are involved. Scientists will use the in situ gathered data instantaneously in near-real time modus as well as long afterwards all around the globe taking climate research to a completely new level. Hence, proper data management, sampling strategies beforehand, and monitoring actual data flow as well as processing, analysis and sharing of data during and long after the MOSAiC expedition are the most essential tools for scientific gain and progress. To prepare for that challenge we adapted and integrated the research data management framework O2A “Data flow from Observations to Archives” to the needs of the MOSAiC expedition on board Polarstern as well as on land for data storage and access at the Alfred Wegener Institute Computing and Data Center in Bremerhaven, Germany. Our O2A-framework assembles a modular research infrastructure comprising a collection of tools and services. These components allow researchers to register all necessary sensor metadata beforehand linked to automatized data ingestion and to ensure and monitor data flow as well as to process, analyze, and publish data to turn the most valuable and uniquely gained arctic data into scientific outcomes. The framework further allows for the integration of data obtained with discrete sampling devices into the data flow. These requirements have led us to adapt the generic and cost-effective framework O2A to enable, control, and access the flow of sensor observations to archives in a cloud-like infrastructure on board Polarstern and later on to land based repositories for international availability. Major roadblocks of the MOSAiC-O2A data flow framework are (i) the increasing number and complexity of research platforms, devices, and sensors, (ii) the heterogeneous interdisciplinary driven requirements towards, e. g., satellite data, sensor monitoring, in situ sample collection, quality assessment and control, processing, analysis and visualization, and (iii) the demand for near real time analyses on board as well as on land with limited satellite bandwidth. The key modules of O2A's digital research infrastructure established by AWI are implementing the FAIR principles: SENSORWeb, to register sensor applications and sampling devices and capture controlled meta data before and alongside any measurements in the field Data ingest, allowing researchers to feed data into storage systems and processing pipelines in a prepared and documented way, at best in controlled near real-time data streams Dashboards allowing researchers to find and access data and share and collaborate among partners Workspace enabling researchers to access and use data with research software utilizing a cloud-based virtualized infrastructure that allows researchers to analyze massive amounts of data on the spot Archiving and publishing data via repositories and Digital Object Identifiers (DOI

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

& beta;-amyloid (A & beta;) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, A & beta;-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of A & beta;(A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional A & beta;(AD: & beta;(T) = 0.412 & PLUSMN;0.196 vs. & beta;(A) = 0.142 & PLUSMN;0.123, p < 0.001;AD-CBS: & beta;(T) = 0.385 & PLUSMN;0.176 vs. & beta;(A) = 0.131 & PLUSMN;0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (& beta;(T) = 0.418 & PLUSMN;0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and A & beta;related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

The comorbidity profiles and medication issues of patients with multiple system atrophy:a systematic cross-sectional analysis

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management.OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients.METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®.RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue.CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.</p

Hierarchisierung von Risikofaktoren für schwere COVID-19-Erkrankungsverläufe im Kontext der COVID-19-Schutzimpfungen

Angesichts der derzeitigen Impfstoffknappheit geht mit den bundesweiten Schutzimpfungen gegen COVID-19 die Notwendigkeit einer Priorisierung bestimmter Bevölkerungsgruppen einher. Basierend auf den Empfehlungen der STIKO sollen zunächst Personen mit besonders hohem Risiko für schwere oder tödliche COVID-19-Verläufe oder beruflicher Exposition geimpft werden. Diese Empfehlungen stützen sich überwiegend auf internationale Studien - für den deutschen Versorgungskontext steht nur begrenzt Evidenz zur Bedeutung relevanter Risikofaktoren für einen schweren COVID-19-Verlauf zur Verfügung. Das Ziel der im Epidemiologischen Bulletin 19/2021 vorgestellten Studie war es, die Relevanz ausgewählter Vorerkrankungen für einen schweren COVID-19-Verlauf in der in Deutschland lebenden Bevölkerung empirisch zu überprüfen, Erkrankungen hinsichtlich ihres Risikos für einen schweren COVID-19-Verlauf zu ordnen und damit eine einfache, im Versorgungsalltag unkompliziert umsetzbare und dabei möglichst effektive Grundlage für die Impfrangfolge in der ambulanten ärztlichen Versorgung bilden

The comorbidity and co-medication profile of patients with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients.ObjectivesTo explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease.MethodsCross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik (R).ResultsIn total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions.ConclusionsPSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified