Blood-Based Biomarkers for Early Alzheimer's Disease Diagnosis in Real-World Settings.

As our knowledge about the biology of Alzheimer's disease (AD) expands and we recognize the significance of early intervention for effective treatment, there is a shift in focus toward detecting the disease at an early stage. AD is characterized by the accumulation of misfolded amyloid-ß (Aß) and phosphorylated tau proteins in the brain, leading to the formation of senile plaques and neurofibrillary tangles. While a definitive diagnosis of AD can only be confirmed through autopsy by examining these pathological features, there are now reliable methods available for diagnosing the disease in living individuals. These methods involve analyzing cerebrospinal fluid and using positron emission tomography to accurately assess the presence of Aß and tau proteins. While these diagnostic markers have shown high accuracy in memory-clinic populations, they do have limitations such as the requirement for invasive lumbar puncture or exposure to ionizing radiation. Additionally, they are not easily accessible outside of specialized healthcare settings. Blood-based biomarkers of the core pathological features of AD are being developed, showing promise for less invasive, scalable identification of AD cases in the community. The advantages for the healthcare systems of this development are obvious, but the diagnostic performance of blood-based biomarkers in broader, non-selected populations outside of retrospective analyses and research cohorts still requires further investigation, including the combination with more effective neuropsychological assessments such as digital cognitive test solutions.

Nutrient recovery from wastewater for hydroponic systems: A comparative analysis of fertilizer demand, recovery products, and supply potential of WWTPs.

Nutrient recovery from wastewater treatment plants (WWTPs) for hydroponic cultivation holds promise for closing the nutrient loop and meeting rising food demands. However, most studies focus on solid products for soil-based agriculture, thus raising questions about their suitability for hydroponics. In this study, we address these questions by performing the first in-depth assessment of the extent to which state-of-the-art nutrient recovery processes can generate useful products for hydroponic application. Our results indicate that less than 11.5% of the required nutrients for crops grown hydroponically can currently be recovered. Potassium nitrate (KNO3), calcium nitrate (Ca(NO3)2), and magnesium sulfate (MgSO4), constituting over 75% of the total nutrient demand for hydroponics, cannot be recovered in appropriate form due to their high solubility, hindering their separated recovery from wastewater. To overcome this challenge, we outline a novel nutrient recovery approach that emphasizes the generation of multi-nutrient concentrates specifically designed to meet the requirements of hydroponic cultivation. Based on a theoretical assessment of nutrient and contaminant flows in a typical municipal WWTP, utilizing a steady-state model, we estimated that this novel approach could potentially supply up to 56% of the nutrient requirements of hydroponic systems. Finally, we outline fundamental design requirements for nutrient recovery systems based on this new approach. Achieving these nutrient recovery potentials could be technically feasible through a combination of activated sludge processes for nitrification, membrane-based desalination processes, and selective removal of interfering NaCl. However, given the limited investigation into such treatment trains, further research is essential to explore viable system designs for effective nutrient recovery for hydroponics.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease.

BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-ß-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE Îµ4 carrier status, sex, and education. RESULTS: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. CONCLUSIONS: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES).

BACKGROUND: Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. METHODS: An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment. DISCUSSION: The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort. TRIAL REGISTRATION: NCT05479032.

The structured ambulatory post-stroke care program for outpatient aftercare in patients with ischaemic stroke in Germany (SANO): an open-label, cluster-randomised controlled trial.

BACKGROUND: Patients with ischaemic stroke are at risk of recurrent stroke. In this study, we aimed to compare the effect of a structured ambulatory post-stroke care programme versus usual care on recurrent vascular events and death and control of cardiovascular risk factors. METHODS: We did a prospective, open-label, cluster-randomised controlled trial (SANO) at stroke centres in regions of Germany. A cluster was defined as a region in which acute stroke care is provided by a participating stroke centre. Patients were eligible for participation if they were aged 18 years or older, had no severe disabilities before the index stroke (modified Rankin scale 0-1), had at least one modifiable cardiovascular risk factor, and presented within 14 days of symptom onset of their first ischaemic stroke. The participating regions were randomly assigned (1:1) to the intervention and control group (usual care) by the statistician using block randomisation (block sizes of six), stratified by rural and urban regions. In intervention regions, a cross-sectoral multidisciplinary network was established to provide a 1-year organisational and patient-centred intervention. Due to the type of intervention, masking of participants and study physicians was not possible. Endpoint adjudication was performed by an independent endpoint adjudication committee who were masked to cluster allocation. The primary endpoint was a composite of recurrent stroke, myocardial infarction, and all-cause death within 12 months after baseline assessment, assessed in the modified intention-to-treat (mITT) population, which included all patients who did not withdraw consent and completed the primary endpoint assessment at 12 months. This study was registered with the German Clinical Trials Register, DRKS00015322. FINDINGS: Between Jan 1, 2019 and Dec 22, 2020, 36 clusters were assessed for eligibility, of which 30 were randomly assigned to the intervention group (n=15 clusters) or control group (n=15 clusters). No clusters dropped out of the study. 1203 (86%) of 1396 enrolled patients in the intervention group and 1283 (92%) of 1395 enrolled patients in the control group were included in the mITT population. The primary endpoint was confirmed in 64 (5·3%) of 1203 patients in the intervention group and 80 (6·2%) of 1283 patients in the control group (unadjusted odds ratio [OR] 0·80 [95% CI 0·49-1·30]; adjusted OR [aOR] 0·95 [95% CI 0·54-1·67]). All-cause deaths occurred in 31 (2·4%) of 1203 patients in the intervention group and 12 (1·0%) of 1283 patients in the control group. The incidence of serious adverse events was higher in the intervention group (266 [23·1%] of 1151) than the control group (106 [9·2%] of 1152). Falls (134 [11·4%] of 1203 patients in the intervention group; 39 [3·3%] of 1152 patients in the control group), hypertensive crisis (55 [4·7%]; 34 [2·8%]), and diagnosis of depression (51 [4·3%]; 13 [1·1%]) were the most frequent adverse events in both groups. No differences were identified in the rate of readmission to hospital between groups. INTERPRETATION: No differences were identified between patients with ischaemic stroke in the intervention group and control group with regard to the incidence of vascular events 1 year after baseline assessment, despite positive effects with regard to the control of some cardiovascular risk factors. Longer-term effects and other potentially favourable effects on stroke-related sequelae and quality of life require further evaluation. FUNDING: Innovation Fund of the Federal Joint Committee.

Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aß compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic ß-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.

Ischemia Impaired Wound Healing Model in the Rat-Demonstrating Its Ability to Test Proangiogenic Factors.

Chronic wounds remain a serious clinical problem with insufficient therapeutic approaches. In this study we investigated the dose dependency of rhVEGF165 in fibrin sealant in both ischemic and non-ischemic excision wounds using our recently developed impaired-wound healing model. An abdominal flap was harvested from the rat with unilateral ligation of the epigastric bundle and consequent unilateral flap ischemia. Two excisional wounds were set in the ischemic and non-ischemic area. Wounds were treated with three different rhVEGF165 doses (10, 50 and 100 ng) mixed with fibrin or fibrin alone. Control animals received no therapy. Laser Doppler imaging (LDI) and immunohistochemistry were performed to verify ischemia and angiogenesis. Wound size was monitored with computed planimetric analysis. LDI revealed insufficient tissue perfusion in all groups. Planimetric analysis showed slower wound healing in the ischemic area in all groups. Wound healing was fastest with fibrin treatment-irrespective of tissue vitality. Lower dose VEGF (10 and 50 ng) led to faster wound healing compared to high-dose VEGF. Immunohistochemistry showed the highest vessel numbers in low-dose VEGF groups. In our previously established model, different rhVEGF165 treatments led to dose-dependent differences in angiogenesis and wound healing, but the fastest wound closure was achieved with fibrin matrix alone.

Consistency as a Data Quality Measure for German Corona Consensus Items Mapped from National Pandemic Cohort Network Data Collections.

BACKGROUND: As a national effort to better understand the current pandemic, three cohorts collect sociodemographic and clinical data from coronavirus disease 2019 (COVID-19) patients from different target populations within the German National Pandemic Cohort Network (NAPKON). Furthermore, the German Corona Consensus Dataset (GECCO) was introduced as a harmonized basic information model for COVID-19 patients in clinical routine. To compare the cohort data with other GECCO-based studies, data items are mapped to GECCO. As mapping from one information model to another is complex, an additional consistency evaluation of the mapped items is recommended to detect possible mapping issues or source data inconsistencies. OBJECTIVES: The goal of this work is to assure high consistency of research data mapped to the GECCO data model. In particular, it aims at identifying contradictions within interdependent GECCO data items of the German national COVID-19 cohorts to allow investigation of possible reasons for identified contradictions. We furthermore aim at enabling other researchers to easily perform data quality evaluation on GECCO-based datasets and adapt to similar data models. METHODS: All suitable data items from each of the three NAPKON cohorts are mapped to the GECCO items. A consistency assessment tool (dqGecco) is implemented, following the design of an existing quality assessment framework, retaining their-defined consistency taxonomies, including logical and empirical contradictions. Results of the assessment are verified independently on the primary data source. RESULTS: Our consistency assessment tool helped in correcting the mapping procedure and reveals remaining contradictory value combinations within COVID-19 symptoms, vital signs, and COVID-19 severity. Consistency rates differ between the different indicators and cohorts ranging from 95.84% up to 100%. CONCLUSION: An efficient and portable tool capable of discovering inconsistencies in the COVID-19 domain has been developed and applied to three different cohorts. As the GECCO dataset is employed in different platforms and studies, the tool can be directly applied there or adapted to similar information models.

Pattern and implications of neurological examination findings in autosomal dominant Alzheimer disease.

INTRODUCTION: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. METHODS: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. RESULTS: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. DISCUSSION: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

A Deep Residual Neural Network for Image Reconstruction in Biomedical 3D Magnetic Induction Tomography.

In recent years, it has become increasingly popular to solve inverse problems of various tomography methods with deep learning techniques. Here, a deep residual neural network (ResNet) is introduced to reconstruct the conductivity distribution of a biomedical, voluminous body in magnetic induction tomography (MIT). MIT is a relatively new, contactless and noninvasive tomography method. However, the ill-conditioned inverse problem of MIT is challenging to solve, especially for voluminous bodies with conductivities in the range of biological tissue. The proposed ResNet can reconstruct up to two cuboid perturbation objects with conductivities of 0.0 and 1.0 S/m in the whole voluminous body, even in the difficult-to-detect centre. The dataset used for training and testing contained simulated signals of cuboid perturbation objects with randomised lengths and positions. Furthermore, special care went into avoiding the inverse crime while creating the dataset. The calculated metrics showed good results over the test dataset, with an average correlation coefficient of 0.87 and mean squared error of 0.001. Robustness was tested on three special test cases containing unknown shapes, conductivities and a real measurement that showed error results well within the margin of the metrics of the test dataset. This indicates that a good approximation of the inverse function in MIT for up to two perturbation objects was achieved and the inverse crime was avoided.

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics.

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON's goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36-62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON's design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration https://clinicaltrials.gov/ct2/show/NCT04768998 . https://clinicaltrials.gov/ct2/show/NCT04747366 . https://clinicaltrials.gov/ct2/show/NCT04679584.

Effects of aging on functional connectivity in a neurodegenerative risk cohort: resting state versus task measurement using near-infrared spectroscopy.

Changes in functional brain organization are considered to be particularly sensitive to age-related effects and may precede structural cognitive decline. Recent research focuses on aging processes determined by resting state (RS) functional connectivity (FC), but little is known about differences in FC during RS and cognitive task conditions in elderly participants. The purpose of this study is to compare FC within and between the cognitive control (CCN) and dorsal attention network (DAN) at RS and during a cognitive task using functional near-infrared spectroscopy (fNIRS). In a matched, neurodegenerative high-risk cohort comprising early (n = 98; 50-65 y) and late (n = 98; 65-85 y) elder subjects, FC was measured at RS and during performance of the Trail Making Test (TMT) via fNIRS. Both, under RS and task conditions our results revealed a main effect for age, characterized by reduced FC for late elder subjects within the left inferior frontal gyrus. During performance of the TMT, negative correlations of age and FC were confirmed in various regions of the CCN and DAN. For the whole sample, FC of within-region connections was elevated, while FC between regions was decreased at RS. The results confirm a reorganization of functional brain connectivity with increasing age and cognitive demands.

Effects of the short stitch technique for midline abdominal closure on incisional hernia (ESTOIH): randomized clinical trial.

BACKGROUND: Incisional hernia remains a frequent problem after midline laparotomy. This study compared a short stitch to standard loop closure using an ultra-long-term absorbent elastic suture material. METHODS: A prospective, multicentre, parallel-group, double-blind, randomized, controlled superiority trial was designed for the elective setting. Adult patients were randomly assigned by computer-generated sequence to fascial closure using a short stitch (5 to 8 mm every 5 mm, USP 2-0, single thread HR 26 mm needle) or long stitch technique (10 mm every 10 mm, USP 1, double loop, HR 48 mm needle) with a poly-4-hydroxybutyrate-based suture material (Monomax®). Incisional hernia assessed by ultrasound 1 year after surgery was the primary outcome. RESULTS: The trial randomized 425 patients to short (n = 215) or long stitch technique (n = 210) of whom 414 (97.4 per cent) completed 1 year of follow-up. In the short stitch group, the fascia was closed with more stitches (46 (12 s.d.) versus 25 (7 s.d.); P < 0.001) and higher suture-to-wound length ratio (5.3 (2.2 s.d.) versus 4.0 (1.3 s.d.); P < 0.001). At 1 year, seven of 210 (3.3 per cent) patients in the short and 13 of 204 (6.4 per cent) patients in the long stitch group developed incisional hernia (odds ratio 1.97, 95 per cent confidence interval 0.77 to 5.05; P = 0.173). CONCLUSION: The 1-year incisional hernia development was relatively low with clinical but not statistical difference between short and long stitches. Registration number: NCT01965249 (http://www.clinicaltrials.gov).

N-terminome analyses underscore the prevalence of SPPL3-mediated intramembrane proteolysis among Golgi-resident enzymes and its role in Golgi enzyme secretion.

Golgi membrane proteins such as glycosyltransferases and other glycan-modifying enzymes are key to glycosylation of proteins and lipids. Secretion of soluble Golgi enzymes that are released from their membrane anchor by endoprotease activity is a wide-spread yet largely unexplored phenomenon. The intramembrane protease SPPL3 can specifically cleave select Golgi enzymes, enabling their secretion and concomitantly altering global cellular glycosylation, yet the entire range of Golgi enzymes cleaved by SPPL3 under physiological conditions remains to be defined. Here, we established isogenic SPPL3-deficient HEK293 and HeLa cell lines and applied N-terminomics to identify substrates cleaved by SPPL3 and released into cell culture supernatants. With high confidence, our study identifies more than 20 substrates of SPPL3, including entirely novel substrates. Notably, our N-terminome analyses provide a comprehensive list of SPPL3 cleavage sites demonstrating that SPPL3-mediated shedding of Golgi enzymes occurs through intramembrane proteolysis. Through the use of chimeric glycosyltransferase constructs we show that transmembrane domains can determine cleavage by SPPL3. Using our cleavage site data, we surveyed public proteome data and found that SPPL3 cleavage products are present in human blood. We also generated HEK293 knock-in cells expressing the active site mutant D271A from the endogenous SPPL3 locus. Immunoblot analyses revealed that secretion of select novel substrates such as the key mucin-type O-glycosylation enzyme GALNT2 is dependent on endogenous SPPL3 protease activity. In sum, our study expands the spectrum of known physiological substrates of SPPL3 corroborating its significant role in Golgi enzyme turnover and secretion as well as in the regulation of global glycosylation pathways.

Variant-dependent heterogeneity in amyloid ß burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study.

BACKGROUND: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid ß (Aß) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. METHODS: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aß biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aß1-42 (Aß42), and levels of Aß1-40 (Aß40). FINDINGS: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aß42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. INTERPRETATION: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aß PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aß levels are not interchangeable and might reflect different Aß-driven pathobiological processes. FUNDING: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.

Prion type 2 selection in sporadic Creutzfeldt-Jakob disease affecting peripheral ganglia.

In sporadic Creutzfeldt-Jakob disease (sCJD), the pathological changes appear to be restricted to the central nervous system. Only involvement of the trigeminal ganglion is widely accepted. The present study systematically examined the involvement of peripheral ganglia in sCJD utilizing the currently most sensitive technique for detecting prions in tissue morphologically. The trigeminal, nodose, stellate, and celiac ganglia, as well as ganglia of the cervical, thoracic and lumbar sympathetic trunk of 40 patients were analyzed with the paraffin-embedded tissue (PET)-blot method. Apart from the trigeminal ganglion, which contained protein aggregates in five of 19 prion type 1 patients, evidence of prion protein aggregation was only found in patients associated with type 2 prions. With the PET-blot, aggregates of prion protein type 2 were found in all trigeminal (17/17), in some nodose (5 of 7) and thoracic (3 of 6) ganglia, as well as in a few celiac (4 of 19) and lumbar (1 of 5) ganglia of sCJD patients. Whereas aggregates of both prion types may spread to dorsal root ganglia, more CNS-distant ganglia seem to be only involved in patients accumulating prion type 2. Whether the prion type association is due to selection by prion type-dependent replication, or due to a prion type-dependent property of axonal spread remains to be resolved in further studies.

Abnormally reduced frontal cortex activity during Trail-Making-Test in prodromal parkinson's disease-a fNIRS study.

Parkinson's Disease (PD) is a neurodegenerative disorder leading to typical motor as well as a range of non-motor symptoms, including cognitive decline mainly characterized by executive deficits. The latter are known to appear years before the typical motor signs, thus representing the prodromal phase of PD. However, appropriate methods for measuring executive dysfunction in this context are not well established yet. Traditionally, executive performance is associated with frontal structures. Here, we investigated prodromal, early PD patients and healthy controls regarding their executive functioning on the behavioral and neural level, measured by the Trail-Making-Test (TMT) combined with functional near-infrared spectroscopy. We observed significantly reduced neural activity in the right dorsolateral prefrontal cortex within PD patients compared to controls completing the TMT-A and -B in contrast to the TMT-C, but no differences on a behavioral level. These promising results need to be confirmed and checked for reliability in future studies to extend the spectrum of markers applied in prodromal PD.

[Positive association between successful rehabilitation and patient hospital ratings: Experience reports of patients in rehabilitation on a hospital rating and review site]. / Klinik-Weiterempfehlung bei Reha-Erfolg: Erfahrungsberichte von Rehabilitanden auf einer Klinik-Bewertungsplattform.

INTRODUCTION: Feedback from patients about aspects of rehabilitation services is increasingly provided online, for example, on specialized hospital comparison websites. Therefore, we examined which kind of online statements from rehabilitation patients published on the leading hospital comparison website "Klinikbewertungen.de" (KB) is associated with a positive recommendation of a rehabilitation clinic and which negative aspects are associated with a non-recommendation. METHODS: For eight indication groups stratified online statements of rehabilitants at KB were evaluated qualitatively using content analysis. The relationship between positive (negative) statements and the (non-) recommendation was examined. RESULTS: Content analysis of 911 experience reports revealed 20 categories. Most often, it was the "rehabilitation success" perceived by rehabilitation patients that was significantly associated with a recommendation or a non-recommendation of a hospital, and in five quality assurance (QA) comparison groups the category "catering" was associated with a positive or negative recommendation. In all QS comparison groups, there was an association with at least one of the following process-oriented rehabilitation categories: "rehabilitation measures", "rehabilitation plan and rehabilitation goals" and / or "diagnosis to discharge". DISCUSSION AND CONCLUSION: Patient experiences with the perceived "rehabilitation success" and with the central processes of rehabilitation are particularly important for the recommendation or non-recommendation of a hospital for patients in all eight indication groups. On the basis of these results, rehabilitation hospitals can specifically identify the aspects of care that are important when patients recommend a hospital for rehabilitation. Online narratives of patients provide additional insights into the reasons for patients' satisfaction or dissatisfaction with their rehabilitation. These narratives are available to potential rehabilitation patients as a low-threshold source of information and decision-making aid.

Toughening of a Soft Polar Polythiophene through Copolymerization with Hard Urethane Segments.

Polar polythiophenes with oligoethylene glycol side chains are exceedingly soft materials. A low glass transition temperature and low degree of crystallinity prevents their use as a bulk material. The synthesis of a copolymer comprising 1) soft polythiophene blocks with tetraethylene glycol side chains, and 2) hard urethane segments is reported. The molecular design is contrary to that of other semiconductor-insulator copolymers, which typically combine a soft nonconjugated spacer with hard conjugated segments. Copolymerization of polar polythiophenes and urethane segments results in a ductile material that can be used as a free-standing solid. The copolymer displays a storage modulus of 25 MPa at room temperature, elongation at break of 95%, and a reduced degree of swelling due to hydrogen bonding. Both chemical doping and electrochemical oxidation reveal that the introduction of urethane segments does not unduly reduce the hole charge-carrier mobility and ability to take up charge. Further, stable operation is observed when the copolymer is used as the active layer of organic electrochemical transistors.