A concerted neuron-astrocyte program declines in ageing and schizophrenia.

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

Uncovering elevated tau TPP motif phosphorylation in the brain of Alzheimer's disease patients.

INTRODUCTION: A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine-proline-proline (TPP). METHODS: We validated new and existing antibodies against pT217, pT231, pT175, and pT181, then combined immunohistochemistry (IHC) and immunoassays (ELISA) to broadly examine the phosphorylation of the tau TPP motif in AD brains. RESULTS: The tau burden, as examined by IHC and ELISA, correlates to Braak stages across all TPP sites. Moreover, we observed regional variability across four TPP motif phosphorylation sites in multiple brains of sporadic AD patients. DISCUSSION: We conclude that there is an elevation of TPP tau phosphorylation in AD brains as disease advances. The regional variability of pTPP tau suggests that examining different phosphorylation sites is essential for a comprehensive assessment of tau pathology.

Plasma amyloid beta X-42/X-40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease.

INTRODUCTION: Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline. METHODS: We measured levels of amyloid beta (Aß)X-40 and AßX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aß42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia. RESULTS: We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AßX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline. DISCUSSION: Our results suggest that assessing the plasma AßX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD. HIGHLIGHTS: New plasma Aß42/Aß40 measurement using immunoprecipitation-immunoassay Plasma Aß42/Aß40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.

Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease.

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.

Detection and quantification of Aß-3-40 (APP669-711) in cerebrospinal fluid.

Neurochemical biomarkers can support the diagnosis of Alzheimer's disease and may facilitate clinical trials. In blood plasma, the ratio of the amyloid-ß (Aß) peptides Aß-3-40/Aß1-42 can predict cerebral amyloid-ß pathology with high accuracy (Nakamura et al., 2018). Whether or not Aß-3-40 (aka. amyloid precursor protein (APP) 669-711) is also present in cerebrospinal fluid (CSF) is not clear. Here, we investigated whether Aß-3-40 can be detected in CSF and to what extent the CSF Aß-3-40/Aß42 ratio is able to differentiate between individuals with or without amyloid-ß positron emission tomography (PET) evidence of brain amyloid. The occurrence of Aß-3-40 in human CSF was assessed by immunoprecipitation followed by mass spectrometry. For quantifying the CSF concentrations of Aß-3-40 in 23 amyloid PET-negative and 17 amyloid PET-positive subjects, we applied a sandwich-type immunoassay. Our findings provide clear evidence of the presence of Aß-3-40 and Aß-3-38 in human CSF. While there was no statistically significant difference in the CSF concentration of Aß-3-40 between the two diagnostic groups, the CSF Aß-3-40/Aß42 ratio was increased in the amyloid PET-positive individuals. We conclude that Aß-3-40 appears to be a regular constituent of CSF and may potentially serve to accentuate the selective decrease in CSF Aß42 in Alzheimer's disease.

Identification of risk factors for delirium, cognitive decline, and dementia after cardiac surgery (FINDERI-find delirium risk factors): a study protocol of a prospective observational study.

BACKGROUND: Postoperative delirium is a common complication of cardiac surgery associated with higher morbidity, longer hospital stay, risk of cognitive decline, dementia, and mortality. Geriatric patients, patients undergoing cardiac surgery, and intensive care patients are at a high risk of developing postoperative delirium. Gold standard assessments or biomarkers to predict risk factors for delirium, cognitive decline, and dementia in patients undergoing cardiac surgery are not yet available. METHODS: The FINDERI trial (FINd DElirium RIsk factors) is a prospective, single-center, observational study. In total, 500 patients aged ≥ 50 years undergoing cardiac surgery at the Department of Cardiovascular and Thoracic Surgery of the University of Göttingen Medical Center will be recruited. Our primary aim is to validate a delirium risk assessment in context of cardiac surgery. Our secondary aims are to identify specific preoperative and perioperative factors associated with delirium, cognitive decline, and accelerated dementia after cardiac surgery, and to identify blood-based biomarkers that predict the incidence of postoperative delirium, cognitive decline, or dementia in patients undergoing cardiac surgery. DISCUSSION: This prospective, observational study might help to identify patients at high risk for delirium prior to cardiac surgery, and to identify important biological mechanisms by which cardiac surgery is associated with delirium. The predictive value of a delirium screening questionnaire in cardiac surgery might be revealed. Finally, the identification of specific blood biomarkers might help to predict delirium, cognitive decline, and dementia in patients undergoing cardiac surgery. TRIAL REGISTRATION: Ethics approval for this study was obtained from the IRB of the University of Göttingen Medical Center. The investigators registered this study in the German Clinical Trials Register (DRKS; https://www.drks.de ) (DRKS00025095) on April 19th, 2021.

Evolution of psychosocial burden and psychiatric symptoms in patients with psychiatric disorders during the Covid-19 pandemic.

The Covid-19 pandemic highly impacts mental health worldwide. Patients with psychiatric disorders are a vulnerable risk population for worsening of their condition and relapse of symptoms. This study investigates the pandemic-related course of psychosocial burden in patients with pre-existing mental disorders. With the newly developed Goettingen psychosocial Burden and Symptom Inventory (Goe-BSI) psychosocial burden has been traced retrospectively (1) before the pandemic (beginning of 2020), (2) at its beginning under maximum lockdown conditions (March 2020), and (3) for the current state after maximum lockdown conditions (April/May 2020). The Goe-BSI also integrates the Adjustment Disorder New Module (ADNM-20), assesses general psychiatric symptoms, and resilience. A total of 213 patients covering all major psychiatric disorders (ICD-10 F0-F9) were interviewed once in the time range from April, 24th until May 11th, 2020. Across all diagnoses patients exhibited a distinct pattern with an initial rise followed by a decline of psychosocial burden (p < 0.001, partial η2 = 0.09; Bonferroni-corrected pairwise comparisons between all three time-points: p < 0.05 to 0.001). Female gender and high ADNM-20 scores were identified as risk factors for higher levels and an unfavorable course of psychosocial burden over time. Most psychiatric symptoms remained unchanged. Trajectories of psychosocial burden vary in parallel to local lockdown restrictions and seem to reflect an adaptive stress response. For female patients with pre-existing mental disorders and patients with high-stress responses, timely and specific treatment should be scheduled. With the continuation of the pandemic, monitoring of long-term effects is of major importance, especially when long incubation times for the development of mental health issues are considered.

Medium-term and peri-lockdown course of psychosocial burden during the ongoing COVID-19 pandemic: a longitudinal study on patients with pre-existing mental disorders.

While the COVID-19 pandemic continues, patients with pre-existing mental disorders are increasingly recognized as a risk group for adverse outcomes. However, data are conflicting and cover only short time spans so far. Here, we investigate the medium-term and peri-lockdown-related changes of mental health outcomes in such patients in a longitudinal study. A cohort of 159 patients comprising all major mental disorders (ICD-10 F0-F9) were interviewed twice with the Goettingen psychosocial Burden and Symptom Inventory (Goe-BSI) to evaluate psychosocial burden, psychiatric symptoms and resilience at the end of the first (April/May 2020) and the second lockdown in Germany (November/December 2020). For the primary outcome "psychosocial burden" ratings also comprised retrospective pre-pandemic (early 2020) and very early states during the pandemic (March 2020). For all diagnostic groups, psychosocial burden varied significantly over time (p < 0.001) with an increase from the pre-pandemic to the initial phase (p < 0.001), followed by a steady decrease across both lockdowns, normalizing in November/December 2020. Female gender, high adjustment disorder symptom load at baseline and psychiatric comorbidities were risk factors for higher levels and an unfavorable course of psychosocial burden. Most psychiatric symptoms changed minimally, while resilience decreased over time (p = 0.044 and p = 0.037). The longitudinal course of psychosocial burden indicates an initial stress response, followed by a return to pre-pandemic levels even under recurrent lockdown conditions, mimicking symptoms of an adjustment disorder. Strategies for proactive, specific and continuous treatment have to address resilience capacities before their depletion in the pandemic aftermath, especially for patients with additional risk factors.

Autoantibody-associated psychiatric syndromes in children: link to adult psychiatry.

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

Current clinical practice of electroconvulsive therapy and repetitive transcranial magnetic stimulation in psychiatry, a German sample.

The purpose of the study was to evaluate the current clinical practice of Electroconvulsive Therapy and Repetitive Transcranial Magnetic Stimulation in German psychiatry. Case-based data (> 1.000.000 cases) were collected according to §21 of the German hospital remuneration law from January 2015 to December 2017. The study cohort comprises approximately 35-40% of the annual psychiatric cases and hospitals in Germany. Frequency of ECT and rTMS cases were investigated considering main diagnoses according to ICD-10 and treatment settings (inpatient vs. day-care). ECT cases with short-term hospitalization (≤ 4 days) were supposed to be maintenance ECT cases. A linear regression analysis was conducted to estimate trends in the use of ECT and rTMS. Different groups were compared using Chi-square tests. ECT and rTMS cases appear to increase in total during the observation period possibly due to facilities newly introducing ECT and rTMS but also to increased frequency of treatments. Both treatments were rarely performed in day-care settings (0.89% and 11.25%). ECT was performed in 1.72% of all cases with affective disorders and in 1.48% with major depressions, respectively. Age ≥ 65 years, females, severe and psychotic depression were significantly associated with a higher rate of ECT cases. > 40% of all ECT cases were possibly maintenance ECT cases. Only 0.60% of these were performed in day- care settings. rTMS was primarily performed in major depression (86,7% of all rTMS cases). This study suggests a growing demand for ECT and rTMS. Nevertheless, the use of ECT is still low compared to the high prevalence of treatment resistant depression. The use of rTMS is even lower and seems to be restricted to specialized institutions. Maintenance ECT is frequently carried out in an inpatient setting. Limitations of this study are the case- and group-based analysis, missing data on outpatient services and treatment sessions per case. Therefore, the database is not necessarily representative for the entire German healthcare system. Further studies are needed to verify the presented findings and should address the feasibility of ambulatory and day-care ECT services.

Exosomal Aß-Binding Proteins Identified by "In Silico" Analysis Represent Putative Blood-Derived Biomarker Candidates for Alzheimer´s Disease.

The potential of exosomes as biomarker resources for diagnostics and even for therapeutics has intensified research in the field, including in the context of Alzheimer´s disease (AD). The search for disease biomarkers in peripheral biofluids is advancing mainly due to the easy access it offers. In the study presented here, emphasis was given to the bioinformatic identification of putative exosomal candidates for AD. The exosomal proteomes of cerebrospinal fluid (CSF), serum and plasma, were obtained from three databases (ExoCarta, EVpedia and Vesiclepedia), and complemented with additional exosomal proteins already associated with AD but not found in the databases. The final biofluids' proteomes were submitted to gene ontology (GO) enrichment analysis and the exosomal Aß-binding proteins that can constitute putative candidates were identified. Among these candidates, gelsolin, a protein known to be involved in inhibiting Abeta fibril formation, was identified, and it was tested in human samples. The levels of this Aß-binding protein, with anti-amyloidogenic properties, were assessed in serum-derived exosomes isolated from controls and individuals with dementia, including AD cases, and revealed altered expression patterns. Identification of potential peripheral biomarker candidates for AD may be useful, not only for early disease diagnosis but also in drug trials and to monitor disease progression, allowing for a timely therapeutic intervention, which will positively impact the patient's quality of life.

CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer's disease.

OBJECTIVE: There is still an urgent need for supportive minimally invasive and cost-effective biomarkers for early diagnosis of Alzheimer's disease (AD). Previous work in our lab has identified Kallikrein-8 (KLK8) as a potential candidate since it shows an excessive increase in human brain in preclinical disease stages. The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) and blood KLK8 for AD and mild cognitive impairment (MCI) due to AD. METHODS: In this multi-centre trans-sectional study, clinical and laboratory data as well as CSF and/or blood serum samples of 237 participants, including 98 patients with mild AD, 21 with MCI due to AD and 118 controls were collected. CSF and/or serum KLK8 levels were analysed by ELISA. The diagnostic accuracy of KLK8 in CSF and blood was determined using receiver operating characteristic (ROC) analyses and compared with that of CSF core biomarkers Aß42, P-tau and T-tau. RESULTS: The diagnostic accuracy of CSF KLK8 was as good as that of core CSF biomarkers for AD (area under the curve (AUC)=0.89) and in case of MCI (AUC=0.97) even superior to CSF Aß42. Blood KLK8 was a similarly strong discriminator for MCI (AUC=0.94) but slightly weaker for AD (AUC=0.83). CONCLUSIONS: This is the first study to demonstrate the potential clinical utility of blood and CSF KLK8 as a biomarker for incipient AD. Future prospective validation studies are warranted.

Prevalence of affective disorders and dementia in inflammatory polyarthropathies.

Comorbid disorders are common in psychiatric diseases and understanding the risk of secondary diseases can aid successful clinical treatment. The objective of this study was to compare the frequency of comorbid dementia, affective disorders, and inflammatory polyarthropathies. Healthcare data obtained via the German Hospital Fees Act from two independent databases with more than 7.4 million cases were analyzed to compare the prevalence of comorbid disorders. Comorbid inflammatory polyarthropathy was observed in 2.27% of patients diagnosed with affective disorders and 1.35% of patients with dementia (p < 0.001). Among patients with a primary diagnosis of inflammatory polyarthropathy, 1.27% of patients were diagnosed with dementia, whereas 4.55% of age-matched patients without inflammatory polyarthropathies had comorbid dementia (p < 0.001). The opposite effect was demonstrated for affective disorders, as 5.77% of patients with a primary diagnosis of inflammatory polyarthropathy also had comorbid affective disorders, while 4.87% of age-matched patients without inflammatory polyarthropathy had an accompanying affective disease (p < 0.001). These findings show an association between the occurrence of inflammatory polyarthropathies, dementia, and affective disorders. This correlation might improve diagnosis and treatment for patients with comorbidities. Moreover, further exploration of the molecular pathophysiology underlying these relationships could be relevant for the development of novel treatment options.

Nuclear medical imaging as part of dementia diagnostics in psychiatric day-care clinics and inpatient care settings.

BACKGROUND: Current guidelines support the use of nuclear medical imaging (NMI) techniques for differential diagnostics of certain cases of dementia. AIMS: We aimed at studying the association between using NMI and the accuracy of dementia diagnoses. Additionally, we evaluated the effect of conducting NMI on the duration of hospital treatment. METHODS: This study was based on data collected according to §21 of the German hospital remuneration law, including relevant diagnostic and procedural codes for NMI in dementia patients. In total, more than 7.2 million cases treated in German psychiatric and somatic hospitals between 2015 and 2017 were included. Associations between the frequency of NMI and the accuracy of dementia diagnoses in terms of specific vs. unspecific diagnostic codes were analyzed using Fischer's exact test. RESULTS: In total, 351,106 cases with a dementia diagnosis were encoded during the study period. NMI was performed in 1.03% or 0.15% of all patients with dementia in psychiatric or somatic clinics, respectively. In psychiatric clinics, the proportion of unspecific dementia diagnoses decreased from 20.86% in 2015 to 17.73% in 2017. NMI was mainly performed within psychiatric day-care settings. Interestingly, patients receiving NMI stayed shorter within day-care settings (8.1 ± 16.0 days) compared to inpatient settings (38.3 ± 44.7 days). CONCLUSIONS: Nuclear medical imaging is often performed in psychiatric day-care settings. Further studies are warranted to understand the predictive diagnostic value of NMI in dementia diagnosis compared with clinical, CSF and structural imaging in different healthcare settings.

Development and Technical Validation of an Immunoassay for the Detection of APP669-711 (Aß-3-40) in Biological Samples.

The ratio of amyloid precursor protein (APP)669-711 (Aß-3-40)/Aß1-42 in blood plasma was reported to represent a novel Alzheimer's disease biomarker. Here, we describe the characterization of two antibodies against the N-terminus of Aß-3-x and the development and "fit-for-purpose" technical validation of a sandwich immunoassay for the measurement of Aß-3-40. Antibody selectivity was assessed by capillary isoelectric focusing immunoassay, Western blot analysis, and immunohistochemistry. The analytical validation addressed assay range, repeatability, specificity, between-run variability, impact of pre-analytical sample handling procedures, assay interference, and analytical spike recoveries. Blood plasma was analyzed after Aß immunoprecipitation by a two-step immunoassay procedure. Both monoclonal antibodies detected Aß-3-40 with no appreciable cross reactivity with Aß1-40 or N-terminally truncated Aß variants. However, the amyloid precursor protein was also recognized. The immunoassay showed high selectivity for Aß-3-40 with a quantitative assay range of 22 pg/mL-7.5 ng/mL. Acceptable intermediate imprecision of the complete two-step immunoassay was reached after normalization. In a small clinical sample, the measured Aß42/Aß-3-40 and Aß42/Aß40 ratios were lower in patients with dementia of the Alzheimer's type than in other dementias. In summary, the methodological groundwork for further optimization and future studies addressing the Aß42/Aß-3-40 ratio as a novel biomarker candidate for Alzheimer's disease has been set.

Validation of a prototype tau Thr231 phosphorylation CSF ELISA as a potential biomarker for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques (senile plaques) and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. This process leads to neuronal degradation and neuronal death. Phosphorylation of tau protein at threonine 231 (p-tau231) has been shown to be characteristic in post-mortem brain tissue of patients with AD and it can be sensitively detected in cerebrospinal fluid (CSF). Therefore, it may serve as a biomarker to support the diagnosis of AD. In this study, we analysed how well p-tau231 could differentiate between patients suffering from dementia either due or not due to AD by a sandwich enzyme immunoassay. CSF p-tau231 was significantly higher in patients with dementia due to AD than in those with dementia due to other causes. In addition, we studied different factors affecting p-tau231 levels in CSF. We found that apolipoprotein E genotype influences p-tau231 CSF levels. Gender and age did not affect p-tau231 levels in CSF. Our findings indicate that p-tau231 levels in CSF can be a valuable marker for the clinical diagnosis of AD.

[New biomarkers for Alzheimer's disease in cerebrospinal fluid and blood]. / Neue Biomarker für die Alzheimer-Krankheit in Liquor und Blut.

In accordance with the current German dementia guidelines, the dementia biomarkers amyloid beta 42, the tau peptides total tau and phosphorylated tau 181 are recommended for cerebrospinal fluid (CSF)-based diagnostics of dementia. Several studies have clearly shown that determination of the amyloid beta 42 to amyloid beta 40 peptide ratio is superior to the interpretation of amyloid beta 42 alone and should be implemented in the clinical work-up; however, in recent years different studies have presented many other innovative CSF and blood-based biomarkers. Besides CSF-based neurochemical diagnostics of dementia promising novel protocols for the detection of amyloid beta peptides in blood have meanwhile been published, which can currently be used in clinical studies for blood-based early diagnostics of Alzheimer's dementia. Following further validation and assay optimization these blood assays should be available for routine diagnostics in the near future.

Multiplex immunoassay measurement of amyloid-ß42 to amyloid-ß40 ratio in plasma discriminates between dementia due to Alzheimer's disease and dementia not due to Alzheimer's disease.

The cerebrospinal fluid (CSF) biomarkers amyloid-ß42 (Aß42), total Tau, and phospho-181-Tau represent important diagnostic tools to support the clinical diagnosis of Alzheimer's disease (AD). Acquiring CSF by lumbar puncture is considered a moderately invasive procedure, while blood sampling is minimally invasive with calculable risks and can be performed by trained non-medical staff. Thus, the identification of reliable and robust blood biomarkers of AD-related neuropathology would be significantly advantageous in daily practice and would allow more patients to be screened. In this study, we performed a multiplex amyloid-ß assay to simultaneously measure Aß40 and Aß42. We analyzed how well Aß40, Aß42, and the Aß42 to Aß40 ratio (Aß42/40) could differentiate between patients suffering from dementia either due or not due to AD. In addition, we studied different factors affecting Aß levels in plasma. Plasma Aß42/40 level was significantly lower in patients with dementia due to AD than in those with dementia due to other causes. Aß42/40 correlated weakly between plasma and CSF, but did not differ between amyloid-PET positive or negative patients. Furthermore, we found that kidney function influences Aß40 and Aß42 plasma levels, but not Aß42/40 level. Liver function, age, and sex do not affect Aß levels in plasma.

Cardiovascular and metabolic comorbidities in patients with Alzheimer's disease and vascular dementia compared to a psychiatric control cohort.

BACKGROUND: Multimorbidity in dementia is associated with an increased risk of complications and a higher need for care. Having knowledge of cardiovascular and metabolic comorbidities is crucial when making decisions about diagnostic procedures and therapies. We compared the prevalence of comorbidities in hospitalized patients with Alzheimer's disease (AD), vascular dementia, and psychiatric diseases other than dementia. Additionally, we compared clinically relevant health-care indicators (length of hospital stay, rate of re-hospitalization) between these groups. METHODS: We used information from a database of treatment-relevant indicators from psychiatric and psychosomatic hospitals throughout Germany. This database contains routinely recorded data collected from 85 German hospitals from 2011 to 2015. In total, 14 411 AD cases, 7156 vascular dementia cases, and 34 534 cases involving non-demented psychiatric patients (used as controls) were included. To analyze comorbidities and health-care indicators, χ2 tests and t-tests were used. RESULTS: Diabetes mellitus, lipoprotein disorders, coronary artery diseases, cardiac arrhythmia and insufficiency, and atherosclerosis were significantly more prevalent in patients with vascular dementia than in those with AD and psychiatric controls. Hypertension and coronary artery diseases were less frequently associated with AD than with non-demented psychiatric controls (P < 0.001). Additionally, dementia patients with cardiovascular or metabolic diseases exhibited longer hospital stays (+ 1.4 days, P < 0.001) and were more often re-hospitalized within 3 weeks (P < 0.001) and 1 year (P < 0.001) compared to dementia patients without these comorbidities. CONCLUSIONS: Awareness of somatic comorbidities in patients with dementia is crucial to avoid complications during inpatient treatment. The occurrence of comorbid disorders was associated with longer and more frequent hospital stays, which potentially lead to higher health-care costs. Further studies should evaluate the causative association between somatic comorbidities and inpatient costs in dementia patients.

Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson's disease.

Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD.