Plasma glucose is not associated with performance on standard cognitive screening tests in a mixed memory clinic cohort-An observational cross-sectional study.

BACKGROUND: It has been shown under experimental conditions that cognitive performance, especially working memory, is impaired in patients with type I and type II diabetes mellitus during hyperglycemic and hypoglycemic conditions, perhaps due to altered cerebral glucose metabolism. It is not known if patients with neurodegenerative diseases, who also exhibit pathological cerebral glucose metabolism, are affected in a similar manner by their plasma glucose levels. OBJECTIVE: We aimed to test if performance on two cognitive screening tests was associated with plasma glucose levels in a memory clinic cohort. METHODS: We included patients from the Copenhagen Memory Clinic Cohort with an available Mini Mental-State Examination (MMSE) test score and a plasma glucose measurement performed in conjunction with cognitive testing. We built linear regression models with MMSE and Addenbrooke's Cognitive Examination (ACE) test scores as the outcome and plasma glucose as the explaining variable and adjusted models for age, sex, and diabetes (plasma glucose measurement >11.1 mmol/L). We explored non-linear relationships by adding quadratic terms and by fitting a cubic spline regression model. RESULTS: In total, 2714 patients had an available MMSE score and a plasma glucose measurement. MMSE and ACE total scores were not associated with plasma glucose in a linear or non-linear fashion when we adjusted for age, sex, and diabetes. CONCLUSION: Plasma glucose levels, predominantly within normal ranges, were not associated with performance on routinely applied cognitive tests and do not need to be taken into consideration when interpreting test results from memory clinic patients.

Associations between oxidative stress and perceived stress in patients with bipolar disorder and healthy control individuals.

OBJECTIVE: Patients with neurodegenerative disorders, schizophrenia, and bipolar disorder present with increased oxidative stress markers. Not only is oxidative stress associated with development of disease, but also with increased disease progression and mortality. Oxidative stress reflects an increase in pro-oxidants, which subsequently leads to oxidative modifications of cellular components, such as RNA and DNA. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the valid marker of whole-body RNA and DNA damage, respectively. Recently, cerebrospinal fluid (CSF) oxidative stress markers of RNA damage (8-oxoGuo) have showed both state and trait dependence in patients with bipolar disorder. However, the relation to subjective measures of stress and quality of life (QoL) is unknown. MATERIALS AND METHODS: This prospective, longitudinal 1-year follow-up case-control study investigated the association between the oxidative stress markers, 8-oxoGuo and 8-oxodG and, perceived stress and QoL in patients with bipolar disorder (n = 86, 51% female) and gender-and-age-matched healthy control (HC) individuals (n = 44, 44% female). Oxidative stress markers obtained in CSF and urine were analysed using ultra-performance liquid chromatography-tandem mass spectrometry. The subjective perception of stress was assessed using the Perceived Stress Scale. Subjective evaluation of QoL was assessed using the World Health Organization Quality of Life questionnaire. RESULTS AND CONCLUSION: We found that markers of oxidative stress in CSF and urine were not associated with perceived stress and QoL quality in patients with bipolar disorder. However, a putative association between urinary 8-oxoGuo oxidative stress marker for RNA damage and perceived stress in HC encourages further investigations.

Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia.

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-ß1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-ß1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia.

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-ß42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

Human Cerebrospinal Fluid Sample Preparation and Annotation for Integrated Lipidomics and Metabolomics Profiling Studies.

Cerebrospinal fluid (CSF) is a metabolically diverse biofluid and a key specimen for exploring biochemical changes in neurodegenerative diseases. Detecting lipid species in CSF using mass spectrometry (MS)-based techniques remains challenging because lipids are highly complex in structure, and their concentrations span over a broad dynamic range. This work aimed to develop a robust lipidomics and metabolomics method based on commonly used two-phase extraction systems from human CSF samples. Prioritizing lipid detection, biphasic extraction methods, Folch, Bligh and Dyer (B&D), Matyash, and acidified Folch and B&D (aFolch and aB&D) were compared using 150 µL of human CSF samples for the simultaneous extraction of lipids and metabolites with a wide range of polarity. Multiple chromatographical separation approaches, including reversed-phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), and gas chromatography (GC), were utilized to characterize human CSF metabolome. The aB&D method was found as the most reproducible technique (RSD < 15%) for lipid extraction. The aB&D and B&D yielded the highest peak intensities for targeted lipid internal standards and displayed superior extracting power for major endogenous lipid classes. A total of 674 unique metabolites with a wide polarity range were annotated in CSF using, combining RPLC-MS/MS lipidomics (n = 219), HILIC-MS/MS (n = 304), and GC-quadrupole time of flight (QTOF) MS (n = 151). Overall, our findings show that the aB&D extraction method provided suitable lipid coverage, reproducibility, and extraction efficiency for global lipidomics profiling of human CSF samples. In combination with RPLC-MS/MS lipidomics, complementary screening approaches enabled a comprehensive metabolite signature that can be employed in an array of clinical studies.

Biomarkers for neurodegeneration impact cognitive function: a longitudinal 1-year case-control study of patients with bipolar disorder and healthy control individuals.

BACKGROUND: Abnormalities in cerebrospinal fluid (CSF)-amyloid-beta (Aß)42, CSF-Aß40, CSF-Aß38, CSF-soluble amyloid precursor proteins α and ß, CSF-total-tau, CSF-phosphorylated-tau, CSF-neurofilament light protein (NF-L), CSF-neurogranin, plasma-Aß42, plasma-Aß40, plasma-total-tau, plasma-NF-L and, serum-S100B during affective episodes may reflect brain changes that could impact cognitive function in patients with bipolar disorder (BD). The study aimed to investigate the association between these biomarkers indicative of Alzheimer's disease and those reflecting neurodegeneration alongside their impact on cognitive function in patients with BD and healthy control individuals (HC). The primary hypothesis was that GL and VL would increase with increasing levels of CSF-Aß42 based on data from T0 and T3 in BD and HC jointly. METHODS: In a prospective, longitudinal case-control study euthymic patients with BD (N = 85) and HC (N = 44) were evaluated with clinical assessment and neuropsychological testing at baseline (T0) and during euthymia after a year (T3). Patients' affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. If an episode occurred during follow-up, the patient was also assessed in post-episode euthymia. Cognitive performance was measured as a global cognitive score (GL) for four cognitive domains including verbal learning and memory (VL). RESULTS: Estimated in a linear mixed model GL increased with 0.001 for each increase of 1 pg/ml of CSF-Aß42 (97.5%, CI 0.00043-0.0018, adjusted-p = 0.0005) while VL increased by 0.00089 (97.5%, CI 0.00015-0.0018, adjusted-p = 0.045) in BD and HC jointly. The association was weak, however stronger in patients with BD compared to HC. Associations between other biomarkers including CSF-neurogranin, and cognitive domains were overall weak, and none remained significant after adjustment for multiple testing. LIMITATIONS: Modest sample size. A complete data set regarding both CSF-AB-42 and cognitive test scores was obtained from merely 61 patients with BD and 38 HC individuals. CONCLUSION: CSF-Aß42 may be associated with cognitive dysfunction in patients with BD and HC individuals. The association appeared to be stronger in BD but with overlapping confidence intervals. Hence it remains uncertain whether the association is a general phenomenon or driven by BD.

Cerebrospinal fluid synaptic biomarker changes in bipolar disorder - A longitudinal case-control study.

BACKGROUND: This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections. METHODS: Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes. RESULTS: The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up. LIMITATION: It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect. CONCLUSION: This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.

Preserving cognition, quality of life, physical health and functional ability in Alzheimer's disease: the effect of physical exercise (ADEX trial): rationale and design.

BACKGROUND: Exercise is hypothesized to improve cognition, physical performance, functional ability and quality of life, but evidence is scarce. Previous studies were of short duration, often underpowered and involving home-based light exercise programs in patients with undefined dementia. The aim of the ADEX ('Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: the Effect of Physical Exercise') trial is to establish whether aerobic exercise is effective in improving cognition as well as in reducing the prevalence of psychiatric symptoms among patients with Alzheimer's disease (AD). METHODS: The ADEX study is a multicenter, single-blind, randomized trial with two arms: an intervention group attending 16 weeks of continuously supervised moderate-to-high intensity aerobic exercise and a control group receiving usual care. We plan to recruit 192 patients with mild AD. The primary outcome measure is change from baseline in cognitive performance at 16 weeks (as measured by the Symbol Digit Modalities test). CONCLUSIONS: To our knowledge this is the first large-scale controlled study to investigate the effects of supervised moderate aerobic exercise on cognition in patients with AD. Recruitment began in January 2012 and results are expected to be available in 2014. We summarize the methodological challenges we and other studies have faced in this type of complex multicenter intervention with unique challenges to study design.

Progression of Blood-Brain Barrier Leakage in Patients with Alzheimer's Disease as Measured with the Cerebrospinal Fluid/Plasma Albumin Ratio Over Time.

Background: Studies have found a disruption of the blood-brain barrier (BBB) in patients with Alzheimer's disease (AD), but there is little evidence of the changes in the BBB over time. The cerebrospinal fluid's (CSF) protein concentration can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate the changes in Q-Alb in patients with AD over time. Methods: A total of 16 patients diagnosed with AD, who had at least two lumbar punctures performed, were included in the current study. Results: The difference in Q-Alb over time did not show a significant change. However, Q-Alb increased over time if the time interval was > 1 year between the measurements. No significant associations between Q-Alb and age, Mini-Mental State Examination, or AD biomarkers were found. Conclusion: The increase in Q-Alb suggests that there is an increased leakage through the BBB, which may become more prominent as the disease progresses. This may be a sign of progressive underlying vascular pathology, even in patients with AD without major vascular lesions. More studies are needed to further understand the role of BBB integrity in patients with AD over time and the association with the progression of the disease.

Cerebrospinal fluid glucose is not altered in patients with dementia.

BACKGROUND: Studies have shown that the pathological changes of many dementia disorders begin several years before clinical onset. A connection between some of these pathophysiological changes and brain hypometabolism, seen in dementia disorders, is well established. Glucose is transported from the blood into the interstitial space, and the decreased demand for glucose by the degenerating brain tissue may thereby mirror increased levels of cerebrospinal fluid (CSF) glucose. In this study, the levels of CSF and plasma glucose and the CSF/plasma glucose ratio were investigated in a large cohort from a mixed memory clinic population in order to evaluate its diagnostic potential. METHOD: CSF and plasma samples were taken from 446 patients (Alzheimer's Disease (AD) (n = 320), vascular dementia (VaD) (n = 64), frontotemporal dementia (FTD) (n = 27) and dementia with Lewy bodies (DLB) (n = 35)), and 130 healthy controls (HC) (healthy subjects (HS) (n = 34), non-demented HS (n = 96)). RESULTS: No significant differences were found for CSF and plasma glucose or the CSF/plasma glucose ratio between patients with dementia disorders and HC. In addition, no significant differences were observed between the different dementia etiologies. CONCLUSION: CSF and plasma glucose were not useful to differentiate between HC and patients with various dementia disorders.

Neurofilament light chain levels in serum among a large mixed memory clinic cohort: Confounders and diagnostic usefulness.

INTRODUCTION: Early and accurate diagnosis of neurocognitive disorders including neurodegenerative dementia remains challenging. This study explores the impact of biological factors on serum neurofilament light chain (NfL) levels and clinical usefulness for the detection of neurocognitive disorders in a mixed memory clinic. METHODS: Serum samples and clinical data were obtained from 1188 patients who underwent diagnostic investigations for memory complaints between January 2018 and September 2019. Serum NfL was measured using single molecule array technology. RESULTS: NfL exhibited a moderate association with age, estimated glomerular filtration rate (eGFR), and Fazekas score. NfL was able to differentiate between patients with neurocognitive disorders and those without with a sensitivity and specificity of 80%. NfL could, however, not distinguish between different dementia etiologies. DISCUSSION: Serum NfL could aid early diagnostic triage by identifying patients requiring further diagnostic procedures and therefore aid in a more focused use of health-care resources.

Aerobic exercise does not affect serum neurofilament light in patients with mild Alzheimer's disease.

Introduction: Aerobic exercise has been shown to modify Alzheimer pathology in animal models, and in patients with multiple sclerosis to reduce neurofilament light (NfL), a biomarker of neurodegeneration. Objective: To investigate whether a 16-week aerobic exercise program was able to reduce serum NfL in patients with mild Alzheimer's disease (AD). Methods: This is a secondary analysis of data from the multi-center Preserving Cognition, Quality of Life, Physical Health, and Functional Ability in Alzheimer's disease: The Effect of Physical Exercise (ADEX) study. Participants were randomized to 16 weeks of moderate intensity aerobic exercise or usual care. Clinical assessment and measurement of serum NfL was done at baseline and after the intervention. Results: A total of 136 participants were included in the analysis. Groups were comparable at baseline except for APOEε4 carriership which was higher in the usual care group (75.3 versus 60.2%; p = 0.04). There was no effect of the intervention on serum NfL [intervention: baseline NfL (pg/mL) 25.76, change from baseline 0.87; usual care: baseline 27.09, change from baseline -1.16, p = 0.09]. Conclusion: The findings do not support an effect of the exercise intervention on a single measure of neurodegeneration in AD. Further studies are needed using other types and durations of exercise and other measures of neurodegeneration. Clinical trial registration: clinicaltrials.gov, identifier NCT01681602.

Differential proteomic profile of lumbar and ventricular cerebrospinal fluid.

BACKGROUND: Pathological cerebral conditions may manifest in altered composition of the cerebrospinal fluid (CSF). Although diagnostic CSF analysis seeks to establish pathological disturbances in the brain proper, CSF is generally sampled from the lumbar compartment for reasons of technical ease and ethical considerations. We here aimed to compare the molecular composition of CSF obtained from the ventricular versus the lumbar CSF compartments to establish a relevance for employing lumbar CSF as a proxy for the CSF bathing the brain tissue. METHODS: CSF was collected from 46 patients with idiopathic normal pressure hydrocephalus (iNPH) patients during their diagnostic workup (lumbar samples) and in connection with their subsequent CSF diversion shunt surgery (ventricular samples). The mass-spectrometry-based proteomic profile was determined in these samples and in addition, selected biomarkers were quantified with ELISA (S100B, neurofilament light (NfL), amyloid-ß (Aß40, Aß42), and total tau (T-tau) and phosphorylated tau (P-tau) forms). The latter analysis was extended to include paired porcine samples obtained from the lumbar compartment and the cerebromedullary cistern closely related to the ventricles. RESULTS: In total 1231 proteins were detected in the human CSF. Of these, 216 distributed equally in the two CSF compartments, whereas 22 were preferentially (or solely) present in the ventricular CSF and four in the lumbar CSF. The selected biomarkers of neurodegeneration and Alzheimer's disease displayed differential distribution, some with higher (S100B, T-tau, and P-tau) and some with lower (NfL, Aß40, Aß42) levels in the ventricular compartment. In the porcine samples, all biomarkers were most abundant in the lumbar CSF. CONCLUSIONS: The overall proteomic profile differs between the ventricular and the lumbar CSF compartments, and so does the distribution of clinically employed biomarkers. However, for a range of CSF proteins and biomarkers, one can reliably employ lumbar CSF as a proxy for ventricular CSF if or a lumbar/cranial index for the particular molecule has been established. It is therefore important to verify the compartmental preference of the proteins or biomarkers of interest prior to extrapolating from lumbar CSF to that of the ventricular fluid bordering the brain.

Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer's disease.

BACKGROUND: Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for the effects of exercise in Alzheimer's disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF, and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX. METHODS: proBDNF, BDNF, and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, and collected at baseline and 16 weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues. RESULTS: NDEV levels of proBDNF, BDNF, and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged. CONCLUSIONS: Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders. TRIAL REGISTRATION: The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered in ClinicalTrials.gov on April 30, 2012 with the identifier NCT01681602.

Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation.

Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD).31 members of the Danish CHMP2B-FTD family were included.We used solid-phase extraction and parallel reaction monitoring mass spectrometry.Six protein levels were significantly altered in CHMP2B-FTD compared with controls.Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer's disease neurons.

Alzheimer's disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied amyloid beta (Aß) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD phenotypes, such as increased Aß secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.

Effect of ageing on the passive and active tension and pharmacodynamic characteristics of rat coronary arteries: age-dependent increase in sensitivity to 5-HT and K+.

The influence of ageing on the passive and active tension and pharmacodynamic characteristics of intramural coronary arteries from 3-month-old and 2-year-old male Wistar rats was investigated using an isometric myograph. The passive vessel wall tension measured in Ca(2+)-free physiological salt solution at L(0) was significantly greater in arteries from old rats (1.46 ± 0.10 Nm(-1), n = 7) than in young rats (1.13 ± 0.13 Nm(-1), n = 6). However, the maximal active tension at L(0) was similar. The spontaneous myogenic tone was increased by age and the vasorelaxation induced by extracellular K(+) was significantly higher in coronary arteries of old rats. The sensitivity (pD(2)) to 5-HT was significantly higher in arteries from old (6.43 ± 0.11, n = 22) than from young rats (6.16 ± 0.08, n = 29). Ketanserin induced a concentration-dependent rightward shift of the 5-HT concentration-response curve in arteries from both young and old rats. The slopes of the regression lines of the Schild plots were not significantly different from unity and the estimated pK(B) values for ketanserin were similar. In conclusion, ageing is associated with changes in passive mechanical characteristics as well as changes in pharmacological properties in rat coronary small arteries.

The Added Value of Cerebrospinal Fluid Neurofilament Light Chain to Existing Diagnostic Methods and Biomarkers in a Mixed Memory Clinic Cohort of Consecutive Patients.

The added value of neurofilament light chain (NfL) to the existing diagnostic methods is unknown, although a plethora of studies have shown increased levels in cerebrospinal fluid (CSF) and blood in many neurodegenerative and neurological disorders. The added value of CSF NfL was determined in a mixed memory clinic cohort of consecutive patients for 136 patients with Alzheimer's disease (AD) (n = 69), mild cognitive impairment (n = 24), non-AD (n = 34), and also healthy controls (n = 9). This study found no increase in the diagnostic accuracy of the etiological diagnoses but knowing the CSF NfL value led to increased diagnostic certainty for the specialist in neurology.