Results from the DELCODE study

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids

Results from the DELCODE study

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids

Theory of Magneto--Acoustic Transport in Modulated Quantum Hall Systems Near ν=1/2\nu=1/2

Motivated by the experimental results of Willett et al [Phys.Rev. Lett., {\bf 78}, 4478 (1997)] we develop a magneto-transport theory for the response of a two dimensional electron gas (2DEG) in the Fractional Quantum Hall Regime near Landau level filling factor $\nu = 1/2$ to the surface acoustic wave (SAW) in the presence of an added periodic density modulation. We assume there exists a Composite Fermion Fermi Surface (CF-FS) at $\nu = 1/2$, and we show that the deformation of the (CF-FS) due to the density modulation can be at the origin of the observed transport anomalies for the experimental conditions. Our analysis is carried out particularly for the non-local case which corresponds to the SAW experiments. We introduce a new model of a deformed CF-FS. The model permits us to explain anomalous features of the response of the modulated 2DEG to the SAW near $\nu = 1/2:$ namely the nonlinear wave vector dependence of the electron conductivity, the appearance of peaks in the SAW velocity shift and attenuation and the anisotropy of the effect, all of which originate from contributions to the conductivity tensor due to the regions of the CF-FS which are flattened by the applied modulation.Comment: 13 pages, 4 figures, the published versio

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas and pancreatic neuroendocrine tumors.

BACKGROUND Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown. METHODS We performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas. RESULTS Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. CONCLUSIONS Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification

The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity

Neue Ansätze zur Differenzierung zwischen Personen mit präklinischer und klinischer Alzheimer-Erkrankung und gesunden Probanden validiert durch Cerebrospinalflüssigkeit

Introduction: Diagnosing Alzheimer’s Disease (AD) is complex, the earlier the disease's stage, the more difficult. Various factors are hindering an effortless diagnosis of the disease. Depressive symptoms can be a confounding variable, and the established diagnostic tools to find neurobiological evidence for a developing AD are high in cost and effort. Therefore, novel approaches providing differential diagnostic information are wanted. Methods: For Menne et al., 2020, sensitivity and specificity of different neuropsychological tests to discriminate between 190 CSF-positive and 307 CSF-negative subjects with varying numbers of depressive symptoms were calculated. For Schipke & Menne et al., 2020, a logistic algorithm with 6 serum biomarkers was trained and validated to be used for dichotomous classification (suspicious/not suspicious of AD) on 55 subjects with MCI AD, 25 subjects with MCI non-AD, and 68 healthy controls. For Miebach et al., 2019, a semi-structured interview on subjective cognitive decline was conducted with memory clinic patients and controls without objective cognitive decline (healthy controls n=76, AD relatives n=24, subjective cognitive decline n=105). Subsequently, interview questions were associated with CSF biomarkers. Results: For Menne et al., 2020, we found that the neuropsychological test TMT-B is best in discriminating between patients with and without CSF values typical for AD in subjects with elevated numbers of depressive symptoms. For Schipke & Menne et al., 2020, it could be shown that the biomarker panel can differentiate between MCI due to AD patients and healthy controls with an accuracy of 86%. For Miebach et al., 2019, it was found that reported decline in memory and language abilities is associated with lower Aß-42 levels in CSF. Discussion: Early and differential diagnostic for AD is crucial for taking preventive action as early as possible. The established diagnostic gold standard, for which neurobiological evidence for AD is essential, is not readily available to the broader public for various reasons. With the findings presented here, we demonstrate alternative approaches to the established diagnostic measures, which are possible to be performed outside of specialized memory clinics. Furthermore, they are lower in cost and effort and less invasive.Einleitung: Die Diagnose der Alzheimer-Krankheit (AD) ist komplex, je früher das Stadium der Erkrankung, desto schwieriger. Es gibt verschiedene Faktoren, die eine einfache Diagnose der Krankheit erschweren. Depressive Symptome können dabei eine Stör-Variable sein, und die etablierten Diagnosewerkzeuge, um neurobiologische Hinweise für eine beginnende AD zu finden, sind mit hohen Kosten und Aufwand verbunden. Daher sind neuartige Ansätze nötig, die differentialdiagnostische Informationen liefern. Methoden: Für Menne et al., 2020, wurden Sensitivität und Spezifität verschiedener neuropsychologischer Tests zur Unterscheidung zwischen 190 CSF-positiven und 307 CSF-negativen Probanden mit verschiedener Anzahl depressiver Symptome berechnet. Für Schipke & Menne et al., 2020, wurde ein logistischer Algorithmus mit 6 Serumbiomarkern trainiert und validiert, um dann für eine dichotome Klassifizierung (hinweisgebend / nicht hinweisgebend auf AD) bei 55 Probanden mit MCI bei AD, 25 Probanden mit non-AD MCI sowie 68 gesunden Kontrollen angewendet zu werden. Für Miebach et al., 2019, wurde ein halbstrukturiertes Interview zu subjektiven Gedächtnisbeschwerden mit Patienten und Kontrollen ohne objektivierbare kognitive Einschränkungen aus verschiedenen Memory Clinics durchgeführt (gesunde Kontrollen n=76, AD-Verwandte n=24, subjektive Gedächtnisbeschwerden n=105). Anschließend wurden die Interviewfragen mit CSF-Biomarkern assoziiert. Ergebnisse: Für Menne et al., 2020, fanden wir, dass bei einer erhöhten Anzahl depressiver Symptome der neuropsychologische Test TMT-B am besten zur Unterscheidung zwischen Patienten mit und ohne AD-typische Liquor-Werte geeignet ist. Für Schipke & Menne et al., 2020, konnte gezeigt werden, dass das Biomarker-Panel mit einer Genauigkeit von 86% zwischen MCI aufgrund von AD-Patienten und gesunden Kontrollen unterscheiden kann. Für Miebach et al., 2019, wurde festgestellt, dass ein subjektiver Rückgang der Gedächtnis- und Sprachfähigkeiten mit niedrigeren Aß-42-Spiegeln im Liquor verbunden ist. Diskussion: Früh- und Differentialdiagnostik für AD ist essenziell zur frühestmöglichen Prävention. Der etablierte diagnostische Goldstandard, für den neurobiologische Hinweise auf AD unerlässlich sind, ist aus verschiedenen Gründen für die breite Öffentlichkeit nicht niedrigschwellig zugänglich. Mit den hier vorgestellten Ergebnissen zeigen wir, dass es alternative Ansätze zu den etablierten diagnostischen Maßnahmen gibt, die außerhalb spezialisierter Gedächtnisambulanzen durchgeführt werden können. Darüber hinaus sind sie kostengünstiger und weniger invasiv

Long-term stability and age-dependence of six regulatory serum proteins

Aim: The development of biomarker-based diagnostic procedures often relies on samples stored for several years. We aimed to investigate the influence of storage time and patient age on six neuroregulatory and immunoregulatory serum biomarkers. Materials & methods: We quantified six biomarkers in serum from 151 individuals using ELISA. Serum was stored at -80°C for up to 9.5 years. Results: When associating storage time with biomarker values, BDNF, VEGF-A and TGF-β1 showed a significant increase over time; IGF-1, MCP-1 and IL-18 did not. Associating participant age with biomarkers, only IL-18 in Alzheimer's disease patients showed a significant increase. Conclusion: Storage time can influence results of biomarkers in human serum. This needs to be considered when assessing samples stored for several years. Keywords: Alzheimer’s disease; age-dependence; biobanking; biomarkers; blood serum; cognitive impairment; long-term storage; neuroinflammation; neuroprotection; storage time

Comparison of diagnostic routines for suspected Alzheimer’s disease patients in US–American and German primary care supplement

Aim: Thorough diagnostics are a prerequisite for the optimal treatment of Alzheimer’s disease (AD). Biomarker-based diagnostics are standard in academia, data on practitioners’ diagnostic workups is scarce. Materials & methods: Surveys in German and US healthcare providers (HCP) were conducted regarding diagnostics in presumed AD patients. A subsample of 153 German and 88 US professionals was analyzed in detail. Results: Fewer German physicians conduct AD diagnostics themselves compared with US colleagues (67% vs 99%; p Conclusion: Diagnostic routines for suspected AD patients differ between German and US–American healthcare providers. Plain language summary: It is important to conduct the best-possible tests to come to a correct diagnosis of Alzheimer’s disease (AD). This ensures choosing the optimal treatment. In academic surroundings such as specialized memory clinics, so called biomarkers (found for example in blood) are an important component in finding the correct diagnosis. However, there is limited data on the methods healthcare providers (HCP) use in their everyday clinical practice. With this study, we aimed to get a clearer picture of the differences in the diagnostic routines for potential AD patients implemented by HCPs in two highincome countries, Germany and the USA. We conducted two surveys in 500 German and 100 US HCPs on their AD-diagnostic routines. A comparable subsample of 153 German and 88 US professionals was analyzed in detail.We found that fewer German physicians conduct AD diagnostics themselves compared with their US–American colleagues (67% vs 99%). The other way around, German doctors more often order diagnostics at other institutions (65% vs 45%). However, there were no significant differences in the type of diagnostic procedures ordered at other institutions. In conclusion, diagnostic routines for suspected AD patients differ between German and US–American healthcare providers, such as biomarkerbased diagnostics, which German physicians significantly perform less often.</p