200 results found
Perneczky R, Dom G, Chan A, et al., 2023, Anti-amyloid antibody treatments for Alzheimer's disease., Eur J Neurol
Our aim is to review the most recent evidence on novel antibody therapies for Alzheimer's disease directed against amyloid-β. This is a joint statement of the European Association of Neurology and the European Psychiatric Association. After numerous unsuccessful endeavors to create a disease-modifying therapy for Alzheimer's disease, substantial and consistent evidence supporting the clinical effectiveness of monoclonal antibodies aimed at amyloid-β is finally emerging. The latest trials not only achieved their primary objective of slowing the progression of the disease over several months but also demonstrated positive secondary clinical outcomes and a decrease in amyloid-β levels as observed through positron emission tomography scans. Taken as a whole, these findings mark a significant breakthrough by substantiating that reducing amyloid-β yields tangible clinical benefits, beyond mere changes in biomarkers. Concurrently, the regular utilization of the new generation of drugs will determine whether statistical efficacy translates into clinically meaningful improvements. This may well signify the dawning of a new era in the development of drugs for Alzheimer's disease.
Finze A, Biechele G, Rauchmann B-S, et al., 2023, Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies., Mol Psychiatry
β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neu
Jiang X, Hu X, Daamen M, et al., 2023, Altered limbic functional connectivity in individuals with subjective cognitive decline: Converging and diverging findings across Chinese and German cohorts., Alzheimers Dement
INTRODUCTION: It remains unclear whether functional brain networks are consistently altered in individuals with subjective cognitive decline (SCD) of diverse ethnic and cultural backgrounds and whether the network alterations are associated with an amyloid burden. METHODS: Cross-sectional resting-state functional magnetic resonance imaging connectivity (FC) and amyloid-positron emission tomography (PET) data from the Chinese Sino Longitudinal Study on Cognitive Decline and German DZNE Longitudinal Cognitive Impairment and Dementia cohorts were analyzed. RESULTS: Limbic FC, particularly hippocampal connectivity with right insula, was consistently higher in SCD than in controls, and correlated with SCD-plus features. Smaller SCD subcohorts with PET showed inconsistent amyloid positivity rates and FC-amyloid associations across cohorts. DISCUSSION: Our results suggest an early adaptation of the limbic network in SCD, which may reflect increased awareness of cognitive decline, irrespective of amyloid pathology. Different amyloid positivity rates may indicate a heterogeneous underlying etiology in Eastern and Western SCD cohorts when applying current research criteria. Future studies should identify culture-specific features to enrich preclinical Alzheimer's disease in non-Western populations. HIGHLIGHTS: Common limbic hyperconnectivity across Chinese and German subjective cognitive decline (SCD) cohorts was observed. Limbic hyperconnectivity may reflect awareness of cognition, irrespective of amyloid load. Further cross-cultural harmonization of SCD regarding Alzheimer's disease pathology is required.
Kurz C, Stoeckl L, Schrurs I, et al., 2023, Impact of pre-analytical sample handling factors on plasma biomarkers of Alzheimer's disease, JOURNAL OF NEUROCHEMISTRY, ISSN: 0022-3042
Brosseron F, Maass A, Kleineidam L, et al., 2023, Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer's disease: results from the DELCODE study, ALZHEIMERS RESEARCH & THERAPY, Vol: 15
Sadlon A, Takousis P, Evangelou E, et al., 2022, A multi-omics approach identifies a blood-based miRNA signature of cognitive decline in two large observational trials
<jats:title>Abstract</jats:title><jats:p>Identifying individuals before the onset of overt symptoms is a key prerequisite for the prevention of Alzheimer’s disease (AD). A wealth of data reports dysregulated microRNA (miRNA) expression in the blood of individuals with AD, but evidence in individuals at subclinical stages is sparse. In this study, a qPCR analysis of a prioritised set of 38 candidate miRNAs in the blood of 830 healthy individuals from the CHARIOT PRO cohort (West London, UK) was undertaken. Here, we identified six differentially expressed miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A pathway enrichment analysis for the six miRNAs indicated involvement of apoptosis and inflammation, relevant in early AD stages. Subsequently, we used whole genome sequencing (WGS) data from 750 individuals from the AD Neuroimaging Initiative (ADNI) to perform a genetic association analysis for polymorphisms within the significant miRNAs’ genes and CSF concentrations of phosphorylated-tau, total-tau, amyloid-β42 and soluble-TREM2 and BACE1 activity. Our analysis revealed 24 SNPs within <jats:italic>MIR29C</jats:italic> to be associated with CSF levels of amyloid-β42 and soluble-TREM2 and BACE1 activity. Our study shows the potential of a six-miRNA set as diagnostic blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within <jats:italic>MIR29C</jats:italic> suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.</jats:p>
Brosseron F, Maass A, Kleineidam L, et al., 2022, Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer's disease, NEURON, Vol: 110, Pages: 1009-+, ISSN: 0896-6273
Franzmeier N, Brendel M, Beyer L, et al., 2022, Tau deposition patterns are associated with functional connectivity in primary tauopathies, NATURE COMMUNICATIONS, Vol: 13
Ersoezlue E, Perneczky R, Tatò M, et al., 2022, A residual marker of cognitive reserve is associated with resting-state intrinsic functional connectivity along the Alzheimer’s disease continuum
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Cognitive reserve (CR) explains interindividual differences in the impact of neurodegenerative burden on cognitive and daily functioning. A residual model was proposed to estimate CR more accurately compared to static measures, such as years of education. However, the functional brain correlates of residual CR markers (CRM) remain unexplored.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>From the DELCODE cohort, 318 participants with resting-state functional and structural MRI data were included and stratified using cerebrospinal fluid (CSF) biomarkers according to the A(myloid-β, Aβ)/T(au)/N(eurodegeneration) classification scheme, resulting in 112 Aβ-negative healthy controls and 206 Aβ-positive patients in the Alzheimer’s disease (AD) spectrum.. CRM was calculated utilizing residuals obtained from a multilinear regression model using global cognition as dependent variable and demographic and disease burden measures as predictors. Associations between the CRM and intrinsic network connectivity (INC) in resting-state networks associated with cognition were explored, including the default mode network (DMN), frontoparietal network (FPN), salience network (SAL) and dorsal attention network (DAN). Moreover, the association between memory performance-associated regional INC and CRM was assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>CRM was positively associated with INC in the DMN in the entire cohort. In a subgroup analysis, the A+T+N+ group revealed an anti-correlation between SAL and DMN. Furthermore, CRM was positively associated with the anti-correlation between the memory-related regions in the FPN and the DMN in the A+ and A+T/N+ subgroups.</jats:p></jats:sec><jats:sec><j
Kolabas ZI, Kuemmerle LB, Perneczky R, et al., 2021, Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation
<jats:title>SUMMARY</jats:title><jats:p>The meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific alterations including increased calvaria cell numbers. Moreover, TSPO-positron-emission-tomography imaging of stroke, multiple sclerosis and neurodegenerative disease patients demonstrate disease-associated uptake patterns in the human skull, mirroring the underlying brain inflammation. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies.</jats:p><jats:sec><jats:title>Graphical Abstract</jats:title><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="473988v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:list list-type="order"><jats:list-item><jats:p>Bone marrow across the mouse body display heterogeneity in their molecular profile</jats:p></jats:list-item><jats:list-item><jats:p>Calvaria cells have a distinct profile that is relevant to brain pathologies</jats:p></jats:list-item><jats:list-item>&
Rauchmann BS, Schneider-Axmann T, Perneczky R, 2021, Associations of longitudinal plasma p-tau181 and NfL with tau-PET, A beta-PET and cognition, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 92, Pages: 1289-1295, ISSN: 0022-3050
Xiang X, Wind K, Wiedemann T, et al., 2021, Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases, SCIENCE TRANSLATIONAL MEDICINE, Vol: 13, ISSN: 1946-6234
Islam MR, Kaurani L, Berulava T, et al., 2021, A microRNA signature that correlates with cognition and is a target against cognitive decline, EMBO MOLECULAR MEDICINE, Vol: 13, ISSN: 1757-4676
Ballarini T, van Lent DM, Brunner J, et al., 2021, Mediterranean Diet, Alzheimer Disease Biomarkers, and Brain Atrophy in Old Age, NEUROLOGY, Vol: 96, Pages: E2920-E2932, ISSN: 0028-3878
Franzmeier N, Ren J, Damm A, et al., 2021, The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease, MOLECULAR PSYCHIATRY, Vol: 26, Pages: 614-628, ISSN: 1359-4184
Rauchmann B-S, Ghaseminejad F, Mekala S, et al., 2020, Cerebral Microhemorrhage at MRI in Mild Cognitive Impairment and Early Alzheimer Disease: Association with Tau and Amyloid beta at PET Imaging, RADIOLOGY, Vol: 296, Pages: 134-142, ISSN: 0033-8419
Schoeberl F, Pradhan C, Irving S, et al., 2020, Real-space navigation testing differentiates between amyloid-positive and -negative aMCI, NEUROLOGY, Vol: 94, Pages: E861-E873, ISSN: 0028-3878
Schumann C, Alexopoulos P, Perneczky R, 2019, Determinants of self- and carer-rated quality of life and caregiver burden in Alzheimer disease, INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Vol: 34, Pages: 1378-1385, ISSN: 0885-6230
Sadlon A, Takousis P, Alexopoulos P, et al., 2019, miRNAs identify shared pathways in Alzheimer's and Parkinson's Diseases, Trends in Molecular Medicine, Vol: 25, Pages: 662-672, ISSN: 1471-4914
Despite the identification of several dozens of common genetic variants associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD), most of the genetic risk remains uncharacterised. Therefore, it is important to understand the role of regulatory elements, such as miRNAs. Dysregulated miRNAs are implicated in AD and PD, with potential value in dissecting the shared pathophysiology between the two disorders. miRNAs relevant to both neurodegenerative diseases are related to axonal guidance, apoptosis, and inflammation, therefore, AD and PD likely arise from similar underlying biological pathway defects. Furthermore, pathways regulated by APP, L1CAM, and genes of the caspase family may represent promising therapeutic miRNA targets in AD and PD since they are targeted by dysregulated miRNAs in both disorders.
Gallo V, Vineis P, Cancellieri M, et al., 2019, Exploring causality of the association between smoking and Parkinson's disease, International Journal of Epidemiology, Vol: 48, Pages: 912-925, ISSN: 1464-3685
Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding. Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.
Riso L, Kaaks R, Kühn T, et al., 2019, General and abdominal adiposity and the risk of parkinson's disease.A prospective chort study, Parkinsonism and Related Disorders, Vol: 62, Pages: 98-104, ISSN: 1353-8020
IntroductionDue to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD.MethodsIn 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking.ResultsWe found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD.ConclusionOur data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.
Perneczky R, Kempermann G, Korczyn AD, et al., 2019, Translational research on reserve against neurodegenerative disease: consensus report of the International Conference on Cognitive Reserve in the Dementias and the Alzheimer's Association Reserve, Resilience and Protective Factors Professional Interest Area working groups, BMC MEDICINE, Vol: 17, ISSN: 1741-7015
Rauchmann B-S, Schneider-Axmann T, Alexopoulos P, et al., 2019, CSF soluble TREM2 as a measure of immune response along the Alzheimer's disease continuum, NEUROBIOLOGY OF AGING, Vol: 74, Pages: 182-190, ISSN: 0197-4580
Beyer L, Schnabel J, Kazmierczak P, et al., 2019, Neuronal injury biomarkers for assessment of the individual cognitive reserve in clinically suspected Alzheimer's disease, NEUROIMAGE-CLINICAL, Vol: 24, ISSN: 2213-1582
Brugnolo A, De Carli F, Pagani M, et al., 2019, Head-to-Head Comparison among Semi-Quantification Tools of Brain FDG-PET to Aid the Diagnosis of Prodromal Alzheimer's Disease, JOURNAL OF ALZHEIMERS DISEASE, Vol: 68, Pages: 383-394, ISSN: 1387-2877
Beyer L, Schnabel J, Kazmierczak P, et al., 2018, Neuronal Injury Biomarkers for Assessment of Cognitive Reserve in Alzheimer's Disease, 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S228-S229, ISSN: 1619-7070
Zhang M, Ferrari R, Tartaglia MC, et al., 2018, A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers, BRAIN, Vol: 141, Pages: 2895-2907, ISSN: 0006-8950
Beyer L, Meyer-Wilmes J, Schoenecker S, et al., 2018, Left Temporal Hypometabolism in FDG-PET underlines Cognitive Reserve Hypothesis in Frontotemporal Dementia, 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S408-S408, ISSN: 1619-7070
Alexopoulos P, Gleixner L-S, Werle L, et al., 2018, Plasma levels of soluble amyloid precursor protein beta in symptomatic Alzheimer's disease, EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, Vol: 268, Pages: 519-524, ISSN: 0940-1334
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