194 results found
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., Nat Commun, Vol: 13
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.
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
Fan Z, Calsolaro V, Mayers J, et al., 2018, Relationship between astrocyte activation using [11C]BU99008 PET, glucose metabolism and amyloid in Alzheimer’s disease: a Dementia Platform UK experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P1640-P1640, ISSN: 1552-5260
Calsolaro V, Mayers J, Fan Z, et al., 2018, Evaluation of novel astrocyte marker [11C]BU99008 PET in Alzheimer’s disease: a Dementia Platform U.K. experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P842-P843, ISSN: 1552-5260
Beyer L, Meyer-Wilmes J, Schönecker S, et al., 2018, Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging?, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295
Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET. Methods: A total of 117 patients (age 68.4 ± 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis. Results: Suspected diagnoses were confirmed by clinical follow-up (≥1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high. Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods.
Alexopoulos P, Thierjung N, Grimmer T, et al., 2018, Cerebrospinal fluid BACE1 activity and sAβPPβ as biomarker candidates of Alzheimer's Disease, Dementia and Geriatric Cognitive Disorders, Vol: 45, Pages: 152-161, ISSN: 1420-8008
BACKGROUND/AIMS: The utility of β-site amyloid-β precursor protein (AβPP) cleaving enzyme 1 (BACE1) activity and soluble AβPP β (sAβPPβ) levels in cerebrospinal fluid (CSF) in detecting Alzheimer's disease (AD) is still elusive. METHODS: BACE1 activity and sAβPPβ concentration were measured in patients with AD dementia (n = 56) and mild cognitive impairment (MCI) due to AD (n = 76) with abnormal routine AD CSF markers, in patients with MCI with normal CSF markers (n = 39), and in controls without preclinical AD (n = 48). In a subsample with available 18F-fluorodeoxyglucose positron emission tomography (FDG PET) data, ordinal regression models were employed to compare the contribution of BACE1 and sAβPPβ to correct diagnostic classification to that of FDG PET. RESULTS: BACE1 activity was significantly higher in patients with MCI due to AD compared to both controls and patients with MCI with normal CSF markers. sAβPPβ did not differ between any of the studied groups. Interestingly, BACE1 activity was not found to be inferior to FDG PET as predictive covariate in differentiating between the diagnostic groups. CONCLUSIONS: Further studies using biomarker-underpinned diagnoses are warranted to shed more light on the potential diagnostic utility of BACE1 activity as AD biomarker candidate in MCI.
Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.
Franzmeier N, Düzel E, Jessen F, et al., 2018, Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease, Brain, Vol: 141, Pages: 1186-1200, ISSN: 1460-2156
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
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