Imperial College London

DrRobertPerneczky

Faculty of MedicineSchool of Public Health

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 0611r.perneczky

 
 
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Location

 

10L05Lab BlockCharing Cross Campus

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Summary

 

Publications

Publication Type
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188 results found

Rauchmann BS, Schneider-Axmann T, Perneczky R, Alzheimer's Disease Neuroimaging Initiative ADNIet al., 2021, Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Aβ-PET and cognition., J Neurol Neurosurg Psychiatry

OBJECTIVE: To explore if changes over time of plasma phosphorylated tau (p-tau)181 and neurofilament light chain (NfL) predict future tau and amyloid β (Aβ) PET load and cognitive performance, we studied a subsample of the Alzheimer's disease (AD) neuroimaging cohort with longitudinal blood peptide assessments. METHODS: Eight hundred and sixty-five AD Neuroimaging Initiative participants were included. Using established AD cut-points for the cerebrospinal fluid concentrations of Aβ42, total-tau and p-tau181, subjects were classified according to the National Institute on Aging-Alzheimer's Association research framework, grouping markers into those of Aβ deposition (A), tau pathology (T) and neurodegeneration (N). Analysis of variance was used to compare the plasma biomarker data between the ATN groups. The rate of change over time of p-tau181 and NfL was obtained from linear mixed effects models and compared between the ATN groups. Linear regression analysis was used to investigate the association of baseline plasma biomarker concentrations and rates of change with future PET tau and Aβ load and cognitive performance. RESULTS: P-tau181 and NfL plasma concentrations increased along the AD spectrum, but only NfL showed greater rates of change in AD patients versus controls. Cognitive performance was associated cross-sectionally with NfL in all subgroups, and with p-tau181 only in AD spectrum individuals. The baseline concentrations of both plasma markers predicted PET Aβ and tau load and cognitive performance. The rate of change of NfL predicted future PET tau and cognitive performance. CONCLUSIONS: P-tau and NfL behave differently within the same individuals over time and may therefore offer complementary diagnostic information. TRIAL REGISTRATION NUMBER: NCT02854033, NCT01231971.

Journal article

Ballarini T, Melo van Lent D, Brunner J, Schröder A, Wolfsgruber S, Altenstein S, Brosseron F, Buerger K, Dechent P, Dobisch L, Duzel E, Ertl-Wagner B, Fliessbach K, Freiesleben SD, Frommann I, Glanz W, Hauser D, Haynes JD, Heneka MT, Janowitz D, Kilimann I, Laske C, Maier F, Metzger CD, Munk M, Perneczky R, Peters O, Priller J, Ramirez A, Rauchmann B, Roy N, Scheffler K, Schneider A, Spottke A, Spruth EJ, Teipel SJ, Vukovich R, Wiltfang J, Jessen F, Wagner M, DELCODE study groupet al., 2021, Mediterranean Diet, Alzheimer Disease Biomarkers and Brain Atrophy in Old Age., Neurology

OBJECTIVE: To determine if following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer's disease (AD), we analyzed cross-sectional data from the German Longitudinal Cognitive Impairment and Dementia Study METHOD: The sample (n=512, mean age: 69.5±5.9 years) included 169 cognitively normal participants and subjects at higher AD risk (53 AD relatives, 209 SCD and 81 MCI). We defined MeDi adherence based on the Food Frequency Questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI and cognitive performance with an extensive neuropsychological battery. AD-related biomarkers (Aβ42/40 ratio, pTau181) in cerebrospinal fluid were assessed in n=226 individuals. We analyzed the associations between MeDi and the outcomes with linear regression models controlling for several covariates. Additionally, we applied hypothesis-driven mediation and moderation analysis. RESULTS: Higher MeDi adherence related to larger mediotemporal gray matter volume (p<0.05 FWE corrected), better memory (β±SE = 0.03 ± 0.02; p=0.038), and less amyloid (Aβ42/40 ratio, β±SE = 0.003 ± 0.001; p=0.008) and pTau181 pathology (β±SE = -1.96±0.68; p=0.004). Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations between Aβ42/40 ratio, pTau181 and mediotemporal atrophy. Results were consistent correcting for ApoE-ε4 status. CONCLUSION: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. Importantly, they suggest that these associations might be explained by a decrease of amyloidosis and tau-pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.

Journal article

Franzmeier N, Ren J, Damm A, Monte-Rubio G, Boada M, Ruiz A, Ramirez A, Jessen F, Duezel E, Rodriguez Gomez O, Benzinger T, Goate A, Karch CM, Fagan AM, McDade E, Buerger K, Levin J, Duering M, Dichgans M, Suarez-Calvet M, Haass C, Gordon BA, Lim YY, Masters CL, Janowitz D, Catak C, Wolfsgruber S, Wagner M, Milz E, Moreno-Grau S, Teipel S, Grothe MJ, Kilimann I, Rossor M, Fox N, Laske C, Chhatwal J, Falkai P, Perneczky R, Lee J-H, Spottke A, Boecker H, Brosseron F, Fliessbach K, Heneka MT, Nestor P, Peters O, Fuentes M, Menne F, Priller J, Spruth EJ, Franke C, Schneider A, Westerteicher C, Speck O, Wiltfang J, Bartels C, Araque Caballero MA, Metzger C, Bittner D, Salloway S, Danek A, Hassenstab J, Yakushev I, Schofield PR, Morris JC, Bateman RJ, Ewers Met 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

Journal article

Rauchmann B-S, Ghaseminejad F, Mekala S, Perneczky Ret 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

Journal article

Schoeberl F, Pradhan C, Irving S, Buerger K, Xiong G, Kugler G, Kohlbecher S, Engmann J, Werner P, Brendel M, Schneider E, Perneczky R, Jahn K, la Fougere C, Bartenstein P, Brandt T, Dieterich M, Zwergal Aet al., 2020, Real-space navigation testing differentiates between amyloid-positive and -negative aMCI, NEUROLOGY, Vol: 94, Pages: E861-E873, ISSN: 0028-3878

Journal article

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

Journal article

Sadlon A, Takousis P, Alexopoulos P, Evangelou E, Prokopenko I, Perneczky Ret 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.

Journal article

Gallo V, Vineis P, Cancellieri M, Chiodini P, Barker RA, Brayne C, Pearce N, Vermeulen R, Panico S, Bueno-de-Mesquita B, Vanacore N, Forsgren L, Ramat S, Ardanaz E, Arriola L, Peterson J, Hansson O, Gavrila D, Sacerdote C, Sieri S, Kühn T, Katzke VA, van der Schouw YT, Kyrozis A, Masala G, Mattiello A, Perneczky R, Middleton L, Saracci R, Riboli Eet 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.

Journal article

Riso L, Kaaks R, Kühn T, Sookthai D, Forsgren L, Trupp M, Trichopoulou A, La Vecchia C, Karakatsani A, Gavrila D, Ferrari P, Freisling H, Petersson J, Lewan S, Vermeulen RC, Panico S, Masala G, Ardanaz E, Krogh V, Perneczky RG, Middleton LT, Mokoroa O, Sacerdote C, Sieri S, Hayat SA, Brayne C, Riboli E, Vineis P, Gallo V, Katzke VAet 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.

Journal article

Rauchmann B-S, Schneider-Axmann T, Alexopoulos P, Perneczky Ret 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

Journal article

Beyer L, Schnabel J, Kazmierczak P, Ewers M, Schoenecker S, Prix C, Meyer-Wilmes J, Unterrainer M, Catak C, Pogarell O, Perneczky R, Albert NL, Bartenstein P, Danek A, Buerger K, Levin J, Rominger A, Brendel Met 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

Journal article

Brugnolo A, De Carli F, Pagani M, Morbelli S, Jonsson C, Chincarini A, Frisoni GB, Galluzzi S, Perneczky R, Drzezga A, van Berckel BNM, Ossenkoppele R, Didic M, Guedj E, Arnaldi D, Massa F, Grazzini M, Pardini M, Mecocci P, Dottorini ME, Bauckneht M, Sambuceti G, Nobili Fet 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

Journal article

Beyer L, Schnabel J, Kazmierczak P, Schoenecker S, Prix C, Meyer-Wilmes J, Unterrainer M, Catak C, Pogarell O, Perneczky R, Ewers M, Bartenstein P, Danek A, Buerger K, Levin J, Rominger A, Brendel Met 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

Conference paper

Zhang M, Ferrari R, Tartaglia MC, Keith J, Surace EI, Wolf U, Sato C, Grinberg M, Liang Y, Xi Z, Dupont K, McGoldrick P, Weichert A, McKeever PM, Schneider R, McCorkindale MD, Manzoni C, Rademakers R, Graff-Radford NR, Dickson DW, Parisi JE, Boeve BF, Petersen RC, Miller BL, Seeley WW, van Swieten JC, van Rooij J, Pijnenburg Y, van der Zee J, Van Broeckhoven C, Le Ber I, Van Deerlin V, Suh E, Rohrer JD, Mead S, Graff C, Oijerstedt L, Pickering-Brown S, Rollinson S, Rossi G, Tagliavini F, Brooks WS, Dobson-Stone C, Halliday GM, Hodges JR, Piguet O, Binetti G, Benussi L, Ghidoni R, Nacmias B, Sorbi S, Bruni AC, Galimberti D, Scarpini E, Rainero I, Rubino E, Clarimon J, Lleo A, Ruiz A, Hernandez I, Pastor P, Diez-Fairen M, Borroni B, Pasquier F, Deramecourt V, Lebouvier T, Perneczky R, Diehl-Schmid J, Grafman J, Huey ED, Mayeux R, Nalls MA, Hernandez D, Singleton A, Momeni P, Zeng Z, Hardy J, Robertson J, Zinman L, Rogaeva Eet al., 2018, A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers, BRAIN, Vol: 141, Pages: 2895-2907, ISSN: 0006-8950

Journal article

Beyer L, Meyer-Wilmes J, Schoenecker S, Schnabel J, Brendel E, Unterrainer M, Catak C, Pogarell O, Perneczky R, Danek A, Buerger K, Bartenstein P, Levin J, Rominger A, Brendel Met 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

Conference paper

Häckert J, Falkai P, Perneczky R, Pogarell Oet al., 2018, [The speechless patient]., MMW Fortschr Med, Vol: 160, Pages: 53-56

Journal article

Alexopoulos P, Gleixner L-S, Werle L, Buhl F, Thierjung N, Giourou E, Kagerbauer SM, Gourzis P, Kuebler H, Grimmer T, Yakushev I, Martin J, Kurz A, Perneczky Ret 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

Journal article

Fan Z, Calsolaro V, Mayers J, Tyacke R, Venkataraman A, Femminella G, Perneczky R, Gunn R, Rabiner E, Matthews P, Nutt D, Edison Pet 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

Journal article

Calsolaro V, Mayers J, Fan Z, Tyacke R, Venkataraman A, Femminella G, Perneczky R, Gunn R, Rabiner E, Matthews P, Nutt D, Edison Pet 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

Journal article

Beyer L, Meyer-Wilmes J, Schönecker S, Schnabel J, Brendel E, Prix C, Nübling G, Unterrainer M, Albert NL, Pogarell O, Perneczky R, Catak C, Bürger K, Bartenstein P, Bötzel K, Levin J, Rominger A, Brendel Met 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.

Journal article

Alexopoulos P, Thierjung N, Grimmer T, Ortner M, Economou P, Assimakopoulos K, Gourzis P, Politis A, Perneczky R, TheAlzheimersDiseaseNeuroimagingInitiativeet 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.

Journal article

Bonham LW, Karch CM, Fan CC, Tan C, Geier EG, Wang Y, Wen N, Broce IJ, Li Y, Barkovich MJ, Ferrari R, Hardy J, Momeni P, Höglinger G, Müller U, Hess CP, Sugrue LP, Dillon WP, Schellenberg GD, Miller BL, Andreassen OA, Dale AM, Barkovich AJ, Yokoyama JS, Desikan RS, International FTD-Genomics Consortium IFGC, International Parkinsons Disease Genetics Consortium IPDGC, International Genomics of Alzheimers Project IGAPet al., 2018, CXCR4 involvement in neurodegenerative diseases., Transl Psychiatry, Vol: 8

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.

Journal article

Franzmeier N, Düzel E, Jessen F, Buerger K, Levin J, Duering M, Dichgans M, Haass C, Suárez-Calvet M, Fagan AM, Paumier K, Benzinger T, Masters CL, Morris JC, Perneczky R, Janowitz D, Catak C, Wolfsgruber S, Wagner M, Teipel S, Kilimann I, Ramirez A, Rossor M, Jucker M, Chhatwal J, Spottke A, Boecker H, Brosseron F, Falkai P, Fliessbach K, Heneka MT, Laske C, Nestor P, Peters O, Fuentes M, Menne F, Priller J, Spruth EJ, Franke C, Schneider A, Kofler B, Westerteicher C, Speck O, Wiltfang J, Bartels C, Araque Caballero MÁ, Metzger C, Bittner D, Weiner M, Lee J-H, Salloway S, Danek A, Goate A, Schofield PR, Bateman RJ, Ewers Met 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

Journal article

Perneczky R, 2018, Population-based approaches to Alzheimer's disease prevention., Biomarkers for Alzheimer’s Disease Drug Development, Editors: Perneczky, Publisher: Springer, Pages: 15-29

Progress in prevention and treatment of Alzheimer's disease (AD) and dementia is hampered by the restricted understanding of the biological and environmental causes underlying pathophysiology. It is widely accepted that certain genetic factors are associated with AD and a number of lifestyle and other environmental characteristics have also been linked to dementia risk. However, interactions between genes and the environment are not yet well understood, and coordinated global action is required to utilize existing cohorts and other resources effectively and efficiently to identify new avenues for dementia prevention. This chapter provides a brief summary of current research on risk and protective factors and opportunities and challenges in relation to population-based approaches are discussed.

Book chapter

Skrobot OA, Black SE, Chen C, DeCarli C, Erkinjuntti T, Ford GA, Kalaria RN, O'Brien J, Pantoni L, Pasquier F, Roman GC, Wallin A, Sachdev P, Skoog I, Ben-Shlomo Y, Passmore AP, Love S, Kehoe PG, Taragano FE, Kril J, Cavalieri M, Jellinger KA, Kovacs GG, Engelborghs S, Lafosse C, Bertolucci PH, Brucki S, Caramelli P, Alves TCDTF, Bocti C, Fulop T, Hogan DB, Hsiung GR, Kirk A, Leach L, Robillard A, Sahlas DJ, Guo Q, Tian J, Hokkanen L, Jokinen H, Benisty S, Deramecourt V, Hauw J, Lenoir H, Tsatali M, Tsolaki M, Sundar U, Coen RF, Korczyn AD, Altieri M, Baldereschi M, Caltagirone C, Caravaglios G, Di Carlo A, Di Piero V, Gainotti G, Galluzzi S, Logroscino G, Mecocci P, Moretti DV, Padovani A, Fukui T, Ihara M, Mizuno T, Kim SY, Akinyemi R, Baiyewu O, Ogunniyi A, Szczudlik A, Bastos-Leite AJ, Firmino H, Massano J, Verdelho A, Kruglov LS, Ikram MK, Kandiah N, Arana E, Barroso-Ribal J, Calatayud T, Cruz-Jentoft AJ, Lopez-Pousa S, Martinez-Lage P, Mataro M, Borjesson-Hanson A, Englund E, Laukka EJ, Qiu C, Viitanen M, Biessels GJ, de Leeuw F-E, den Heijer T, Exalto LG, Kappelle LJ, Prins ND, Richard E, Schmand B, van den Berg E, van der Flier WM, Bilgic B, Allan LM, Archer J, Attems J, Bayer A, Blackburn D, Brayne C, Bullock R, Connelly PJ, Farrant A, Fish M, Harkness K, Ince PG, Langhorne P, Mann J, Matthews FE, Mayer P, Pendlebury ST, Perneczky R, Peters R, Smithard D, Stephan BC, Swartz JE, Todd S, Werring DJ, Wijayasiri SN, Wilcock G, Zamboni G, Au R, Borson S, Bozoki A, Browndyke JN, Corrada MM, Crane PK, Diniz BS, Etcher L, Fillit H, Greenberg SM, Grinberg LT, Hurt SW, Lamar M, Mielke M, Ott BR, Perry G, Powers WJ, Ramos-Estebanez C, Reed B, Roberts RO, Romero JR, Saykin AJ, Seshadri S, Silbert L, Stern Y, Zarow Cet al., 2018, Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study, ALZHEIMERS & DEMENTIA, Vol: 14, Pages: 280-292, ISSN: 1552-5260

Journal article

Perneczky R, Alexopoulos P, 2018, Soluble amyloid precursor proteins in blood: Methods and challenges, Neuromethods, Pages: 179-187

Soluble amyloid precursor proteins (sAPP) are under investigation as novel biomarkers of Alzheimer’s disease (AD) pathophysiology, but protein levels in cerebrospinal fluid do not seem to follow a consistent pattern, which limits their usefulness as diagnostic and prognostic tool. More recently, evidence has been presented for sAPP blood plasma concentration differences between patients with AD dementia and healthy control subjects. Blood can be easily accessed, which makes it an interesting target for biomarker discovery. This chapter presents a brief overview of sAPP in blood as a new AD biomarker candidate. Issues and challenges are discussed, both from a perspective of laboratory assessment and clinical application. A relevant technique for sAPP ascertainment is also provided.

Book chapter

Broce I, Karch CM, Wen N, Fan CC, Wang Y, Tan CH, Kouri N, Ross OA, Höglinger GU, Muller U, Hardy J, International FTD-Genomics Consortium, Momeni P, Hess CP, Dillon WP, Miller ZA, Bonham LW, Rabinovici GD, Rosen HJ, Schellenberg GD, Franke A, Karlsen TH, Veldink JH, Ferrari R, Yokoyama JS, Miller BL, Andreassen OA, Dale AM, Desikan RS, Sugrue LPet al., 2018, Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies., PLoS Med, Vol: 15

BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5

Journal article

Alexopoulos P, Roesler J, Werle L, Thierjung N, Lentzari I, Ortner M, Grimmer T, Laskaris N, Politis A, Gourzis P, Kurz A, Perneczky R, Alzheimers Disease Neuroimaging Initiativeet al., 2017, Fluid biomarker agreement and interrelation in dementia due to Alzheimer's disease., Journal of Neural Transmission, ISSN: 0300-9564

The cerebrospinal fluid (CSF) levels of β-amyloid 42, total tau, and phosphorylated tau 181 are supposed to be all continuously abnormal in dementia due to Alzheimer's disease (AD), being the most advanced disease stage. The aim of the present study, which included a monocentric and a multicentric sample (N = 119 and 178, respectively), was to investigate the degree of CSF biomarker agreement and interrelation in AD dementia. Based on previously published cut-off values, biomarker values were categorized as positive or negative for AD (dichotomization strategy) and as either positive, negative, or borderline (trichotomization strategy). The statistical analyses relied on distance correlation analysis and kappa (k) statistics. Poor agreement (k < 0.4) and low interrelations between the studied biomarkers were detected in all cases with the exception of the interrelation between the markers total tau and phosphorylated tau 181, especially in the monocentric sample. Interestingly, lower interrelation and agreement degrees were observed in carriers of the Apolipoprotein E ε4 allele compared to non-carriers. The clinical phenotype currently referred to as "AD dementia" is characterized by an inhomogeneous CSF biomarker profile, possibly mirroring the complex genesis of AD-typical dementia symptoms and pointing to the necessity of shedding more light on the hypothesis of biomarker stability over time in symptomatic AD.

Journal article

Webster L, Groskreutz D, Grinbergs-Saull A, Howard R, O'Brien JT, Mountain G, Banerjee S, Woods B, Perneczky R, Lafortune L, Roberts C, McCleery J, Pickett J, Bunn F, Challis D, Charlesworth G, Featherstone K, Fox C, Goodman C, Jones R, Lamb S, Moniz-Cook E, Schneider J, Shepperd S, Surr C, Thompson-Coon J, Ballard C, Brayne C, Burns A, Clare L, Garrard P, Kehoe P, Passmore P, Holmes C, Maidment I, Robinson L, Livingston Get al., 2017, Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations, PLOS One, Vol: 12, ISSN: 1932-6203

BackgroundThere are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia.Methods and findingsWe defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer’s disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer’s society focus groups. Attendees at a consensus conference (experts in dementia research, disease-modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification.LimitationsMost trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties.InterpretationThis is the first review to ident

Journal article

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