Your search for: 'author:("Zetterberg, Henrik")' has returned 133 results. (0.016s) Save search

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer’s disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which …are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, plasma, serum, tau

DOI: 10.3233/JAD-179926

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S271-S279, 2018

Authors: Blennow, Kaj | Zetterberg, Henrik

Article Type: Research Article

Abstract: Research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer's disease (AD), which has been translated into an ongoing development of disease-modifying treatments. These new drug candidates are targeted on inhibiting amyloid-β (Aβ) production and aggregation or tau aggregation. If these drugs prove to be efficient, diagnostic tools enabling early diagnosis of AD will be of great value. Also in drug development, it is important to co-develop biomarkers to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). …The core candidate CSF biomarkers Aβ42 , total tau (T-tau), and phosphorylated tau (P-tau) have been shown to have a high diagnostic performance to identify AD also in the early phase of the disease. This paper reviews recent research advances on these CSF biomarkers for use in clinical diagnosis and in clinical trials in AD. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, diagnosis

DOI: 10.3233/JAD-2009-1177

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 413-417, 2009

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past decades have witnessed an enormous expansion of the literature on cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD). It is now clear that a triplet of CSF biomarkers (total-tau, phospho-tau, and the 42 amino acid fragment of amyloid-β) reflects core neuropathological features of AD and contributes diagnostically relevant information if measured in a proper manner. Here, we discuss what is needed for these biomarkers to become generally implemented in the clinical routine. We also discuss novel CSF biomarkers, the challenge of differential diagnosis-making in diseases with shared pathologies, and if CSF biomarkers will survive in the long run, …given the advancements in molecular neuroimaging and ultra-sensitive blood tests. Show more

Keywords: Alzheimer's disease, amyloid, biomarkers, cerebrospinal fluid, tau

DOI: 10.3233/JAD-2012-129035

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S361-S369, 2013

Authors: Blennow, Kaj | Zetterberg, Henrik

Article Type: Review Article

Abstract: Following the development of the first methods to measure the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42 ), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer ’s Disease , we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. …We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42 , the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, neurogranin, plasma, tau

DOI: 10.3233/JAD-170773

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1125-1140, 2018

Authors: Chen-Plotkin, Alice S. | Zetterberg, Henrik

Article Type: Review Article

Abstract: Clinical definitions of Parkinson’s disease (PD) are over 200 years old, while neuropathological definitions— which are still the basis of how we define the disease now— are over 100 years old. We argue that for both clinical care and therapeutic development, these definitions need updating for the molecular age in which we live. We highlight specific instances in which genetic or biochemical biomarkers are increasingly used for clinical trial enrollment in the neurodegenerative diseases, suggesting that molecular definition(s) of PD are already emerging. We review candidate biomarkers for PD-related pathologies and highlight the need for further validation.

Keywords: Alpha-synuclein, biomarkers, genetic subtypes, Parkinson’s disease

DOI: 10.3233/JPD-181487

Citation: Journal of Parkinson's Disease, vol. 8, no. s1, pp. S53-S57, 2018

Authors: Rahman, M. Mahafuzur | Westermark, Gunilla T. | Zetterberg, Henrik | Härd, Torleif | Sandgren, Mats

Article Type: Research Article

Abstract: Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer’s disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ42 (Aβ42 CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ42 fibrils in AD and non-AD CSF and compared these with protofibrillar Aβ42 CC-binding partners. …Aβ42 fibrils sequestered 2.4-fold more proteins than Aβ42 CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ42 CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils

DOI: 10.3233/JAD-180596

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1053-1064, 2018

Authors: Halaas, Nathalie Bodd | Zetterberg, Henrik | Idland, Ane-Victoria | Knapskog, Anne-Brita | Watne, Leiv Otto | Blennow, Kaj

Article Type: Research Article

Abstract: Background: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer’s disease (AD), likely reflecting synaptic dysfunction and/or degeneration. Objective: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. Methods: The cohort included hip fracture patients with (n … = 70) and without delirium (n  = 58), CUA undergoing elective surgery (n  = 127), and AD patients (n  = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. Results: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p  = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p  = 0.001) and CUA (p  = 0.035) in age-adjusted sensitivity analyses. Conclusion: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid proteins, delirium, neurotransmitter agents

DOI: 10.3233/JAD-201341

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 667-677, 2021

Authors: Kehoe, Patrick G. | Al Mulhim, Noura | Zetterberg, Henrik | Blennow, Kaj | Miners, James S.

Article Type: Research Article

Abstract: Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer’s disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 (ACE1) and …ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA; and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42 , total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p  = 0.008) and positively correlated with ACE2 in AD (r  = 0.420, p  = 0.007). CSF ACE1 weakly correlated with t-tau (r  = 0.294, p  = 0.066) and p-tau (r  = 0.329, p  = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r  = 0.426, p  = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r  = 0.422, p  = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD. Show more

Keywords: Alzheimer’s disease, angiotensin-II, angiotensin-(1-7), angiotensin-II converting enyme-1 (ACE1), angiotensin-II converting enyme-2 (ACE2), cerebrospinal fluid, renin-angiotensin system

DOI: 10.3233/JAD-190721

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 525-535, 2019

Authors: Skillbäck, Tobias | Kornhuber, Johannes | Blennow, Kaj | Zetterberg, Henrik | Lewczuk, Piotr | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: To alleviate the interpretation of the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid β1–42 (Aβ42 ), total tau (T -tau), and phosphorylated tau (P -tau), the Erlangen Score (ES) interpretation algorithm has been proposed. Objective: In this study, we aim to assess the predictive properties of the ES algorithm on cognitive and neuroimaging outcomes in mild cognitive impairment (MCI). Methods: All MCI subjects with an available baseline CSF sample from ADNI-1 were included (n  = 193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile. Structural magnetic resonance imaging brain scans and …MMSE and ADAS-Cog scores were collected at up to 7 times in follow-up examinations. Results: We observed strong and significant correlations between the ES at baseline and neuroimaging and cognitive results with patients with neurochemically probable AD (ES = 4) progressing significantly (p ≤0.01) faster than those with a neurochemically improbable AD (ES = 0 or 1), and the subjects with neurochemically possible AD (ES = 2 or 3) in-between these two groups. Conclusion: This study further demonstrates the utility of the ES algorithm as a as a tool in predicting cognitive and imaging progression in MCI patients. Show more

Keywords: Aβ1–42, Alzheimer’s disease, biomarkers, cerebrospinal fluid, Erlangen score, P-tau, T-tau

DOI: 10.3233/JAD-190067

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 551-559, 2019

Authors: Minta, Karolina | Portelius, Erik | Janelidze, Shorena | Hansson, Oskar | Zetterberg, Henrik | Blennow, Kaj | Andreasson, Ulf

Article Type: Research Article

Abstract: Background: Brevican, neurocan, tenascin-C, and tenascin-R are extracellular matrix (ECM) proteins that are mainly expressed in the brain. They play important roles in proliferation and migration of neurons and other cell types in the brain. These ECM proteins may also be involved in various pathologies, including reactive gliosis. Objective: The aim of the study was to investigate if ECM protein concentrations in cerebrospinal fluid (CSF) are linked to the neurodegenerative process in Alzheimer’s disease (AD). Methods: Lumbar CSF samples from a non-AD control group (n  = 50) and a clinically diagnosed AD group (n  = 42), matched for age and gender, were …analyzed using commercially available ELISAs detecting ECM proteins. Mann-Whitney U test was used to examine group differences, while Spearman’s rho test was used for correlations. Results: Brevican, neurocan, tenascin-R, and tenascin-C concentrations in AD patients did not differ compared to healthy controls or when the groups were dichotomized based on the Aβ42/40 cut-off. CSF tenascin-C and tenascin-R concentrations were significantly higher in women than in men in the AD group (p  = 0.02). Conclusion: ECM proteins do not reflect AD-pathology in CSF. CSF tenascin-C and tenascin-R upregulation in women possibly reveal sexual dimorphism in the central nervous system immunity during AD. Show more

Keywords: Alzheimer’s disease, brevican, neurocan, tenascin-C, tenascin-R

DOI: 10.3233/JAD-190187

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1213-1220, 2019