| 1. |
- Hampel, Harald, et al.
(författare)
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Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ1-42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40.
- 2018
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 14:4, s. 492-501
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Tidskriftsartikel (refereegranskat)abstract
- The diagnostic and classificatory performances of all combinations of three core (amyloid β peptide [i.e., Aβ1-42], total tau [t-tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation.The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified.The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination [amyloid β peptide + phosphorylated tau + neurofilament light chain] for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78).Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor.
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| 2. |
- Hampel, Harald, et al.
(författare)
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Perspective on Future Role of Biological Markers in Clinical Therapy Trials of Alzheimer's Disease: A Long-Range Point of View Beyond 2020.
- 2014
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 88:4
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in understanding the molecular mechanisms underlying various paths towards the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD.
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| 3. |
- Lista, Simone, et al.
(författare)
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Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study.
- 2017
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908.
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Tidskriftsartikel (refereegranskat)abstract
- We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n = 35), FTD (n = 9), MCI (n = 41), cognitively HC (n = 23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-β peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases.
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| 4. |
- Lista, Simone, et al.
(författare)
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Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease.
- 2017
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Ingår i: Neurochemistry international. - : Elsevier BV. - 1872-9754 .- 0197-0186. ; 108, s. 355-360
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) neurofilament light chain (NFL) protein in the classification of patients with Alzheimer's disease (AD) and cognitively healthy control individuals (HCs) and patients with frontotemporal dementia (FTD) as comparisons. Particularly, we tested the performance of CSF NFL concentration in differentiating patient groups stratified by fluid biomarker profiles, independently of the severity of cognitive impairment (mild cognitive impairment (MCI) and AD dementia individuals), using a biomarker-guided descriptive classification system for AD. CSF NFL concentrations were examined in a multicenter cross-sectional study of 108 participants stratified in AD pathophysiology-negative (both CSF tau and the 42-amino acid-long amyloid-beta (Aβ) peptide (Aβ1-42)) (n = 15), tau pathology-positive only (n = 15), Aβ pathology-positive only (n = 13), AD pathophysiology-positive (n = 33), FTD (n = 9) patients, and HCs (n = 23), according to the biomarker-based classification system. The performance of CSF NFL in discriminating AD pathophysiology-positive patients from HCs is fair, whereas the ability in differentiating tau-positive patients from HCs is poor. The classificatory performance in distinguishing AD pathophysiology-positive patients from FTD is unsatisfactory.
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| 5. |
- Toschi, Nicola, et al.
(författare)
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Biomarker-guided clustering of Alzheimer's disease clinical syndromes.
- 2019
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 83, s. 42-53
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) neuropathology is extremely heterogeneous, and the evolution from preclinical to mild cognitive impairment until dementia is driven by interacting genetic/biological mechanisms not fully captured by current clinical/research criteria. We characterized the heterogeneous "construct" of AD through a cerebrospinal fluid biomarker-guided stratification approach. We analyzed 5 validated pathophysiological cerebrospinal fluid biomarkers (Aβ1-42, t-tau, p-tau181, NFL, YKL-40) in 113 participants (healthy controls [N = 20], subjective memory complainers [N = 36], mild cognitive impairment [N = 20], and AD dementia [N = 37], age: 66.7 ± 10.4, 70.4 ± 7.7, 71.7 ± 8.4, 76.2 ± 3.5 years [mean ± SD], respectively) using Density-Based Spatial Clustering of Applications with Noise, which does not require a priori determination of the number of clusters. We found 5 distinct clusters (sizes: N = 38, 16, 24, 14, and 21) whose composition was independent of phenotypical groups. Two clusters showed biomarker profiles linked to neurodegenerative processes not associated with classical AD-related pathophysiology. One cluster was characterized by the neuroinflammation biomarker YKL-40. Combining nonlinear data aggregation with informative biomarkers can generate novel patient strata which are representative of cellular/molecular pathophysiology and may aid in predicting disease evolution and mechanistic drug response.
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