<scp>CSF</scp>
            progranulin increases in the course of Alzheimer's disease and is associated with
            <scp>sTREM</scp>
            2, neurodegeneration and cognitive decline

Suárez‐Calvet, Marc; Capell, Anja; Caballero, Miguel Ángel Araque; Morenas‐Rodríguez, Estrella; Fellerer, Katrin; Franzmeier, Nicolai; Kleinberger, Gernot; Eren, Erden; Deming, Yuetiva; Piccio, Laura; Karch, Celeste M.; Cruchaga, Carlos; Paumier, Katrina L.; Bateman, Randall J.; Fagan, Anne M.; Morris, John C.; Levin, Johannes; Danek, Adrian; Jucker, Mathias; Masters, Colin L.; Rossor, Martin N.; Ringman, John M.; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Ewers, Michael; Haass, Christian

doi:10.15252/emmm.201809712

Cited by 76 publications

(74 citation statements)

References 105 publications

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“…However, clinical manifestations of GRN mutations can also extend to AD 63 . The possibility of using progranulin as an AD biomarker was recently investigated in a large population of patients with familial and late-onset sporadic AD (Dominant Inherited Alzheimer's Disease Network and Alzheimer's Disease Neuroimaging Initiative cohorts) 64 . The CSF levels of progranulin were reportedly increased 10 years before the clinical onset of disease in AD mutation carriers.…”

Section: Progranulinmentioning

confidence: 99%

“…The CSF levels of progranulin were reportedly increased 10 years before the clinical onset of disease in AD mutation carriers. In patients with sporadic AD, increased CSF levels of progranulin were evident when neurodegeneration developed 64 . Increased levels of progranulin in CSF were also detected in suspected non-AD pathophysiology (SNAP) cases (i.e., normal Aβ biomarkers despite abnormalities in tau or neurodegeneration biomarkers; A −/TN+ 4 ) 64 .…”

Section: Progranulinmentioning

confidence: 99%

“…In patients with sporadic AD, increased CSF levels of progranulin were evident when neurodegeneration developed 64 . Increased levels of progranulin in CSF were also detected in suspected non-AD pathophysiology (SNAP) cases (i.e., normal Aβ biomarkers despite abnormalities in tau or neurodegeneration biomarkers; A −/TN+ 4 ) 64 . However, correlations of CSF progranulin levels with cognitive functions and CSF tau protein levels were present only in patients with AD, not in patients with SNAP 64 .…”

Section: Progranulinmentioning

confidence: 99%

See 2 more Smart Citations

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

2020

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Cerebrospinal fluid (CSF) biomarkers based on the core pathological proteins associated with Alzheimer's disease (AD), i.e., amyloid-β (Aβ) and tau protein, are widely regarded as useful diagnostic biomarkers. However, a lack of biomarkers for monitoring the treatment response and indexing clinical severity has proven to be problematic in drug trials targeting Aβ. Therefore, new biomarkers are needed to track non-Aβ and non-tau pathology. Many proteins involved in the pathophysiological progression of AD have shown promise as new biomarkers. Neurodegeneration-and synapse-related biomarkers in CSF (e.g., neurofilament light polypeptide [NFL], neurogranin, and visinin-like protein 1) and blood (e.g., NFL) aid prediction of AD progress, as well as early diagnosis. Neuroinflammation, lipid dysmetabolism, and impaired protein clearance are considered important components of AD pathophysiology. Inflammation-related proteins in the CSF, such as progranulin, intercellular adhesion molecule 1, and chitinase-3-like protein 1 (YKL-40), are useful for the early detection of AD and can represent clinical severity. Several lipid metabolism-associated biomarkers and protein clearance-linked markers have also been suggested as candidate AD biomarkers. Combinations of subsets of new biomarkers enhance their utility in terms of broadly characterizing AD-associated pathological changes, thereby facilitating precise selection of susceptible patients and comprehensive monitoring of the treatment response. This approach could facilitate the development of effective treatments for AD.

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Section: Progranulinmentioning

confidence: 99%

Section: Progranulinmentioning

confidence: 99%

Section: Progranulinmentioning

confidence: 99%

See 1 more Smart Citation

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

2020

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“…Plasma sTREM2 was significantly elevated in DS, in agreement with previously described elevation of sTREM2 in DS sera from young adults with DS prior to dementia onset 33 . Interestingly, sTREM2 is elevated in cerebrospinal fluid in the mild cognitive impairment stage of AD and in early onset forms of AD, but not in peripheral biofluids, such as plasma 24,25,27,28,54 . The elevation of sTREM2 in young DS pre-dementia in plasma and sera suggests that peripheral sTREM2 may increase very early in individuals with elevated Aβ.…”

Section: Discussionmentioning

confidence: 97%

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Weber

Koenig

Khrestian

et al. 2019

Preprint

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Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) -related neuropathology, characterized by amyloid plaques with amyloid β (Aβ) and neurofibrillary tangles with tau accumulation more frequently and at an earlier age than their neurotypical counterparts. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble cleavage product of TREM2 (sTREM2) has been described as elevated in AD cerebrospinal fluid and positively correlates with Aβ and cognitive decline. There is relatively little information about TREM2 in DS. The objective of this study was to examine the relationship between sTREM2 and inflammatory markers in DS, prior to the development of dementia symptoms. Since TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS pre-dementia (n=15, mean age 29.5 years) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared to neurotypical, agematched controls (n=16, mean age 29.6 years). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. In addition, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, while there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the group with DS and controls, supporting the hypothesis that its function is altered in people with DS predementia. This exploratory study provides a basis for future studies investigating the relationship between TREM2 and the broader immune response pre-dementia.

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“…We previously reported that levels of multiple in ammatory markers (e.g., soluble tumor necrosis factor receptor [sTNFRs], intercellular cell adhesion molecule-1 [ICAM1], and vascular cell adhesion molecule-1 [VCAM1]) in the cerebrospinal uid (CSF) were signi cantly elevated in AD patients compared to healthy controls [9]. Interestingly, CSF PGRN was also found to be increased over the course of AD [10]. However, little is known about the associations of PGRN with these neuroin ammation markers.…”

Section: Introductionmentioning

confidence: 99%

Pgrn Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

Tan

Cao

et al. 2020

Preprint

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Background: Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods: A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results: Increases of CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were associated with tau-related neurodegeneration, but not with Aβ pathology. PGRN was positively linked with these neuroinflammatory markers only in the presence of tau pathologies (TN+). In TN+ profile, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could also predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions: PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.

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CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM 2, neurodegeneration and cognitive decline

Cited by 76 publications

References 105 publications

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Pgrn Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

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