Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: DIAN participants' characteristics

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Mutagenesis

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: CSF PGRN is increased in mutation carriers (MC) compared to non‐carriers (NC). CSF PGRN is not associated with age in either NC or MC. CSF PGRN is increased in males compared to females. CSF PGRN levels do not differ among MC participants carrying a PSEN1 , PSEN2 or APP mutation. Data information: The blue or red bars in (A), (C) and (D) represent the mean and the standard deviation (SD). Group comparisons were assessed by a linear model adjusting by age, gender and APOE ε4 status. The solid lines in (B) indicate the regression line for each of the groups and the 95% confidence interval (CI) calculated by a linear model adjusting by gender and APOE ε4 status. The standardized regression coefficients (β) and the P ‐values are also shown. In graph (B), the individual values are not shown in order to protect participants' confidentiality. All analysis and graphs are performed excluding 3 PGRN values outliers. Including the outliers in the analysis rendered similar results ( Appendix Table S1 ). APP , amyloid precursor protein; CSF, cerebrospinal fluid; ns, non‐significant; PSEN1 , presenilin 1; PSEN2 , presenilin 2.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Mutagenesis, Standard Deviation

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: CSF PGRN as a function of EYO in mutation carriers (MC, red) and non‐carriers (NC, blue). The solid lines indicate the regression line for each of the groups and the 95% confidence interval (CI) calculated by a linear model adjusting by gender. The interaction term of mutation status and EYO is significant ( P = 0.041), also when including PGRN outliers and participants with EYO > +20 ( P = 0.030). Individual data points are not displayed to prevent disclosure of mutation status. The graph depicts the standardized differences in CSF PGRN between MCs and NCs as a function of EYO, in the context of other biomarker and cognitive changes. The curves were generated by the linear model that best fit each marker (see section and Appendix Table S2 ). CSF PGRN is significantly increased in MC compared to NC 10 years before the expected symptom onset (shadowed area) after brain amyloidosis and brain injury (as measured by CSF T‐tau) have started, and shortly before CSF sTREM2 starts to increase. Data information: Aβ 1–42 : amyloid‐β 42; CSF, cerebrospinal fluid; MC, mutation carrier; MMSE, Mini‐Mental State Examination; NC, non‐carrier; T‐tau, total tau.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Mutagenesis, Biomarker Discovery, Generated, Marker

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: ADNI participants' characteristics for the control and Alzheimer's continuum groups in ADNI

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Control

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: Scatter plot representing the levels of CSF PGRN in healthy controls (depicted in blue) and the different stages of the Alzheimer's continuum (depicted in red). The blue and the red bars represent the mean and the standard deviation (SD). The analysis and graphs were performed excluding CSF PGRN outliers (1 “healthy control”, 1 “Preclinical AD A+/TN−”, 4 “AD CDR = 0.5” and 1 “AD CDR = 1”). Including them yielded a similar result, and CSF PGRN was still significantly higher in the “AD CDR = 1” group compared to the “healthy controls” ( P = 0.001) and “Preclinical AD A+/TN−” ( P = 0.0001) groups. P ‐values were assessed by a one‐way analysis of covariance adjusted for age, gender and APOE ε4, followed by Bonferroni corrected pair‐wise post hoc comparisons. A: amyloid‐β biomarker status; AD: Alzheimer's disease; CDR: clinical dementia rating; CSF, cerebrospinal fluid; N, neurodegeneration biomarker status; T: tau pathology biomarker status.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Standard Deviation, Control, Biomarker Discovery

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: Associations of CSF PGRN with cognitive measures in the Alzheimer's continuum category (ADNI sample)

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques:

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: Scatter plots representing the association of CSF PGRN with different cognitive tests. Only the subjects of the Alzheimer's continuum group ( n = 474) were included. In all tests studied, higher levels of CSF PGRN were associated with worse cognitive performance (namely lower scores in ADNI‐Mem, ADNI‐EF and MMSE and higher scores in ADAS‐Cog11, ADAS‐Cog13 and CDR‐SB). The analysis and the graphs are excluding PGRN outliers; including them rendered similar results ( Appendix Table S6 ). Each point depicts the value of CSF PGRN and the corresponding cognitive test score of a participant. The solid lines indicate the regression line and the 95% confidence interval (CI) calculated by a linear model (Model 1, unadjusted). Table shows the standardized regression coefficients (β) and the P ‐values calculated by different models. ADAS‐Cog, Alzheimer's disease Assessment Scale—cognitive subscale; ADNI‐Mem: ADNI memory composite score; ADNI‐EF: ADNI executive function composite score; CDR‐SB: clinical dementia rating sum of boxes; MMSE, Mini‐Mental State Examination.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques:

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: A, B Scatter plots representing the association of CSF PGRN with temporo‐parietal FDG‐PET uptake (A) and total hippocampal volume (B) within the subjects of the Alzheimer's continuum group ( n = 474). Each point depicts the value of CSF PGRN and the corresponding neuroimaging biomarker of a participant. The solid lines indicate the regression line and the 95% confidence interval (CI). The regression coefficients (β) and the P ‐values calculated by a linear model adjusted for age, gender, APOE ε4 and education. FDG‐PET: fludeoxyglucose positron emission tomography; SUVR: standardized uptake value ratio.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Biomarker Discovery, Positron Emission Tomography

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: Scatter plot representing the levels of CSF PGRN for each of the four biomarker profiles within each clinical staging, as defined by CDR. CDR = 1 stage comprises some biomarker profiles that do not contain enough participants to perform statistical analysis but are nevertheless shown in the figure for completeness. Each biomarker category is represented in a different colour. Healthy controls are depicted in blue, Alzheimer's continuum category in red and SNAP category in green. Purple depicts biomarker profiles not assigned in any category in the present study. Scatter plot grouping the three biomarker categories: healthy controls, all the participants belonging to the Alzheimer's continuum category and the suspected non‐Alzheimer's pathophysiology (SNAP) category. Solid bars represent the mean and the standard deviation (SD). P ‐values were assessed by a one‐way analysis of covariance adjusted for age, gender and APOE ε4, followed by Bonferroni corrected pair‐wise post hoc comparisons. The analysis and graphs were performed excluding PGRN outliers (1 “healthy control”, 1 “Preclinical AD A+/TN−”, 4 “AD CDR = 0.5”, 3 “CDR = 0.5 A−TN−”, 1 “CDR = 0.5 A+TN−”, 1 “AD CDR = 1”). Including them yielded a similar result. Data information: A: amyloid‐β biomarker status; AD: Alzheimer's disease; CDR: clinical dementia rating; CSF, cerebrospinal fluid; N: neurodegeneration biomarker status; SNAP: suspected non‐Alzheimer's pathophysiology; T: tau pathology biomarker status.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Biomarker Discovery, Standard Deviation, Control

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: A–H Scatter plots representing the associations of CSF PGRN with CSF sTREM2 and each of the AD CSF core biomarkers (T‐tau, P‐tau 181P and Aβ 1−42 ) in non‐carriers (NC, blue; A, C, E and G) and in mutation carriers (MC, red; B, D, F and H). Each point depicts the value of CSF PGRN and the corresponding biomarker of a subject and the solid lines indicate the regression line and the 95% confidence interval (CI) for each of the groups. The standardized regression coefficients (β) and the P ‐values are shown and were computed using a linear model adjusting for age, gender and APOE ε4. The sample contained some outliers (defined as 3 SDs below or above the group mean) of the CSF core markers of AD. The results shown in the figure are excluding these outliers. We also performed the analysis including these outliers which yielded similar results ( Appendix Table S8 ). Aβ 1–42 : amyloid‐β 42; T‐tau: total tau; P‐tau: tau phosphorylated at threonine 181.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Mutagenesis, Biomarker Discovery

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: A–L Scatter plots representing the associations of CSF PGRN with CSF sTREM2 and each of the AD CSF core biomarkers (T‐tau, P‐tau 181P and Aβ 1–42 ) in healthy controls (blue; A, D, G and J), Alzheimer's continuum (red; B, E, H and K) and “suspected non‐Alzheimer's pathophysiology (SNAP)” groups (green; C, F, I and L). Each point depicts the value of CSF PGRN and the corresponding biomarker of a subject, and the solid lines indicate the regression line and the 95% confidence interval (CI) for each of the groups. The standardized regression coefficients (β) and the P ‐values are shown and were computed using a linear model adjusting for age, gender and APOE ε4. The sample contained some outliers (defined as 3 SDs below or above the group mean) of the CSF core markers of AD, and the analysis including these outliers yielded similar results ( Appendix Table S8 ). The Aβ 1–42 values used for the association test are those based on an extrapolation curve since the upper technical limit is 1,700 pg/ml. We also tested the associations with Aβ 1–42 values truncated at the upper technical limit and the result was similar. Aβ 1–42 : amyloid‐β 42; T‐tau: total tau; P‐tau: tau phosphorylated at threonine 181; SNAP: suspected non‐Alzheimer's pathophysiology.

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Biomarker Discovery

Journal: EMBO Molecular Medicine

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

doi: 10.15252/emmm.201809712

Figure Lengend Snippet: CSF PGRN estimates (pg/ml) in MCs and NCs as a function of EYO

Article Snippet: The ELISA consists of a Streptavidin‐coated 96‐well plates (MSD Streptavidin Gold Plates, cat. no. L15SA); a biotinylated polyclonal goat anti‐human PGRN capture antibody (BAF2420, R&D Systems; 0.2 μg/ml, 25 μl/well); a monoclonal mouse anti‐human PGRN detection antibody (MAB2420, R&D Systems; 0.25 μg/ml, 25 μl/well); and a SULFO‐TAG‐labelled goat polyclonal anti‐mouse IgG secondary antibody (MSD, cat. no. R32AC; 0.5 μg/ml, 25 μl/well).

Techniques: Mutagenesis

Journal: Journal of Neuropathology & Experimental Neurology

Article Title: Microglial Upregulation of Progranulin as a Marker of Motor Neuron Degeneration

doi: 10.1097/nen.0b013e3181fc9aea

Figure Lengend Snippet: FIGURE 1. Progranulin (PGRN) mRNA and protein levels increase with motor neuron degeneration in mutant SOD1G93A mice. (A) Spinal cord PGRN mRNA levels measured by quantitative PCR and normalized to presymptomatic stage and A-actin levels in nontransgenic (NTG) and mutant SOD1G93A mice (analysis of variance, F value = 6.5; overall, p = 0.002). (B) Spinal cord PGRN protein levels measured by ELISA normalized to protein content (analysis of variance, F value = 4.9; overall, p = 0.002).

Article Snippet: In some experiments, serial sections of the cords were alternatively stained with hematoxylin and eosin or with a biotinylated anti-human PGRN antibody (R&D Systems).

Techniques: Mutagenesis, Real-time Polymerase Chain Reaction, Enzyme-linked Immunosorbent Assay

Journal: Journal of Neuropathology & Experimental Neurology

Article Title: Microglial Upregulation of Progranulin as a Marker of Motor Neuron Degeneration

doi: 10.1097/nen.0b013e3181fc9aea

Figure Lengend Snippet: FIGURE 2. Proganulin (PGRN) expression in the mouse spinal cord. (AYC) PGRN+ motor neurons in the ventral horn of the spinal cord. Progranulin staining (A), SMI32 staining (B), and overlay (C) of ventral part of spinal cord from nontransgenic mouse; inset shows detail of motor neuron. (DYL) Proganulin staining of the ventral part of the spinal cord in presymptomatic, early, and late symptomatic mutant SOD1G93A mice (in red, D, G, J), CD11b staining (in green, E, H, K), and overlay (F, I, L); 2 motor neurons are marked by white arrows in D. (DYL) There is a gradual increase in the number of PGRN+ microglia in the spinal cord of mutant SOD1G93A mice. (MYO) At the end stage, surviving cells with motor neuron morphology (CD11b-negative, white arrows) remained PGRN+ in mutant SOD1G93A mice. Scale bar = 50 Km.

Article Snippet: In some experiments, serial sections of the cords were alternatively stained with hematoxylin and eosin or with a biotinylated anti-human PGRN antibody (R&D Systems).

Techniques: Expressing, Staining, Mutagenesis

Journal: Journal of Neuropathology & Experimental Neurology

Article Title: Microglial Upregulation of Progranulin as a Marker of Motor Neuron Degeneration

doi: 10.1097/nen.0b013e3181fc9aea

Figure Lengend Snippet: FIGURE 4. Progranulin (PGRN) mRNA and protein levels increase with motor neuron degeneration in VEGFC/C and mutant tauP301L

Article Snippet: In some experiments, serial sections of the cords were alternatively stained with hematoxylin and eosin or with a biotinylated anti-human PGRN antibody (R&D Systems).

Techniques: Mutagenesis

Journal: Journal of Neuropathology & Experimental Neurology

Article Title: Microglial Upregulation of Progranulin as a Marker of Motor Neuron Degeneration

doi: 10.1097/nen.0b013e3181fc9aea

Figure Lengend Snippet: FIGURE 5. Motor neurons and reactive microglia express progranulin (PGRN) in the human spinal cord. (AYI) Progranulin staining (red, A, D, I) and CD68 staining (green, B, E, I) of control (AYC) and amyotrophic lateral sclerosis (ALS) (DYF, I) spinal cords. Surviving cells with motor neuron morphology at a higher magnification in the ventral horn of ALS spinal cord on H&E staining remained positive for PGRN (G and H). Fluorescent staining of a CD68-negative PGRN+ cell with motor neuron morphology, surrounded by 2 microglial cells (white arrows) is shown in panel I. Scale bar = 50 Km.

Article Snippet: In some experiments, serial sections of the cords were alternatively stained with hematoxylin and eosin or with a biotinylated anti-human PGRN antibody (R&D Systems).

Techniques: Staining, Control

Journal: Journal of Neuropathology & Experimental Neurology

Article Title: Microglial Upregulation of Progranulin as a Marker of Motor Neuron Degeneration

doi: 10.1097/nen.0b013e3181fc9aea

Figure Lengend Snippet: FIGURE 6. Increased progranulin (PGRN) in CSF with disease progression in mutant SOD1G93A mice. Cerebrospinal fluid PGRN levels measured by ELISA in nontransgenic and mutant SOD1G93A mice (analysis of variance, F value = 15.8; overall, p = 0.000001; ***, p G 0.0001 compared with other groups).

Article Snippet: In some experiments, serial sections of the cords were alternatively stained with hematoxylin and eosin or with a biotinylated anti-human PGRN antibody (R&D Systems).

Techniques: Biomarker Discovery, Mutagenesis, Enzyme-linked Immunosorbent Assay