Cerebrospinal Fluid Progranulin Research Articles

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625.

Progranulin and neuropathological features of Alzheimer’s disease: longitudinal study

BackgroundProgranulin is an anti-inflammatory protein that plays an essential role in the synapse function and the maintenance of neurons in the central nervous system (CNS). It has been shown that the CSF level of progranulin increases in Alzheimer’s disease (AD) patients and is associated with the deposition of amyloid-beta (Aβ) and tau in the brain tissue. In this study, we aimed to assess the longitudinal changes in cerebrospinal fluid (CSF) progranulin levels during different pathophysiological stages of AD and investigate associated AD pathologic features.MethodsWe obtained the CSF and neuroimaging data of 1001 subjects from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A + /TN + , A + /TN−, A−/TN + , and A−/TN−.ResultsBased on our analysis there was a significant difference in CSF progranulin (P = 0.001) between ATN groups. Further ANOVA analysis revealed that there was no significant difference in the rate of change of CSF-progranulin ATN groups. We found that the rate of change of CSF progranulin was associated with baseline Aβ-PET only in the A−/TN + group. A significant association was found between the rate of change of CSF progranulin and the Aβ-PET rate of change only in A−/TN + ConclusionOur findings revealed that an increase in CSF progranulin over time is associated with faster formation of Aβ plaques in patients with only tau pathology based on the A/T/N classification (suspected non-Alzheimer’s pathology). Together, our findings showed that the role of progranulin-related microglial activity on AD pathology can be stage-dependent, complicated, and more prominent in non-AD pathologic changes. Thus, there is a need for further studies to consider progranulin-based therapies for AD treatment.

Microglial Reactivity Correlates with Presynaptic Loss Independent of β-Amyloid and Tau.

Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable. We identified 663 participants with baseline β-amyloid (Aβ) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau181), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aβ PET, CSF p-Tau181, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation. Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aβ burden was associated with attenuated CSF p-Tau181 effects on CSF microglial biomarker increases. Independent of Aβ PET and CSF p-Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase. These findings suggest that higher Aβ burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.

Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia.

Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss-of-function GRN mutations. A first-in-human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple-dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss-of-function GRN mutation (FTD-GRN). Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple-dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD-GRN to levels that approximated those seen in healthy volunteers. Data from the first-in-human phase 1 study support further development of latozinemab for the treatment of FTD-GRN. GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD).Latozinemab is being developed as a PGRN-elevating therapy.Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial.Latozinemab increased PGRN levels in the CNS of symptomatic FTD-GRN participants.

Association of microglial activation with Alzheimer’s pathologies, presynaptic loss, hippocampal atrophy, and cognitive decline

AbstractBackgroundLoss of function of triggering receptor expressed on myeloid cells 2 (TREM2) and progranulin (PGRN), predominantly expressed by microglia in the brain, contribute to the development of Alzheimer’s disease (AD). Although animal studies suggest that the expressions of TREM2 and PGRN increase in activated microglia, their associations with AD‐related pathologies and subsequent outcomes are not well characterized. This study aimed to explore how cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) and PGRN relate to β‐amyloid (Aβ), tau, synaptic loss, neurodegeneration, and cognitive decline.MethodWe identified 610 ADNI participants with Aβ PET and CSF biomarkers measurements at baseline and 250 individuals with longitudinal CSF biomarkers measurements. All participants had concurrent longitudinal structure MRI and Preclinical Alzheimer’s Cognitive Composite (PACC) assessments. Using generalized linear models, we investigated the associations of CSF microglial biomarkers with Aβ PET, CSF p‐Tau181, CSF presynaptic biomarker growth‐associated protein‐43 (GAP‐43), hippocampal atrophy, and cognitive decline.ResultCSF p‐Tau181 levels rather than Aβ PET were positively associated with CSF microglial biomarkers, whereas higher Aβ PET SUVRs were related to attenuated effects of CSF p‐Tau181 on changes in CSF sTREM2 and CSF PGRN (Figure. 1). Mediation analyses further showed that Aβ PET and CSF p‐Tau181 had opposing effects on CSF microglial biomarkers (Figure. 2). In addition, CSF sTREM2 rather than CSF PGRN were positively associated with CSF GAP‐43 cross‐sectionally and longitudinally, independent of Aβ PET and CSF p‐Tau181 (Figure. 3). Furthermore, augmented microglial activation was associated with slower rates of hippocampal atrophy (sTREM2: standard β (βstd) = 0.11, p = 0.007; PGRN: βstd = 0.11, p = 0.003), but only CSF sTREM2 was related to reduced rates of cognitive decline (βstd = 0.11, p = 0.003).ConclusionThis study provides novel insights into the opposing microglial immune response to Aβ and tau pathologies, where elevated CSF p‐Tau181 rather than Aβ plaque is associated with microglial activation. TREM2‐dependent signaling may contribute to the microglia‐related presynaptic loss beyond Aβ and tau pathologies, and microglial activation is protective against hippocampal atrophy and cognitive decline. These findings are critical for understanding the roles of neuroinflammation in AD or other neurodegenerative diseases.

Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia

BackgroundHeterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN.MethodsIn vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans.ResultsIn a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers.ConclusionsThese findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial.Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204.

Repeat IV and SC Dosing of the Anti-Sortilin Antibody AL101 (P7-6.007)

<h3>Objective:</h3> To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 following repeated intravenous (IV) or subcutaneous (SC) administration. <h3>Background:</h3> Variants in <i>GRN</i>, the coding gene for progranulin (PGRN), have been implicated in a number of neurodegenerative disorders, including frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease. Sortilin, expressed on neurons and microglia, is a key regulator of PGRN levels through sortilin-mediated degradation. Increasing PGRN levels may reduce rates of neuronal loss and clinical decline in neurodegeneration. AL101 is a human IgG1 monoclonal antibody that decreases sortilin and increases PGRN levels in preclinical models and in single-dosed healthy volunteers, and is being developed for neurodegenerative disorders. <h3>Design/Methods:</h3> Healthy volunteers received repeat doses of AL101 in two cohorts: 300 mg SC q2w for a total of 7 doses and 30 mg/kg IV q4w for a total of 4 doses. Safety measures and PK/PD markers in plasma and cerebrospinal fluid (CSF) were assessed at up to 16 and 20 weeks for SC and IV cohorts, respectively. <h3>Results:</h3> Adverse events were generally mild to moderate in severity and self-limiting, consistent with preliminary single-dose AL101 data. There were no severe or serious adverse events related to repeat-dose administration. Subjects in the SC repeat-dose cohort reported a higher number of overall injection site reactions that were mild in severity. Repeat-dose AL101 increased CSF PGRN levels of healthy volunteers up to approximately 80% above baseline. PK/PD modeling based on data from these repeat-dose cohorts supports dosing intervals of up to q8w. <h3>Conclusions:</h3> Repeat IV or SC administration of AL101 is generally safe and well tolerated. AL101 is a potent modulator of PGRN levels in the CSF, with a PK/PD profile that supports its further development in neurodegenerative diseases. <b>Disclosure:</b> Dr. Park has received personal compensation for serving as an employee of Alector. Dr. Park has received personal compensation for serving as an employee of Supernus Pharmaceuticals. Dr. Park has stock in Alector. Dr. Maslyar has received personal compensation for serving as an employee of Alector. Dr. Maslyar has stock in Alector. Michael Ward has received personal compensation for serving as an employee of Alector. Michael Ward has stock in Alector. Michael Ward has received intellectual property interests from a discovery or technology relating to health care. Michael Ward has a non-compensated relationship as a Reviewer with ADDF that is relevant to AAN interests or activities. Dr. Yeh has received stock or an ownership interest from Alector. Dr. Yeh has received stock or an ownership interest from Genentech. Dr. Yeh has received personal compensation in the range of $100,000-$499,999 for serving as a Scientist with Genentech. Dr. Yeh has received personal compensation in the range of $100,000-$499,999 for serving as a Head of Biomarkers with Alector. Hua Long has received personal compensation for serving as an employee of Alector. Hua Long has received stock or an ownership interest from Alector. Hua Long has received intellectual property interests from a discovery or technology relating to health care. Michael Kurnellas has received personal compensation for serving as an employee of Alector. Michael Kurnellas has received stock or an ownership interest from Alector. Michael Kurnellas has received intellectual property interests from a discovery or technology relating to health care. Ms. Vadhavkar has received personal compensation for serving as an employee of Alector. Ms. Vadhavkar has received personal compensation for serving as an employee of Ardelyx. Ms. Vadhavkar has stock in Alector. Ms. Vadhavkar has stock in Ardelyx. Dr. Budda has received personal compensation for serving as an employee of Alector. Dr. Budda has received personal compensation for serving as an employee of Acceleron Pharma. Dr. Budda has stock in Alector. Dr. Budda has stock in Acceleron Pharma.

Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer's Disease Continuum.

PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Potential Value of Cerebrospinal Fluid Progranulin in the Identification of Postoperative Delirium in Geriatrics Patients Undergoing Knee Replacement: The Perioperative Neurocognitive Disorder and Biomarker LifestylE Study.

Objective: The aim of this study was to investigate whether progranulin (PGRN) levels in cerebrospinal fluid (CSF) were associated with postoperative delirium (POD) in geriatric patients undergoing knee replacement.Method: A total of 600 Han Chinese patients aged 65–90 years and who underwent unilateral total knee arthroplasty were included in the Perioperative Neurocognitive Disorder And Biomarker LifestylE (PNDABLE) study from June 2020 to November 2020. All participants were assessed using the Confusion Assessment Method and the Memorial Delirium Assessment Scale on postoperative days 1–7 (or before discharge) by an anesthesiologist. CSF PGRN and CSF biomarkers of POD were measured by ELISA. We analyzed the risk and protective factors of POD using the multivariate logistic regression, and the associations between CSF PGRN and CSF biomarkers of POD using multiple linear regression. We also explored whether the influence of CSF PGRN on POD was mediated by POD core pathology in linear regression models.Results: Postoperative delirium incidence was 9.7% (53/545). There were significant differences in preoperative CSF PGRN between patients with POD and non-POD (NPOD). As for CSF biomarkers, CSF Aβ40, T-tau, and P-tau were risk factors for POD, while CSF PGRN, Aβ42, and Aβ42/Aβ40 were protective factors for POD, as shown by the multivariate logistic regression analysis. CSF PGRN was positively associated with CSF Aβ42 and was negatively associated with CSF Aβ40, T-tau, and P-tau in patients with POD. We found that the AUC was 0.795 (95% CI = 0.706, 0.867) for PGRN between POD and NPOD groups. We found the influence of CSF PGRN on POD was mediated by POD core pathology. The effect was considered partial mediation with the proportion of mediation varying from 44.92 to 62.07%.Conclusion: Cerebrospinal fluid PGRN may be a reasonably good prognostic factor for POD development. Overall, amyloid pathology and tau protein might partially mediate the influence of PGRN on POD.Clinical Trial Registration: www.clinicaltrials.gov, identifier ChiCTR2000033439.

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency

Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. ClinicalTrials.gov Identifier: NCT02149160.

Neuroinflammation modulates the association of PGRN with cerebral amyloid-β burden

Progranulin (PGRN) and neuroinflammatory markers increased over the course of Alzheimer's disease (AD). We aimed to determine whether neuroinflammation could modulate the association of PGRN with amyloid pathologies. Baseline cerebrospinal fluid (CSF) PGRN and AD pathologies were measured for 965 participants, among whom 228 had measurements of CSF neuroinflammatory markers. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects within the framework of A/T/N biomarker profile. Increased levels of CSF PGRN and inflammatory markers (sTNFR1, sTNFR2, TGF-β1, ICAM1, and VCAM1) were associated with T- or N-positive (TN+) profile, irrespective of the amyloid pathology. In TN+ group, CSF PGRN was associated with increased levels of these inflammatory markers and CSF amyloid-β1-42 (p < 0.01). The neuroinflammatory markers significantly modulated (proportion: 20%~60%) the relationship of amyloid burden with CSF PGRN, which could predict slower cognitive decline and lower AD risk in the TN+ group. The abovementioned associations became non-significant in the TN- group. These findings revealed a close relationship between neuroinflammation and CSF PGRN in contributing to AD pathogenesis, and also highlighted the specific roles of PGRN in neurodegenerative conditions. Future experiments are warranted to verify the causal relationship.

Sleep Characteristics and Cerebrospinal Fluid Progranulin in Older Adults: The CABLE Study.

Cerebrospinal fluid (CSF) progranulin (PGRN) is related to various neurodegeneration diseases. And sleep problems can cause abnormality in protein metabolism in vivo. We aim to explore the potential associations between the self-reported sleep characteristics and CSF PGRN in cognitively intact older adults. Our study recruited 747 participants (mean (standard deviation (SD)) age, 61.99 (10.52)years, 329 (42.89%) females) who had normal cognition from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF PGRN and sleep characteristics measured. The multiple linear regression and nonlinear regression adjusted for age, gender, education, and apolipoprotein E-epsilon 4 gene (APOE4) status were used to assess the associations between sleep characteristics and PGRN. Interaction effects were explored between APOE4 status and sleep characteristics on CSF PGRN level. Sleep disturbances indicated lower CSF PGRN (β=-0.0186, p=0.0160). For detailed items in sleep disturbances, lower CSF PGRN was found in males who woke up during sleep (β=-0.0121, p=0.0062) and in females who had breathing difficulties (β=-0.0258, p=0.0271). Meanwhile, sleep efficiency was associated with CSF PGRN (β=-0.0512, p=0.0497). No significant interaction effects between sleep characteristics and APOE4 status were found. Meanwhile, we did not find a nonlinear relationship between nocturnal sleep duration and CSF PGRN. Sleep problems may influence the metabolism of PGRN, thus attenuating the protective effects of PGRN on neurodegeneration diseases.

AL001 restores CSF PGRN levels and normalizes disease‐associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene

AbstractBackgroundAL001 is a recombinant humanized anti‐Sortilin monoclonal antibody in development for frontotemporal dementia (FTD). Mutations in a single copy of the progranulin gene (GRN) leads to a 50% or greater decrease in the level of circulating progranulin (PGRN) protein levels and are causative of FTD. The disease is associated with increased inflammation and impaired lysosomal function in the brain. The INFRONT Phase 1/1b clinical study AL001‐1 investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered AL001 in healthy volunteers (HV) and participants with a GRN mutation causative of FTD (FTD‐GRN). In addition, the study investigated the effect of AL001 on disease‐associated biomarkers.MethodA total of 64 participants were enrolled in the AL001‐1 study. In the single dose ascending part of the study, 50 healthy volunteer participants were enrolled with 38 exposed to AL001 and 12 exposed to placebo. The study enrolled 6 asymptomatic FTD‐GRN and 8 symptomatic FTD‐GRN participants. The 8 symptomatic FTD‐GRN participants received 3 doses of 30 mg/kg of AL001 over 4 weeks.ResultTreatment of symptomatic FTD‐GRN participants with AL001 over 4 weeks restored PGRN levels in the cerebrospinal fluid (CSF) to normal levels for more than 8 weeks. To further investigate the effects of restoring PGRN levels, partial normalization of a FTD disease proteomic signature was observed in the CSF 4 weeks after the last dose in multidose treatment group. Compared to healthy volunteers, AL001 treatment rescued cathepsin B (CTSB), a marker of lysosomal function, by 58%. AL001 treatment also partially normalized markers of inflammation and gliosis, osteopontin (SPP1) and chitotriosidase (CHIT1) by 52% and 22%, respectively. In addition to the reversal of these disease phenotypes, a 14% reduction (n.s.) in plasma neurofilament light chain (NfL), a marker of neuron injury and stress, was observed after 8 weeks after the last dose.ConclusionAL001 treatment resulted in a sustained increase in plasma and CSF PGRN in FTD‐GRN mutation carriers. New data showed reduction of NfL and normalization of proteins associated with the disease after one month of dosing. These results have supported progressing AL001 to Phase 2 and pivotal Phase 3 studies.

Cerebrospinal fluid progranulin is associated with increased cortical thickness in early stages of Alzheimer's disease

Progranulin plays an important role in neuroinflammation in Alzheimer's disease (AD) pathophysiology, being upregulated by activated microglia. This study assessed whether cerebrospinal fluid levels of progranulin correlated with structural neuroimaging measures and cognition in 122 cognitively normal individuals, 81 mild cognitive impairment, and 70 AD patients from the Alzheimer's Disease Neuroimaging Initiative. Cognitively normal subjects were classified into 3 groups using the AT(N) system, whereas all mild cognitive impairment and AD patients were A+/TN+. Correlations between progranulin with neuroanatomical measures and cognitive decline were performed within each group. Progranulin was associated with cortical thickening in parietal, occipital, and frontal regions in cognitively normal individuals with amyloid pathology. These subjects also showed cortical thickening compared with A−/TN− subjects, an effect that was partially mediated by progranulin. In addition, higher progranulin correlated with longitudinal cognitive decline. The association between progranulin and cortical thickening, together with regional “brain swelling” in A+/TN− subjects, suggests progranulin contributes to the neuroinflammatory structural changes in preclinical AD.

A Highly Sensitive Sandwich ELISA to Detect CSF Progranulin: A Potential Biomarker for CNS Disorders.

Progranulin (PGRN) plays critical roles in inflammation, tumorigenesis, and neurodegeneration. PGRN levels in blood and cerebrospinal fluid (CSF) are being increasingly investigated as potential biomarkers for these disorders. However, the value of CSF PGRN as a biomarker has been limited because currently available commercial enzyme-linked immunosorbent assay (ELISA) kits have suboptimal sensitivity for detecting CSF PGRN. In this study, pairs of monoclonal antibodies (MAbs) were first screened from eleven monoclonal antiPGRN antibodies using indirect ELISA, then a sandwich ELISA was established using the 2 optimized MAbs. This system displayed high sensitivity, with a lower limit of detection of 60.0 pg/mL and a lower limit of quantification of 150 pg/mL. By using this ELISA system, we showed varied CSF PGRN levels in different brain disorders. For example, as compared with the normal controls, patients with Alzheimer disease or multiple sclerosis showed mildly increased CSF PGRN; those with aseptic encephalitis or neuropsychiatric systemic lupus erythematosus showed moderately increased CSF PGRN; those with bacterial leptomeningitis showed severely increased CSF PGRN. Additionally, determining CSF PGRN levels could monitor CNS metastasis and CSF seeding of carcinomas. These results indicate that this system can be valuable in studying the diagnostic and prognostic value of CSF PGRN in brain disorders.

CSF-Progranulin and Neurofilament Light Chain Levels in Patients With Radiologically Isolated Syndrome-Sign of Inflammation.

Background: Cerebrospinal fluid (CSF) markers of disease in patients with radiologically isolated syndrome (RIS) are the subject of intense investigation, because they have the potential to enhance our understanding of the natural disease course and provide insights into similarities and differences between RIS and other multiple sclerosis (MS) disease identities.Methods: Here we compared neurofilament light chain (NFL) and progranulin (PGRN) levels in the CSF in RIS patients with levels in patients with different subtypes of MS and healthy controls (HC) using Kruskal–Wallis one-way analysis of variance.Results: Median CSF NFL concentrations in RIS patients did not differ to those in HC and clinically isolated syndrome (CIS) patients, but were significantly lower than in relapsing remitting (RRMS) and primary progressive (PPMS) MS patients. In contrast, RIS patients exhibited higher median CSF PGRN levels than HC and showed no significant differences compared with CIS, RRMS, and PPMS cases.Conclusion: We postulate that elevated PGRN values in the CSF of RIS patients might indicate inflammatory and repair activity prior to axonal disintegration.

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity‐specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best‐characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross‐sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non‐carriers 10 years before the expected symptom onset. In late‐onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.

Biomarkers of Neurodegeneration in Autoimmune-Mediated Encephalitis.

Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE.

Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis.

Assessing central nervous system (CNS) involvement in patients with lymphoma or carcinoma is important in determining therapy and prognosis. Progranulin (PGRN) is a secreted glycosylated protein with roles in cancer growth and survival; it is highly expressed in aggressive cancer cell lines and specimens from many cancer types. We examined PRGN levels by Enzyme Immuno-Assay (EIA) in cerebrospinal fluid (CSF) samples from 230 patients, including 18 with lymphoma [12 with CNS metastasis (CNS+); 6 without CNS metastasis (CNS-)], 21 with carcinomas (10 CNS+; 11 CNS-), and 191 control patients with non-cancer neurological diseases, and compared PRGN levels among these disease groups. Median CSF PGRN levels in the CNS+ lymphoma group were significantly higher than in the CNS- lymphoma and control non-cancer groups; and were also significantly higher in the CNS+ carcinoma group than in the CNS- carcinoma and control groups, except for patients with infectious neurological disorders. Receiver operating characteristic curve analyses revealed that CSF PGRN levels distinguished CNS+ lymphoma from CNS- lymphoma and non-cancer neurological diseases [area under curve (AUC): 0.969]; and distinguished CNS+ carcinomas from CNS- carcinomas and non-cancer neurological diseases (AUC: 0.918). We report here, for the first time, that CSF PGRN levels are higher in patients with CNS+ lymphoma and carcinomas compared to corresponding CNS- diseases. This would imply that measuring CSF PGRN levels could be used to monitor CNS+ lymphoma and metastasis.

Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis.

We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN, and serum PGRN measures available. CSF PGRN was normalized against the CSF / serum albumin ratio (Qalb ). Using age, sex, height, and weight adjusted general linear models, we examined CSA × CSF PGRN interaction effects on various measures. There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. Muscle Nerve 57: 273-278, 2018.