P1-101: Altered cerebrospinal fluid phospholipid composition in presenilin1 mutation carriers: Baseline data from a dian cohort subset

Background: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls. Results: Plasma PGRN levels were lower in carriers than in controls and showed a mean coefficient of variation of 5.3% in carriers over 1 week. Although plasma PGRN correlated with CSF PGRN in carriers (r = 0.54, p = 0.02), plasma only explained 29% of the variability in CSF PGRN. rs5848, rs646776 and rs1990622 genotypes only partly explained the variability of PGRN levels between subjects. Conclusions: Plasma PGRN is relatively stable over 1 week and therefore seems suitable for treatment monitoring of PGRN-enhancing agents. Since plasma PGRN only moderately correlated with CSF PGRN, CSF sampling will additionally be needed in therapeutic trials.

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Inflammatory molecules in Frontotemporal Dementia: Cerebrospinal fluid signature of progranulin mutation carriers

Brain Behavior and Immunity ◽

10.1016/j.bbi.2015.05.006 ◽

2015 ◽

Vol 49 ◽

pp. 182-187 ◽

Cited By ~ 22

Author(s):

D. Galimberti ◽

R. Bonsi ◽

C. Fenoglio ◽

M. Serpente ◽

S.M.G. Cioffi ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Frontotemporal Dementia ◽

Mutation Carriers ◽

Inflammatory Molecules

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Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington’s disease

10.1101/2020.11.02.20222166 ◽

2020 ◽

Author(s):

Zhen-Yi Andy Ou ◽

Lauren M. Byrne ◽

Filipe B. Rodrigues ◽

Rosanna Tortelli ◽

Eileanoir B. Johnson ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurotrophic Factor ◽

Limit Of Detection ◽

Brain Derived Neurotrophic Factor ◽

Striatal Neurons ◽

Mutation Carriers ◽

Potential Biomarker ◽

And Gender

AbstractBrain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD.BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) were quantified using conventional ELISAs and an ultra-sensitive immunoassay.BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD.BDNF in CSF and plasma is unlikely to be a biomarker of HD progression, and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.

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Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

10.1101/2019.12.13.19014217 ◽

2019 ◽

Cited By ~ 2

Author(s):

Sonia M Vallabh ◽

Eric Vallabh Minikel ◽

Victoria J Williams ◽

Becky C Carlyle ◽

Alison J McManus ◽

...

Keyword(s):

At Risk ◽

Cerebrospinal Fluid ◽

Prion Protein ◽

Prion Disease ◽

Neuronal Damage ◽

Massachusetts General Hospital ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Mutation Carriers ◽

One Year

ABSTRACTBACKGROUNDFluid biomarkers are important in the development of therapeutics to delay or prevent prion disease, but have not been systematically evaluated in pre-symptomatic individuals at risk for genetic prion disease.METHODSWe recruited pre-symptomatic individuals with pathogenic mutations in the prion protein gene (PRNP; N=27) and matched controls (N=16), to donate cerebrospinal fluid (CSF) and blood at multiple timepoints to a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF, and the neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in both CSF and plasma. We compared these markers cross-sectionally between mutation carriers and controls, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months for a subset of participants.FINDINGSCSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% both over 2-4 months in N=29 participants and over 10-20 months in N=10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with others, though still within the normal range, and remained asymptomatic one year later. Overall, tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.INTERPRETATIONCSF PrP will be interpretable as a pharmacodynamic readout of the effects of a PrP-lowering therapeutic in pre-symptomatic individuals, and may serve as a surrogate biomarker in a “primary prevention” trial paradigm. In contrast, current markers of prion seeding activity and of neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls, arguing against the feasibility of a “secondary prevention” paradigm in which trials specifically recruit pre-symptomatic participants with prodromal evidence of pathology.

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