2013 Emerging Science Abstracts
William T. HuKelly D. WattsMurray GrossmanJonathan GlassJames J. LahJohn Q. TrojanowskiAllan I. LeveyJuha RouruKeith WesnesJutta HänninenMichael MurphyHenry RiordanJuha O. Rinne
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OBJECTIVE:To validate five previously identified CSF biomarkers for FTLD-TDP, and to report a novel, robust, stand-alone CSF biomarker for FTLD-TDP.BACKGROUND: There is currently no reliable way to predict the underlying FTLD pathology while the patients are still living, and an ante-mortem biomarker for one of the main FTLD subtypes (FTLD-TDP or FTLD-Tau) can significantly enhance the pathology-based FTLD diagnosis and clinical trials for FTLD-TDP and FTLD-Tau.DESIGN/METHODS: Two independent cohorts of patients with frontotemporal dementia (FTD) were recruited independently from Emory University (Atlanta, GA) and University of Pennsylvania (Penn; Philadelphia, PA) to undergo CSF analysis.These include patients with high likelihood FTLD-TDP (FTD patients with amyotrophic lateral sclerosis or FTD patients with mutations in PGRN or C9ORF72) and patients with high likelihood FTLD-Tau (FTD patients with progressive supranuclear palsy or FTD patients with mutations in MAPT).Levels of five CSF previously identified proteins were measured, along with levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau 181 ).RESULTS: 29 Emory patients and 40 Penn patients participated in the study, including 43 patients with high likelihood FTLD-TDP and 26 patients with high likelihood FTLD-Tau.Using the Emory cohort, we validated the group level differences in CSF eotaxin-3, Fas, and IL-23 (p , 0.01) previously identified using the Penn cohort.We also identified the ratio of p-Tau 181 to t-Tau (p/t-Tau ratio) to be significantly lower in Emory FTLD-TDP cases compared to Emory FTLD-Tau and AD cases.Using the Penn cohort as a validation set, p/t-Tau ratio alone is sufficient to identify FTLD-TDP with 88% sensitivity and 73% specificity.CONCLUSIONS: CSF biomarkers have the potential of accurately identifying FTLD-TDP, and further development of this and other FTLD-TDP biomarkers will significantly accelerate the ante-mortem prediction of FTLD-TDP pathology and design of substrate-specific FTLD clinical trials.Keywords:
C9ORF72
Grossman
Frontotemporal lobar degeneration
Tauopathy
C9ORF72
Frontotemporal lobar degeneration
Neurofibrillary tangle
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Abstract Background The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category “probable 4‐repeat (4R)‐tauopathy” for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration. Objectives To validate the accuracy of these clinical criteria for “probable 4R‐tauopathy” to predict underlying 4R‐tauopathy pathology. Methods Diagnostic accuracy for 4R‐tauopathies according to the established criteria was estimated retrospectively in autopsy‐confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R‐tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non‐4R‐tauopathies). Results We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non‐4R‐tauopathies (N = 161). Sensitivity and specificity of “probable 4R‐tauopathy” was 10% and 99% in the first year and 59% and 88% at final record. Conclusions The new diagnostic category “probable 4R‐tauopathy” showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R‐tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society
Tauopathy
Corticobasal degeneration
Frontotemporal lobar degeneration
Movement Disorders
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C9ORF72
Frontotemporal lobar degeneration
Degeneration (medical)
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C9ORF72
Frontotemporal lobar degeneration
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Tauopathy
Corticobasal degeneration
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OBJECTIVE: To evaluate TMEM106B as a genetic modifier in C9orf72-associated frontotemporal lobar degeneration.
BACKGROUND: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA binding protein of 43kDa (FTLD-TDP).
DESIGN/METHODS: Discovery cohort-Replication cohort design to investigate the influence of TMEM106B genotype on age at onset and age at death for FTLD-TDP associated with C9orf72 expansions.
RESULTS: We report that TMEM106B rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n=14), with the minor allele correlated with earlier age at death (p=0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n=75), again finding that the minor allele associates with earlier age at death (p=0.016), as well as earlier age at onset (p=0.019). Indeed, in our international replication cohort, with each additional minor allele at rs1990622, patients had a decrease of >3 years in age at death and age at FTLD onset. In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions.
CONCLUSIONS: TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers decreased risk for developing FTLD-TDP (minor, or C, allele of rs1990622) is associated with earlier age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease. Disclosure: Dr. Chen-Plotkin has received research support from Pfizer Inc. Dr. Gallagher has nothing to disclose. Dr. Suh has nothing to disclose. Dr. Grossman has received personal compensation for activities with Allon Therapeutics. Dr. Elman has nothing to disclose. Dr. McCluskey has nothing to disclose. Dr. Trojanowksi has received personal compensation for activities with Pfizer Inc., Johnson & Johnson, MetLife, and Bristol-Myers Squibb Co. as a consultant. Dr. Trojanowski has received royalty payments through Penn licenses. Dr. Trojanowksi has received research support from AstraZeneca and Bristol-Myers Squibb Co. Dr. Lee has received personal compensation for activities with Pfizer Inc., Johnson & Johnson, MetLife, and Bristol-Myers Squibb Co. Dr. Lee has received royalty payments from PENN licenses and Eli Lily & Co., Inc. Dr. Lee has received research support from AstraZeneca and Bristol-Myers Squibb Co. Dr. Van Deerlin has nothing to disclose.
C9ORF72
Frontotemporal lobar degeneration
Degeneration (medical)
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TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables.The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, AΒ1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits.There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort).CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.
C9ORF72
Frontotemporal lobar degeneration
Motor neurone disease
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C9ORF72
Frontotemporal lobar degeneration
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A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by the C9ORF72 repeat expansion. In serial neuropsychological examinations, the patient’s cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration of C9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present.
C9ORF72
Frontotemporal lobar degeneration
Degeneration (medical)
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A 74‐year‐old man developed abnormal forgetfulness, soon followed by unstable speech content and marked disorientation. At 77 years of age, the patient started to occasionally fall, an aspect of progressive supranuclear palsy. He then became bedridden. The patient eventually died of pneumonia at 79 years of age. Neuropathological examination revealed profiles of both progressive supranuclear palsy and Alzheimer's disease. Although the two conditions both belong to tauopathy, their pathologically proven combination was rare. Furthermore, the case had the possibility of being a subgroup of tauopathy.
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