Csf p-tau 181 /tau ratio as biomarker for TDP pathology in frontotemporal dementia

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Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014; Early Online: 1–6

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Csf p-tau181/tau ratio as biomarker for TDP pathology in frontotemporal dementia Barbara Borroni1, Alberto Benussi1, Silvana Archetti2, Daniela Galimberti3, Lucilla Parnetti4, Benedetta Nacmias5, Sandro Sorbi5, Elio Scarpini3 & Alessandro Padovani1 1Centre

of Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, 2III Laboratory of Analysis, Brescia Hospital, Brescia, 3Dino Ferrari Centre, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Department of Neurological Sciences, Milan, 4Section of Neurology, Centre for Memory Disturbances, University of Perugia, Perugia, and 5Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

Abstract Our objective was to evaluate the CSF phospho-Tau181/total-Tau (p/t-Tau) ratio to distinguish between the two main forms of frontotemporal lobar degeneration (FTLD): FTLD with TDP-43 (FTLD-TDP) and FTLD with Tau inclusions (FTLDTau). CSF p/t-Tau ratio was examined in 79 FTLD patients with predictable neuropathology, i.e. Tau (affected by progressive supranuclear palsy or carriers of mutations within the MAPT gene) or TDP-43 (carriers of mutations within granulin, C9orf72, TARDBP genes or affected by FTD with motor neuron disease). FTLD patients were randomly grouped in a training cohort (n  39) to assess the best CSF p/t-Tau cut-off score according to ROC analysis, and a validation cohort (n  40) to evaluate accuracy values of the identified marker. Results showed that, in the training cohort, we found a significantly reduced CSF p/t-Tau ratio in FTLD-TDP relative to FTLD-Tau. ROC analysis for p/t-Tau ratio was 0.873 and cut-off score of 0.136 allowed to differentiate FTLD-TDP and FTLD-Tau with 81.8% sensitivity and 88.2% specificity, respectively. Analysis in the validation cohort showed CSF p/t-Tau ratio  0.136 to distinguish FTLD-TDP from FTLD-Tau with 83.3% specificity and 63.6% sensitivity, respectively. The positive predictive value of detecting TDP neuropathology was 82.4%. In conclusion, a reduced CSF p/t-Tau ratio represents a viable biomarker to correctly identify TDP pathology in FTLD. Key words: Amyloid beta-peptides/cerebrospinal fluid, biological markers/cerebrospinal fluid, frontotemporal lobar degeneration/ cerebrospinal fluid, peptide fragments/cerebrospinal fluid, tau proteins/cerebrospinal fluid

Introduction Frontotemporal dementia (FTD) is a highly clinical heterogeneous neurodegenerative disorder characterized by behavioural and personality changes, language impairment and deficits of executive functions (1). In a number of cases, extrapyramidal symptoms and motor neuron disease are associated features (1–3). Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e. the behavioural variant of FTD (bvFTD), the agrammatic variant of primary progressive aphasia (avPPA), the semantic variant of PPA (svPPA), and the FTD associated with motor neuron disease (FTD-MND) (2–5). Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are

also considered under the same label of FTD spectrum (4–6). Neuropathologically, frontotemporal lobar degeneration (FTLD) is variably associated with two predominant hallmarks, namely FTLD with Tau inclusions (FTLD-Tau) and FTLD with TAR DNAbinding protein 43 inclusions (FTLD-TDP) (1,7). Only genetic aetiologies resulting in FTLD are associated with specific underlying neuropathologies. These include pathogenic mutations in the Microtubule Associated Protein Tau (MAPT) (2,3,8) gene, underlying Tau pathology, and mutations in the progranulin (GRN) (4,5,9,10), Transactive Response DNA-Binding Protein (TARDBP) (6,11,12) and C9orf72 (13,14) genes associated with TDP pathology. Furthermore,

Correspondence: B. Borroni, Clinica Neurologica, Università degli Studi di Brescia Piazza Spedali Civili 1, Brescia, Italy. E-mail: [email protected] (Received 3 July 2014; accepted 28 September 2014) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.971812 MALS_A_971812.indd 1

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it has been proved that PSP phenotype is consistently associated with FTLD-Tau (15), while FTD-MND predicted FTLD-TDP pathology (16–18). Numerous attempts have been made to identify an in vivo biomarker that can accurately predict the underlying neuropathology in the other cases, but a clear-cut association between clinical or neuroradiological features and characteristic histological inclusions has not been yet established (19–22). A recent study by Hu et al. has identified in the cerebrospinal fluid (CSF) phospho-Tau181 to total Tau (p/t-Tau) ratio a viable biomarker to identify FTLD with TDP pathology compared to FTLDTau (23). In this view, p/t-Tau ratio has been proposed as useful in detecting patients with amyotrophic lateral sclerosis (ALS), which is associated with TDP neuropathology (24). All the above observations defined the object of this work, aimed at testing the CSF p/t-Tau ratio in a cohort of FTLD cases with predictable underlying neuropathology and to obtain cut-off values with highest sensitivity and specificity in discriminating FTLD-TDP from FTLD-Tau. Results were then assessed in a separate multicentre validation cohort. Methods Subjects Patients complying with current clinical criteria for FTD (4,5) were consecutively recruited from the Centre for Aging Brain and Neurodegenerative Disorders, University of Brescia, the Neurology Unit, University of Milan, the Centre for Memory Disturbances, University of Perugia, and the Neurology Unit, University of Florence, Italy. The diagnostic assessment involved a review of full medical history, a semi-structured neurological examination, and a complete mental status evaluation by at least two independent and experienced reviewers. A standardized cognitive and behavioural assessment was carried out, as previously published (25). Patients were screened for the most common monogenic forms of MAPT, GRN, TARDBP mutations and C9orf72 hexanucleotide expansion, as already reported (26). Diagnosis of bvFTD, avPPA, svPPA, FTD-MND, PSP, or CBS and available CSF analysis were considered as inclusion criteria for biomarker assessment. Neuroimaging findings supportive of clinical diagnosis and diagnosis confirmed after at least two-year follow-up were adjunctive inclusion criteria. Furthermore, 49 subjects without cognitive deficits who underwent lumbar puncture for headache or peripheral neuropathy were included as control group. CSF analyses CSF was obtained during routine diagnostic lumbar puncture according to a standardized protocol, in the

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outpatient clinic, at fasting, from 09.30 to 10.30 hours, after informed written consent had been obtained. CSF was collected in sterile polypropylene tubes and gently mixed to avoid gradient effects. Routine chemical measures were determined.The remaining CSF was centrifuged for 3 min at 3000 rpm and aliquots (0.5 ml) were immediately stored at 80 °C or in liquid nitrogen for subsequent analysis. CSF t-Tau, p-Tau181 and Ab42 concentrations were measured in duplicate with an ELISA test (Innotest hTau Antigen kit and Innotest Phospho-Tau(181P); Innogenetics, Ghent, Belgium) by a single experienced technician blinded to the FTLD grouping. Inter-assay variability was less than 7%. The p/t-Tau ratio was obtained by dividing p-Tau181 concentration by that of t-Tau. According to our laboratory standards, we excluded patients with a CSF Alzheimer’s disease-like pattern, consisting of high CSF t-Tau and low Ab42, as previously outlined (27). Statistical analyses Included patients were randomly assigned to either the training or the validation cohorts using the random sampling function in SPSS. Comparison between clinical subgroups was carried out using Student’s t-test (unpaired), or Pearson’s c2 test, as appropriate. Post hoc Mann-Whitney test was used to establish whether levels of Ab42, p-Tau181, t-Tau and the p/t-Tau ratio differed between the FTLDTau and FTLD-TDP group in the first multicentre training cohort. Receiver operating characteristics (ROC) curve analysis was used to determine the area under the curve (AUC) including 95% confidence interval (CI) values, and cut-off points were set to achieve highest levels of sensitivity and specificity. Cut-off values were then tested in the second, separate multicentre validation cohort assessing levels of sensitivity, specificity and predictive values. To determine the effects of preanalytical factors, linear regression analysis or Kruskal-Wallis test was used to determine the effects of age, collection year or site of collection on the distribution of CSF biomarkers. Statistical significance was assumed at p  0.05. Data analyses were carried out using SPSS 21.0 software. Results Out of 238 included FTD, 79 patients with accurately predictable neuropathology based on specific clinical syndromes or pathogenic gene mutations were considered in the present analysis. The FTLD-Tau cohort (n  35) included 33 patients with clinically diagnosed PSP and two patients carrying a MAPT mutation (Gly304Ser and Pro301Leu). The FTLD-TDP cohort (n  44) comprised 27 patients with GNR mutations (n  22 Thr272fs, n  1 G148fs, n  1 Cys157fs, n  1

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Table I. Demographic and clinical characteristics of FTLD-Tau, FTLD-TDP and healthy controls.

Patients, n Age, years Age at onset, years Gender, % female Education, years MMSE score CSF Ab, pg/ml CSF p-Tau, pg/ml CSF t-Tau, pg/ml CSF p/t-Tau ratio

Healthy controls

FTLD-Tau

FTLD-TDP

49 61.3  15.1 – 44.9 6.4  4.2 29.0  1.2 775.6 (511.0–1044.4) 35.0 (23.3–45.5) 221.8 (143.2–334.0) 0.17 (0.13–0.21)

35 71.3  7.0 67.9  7.3 40.0 6.7  3.4 24.6  3.0 664.0 (515.6–1053.1) 37.3 (30.1–50.4) 242.6 (126.2–318.0) 0.17 (0.14–0.24)

p-value *

44 62.4  7.6  0.0011 60.3  7.6  0.0011 47.7 n.s.2 n.s.1 6.5  2.7 n.s.1 23.0  5.0 831.7 (660.9–997.8) n.s.3 34.0 (24.4–53.9) n.s.3 361.5 (212.0–511.6) 0.0033 0.12 (0.07–0.16)  0.0013

­Demographic characteristics expressed as mean  SD, CSF analytes expressed as median (interquartile range). *Differences between FLTD-TDP and FTLD-Tau. 1Student’s t-test. 2Pearson’s c2 test. 3Mann-Whitney test.

Asp22fs, n  1 Cys139Arg, n  1 Gln341X), three with TARDBP (n  2 g.4988G/A, n  1 g.11297C/T), nine with C9orf72 expansion, and five cases with FTD-MND. Demographic characteristics were comparable in all subgroups except for age and age at disease onset, which showed older onset in the FTLD-Tau group, as reported in Table I. Included patients were randomly assigned to either the training (n  39 of which TDP n  22, Tau n  17) or the validation (n  40 of which TDP n  22, Tau n  18) cohorts and, in all subjects, CSF analysis was carried out. As shown in Table II and Figure 1, in the training cohort, we found a significantly reduced CSF p/tTau ratio in FTLD-TDP relative to FTLD-Tau (p  0.001). CSF t-Tau was significantly different between groups, even though with lower significance (p  0.015), and no differences of CSF p-Tau levels were reported. Receiver operating characteristic (ROC) analyses for p/t-Tau ratio showed an area under the curve (AUC) of 0.873 (p  0.001, 95% CI 0.759–0.987) in differentiating FTLD-Tau and FTLD-TDP cases (see Figure 2). At the best cut-off score of 0.136,

sensitivity was 81.8%, specificity was 88.2%, and accuracy value was 85.0%. When FTLD-TDP cases and healthy controls were considered, the AUC was of 0.777 (p  0.001, 95% CI 0.662–0.892), achieving 81.8% sensitivity and 71.4% specificity, whereas p/t-Tau levels did not reach a significant threshold in differentiating FTLDTau from controls. The second validation cohort was then considered. CSF p/t-Tau ratio in FTLD-TDP relative to FTLD-Tau was also significantly reduced, as reported in Table II and Figure 1. The same cut-off was applied at the second cohort, and CSF p/t-Tau ratio  0.136 was able to distinguish FTLD-TDP from FTLD-Tau with 83.3% specificity and 63.6% sensitivity. The positive predictive value of detecting TDP neuropathology was 82.4%, while the negative predictive value was low (65.2%). Finally, when the cut-off was applied to bvFTD patients with unknown neuropathology (n  93, age  66.0  5.9), 59% (n  55) of patients had values predicting FTLD-TDP and 41% (n  38) predicting FTLD-Tau neuropathology, in accordance with literature autopsy data (6,16,17,28).

Table II. CSF p-Tau, t-Tau and CSF p/t-Tau ratio in the training cohort and validation cohort of FTD patients.

Training cohort Patients, n CSF p-Tau, pg/ml CSF t-Tau, pg/ml CSF p/t-Tau ratio Validation cohort Patients, n CSF p-Tau, pg/ml CSF t-Tau, pg/ml CSF p/t-Tau ratio

FTLD-Tau

FTLD-TDP

p-value *

17 41.0 (28.9–51.9) 242.6 (137.4–342.4) 0.17 (0.14–0.24)

22 33.5 (23.2–65.5) 374.2 (224.0–514.4) 0.12 (0.07–0.16)

n.s. 0.015  0.001

18 41.1 (34.4–52.9) 278.5 (194.6–352.0) 0.17 (0.14–0.21)

22 31.0 (25.1–50.6) 319.5 (202.8–564.0) 0.09 (0.07–0.17)

n.s. n.s. 0.003

­CSF analytes expressed as median (interquartile range). *Mann-Whitney test.

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0.30

p/t-Tau ratio

0.25

0.20

0.15

0.05

0.00 FTLD-Tau FTLD-TDP

HC

FTLD-Tau FTLD-TDP FTLD-Tau FTLD-TDP

All patients

Training cohort

Validation cohort

Figure 1. Levels of CSF p/t-Tau ratio in the entire FTLD cohort, in healthy controls, and in the training and validation cohort for FTLD-Tau and FTLD-TDP. Horizontal thick lines illustrate median CSF values, notches correspond to interquartile range, error bars depict 25th to 75th percentile range of data, and circles represent outliers. HC: healthy controls.

To evaluate if disease duration was correlated to p/t-Tau ratio, linear regression analyses were carried out in both subgroups. In patients with underlying TDP pathology, p/t-Tau ratio was not correlated with disease progression (p  0.44) whereas in patients with Tau pathology, disease progression was associated with an increase in the p/t-Tau ratio (p  0.02). Preanalytical factors were also taken into account. Linear regression analysis revealed that a CSF p/tTau ratio in FTLD was not associated with age (p  0.110), year of CSF collection (p  0.231), or site of CSF collection (p  0.615 for FTLD-Tau; p  0.576 for FTLD-TPD).

1.0

0.8

Sensitivity

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0.10

0.6 AUC = 0.873 0.4

0.2

0.0 0.0

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Figure 2. Receiver Operating Characteristic curve in the validation cohort.

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Discussion Looking at biomarkers able to predict FTLD neuropathology is one of the most significant issues in current literature concerning specific therapeutic strategies targeting either TDP or Tau accumulations. It is now clear that there is no correspondence between clinical features and neuropathology findings in FTLD cases (29,30), and thus biological signatures mirroring the ongoing neuropathological mechanism are desperately needed for disentangling this issue. In a recent paper, it has been demonstrated that CSF p/t-Tau ratio was able to distinguish FTLDTDP and FTLD-Tau with 82% sensitivity and 62% specificity (23), the former group having significantly reduced CSF p/t-Tau ratio scores. In this work we aimed to confirm these findings by an independent sample of patients, obtaining comparable results. In a first training cohort of FTLD patients with predictable pathology, we set up the most accurate biomarker cut-off score and tested this marker on a second validation cohort. CSF p/tTau ratio  0.136 was able to distinguish FTLDTDP from FTLD-Tau with 83.3% specificity and 63.6% sensitivity, with high positive predictive value of detecting TDP neuropathology (82.4%) and low negative predictive value (65.2%). Thus, a reduced CSF p/t-Tau predicted FTLDTDP neuropathology with high accuracy, while values within normal range are not useful for clear-cut conclusions on the ongoing pathological mechanism. This result has been further corroborated in another TDP proteinopathy, namely in cases with amyotrophic lateral sclerosis (ALS) (24). The authors performed a case-control study in a large sample of patients with ALS compared to patients with Tau pathology (i.e. PSP, MAPT mutation or proven

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Csf p-tau181/tau ratio as biomarker for TDP pathology 

autopsy cases), and they reported even higher accuracy values in identifying TDP neuropathology, with a correct classification in 86% of cases (24). The pathological mechanism leading to reduced CSF p/t-Tau in FTLD-TDP is currently unknown and investigating different Tau isoforms and Tau phosphorylation sites may be helpful in elucidating its molecular bases. A more detailed analysis of Tau fragments, i.e. full length Tau and truncated forms (31,32), and the pattern of post-transduction protein modifications will clarify these data. We found a different cut-off score compared to that reported by Hu et al., and this might be due to the different method used for detecting CSF Tau levels; however, the accuracy values were comparable, further confirming the reliability of this biomarker. Furthermore, the analysis of preanalytical factors, such as year of CSF collection or site of collection did not yield significant effects. This is of particular interest as CSF Tau detection is available in most laboratories involved in dementia, thus being quite easy to collect large samples of patients to corroborate the present results, and eventually include this biomarker in clinical pharmacological trials targeting TDP neuropathology. We acknowledge that the present study has some limitations. First, we included patients with known neuropathology on the basis of either genetic trait or predictable clinical phenotype; we cannot thus conclude that the results may be considered valid in sporadic cases of FTLD-TDP, and retrospective autopsy studies are warranted. Moreover, we included almost all cases with four-repeat tauopathy, i.e. PSP, hence a comparison group with three-repeat tauopathy, i.e. Pick’s disease, would be of interest. Finally, a larger cohort of patients is needed. In conclusion, a reduced CSF p/t-Tau ratio has been established as a reliable biomarker in detecting FTLD-TDP cases and should therefore be considered in future clinical trials on FTLD.­­­­ Declaration of interest:  The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Seelaar H, Rohrer JD, Pijnenburg YAL, Fox NC, van Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry. 2011;82:476–86. 2. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;59:1077–9. 3. Murphy JM, Henry RG, Langmore S, Kramer JH, Miller BL, Lomen-Hoerth C. Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol. 2007;64:530–4. 4. Rascovsky K, Rohrer JD, Hodges JR, Knopman D, Mendez MF, Kramer JH, et  al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456–77.

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