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October 23, 2018; 91 (17) Article

CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum

Ignacio Illán-Gala, Daniel Alcolea, Victor Montal, Oriol Dols-Icardo, Laia Muñoz, Noemi de Luna, Janina Turón-Sans, Elena Cortés-Vicente, Ma Belén Sánchez-Saudinós, Andrea Subirana, Isabel Sala, Rafael Blesa, Jordi Clarimón, Juan Fortea, Ricard Rojas-García, Alberto Lleó
First published October 5, 2018, DOI: https://doi.org/10.1212/WNL.0000000000006383
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Abstract

Objective To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Methods We analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness.

Results We found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = −0.41, p < 0.001 and r = −0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions.

Conclusions sAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum.

Classification of evidence This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.

Glossary

AD=
Alzheimer disease;
ALS=
amyotrophic lateral sclerosis;
ALSci-bi=
amyotrophic lateral sclerosis with cognitive or behavioral impairment;
ALSFRS-R=
revised ALS Functional Rating Scale;
ALSni=
amyotrophic lateral sclerosis without cognitive or behavioral impairment;
bvFTD=
behavioral variant of frontotemporal dementia;
CBS=
corticobasal syndrome;
CDR=
Clinical Dementia Rating;
CERAD=
Consortium to Establish a Registry for Alzheimer’s Disease;
ECAS=
Edinburgh Cognitive and Behavioral ALS Screen;
FTD=
frontotemporal dementia;
FTLD=
frontotemporal lobar degeneration;
HR=
hazard ratio;
MND=
motor neuron disease;
MPRAGE=
magnetization-prepared rapid gradient echo;
nfaPPA=
nonfluent agrammatic primary progressive aphasia;
NfL=
neurofilament light chain;
PSP=
progressive supranuclear palsy;
sAPPβ=
soluble β fragment of amyloid precursor protein;
SPIN=
Sant Pau Initiative on Neurodegeneration;
svPPA=
semantic variant of primary progressive aphasia;
TDP-43=
TAR DNA binding protein

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder, defined by motor neuron degeneration.1 However, patients with ALS may also display a continuum of cognitive and behavioral changes and up to 20% of patients with ALS can be also diagnosed with some of the frontotemporal dementia (FTD)–related syndromes.2,3

ALS and FTD share a common pathologic hallmark that consists of the presence of TAR DNA binding protein (TDP-43) inclusions in the brain.4,–,6 Nearly 95% of ALS and 50% of FTD cases show partially overlapping patterns of TDP-43 inclusions across frontotemporal structures.4,–,6 In addition, neuropathologic and genetic studies have suggested that neuroinflammation may play a central role in the pathophysiology of ALS and FTD.7,–,10

CSF biomarkers may provide important insights into this clinical and pathologic continuum by tracking different aspects of the pathophysiology. The axonal marker neurofilament light chain (NfL) is increased in CSF in ALS and FTD, reflects disease severity, and correlates with brain atrophy.11,12 We previously showed that levels of the soluble β fragment of amyloid precursor protein (sAPPβ) are decreased in CSF in FTD and correlate with frontotemporal neurodegeneration.13 In addition, YKL-40 (also known as chitinase-3-like 1 protein or CHI3L1), a marker of astrocytic activity, is increased in CSF in FTD13,14 but reports in the ALS-FTD continuum are limited.15,16

We aimed to investigate the CSF levels of sAPPβ, YKL-40. and NfL in the entire ALS-FTD spectrum, and evaluate their correlation with clinical measures, disease progression, and cortical thickness.

Methods

Study participants and classification

We analyzed CSF samples of 181 participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort: santpaumemoryunit.com/our-research/spin-cohort/). Patients with FTD were evaluated at the Memory Unit and were classified in one of the following clinical groups according to current diagnostic criteria: behavioral variant of frontotemporal dementia (bvFTD),17 semantic variant of primary progressive aphasia (svPPA),18 nonfluent agrammatic primary progressive aphasia (nfaPPA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS).19,20 Patients with FTD and pathophysiologic evidence of Alzheimer disease (AD) (as defined by a total tau/β-amyloid1-42 ratio >0.52)14 were excluded according to the current diagnostic criteria.20 During follow-up, patients with FTD were actively screened for signs or symptoms suggestive of motor neuron involvement, and were referred to the motor neuron disease (MND) clinic for further clinical and electrophysiologic evaluation.

Patients with ALS were prospectively recruited from the MND clinic at the Hospital de Sant Pau. Patients included in the study fulfilled El Escorial revised criteria for probable, probable laboratory-supported, or definite ALS.21 All patients underwent a cognitive and behavioral screening that included a separate interview with a reliable informant and the administration of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).22 Patients with ALS were classified according to previously reported criteria in one of the following groups: ALS without cognitive or behavioral impairment (ALSni), ALS with cognitive or behavioral impairment (ALSci-bi), and ALS-FTD.23 For the main group comparisons, ALS-FTD participants were included in the ALS group.

Finally, a group of age-matched cognitively normal controls was randomly selected from the SPIN cohort.13,24 Eighty-one (47%) participants have been previously reported elsewhere.13

Sample composition

We included 86 patients with FTD, 38 patients with ALS, and 49 cognitively normal controls. Among patients with FTD, we included 46 patients with bvFTD, 8 patients with svPPA, 12 patients with nfaPPA, and 20 patients within the PSP-CBS spectrum.19,20 The ALS group included 10 ALSni, 14 ALSci, 3 ALSci-bi, and 11 ALS-FTD cases.

CSF analysis

Availability of CSF was required for inclusion in the study. All biomarkers were analyzed at the Sant Pau Memory Unit Laboratory with commercially available ELISA kits of sAPPβ, YKL-40, and NfL (human sAPPβ-w, highly sensitive, IBL, Gunma, Japan; MicroVue, Quidel, San Diego, CA; Nf-light, UmanDiagnostics, Umea, Sweden, respectively) following previously reported methods and manufacturer's instructions.13,14,25

Disease staging and cognitive measures

In patients with FTD, we obtained the modified frontotemporal lobar degeneration (FTLD) Clinical Dementia Rating (CDR) as previously described.26 In patients with ALS, we obtained the revised ALS Functional Rating Scale (ALSFRS-R) at the time of CSF sampling, and then calculated the ALS progression rate by dividing its value by the time from disease onset to CSF sampling, as previously described.27 We defined disease onset as the time when the first symptom was observed (cognitive/behavioral or motor) according to the information provided by the patient or the informants. A total of 150 (83%) participants underwent a complete neuropsychological evaluation within 6 months of CSF sampling, using a previously described protocol.24 In the FTD group, we z-transformed the raw values of neuropsychological measures using means and SDs of the group of age- and sex-matched controls selected for this study (all with a CDR sum of boxes of 0). A global cognitive score was calculated by averaging the following scores: Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) list recall, CERAD list recognition, Boston Naming Test, semantic fluency, phonologic fluency, reverse digit span, Trail Making Test part A and B, and the number location subtest of the Visual Object and Space Perception battery. In the ALS group, we z-transformed the raw values of the ECAS total score using means and SDs of the control group selected for this study.

Genetic analysis and neuropathologic study

All patients were screened for the C9orf72 expansion. In addition, patients with familial history of neurodegenerative diseases or psychiatric illness were screened for other known causal genes of FTLD (MAPT, GRN) and ALS (TBK1, VCP, TARDBP). Mutations were found in C9orf72 (n = 5), GRN (n = 1), VCP (n = 1), and TARDBP (n = 1). Four participants in the ALS group (10.5%) and 2 in the FTD group (2.3%) had autopsy confirmation of MND and FTLD, respectively.

Image acquisition, processing, and analysis

A structural MRI was available for quantification in a subsample of 82 patients. Sixty-five participants were scanned on a 3T Philips (Best, the Netherlands) Achieva using a T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) protocol with a repetition time of 8.1 ms, echo time of 3.7 ms, 160 slices, and voxel size of 0.94 × 0.94 × 1 mm. Seventeen participants were scanned on a different 3T Philips Achieva using a T1-weighted MPRAGE protocol with a repetition time of 6.74 ms, echo time of 3.14 ms, 140 slices, and a voxel size of 0.9 × 0.9 × 1.2 mm. Briefly, surface-based cortical reconstruction was performed using FreeSurfer v5.1 software package (surfer.nmr.mgh.harvard.edu) as previously reported.28,29 After a slice-by-slice visual inspection of the pial and white matter surface segmentation, 12 participants were excluded due to processing errors, leading to a final sample of 70 participants (21 ALS and 49 FTD). In this sample, a vertex-wise general lineal model (as implemented in FreeSurfer v5.1) was used to assess the correlation between CSF biomarkers and cortical thickness for each group independently (ALS and FTD). Specifically, for each surface vertex, a general lineal model was computed using cortical thickness as dependent variable and CSF values as independent variable. All these analyses were covaried by age, sex and magnetic resonance equipment. To control for false positives, a Monte Carlo simulation with 10,000 repeats as implemented in FreeSurfer (family-wise error < 0.05) was tested.

Statistical analysis

Differences between groups were assessed using analysis of variance or t test for continuous variables and χ2 for dichotomous or categorical data. Biomarker raw values not following a normal distribution were log-transformed to achieve a normal distribution. We calculated correlations between CSF biomarkers levels using Pearson coefficient. For these analyses, we considered normally distributed log-transformed values of CSF biomarkers when these did not follow a normal distribution. In the ALS group, we performed Cox regression analysis incorporating age at diagnosis, ALSFRS-R score, sex, and onset site (spinal vs bulbar) as prognostic covariates. We also performed a univariate survival analysis by means of the Breslow test due to the high short term mortality in the ALS group. For the NfL survival analysis, participants were dichotomized in 2 groups according to the median NfL levels. For the YKL-40 survival analysis, participants were dichotomized according to the optimal YKL-40 cutoff (best Youden J index) for the differentiation between patients with ALS and controls (area under the curve 0.709 [95% confidence interval (CI) 0.595–0.824], p = 0.001; cutoff = 262). Statistical significance for all tests was set at 5% (α = 0.05) and all statistical tests were 2-sided. All analyses were performed using SPSS 24 (IBM; Armonk, NY).

Standard protocol approvals, registrations, and patient consent

The study was approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. All participants gave their written informed consent to participate in the study.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Primary research question/classification of the evidence

Our primary research question was to determine whether the CSF levels of sAPPβ, YKL-40, and NfL, or their ratios, relate to clinical measures of cognitive impairment, disease progression rate, and frontotemporal cortical thickness within the ALS-FTD continuum. This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.

Results

Demographics and clinical data

Table 1 shows the demographics, clinical data, and biomarker levels in the FTD, ALS, and control groups. There were no differences in age, sex, or disease duration at CSF sampling between groups. Age at CSF sampling showed a mild correlation with YKL-40 levels (r = 0.32, p < 0.001) in the entire cohort. Disease duration at the time of CSF sampling correlated inversely with sAPPβ and NfL levels (r = −0.22, p = 0.02 and r = −0.24, p = 0.01, respectively). As expected, the FTD group had worse cognitive performance than the ALS group and both FTD and ALS groups were more cognitively impaired than the control group (H [2] = 57.2, p < 0.001).

View this table:
Table 1

Clinical and CSF data of the participants

Different sAPPβ levels in the FTD and ALS groups

CSF levels of sAPPβ differed between groups (figure 1). The FTD and ALS groups showed lower sAPPβ levels than controls. The FTD group had lower sAPPβ levels than the ALS group, and this difference remained significant after excluding patients with ALS-FTD from the ALS group. However, the differences in the sAPPβ levels between the ALS and control group were no longer significant when ALS-FTD patients were excluded from the ALS group (post hoc: least significant difference, p = 0.066, 95% CI of the mean difference of log [sAPPβ] −0.44 to 0.01).

Figure 1
Figure 1 Group differences between CSF biomarkers

Group differences between CSF biomarker raw levels of (A) soluble β fragment of amyloid precursor protein (sAPPβ), (B) YKL-40, and (C) neurofilament light chain (NfL). *p < 0.05 for post hoc: Least significant difference, analysis of variance performed with log-transformed values in variables not following a normal distribution (NfL and sAPPβ). ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia.

Higher levels of YKL-40 and NfL in patients with ALS

As shown in table 1 and figure 1, YKL-40 levels were higher and the sAPPβ:YKL-40 ratio was lower in the FTD and ALS groups compared to controls, but no differences were noted between the FTD and ALS groups. As previously reported, CSF NfL levels were different in the 3 groups: the highest NfL levels were observed in the ALS group, followed by the FTD group and the control group. Similar differences were observed between groups for the NfL:sAPPβ and NfL:YKL-40 ratios (table 1).

Imaging correlates of sAPPβ, YKL-40, and the sAPPβ:YKL-40 ratio

We next studied a subset of 70 participants with structural MRI suitable for quantitative analyses. As shown in figure 2, there was a direct correlation of the sAPPβ:YKL-40 ratio with the cortical thickness in the ALS and FTD groups. In ALS, this correlation was found in the superior temporal areas bilaterally, and in the lateral frontal regions in the left hemisphere. In FTD, this correlation was found as a bilateral widespread significant map in both temporal and frontal regions and the precuneus.

Figure 2
Figure 2 Relationship of cortical thickness with the soluble β fragment of amyloid precursor protein (sAPPβ):YKL-40 ratio in the amyotrophic lateral sclerosis (ALS) (n = 21) and frontotemporal dementia (FTD) groups (n = 49)

(A) Relationship of cortical thickness with the sAPPβ:YKL-40 ratio levels in the ALS group (n = 21, including 6 patients with ALS-FTD). (B) Relationship of cortical thickness with the sAPPβ:YKL-40 ratio levels in the FTD group (n = 49, patients without ALS-FTD). Red regions represent a direct correlation. For illustrative purposes, a scatterplot shows the individual log (sAPPβ:YKL-40) and the value of cortical thickness in the corresponding cortical region (marked with an asterisk).

CSF biomarkers across the ALS subgroups

No differences in age, sex, or disease duration at CSF sampling were noted between the ALS subgroups based on cognitive or behavioral symptoms (table e-1; doi.org10.5061/dryad.59sm77d). As expected, the ALSci-bi group showed a lower performance in the ECAS total score than the ALSni group, reflecting lower cognitive performance. No differences in CSF biomarkers were found between the different clinical subgroups of patients with ALS or between patients with ALS with and without FTD, as shown in tables e-1 and e-2 (doi.org10.5061/dryad.59sm77d).

Relationships between CSF biomarkers and cognitive measures

In the whole sample, the global cognitive performance as measured by the cognitive z score showed the highest correlation with NfL levels and the NfL:sAPPβ ratio (r = −0.41, p < 0.001 and r = −0.44, p < 0.001, respectively), with lower correlations for levels of sAPPβ and YKL-40 (r = 0.27, p = 0.001 and r = −0.25, p = 0.002, respectively). However, when we restricted the analysis to the ALS group, no correlations were found between CSF biomarkers and the cognitive z score.

Relationships between CSF biomarkers, disease severity, and progression rate in FTD and ALS

In patients with FTD, the FTLD-CDR score showed the highest correlation with the sAPPβ:YKL-40 ratio (r = −0.42, p = 0.001, figure 3A). The FTLD-CDR score also correlated with sAPPβ and NfL levels (r = −0.38, p = 0.002; r = 0.39, p = 0.002, respectively) but not with YKL-40 (r = 0.12, p = 0.35). In the ALS group, none of the biomarkers correlated with disease severity, as measured by the ALSFRS-R. However, levels of YKL-40 and to a lesser extent levels of NfL correlated with the ALS progression rate (r = 0.51, p = 0.001; and r = 0.39, p = 0.02, respectively; figure 3B).

Figure 3
Figure 3 Relationships between CSF biomarkers and measures of disease severity and progression in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

(A) Correlation between soluble β fragment of amyloid precursor protein (sAPPβ):YKL-40 ratio (log-transformed) and FTLD-CDR score in the FTD group (including the ALS-FTD patients with available frontotemporal lobar degeneration Clinical Dementia Rating [FTLD-CDR] scores, n = 6). (B) Correlation between the raw YKL-40 levels and the ALS progression rate in the ALS group (including the ALS-FTD subgroup).

NfL and YKL-40 CSF levels are associated with a shorter survival in ALS

We finally investigated the relationship between NfL and YKL-40 and survival in the ALS group (mean follow-up of 11.6 months from the baseline assessment [SD 20.4], number of deaths 18 [47.4%]). As shown in table 2, higher baseline levels of both NfL and YKL-40 were associated with a shorter survival in patients with ALS (for NfL, hazard ratio [HR] 1.0004, p = 0.003; for YKL-40, HR 1.012, p = 0.005). When we introduced both NfL and YKL-40 levels in the model, only YKL-40 levels remained significant (HR 1.009, p = 0.048). As shown in figure 4, Kaplan-Meier survival curves showed different survival curves of patients with ALS when stratified by NfL and YKL-40 levels (Breslow test; NfL, p = 0.036, YKL-40, p = 0.045).

View this table:
Table 2

Cox proportional hazards survival models in patients with amyotrophic lateral sclerosis (ALS)

Figure 4
Figure 4 Survival analysis in patients with amyotrophic lateral sclerosis (ALS), stratified by YKL-40 and neurofilament light chain (NfL) CSF levels

Survival analysis in patients with ALS (n = 38), stratified by YKL-40 (A) and NfL CSF levels (B). For the YKL-40 survival analysis, participants were dichotomized according to the optimal YKL-40 cutoff (best Youden J index) for the differentiation between patients with ALS and controls (area under the curve 0.709 [95% confidence interval 0.595–0.824], p = 0.001; cutoff = 262). For the NfL survival analysis, participants were dichotomized in 2 groups according to the median NfL levels. p values of Breslow (generalized Wilcoxon) test are listed.

Discussion

We report decreased levels of sAPPβ and increased levels of YKL-40 in the ALS-FTD clinical spectrum. Importantly, the ratio of sAPPβ:YKL-40 correlated with cortical atrophy in frontotemporal regions in ALS and FTD. We also describe that CSF levels of YKL-40 correlate with progression rate and survival in ALS.

Neuroinflammation is a relevant pathophysiologic component in ALS and other neurodegenerative diseases.30,–,32 In ALS, microglial activation has shown to directly contribute to neuronal death.33 Biomarkers that track neuroinflammatory activity, such as YKL-40, may be a valuable tool for monitoring the inflammatory response during the disease course. YKL-40 (also known in the literature as chitinase-3-like-1 protein) has been found to be expressed by astrocytes in human brain tissue in healthy controls and in different neurodegenerative diseases.30 Interestingly, CSF levels of YKL-40 correlate with disease progression in multiple sclerosis.34 We show that YKL-40 levels in CSF are increased in ALS. Two previous reports have investigated CSF YKL-40 levels in patients with ALS.15,16 In one of these studies, YKL-40 and 2 other chitinases were found differentially abundant between patients with ALS and controls.16 Notably, all chitinase levels correlated with disease progression rate. Our results confirm the increase of YKL-40 in ALS and its correlation with progression rate. Conversely, the authors of this recent work found an association between CHIT1 but not YKL-40 level and survival, while we found that YKL-40 was indeed associated with shorter survival.16 It is possible that methodologic differences in the sample composition (i.e., inclusion of patients with progressive lateral sclerosis and progressive muscular atrophy) and the assay used may explain the observed differences. Taken together, these results reinforce previous evidence underlying the close relation between neuroinflammation and progression rate in ALS.35,36

We also report lower CSF levels of sAPPβ in ALS when compared to age-matched controls. We previously reported a reduction of CSF sAPPβ levels across multiple FTLD-related syndrome levels in a large multicenter study.13 These results have been recently replicated in an autopsy-confirmed FTLD cohort.37 In those previous studies, the correlation of sAPPβ levels with cortical thickness in frontotemporal areas led us to speculate that sAPPβ levels may reflect neuronal loss in frontotemporal areas where the amyloid precursor protein is predominantly expressed.38 We hypothesize that the observed intermediate levels of sAPPβ in patients with ALS could be related to lesser pathologic burden in frontotemporal areas of patients with ALS when compared to patients with FTD. This may explain why the observed differences between the CSF levels of sAPPβ in the ALS group compared to the control group were no longer significant when ALS-FTD patients were excluded from the ALS group. Our imaging findings support this hypothesis as well, as we found a direct correlation of the sAPPβ:YKL-40 ratio with cortical thickness in frontotemporal regions in the ALS and FTD groups.

We also measured the CSF levels of NfL, an established biomarker of neurodegeneration in the ALS-FTD continuum. NfL is an axonal cytoskeletal constituent essential for axonal growth.11 NfL levels have been found elevated in the CSF and serum of patients with ALS as well as in other brain disorders such as AD and traumatic brain injury.39,40 Consistent with the previous evidence supporting the NfL in CSF as a diagnostic biomarker in ALS, we found clear differences in the CSF levels of NfL of patients and controls. NfL levels separated patients from controls in a much cleaner manner than sAPPβ and YKL-40. In addition to its role in diagnosis, NfL levels have also been related to ALS progression.41 We found that NfL and YKL-40 levels at diagnosis predicted a shorter survival in patients with ALS after adjusting for other established prognostic factors. Moreover, when we introduced both biomarkers in the Cox proportional hazards survival model, only YKL-40 levels remained significant. However, caution is needed in drawing firm conclusions around an independent role of YKL-40 levels and further studies are needed to ascertain the specific contribution of NfL and YKL-40 CSF levels to survival in ALS. Our results confirm previous results with NfL and further suggest that YKL-40 may be a useful addition in the prognostic evaluation of ALS.42,43

The main strengths of this study are the prospective design and the detailed cognitive and behavioral evaluation of all patients. We applied a prospective deep phenotyping protocol that allowed us to investigate in detail correlations between CSF biomarkers and cognitive performance, disease severity, and progression rate in the patients within the ALS-FTD continuum. This study has also some limitations. Although we found significant differences in the CSF levels of sAPPβ and YKL-40 between patients and controls, we observed a considerable overlap between groups. Although this overlap may limit its value as diagnostic marker when used in isolation, its combination with other established biomarkers such as NfL may add important prognostic information. Finally, the study lacks pathologic confirmation of the diagnosis in most cases and misdiagnosis could have occurred. However, misdiagnosis in ALS is rare and patients with FTD with evidence of AD pathophysiology in their CSF biomarker profile were excluded to avoid the inclusion of patients with atypical variants of AD that may have been misdiagnosed as FTD.

This study supports the role of neuroinflammation in ALS pathophysiology and progression. Further longitudinal studies should investigate the effect of sAPPβ and YKL-40 (alone or combined with NfL) on the progression rate and prognosis. These are key aspects to accelerate the development of effective disease-modifying treatments for patients with ALS.

Author contributions

Ignacio Illán-Gala contributed to content, study concept and design, analysis and interpretation of data, acquisition of data, and drafting and revision of the manuscript. Daniel Alcolea contributed to drafting/revising the manuscript for content and acquisition of data. Victor Montal contributed to drafting/revising the manuscript for content and analysis and interpretation of data. Oriol Dols-Icardo contributed to data acquisition and drafting/revising the manuscript for content and interpretation of data. Laia Muñoz contributed to data acquisition and drafting/revising the manuscript for content and interpretation of data. Noemi de Luna contributed to data acquisition and drafting/revising the manuscript for content and interpretation of data. Joana Turón-Sans contributed to acquisition of data and revision of the manuscript for content. Elena Cortés-Vicente contributed to acquisition of data and the drafting and revision of the manuscript for content. María Belen Sánchez-Saudinós contributed to the acquisition of data and revision of the manuscript for content. Andrea Subirana contributed to acquisition of data and revision of the manuscript for content. Isabel Sala Matavera contributed to content, study concept and design, analysis and interpretation of data, acquisition of data, and drafting and revision of the manuscript. Rafael Blesa contributed to acquisition of data and revision of the manuscript for content. Jordi Clarimón contributed to acquisition of data and revision of the manuscript for content. Juan Fortea contributed to revising the manuscript for content and acquisition of data. Ricard Rojas-García contributed to analysis and interpretation of data, acquisition of data, and revision of the manuscript; he was also responsible for study supervision and obtaining funding. Alberto Lleó contributed to acquisition of data, contribution of vital reagents/tools, and drafting and revising the manuscript for content; he was also responsible for study supervision and obtaining funding.

Study funding

This study was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI15/01618 to R.R., PI14/1561 and PI17/01896 to A.L.), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa. This work was also supported by Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (SLT002/16/00,408 to A.L.), and Fundació La Marató de TV3 (201437.10 to R.R.). I. Illán-Gala is supported by an i-PFIS grant (IF15/00060) from the FIS, Instituto de Salud Carlos III and the Rio Hortega grant (CM17/00074) from “Acción Estratégica en Salud 2013–2016” and the European Social Fund.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Publication history

Received by Neurology December 4, 2017. Accepted in final form July 17, 2018.

Acknowledgment

The authors thank the patients and their relatives for their support for this study.

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Class of Evidence: NPub.org/coe

  • Received December 4, 2017.
  • Accepted in final form July 17, 2018.

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