Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients
Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients
Makiko Shinomoto 0 1
Takashi KasaiID 0 1
Harutsugu Tatebe 0 1
Masaki Kondo 0 1
Takuma Ohmichi 0 1
Masafumi Morimoto 1
Tomohiro Chiyonobu 1
Naoto Terada 1
David Allsop 1
Isao Yokota 1
Toshiki Mizuno 0 1
Takahiko Tokuda 0 1 2
0 Department of Neurology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science , Kyoto , Japan , 2 Department of Zaitaku (Homecare) Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan, 3 Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science , Kyoto , Japan , 4 Department of Pediatrics, North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan, 5 Hananoki Medical Welfare Center, Kyoto, Japan, 6 Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University , Lancaster , United Kingdom , 7 Department of Biostatistics, Kyoto Prefectural University of Medicine , Kyoto , Japan
1 Editor: Stephen D Ginsberg, Nathan S Kline Institute , UNITED STATES
2 Department of Molecular Pathobiology of Brain Diseases, Kyoto Prefectural University of Medicine , Kyoto , Japan
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Over the last few decades, there have been significant improvements both in the live birth
prevalence and survival rates of people with DS because of better health care in developed
countries. Consequently, their average life expectancy has markedly improved and now
exceeds 50 years [
]. This general aging of the DS population has created an important issue
for neurologists because many of them over 40 years old are at risk of developing dementia.
Pathological brain changes of aged individuals with DS are almost identical to those of patients
with Alzheimer?s disease (AD), consisting of both senile plaques and neurofibrillary tangles
composed of amyloid ? (A?) and phosphorylated tau, respectively [
]. The causative
mechanism is considered to involve the triplication of APP on chromosome 21, leading to a brain
pathology indicative of AD, as well as overexpressions of Dyrk1A and RCAN1 also located on
chromosome 21, which are both involved in tau hyperphosphorylation .
Diagnosing dementia in patients with DS, particularly in the early stage, is difficult due to
their markedly variable baseline cognitive abilities as well as heterogeneity of dementia
]. Meanwhile, there is an urgent need to develop diagnostic tools for early dementia of
DS because disease-modifying therapies under development for AD, aiming at the reduction
of A? and/or tau aggregation, could also be effective for the prevention of dementia in DS
Considering the similarity between dementia in DS and AD patients, a logical approach for
the objective detection of dementia in DS patients would be to employ biomarkers used for the
diagnosis of AD. In fact, A? and tau deposition detected by positron emission tomography
(PET), and the levels of these molecules in cerebrospinal fluid (CSF), were reported to have
diagnostic value for dementia in DS patients [
]. Owing to recent advances in
immunecomplex-based technologies, including single-molecular array (Simoa), these molecules can be
detected even in blood samples and blood markers would be more cost-effective and less
invasive than PET or CSF-based ones [
Neurofilament light chain (NfL) is one of the scaffolding cytoskeleton proteins of
myelinated subcortical axons. NfL, which can now be reliably measured even in sera and plasma
using Simoa, is an indicator of axonal injury due to several neurological diseases, including
neurodegenerative ones. In contrast to A? and tau, altered levels of NfL do not specifically
indicate the presence of AD pathology. However, this lack of specificity is less of an issue
because most cases of dementia in DS patients are thought to be based on AD pathology. To
our knowledge, only two previous studies have reported an age-dependent elevation of plasma
levels of NfL in DS patients [
]. However, it remains unclear whether increased plasma
NfL can be used to predict future cognitive decline, based on longitudinal studies.
Furthermore, age-dependent elevation of plasma NfL was also observed in healthy individuals [
]; therefore, the question of when abnormal elevation of plasma NfL starts in DS
patients remains to be answered by comparing their datasets with those of control individuals.
The aims of this study were: 1) to compare plasma levels of NfL in adults with DS and an
age-matched healthy control population, and 2) to examine whether plasma levels of NfL
in DS patients are correlated with decreased adaptive behavior scores one year after sample
Materials and methods
Study design, ethics statement, and subject recruitment
All study subjects provided written informed consent before participation and the
study protocols were approved by the University Ethics Committee (RBMR-C-1226 for
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participants with DS and ERB-G-12 for controls, Kyoto Prefectural University of Medicine,
Kyoto, Japan). Informed consent from patients in the DS group was obtained when
possible and from the nearest relative. Study procedures were designed and performed in
accordance with the Declaration of Helsinki. We enrolled 24 adult patients with DS (DS group)
from the registration for DS in Kyoto Prefectural University of Medicine and Hananoki
Medical Welfare Center, from February 2013 to January 2018. Age-matched healthy
volunteers or patients presenting with neither neurological symptoms nor head injury within
three months prior to sample collection were enrolled as the control group. Individuals
with any known chromosomal abnormality, neurodegenerative disease, or a family history
of AD involving first-degree relatives, were excluded from this group. Plasma from 24
individuals in the control group was obtained from another registration of Kyoto Prefectural
University of Medicine during the aforementioned period. Plasma samples were obtained
via venous puncture: a total of 8 mL of blood was collected in EDTA-containing tubes.
After collection, plasma was separated by centrifugation for 10 min at 3,000 rpm and
placed in polypropylene vials. Fresh samples obtained from the enrolled subjects were
immediately stored at -80?C until analysis.
Information on the following comorbid diseases and conditions were retrospectively
collected from clinical charts of the DS group at sample collection: treatment or diagnosis
of sleep apnea, epilepsy, hyperuricemia, hypothyroidism, and head injury within the last
The adaptive behavior score in the DS group was estimated as the ?social age? using the
social maturity scale revised (S-M) (S-M scale)(Nihonbuknasha, Tokyo), which is an adaptive
behavior scale developed for Japanese based on the Vineland Social Maturity Scale [
test consists of 130 yes/no questions evaluating self-help (31 questions), locomotion (18
questions), occupation (19 questions), communication (23 questions), socialization (21 questions),
and self-direction (18 questions). Social ages were calculated from raw scores in the conversion
table based on data for typically developing Japanese children. The initial examination was
performed within 3 months after blood collection. We annually evaluated the social age of 13
participants with DS. As a few participants with stable cognition received the assessment
behind schedule, follow-up tests were done from 12 to 18 months after the initial examination.
The same caregiver completed follow-up assessments. Annual decrement of the social age
(referred as %?Social Age) was calculated using the formula: (social age the first time?social
age the second time) x 100 / (social age the first time). Patients with DS were also systematically
screened using Dementia Screening Questionnaires for Individuals with Intellectual
] (DSQIID, the Japanese edition was obtained from the following website: http://www.
nozomi.go.jp/investigation/pdf/report/04/01.pdf ).We previously reported plasma levels of
total tau (t-tau) [
] and phosphorylated tau (p-tau) [
], DSQIID, and the adaptive behavior
score of the 19 participants with DS elsewhere.
Measurement of NfL
The plasma NfL concentration was measured with reagents from a single lot using the Simoa
NF-light assay (a digital sandwich immunoassay employing antibodies directed against the rod
domain of NF-L) on an HD-1 Simoa analyzer according to the protocol issued by the
manufacturer (Quanterix, Lexington, MA, USA). All samples were analyzed in duplicate on one
occasion. All cases and controls were evenly distributed on examination. The plasma NfL was
measured only in samples collected at the time of the initial assessment of the adaptive
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The level of significance was set at P<0.05. A comparison between the two independent
groups was performed using Mann-Whitney?s U test. The Chi-square test was used to evaluate
the significance of categorical variables. Correlation analysis was conducted using Spearman?s
rank correlation coefficient test. Analyses were performed using GraphPad Prism version 6
software (GraphPad software, San Diego, USA). The difference of slopes between the groups
was tested by the significance of the interaction term in multiple regression analysis. The
association between the annual decrement of the social age and biomarkers with adjustment for
age was examined by multiple regression analysis. Analyses were performed using SPSS for
Windows version 23 software (IBM Japan Ltd., Tokyo, Japan).
The demographic characteristics, cognitive assessments, comorbid diseases or condition and
concentration of plasma NfL of participants are summarized in Tables 1 and 2. There was no
DS patient with a history of head injury within the last three months. We found no significant
difference in age (P = 0.858) or sex (P = 1.000) between the DS and control groups. As shown
in Fig 1, levels of plasma NfL were significantly higher in the DS compared with the control
group (P = 0.0004). When the participants were categorized by age into young (aged 14?25
years), middle-aged (aged 26?42 years), and older cases (over 43 years), the significant
Comorbid disease or condition
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Note: We previously reported plasma levels of total tau [
] and phosphorylated tau [
] in cases with an asterisk. The DSQIID total score indicates the sum total of the
scores from parts 2 and 3, which provides maximal sensitivity (0.92) and optimal specificity (0.97) for dementia screening in DS patients [
]. Social ages were estimated
using the social maturity scale revised (S-M). Although data were calculated as units of years and months [
], we recalculated those into units of years for statistical
analysis. Social ages in this figure are presented as units of years. There were seven patients with plasma NfL levels exceeding the cut-off value (13.872 pg/mL: two SD
above the mean of those in the control group) (indicated by gray shading). N/A: not available. Comorbid disease or condition: treatment or diagnosis of sleep apnea,
epilepsy, uricemia, hypothyroidism, and head injury in the last three months. No patient with multiple comorbid diseases was observed in the DS group.
elevation of plasma NfL levels in the DS group was preserved in each age group. There was a
significant correlation between age and level of plasma NfL in both the DS and control groups
(Fig 2A and 2B), while the slope of the age-related change was steeper in the DS compared
with the control group (the interaction term between the age and group was significant:
P<0.001). When we set the cut-off value at 13.872 pg/mL based on the mean value and
standard deviation (SD) in the control group (i.e., two SD above the mean value), the DS group
contained seven patients with abnormally elevated plasma NfL according to this cut-off value
(Table 2, Fig 2B). Six of these seven cases were over the age of 40. Regarding comorbidities, DS
patients with epilepsy were older and had higher plasma NfL levels than those without
epilepsy; however, these trends did not reach significance (P = 0.1097 and P = 0.0553,
respectively). In the control group, plasma NfL levels were not significantly different between
participants with and without epilepsy (P>0.999).
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Fig 1. (A) Scatter plot of the NfL level in plasma in the control (n = 24) and DS (n = 24) groups. Bars indicate median
values. Levels of NfL in the DS group were significantly higher than those in the control group (P = 0.0004). (B) Scatter
plot of the NfL level in plasma in the young (aged 14?25 years; n = 9 in the control group and 9 in the DS group),
middle-aged (aged 26?42 years; n = 7 in the control group and 9 in the DS group), and older (older than 43 years; n = 8
in the control group and 6 in the DS group) patients. Bars indicate median values. Levels of NfL in the DS group were
significantly higher than those of the control group in all age groups (P = 0.0008 in the young, P = 0.0012 in the
middle-aged, and 0.002 in the older patients).
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Fig 2. (A) Correlation between plasma NfL level and age in the control group. They showed a significant correlation.
The P-value obtained from Spearman?s rank correlation coefficient test was <0.0001. (B) Correlation between NfL
levels and ages in the DS group. A significant positive correlation was noted (P<0.0004). Filled circles (black) indicate
the DS cases with NfL levels exceeding the cut-off value (13.872 pg/mL indicated by a dotted horizontal line), estimated
from the control group. The dashed vertical line indicates the position at 40 years of age.
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The relationship between plasma NfL levels and social ages in patients with DS did not
reach significance (P = 0.0887), but there was a significant negative correlation between %
?Social Age scores and plasma NfL levels (P = 0.0001) (Fig 3A and 3B). This negative
correlation remained significant after age-adjustment (P = 0.005). Regarding the data on levels of
plasma t-tau and p-tau that we have reported elsewhere from the same cohort, significant
positive correlations between plasma levels of NfL and those of both t-tau and p-tau were observed
(S1 Fig) [
]. Furthermore, plasma levels of p-tau also showed a significant negative
correlation with %?Social Age, similar to the relationship between plasma NfL vs. %?Social Age,
although plasma t-tau failed to show a significant correlation in this analysis (S2 Fig).
However, this significant correlation disappeared after age-adjustment (P = 0.080). Goodness of fit
in the comparison of %?social age was the most favorable for plasma NfL among these three
The present study showed that plasma levels of NfL were increased with age both in the control
and DS groups. This age-dependent elevation of plasma and/or serum NfL in the healthy
control group is in agreement with several previous reports [
]. The mechanism of this
positive association between NfL concentration in body fluids and normal aging has not been
clearly established, although it is considered to result from age-related subclinical axonal
]. Consistent with a previous study on plasma NfL in DS [
age-dependent increase of plasma NfL levels was noted in the current study. Furthermore, the slope of
this age-dependent elevation of plasma NfL was steeper in the DS than the control group.
Consequently, plasma NfL levels were significantly higher in the DS group. Considering that an
elevation of plasma NfL in patients with AD was repeatedly confirmed in several studies [
] , our results can be interpreted as being a consequence of AD pathology in DS
patients. This is supported by the fact that the majority of the seven patients with abnormally
high levels of plasma NfL were over forty years old, which is around the age when tau
pathology starts in DS individuals [
On the other hand, the significant elevation of plasma NfL in the DS group was observed
not only in middle and older-age individuals, but also even in those under 26 years old.
Actually, one of the seven with abnormal titers of plasma NfL was aged 23. Considering the fact
that AD pathology has been rarely observed in such young individuals [
], elevated plasma
NfL in young individuals with DS might result from DS-specific neurodegenerative factors
distinct from AD pathology, such as disrupted proteostasis by trisomy 21 [
Plasma levels of NfL were negatively correlated with annual changes in the social age of the
DS group even after age-adjustment. This result is consistent with a previous report that
individuals with DS that converted to dementia had higher plasma NfL values compared with
]. Although plasma levels of p-tau were also associated with this annual
adaptive behavioral decrement, p-tau was not an independent predictor of dementia after
ageadjustment. Social Ages of the S-M scale has not been established as a diagnostic or surrogate
assessment for dementia in DS patients. However, we believe that the method is reasonable for
our purpose, considering the following three facts: 1) there are no standard screening or
diagnostic tools regarding how dementia should be detected in DS patients although its clinical
diagnosis is quite robust [
]; 2) similar adaptive behavior scores including those using
the Vineland Social Maturity Scale have been reported to be affected by aging in DS patients
]; 3) the S-M scale is a semi-quantitative assessment standardized with substantial data
on typically developed controls speaking the language of our cohort. A recent study in rodent
models of AD showed that NfL levels in CSF and plasma were attenuated by treatment with a
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Fig 3. Correlation between NfL levels and social ages (A) and between NfL levels and %?Social Age (B) in the DS
group. The Spearman?s rank correlation coefficient test showed a non-significant association (P = 0.0887) between NfL
and social ages (A), while a significant correlation was observed between NfL and %?Social Age (P = 0.0001) (B).
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?-secretase 1 inhibitor [
]. In fact, the normalization of serum/plasma NfL as a response to
treatment has already been demonstrated in clinical trials of multiple sclerosis [
findings provide evidence to support the suggestion that plasma NfL is a potential biomarker
to assess disease progression and monitor treatment effects in individuals receiving
diseasemodifying therapies in future clinical trials.
We acknowledge that the small sample size was a major limitation of this study and
therefore, future studies to validate our findings are needed. Furthermore, the short follow-up
period may have weakened the statistical power to detect the association between functional
decline and the biomarkers. As we did not measure NfL in the follow-up plasma samples,
longitudinal changes of plasma NfL in the DS population remain unknown. In the future,
casecontrol as well as longitudinal studies involving sufficient numbers of participants with a
longer follow-up period and repeated measurements of plasma NfL will be necessary to confirm
our findings and promote the clinical application of the biomarker-supported diagnosis of
dementia in DS patients.
The study showed age-dependent increases in plasma NfL in both DS and control groups. This
age-dependent elevation was steeper in the DS than the control group. Elevated plasma NfL
was associated with decreased adaptive behavior scores one year later, providing evidence to
support the suggestion that plasma NfL has the potential to serve as an objective biomarker to
predict dementia in adult DS patients. The small sample size and the short follow-up period
were major limitations of this study. Future case-control as well as longitudinal studies
involving sufficient numbers of participants with a longer follow-up period and repeated
measurements of plasma NfL are needed to confirm those findings.
S1 Fig. Correlation between plasma NfL level and tau-related biomarkers in the DS group.
Plasma NfL levels were significantly correlated with t-tau (P = 0.0005)(A) and p-tau
(P = 0.0085)(B). (Statistical analyses were conducted using Spearman?s rank correlation
S2 Fig. Correlation between %?Social Age and tau-related biomarkers in the DS group. %
?Social Age decreased with t-tau, but the relationship did not reach significance (P = 0.0741)
(A), while there was a significant negative correlation between %?Social Age and p-tau
(P = 0.0048)(B). (Statistical analyses were conducted using Spearman?s rank correlation
Conceptualization: Takashi Kasai, Masafumi Morimoto, Tomohiro Chiyonobu, Takahiko
Data curation: Makiko Shinomoto, Takashi Kasai, Harutsugu Tatebe.
Formal analysis: Takashi Kasai, Isao Yokota.
Funding acquisition: Takashi Kasai, Takahiko Tokuda.
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Investigation: Takashi Kasai, Harutsugu Tatebe, Masaki Kondo, Takuma Ohmichi, Takahiko
Methodology: Takashi Kasai, Isao Yokota.
Project administration: Takashi Kasai.
Resources: Takashi Kasai, Masaki Kondo, Takuma Ohmichi, Masafumi Morimoto, Tomohiro
Chiyonobu, Naoto Terada.
Supervision: David Allsop, Toshiki Mizuno.
Writing ? original draft: Makiko Shinomoto, Takashi Kasai.
Writing ? review & editing: Makiko Shinomoto, Takashi Kasai, David Allsop, Toshiki
Mizuno, Takahiko Tokuda.
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