Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients

PLOS ONE, Apr 2019

People with Down syndrome (DS) are at high risk of developing Alzheimer disease (AD) with aging. The diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. Plasma neurofilament light chain (NfL) is one of the established biomarkers of AD, suggesting that it may be useful as an indicator of dementia in DS patients. The aims of this study were: 1) to examine whether plasma levels of NfL in DS patients are correlated with decreased adaptive behavior scores one year after sample collection, and 2) to compare plasma levels of NfL in adults with DS and an age-matched healthy control population. In this study, plasma levels of NfL in 24 patients with DS and 24 control participants were measured by the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma NfL levels in the DS compared with the control group. There was a significant correlation between age and levels of plasma NfL in both groups. This age-dependent elevation was steeper in the DS compared with the control group. Moreover, elevated plasma NfL was associated with decreased adaptive behavior scores one year later, after age-adjustment. Previously reported blood-based biomarkers available in Simoa for DS, plasma total tau and phosphorylated tau, were not significantly correlated with the annual decrement of adaptive behavior scores after age-adjustment. These results suggest that plasma NfL has the potential to serve as an objective biomarker to predict dementia in adult DS patients.

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Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients

April 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 Information files. Introduction 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 [ 1, 2 ]. 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 [ 3 ]. 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 [4]. 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 symptoms [ 5 ]. 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 patients. 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 [ 6?8 ]. 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 [ 9 ] [ 10 ] [ 11 ] [ 12 ]. 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 [ 13 ] [ 14 ]. 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 [ 15 ] [ 16 ] [ 17 ]; 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 collection. 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 2 / 13 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 three months. 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 [ 18 ]. The 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 Disabilities [ 19 ] (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) [ 11 ] and phosphorylated tau (p-tau) [ 10 ], 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 behavior score. 3 / 13 Statistics 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). Results 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 Epilepsy Epilepsy Epilepsy None None None Anxiety neurosis Anxiety neurosis None Lumbar radiculopathy None None None None None Cavernous angioma Diabetes mellitus Depression None None None None Epilepsy None NfL (pg/mL) 2.766 7.313 3.257 2.531 4.259 2.551 3.813 4.230 2.528 3.426 5.280 4.422 5.092 4.308 7.677 10.135 10.052 5.433 5.590 6.046 7.611 9.768 20.096 9.372 Mean?SD 6.148?3.862 4 / 13 Note: We previously reported plasma levels of total tau [ 11 ] and phosphorylated tau [ 10 ] 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 [ 19 ]. Social ages were estimated using the social maturity scale revised (S-M). Although data were calculated as units of years and months [ 18 ], 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). 5 / 13 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). 6 / 13 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. 7 / 13 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) [ 10, 11 ]. 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 biomarkers. Discussion 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 [ 15 ] [ 16 ] [ 17 ]. 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 degeneration [ 20 ]. Consistent with a previous study on plasma NfL in DS [ 13 ], an 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 [ 15 ] [ 17 ] [21], 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 [ 3 ]. 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 [ 3 ], 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 [ 22 ]. 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 non-converters [ 13 ]. 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 [ 5, 23?25 ]; 2) similar adaptive behavior scores including those using the Vineland Social Maturity Scale have been reported to be affected by aging in DS patients [ 26?33 ]; 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 8 / 13 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). 9 / 13 ?-secretase 1 inhibitor [ 34 ]. In fact, the normalization of serum/plasma NfL as a response to treatment has already been demonstrated in clinical trials of multiple sclerosis [ 35 ] [ 36 ]. These 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. Conclusions 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. Supporting information 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 coefficient test). (TIF) 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 coefficient test). (TIF) Author Contributions Conceptualization: Takashi Kasai, Masafumi Morimoto, Tomohiro Chiyonobu, Takahiko Tokuda. Data curation: Makiko Shinomoto, Takashi Kasai, Harutsugu Tatebe. Formal analysis: Takashi Kasai, Isao Yokota. Funding acquisition: Takashi Kasai, Takahiko Tokuda. 10 / 13 Investigation: Takashi Kasai, Harutsugu Tatebe, Masaki Kondo, Takuma Ohmichi, Takahiko Tokuda. 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. 11 / 13 21. Weston PSJ, Poole T, Ryan NS, Nair A, Liang Y, Macpherson K, et al. Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration. Neurology. 2017; 89(21):2167?75. Epub 2017/10/27. https://doi.org/10.1212/WNL.0000000000004667 PMID: 29070659 mc5696646. 12 / 13 Wu J , Morris JK . The population prevalence of Down's syndrome in England and Wales in 2011 . Eur J Hum Genet . 2013 ; 21 ( 9 ): 1016 - 9 . Epub 2013/01/17. https://doi.org/10.1038/ejhg. 2012 .294 PMID: 23321618 mc3746270 . 2. de Graaf G , Vis JC , Haveman M , van Hovie G , de Graaf EAB , Tijssen JGP , et al. Assesment of prevalence of presons with Down syndrome: A theory-based demographoc model . Journal of Applied Research in Intellectural Disablities . 2011 ; 24 : 247 - 62 . 3. Mann DM . Cerebral amyloidosis, ageing and Alzheimer's disease; a contribution from studies on Down's syndrome . Neurobiol Aging . 1989 ; 10 ( 5 ): 397 - 9 ; discussion 412- 4 . Epub 1989/09/01. PMID: 2530459 . Wiseman FK , Al-Janabi T , Hardy J , Karmiloff-Smith A , Nizetic D , Tybulewicz VL , et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome . Nat Rev Neurosci . 2015 ; 16 ( 9 ): 564 - 74 . Epub 2015/08/06. https://doi.org/10.1038/nrn3983 PMID: 26243569 mc4678594 . 5. Lautarescu BA , Holland AJ , Zaman SH . The Early Presentation of Dementia in People with Down Syndrome: a Systematic Review of Longitudinal Studies . Neuropsychol Rev . 2017 ; 27 ( 1 ): 31 - 45 . Epub 2017/03/16. https://doi.org/10.1007/s11065-017 -9341-9 PMID: 28289920 mc5359367. 6. Annus T , Wilson LR , Hong YT , Acosta-Cabronero J , Fryer TD , Cardenas-Blanco A , et al. The pattern of amyloid accumulation in the brains of adults with Down syndrome . Alzheimer's & dementia: the journal of the Alzheimer's Association . 2016 ; 12 ( 5 ): 538 - 45 . Epub 2015/09/13. https://doi.org/10.1016/j.jalz. 2015 . 07 .490 PMID: 26362596 . 7. Rafii MS , Lukic AS , Andrews RD , Brewer J , Rissman RA , Strother SC , et al. PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI , and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI) . J Alzheimers Dis . 2017 ; 60 ( 2 ): 439 - 50 . Epub 2017/09/28. https://doi.org/10.3233/JAD-170390 PMID: 28946567. 8. Portelius E , Soininen H , Andreasson U , Zetterberg H , Persson R , Karlsson G , et al. Exploring Alzheimer molecular pathology in Down's syndrome cerebrospinal fluid . Neurodegener Dis . 2014 ; 14 ( 2 ): 98 - 106 . Epub 2014/07/06. https://doi.org/10.1159/000358800 PMID: 24992945 . 9. Lue LF , Guerra A , Walker DG . Amyloid Beta and Tau as Alzheimer's Disease Blood Biomarkers: Promise From New Technologies. Neurology and therapy . 2017 ; 6 ( Suppl 1 ): 25 - 36 . Epub 2017/07/25. https://doi.org/10.1007/s40120-017 -0074-8 PMID: 28733956 mc5520820. 10. Tatebe H , Kasai T , Ohmichi T , Kishi Y , Kakeya T , Waragai M , et al. Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer's disease and down syndrome . Mol Neurodegener . 2017 ; 12 ( 1 ): 63 . Epub 2017/ 09/05. https://doi.org/10.1186/s13024-017-0206-8 PMID: 28866979 . 11. Kasai T , Tatebe H , Kondo M , Ishii R , Ohmichi T , Yeung WTE , et al. Increased levels of plasma total tau in adult Down syndrome . PLoS One . 2017 ; 12 ( 11 ): e0188802 . Epub 2017 /12/01. https://doi.org/10. 1371/journal.pone.0188802 PMID: 29190730 . 12. Lee NC , Yang SY , Chieh JJ , Huang PT , Chang LM , Chiu YN , et al. Blood Beta-Amyloid and Tau in Down Syndrome: A Comparison with Alzheimer's Disease . Front Aging Neurosci . 2016 ; 8 : 316 . Epub 2017/02/02. https://doi.org/10.3389/fnagi. 2016 .00316 PMID: 28144219 . 13. Strydom A , Heslegrave A , Startin CM , Mok KY , Hardy J , Groet J , et al. Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome . Alzheimers Res Ther . 2018 ; 10 ( 1 ): 39 . Epub 2018/04/11. https://doi.org/10.1186/s13195-018-0367 -x PMID : 29631614 mc5891918 . 14. Fortea J , Carmona-Iragui M , Benejam B , Fernandez S , Videla L , Barroeta I , et al. Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study . Lancet Neurol . 2018 . Epub 2018/09/03. https://doi.org/10.1016/s1474- 4422 ( 18 ) 30285 - 0 PMID: 30172624 . 15. Mattsson N , Andreasson U , Zetterberg H , Blennow K. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease . JAMA neurology . 2017 ; 74 ( 5 ): 557 - 66 . Epub 2017/03/28. https://doi.org/10.1001/jamaneurol. 2016 .6117 PMID: 28346578 mc5822204 . 16. Gisslen M , Price RW , Andreasson U , Norgren N , Nilsson S , Hagberg L , et al. Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study . EBioMedicine . 2016 ; 3 : 135 - 40 . Epub 2016/02/13. https://doi.org/10.1016/j.ebiom. 2015 . 11 .036 PMID: 26870824 mc4739412 . 17. Lewczuk P , Ermann N , Andreasson U , Schultheis C , Podhorna J , Spitzer P , et al. Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease . Alzheimers Res Ther . 2018 ; 10 ( 1 ): 71 . Epub 2018/07/30. https://doi.org/10.1186/s13195-018 -0404-9 PMID: 30055655 mc6064615. 18. Suzuki H , Kobayashi C , Ikeda Y , Kanno A , Hashimoto S , Hosokawa K. The developmental characteristics of scoial maturity on children with Down syndrome -using scial maturity scale -revised ( S-M ) - . Shinshinshougaigakukenkyu = Bulletin of Disablity Science . 1997 ; 21 : 139 - 47 . 19. Deb S , Hare M , Prior L , Bhaumik S. Dementia screening questionnaire for individuals with intellectual disabilities . Br J Psychiatry . 2007 ; 190 : 440 - 4 . Epub 2007/05/02. https://doi.org/10.1192/bjp.bp. 106 . 024984 PMID: 17470960 . 20. Vagberg M , Norgren N , Dring A , Lindqvist T , Birgander R , Zetterberg H , et al. Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction . PLoS One . 2015 ; 10 ( 8 ): e0135886 . Epub 2015 /09/01. https://doi. org/10.1371/journal.pone. 0135886 PMID: 26317831 mc4552591. 22. Aivazidis S , Coughlan CM , Rauniyar AK , Jiang H , Liggett LA , Maclean KN , et al. The burden of trisomy 21 disrupts the proteostasis network in Down syndrome . 2017 ; 12 ( 4 ):e0176307. https://doi.org/10. 1371/journal.pone.0176307 PMID: 28430800 . 23. Ballard C , Mobley W , Hardy J , Williams G , Corbett A . Dementia in Down's syndrome . Lancet Neurol . 2016 ; 15 ( 6 ): 622 - 36 . Epub 2016/06/16. https://doi.org/10.1016/S1474- 4422 ( 16 ) 00063 - 6 PMID: 27302127 . 24. Zeilinger EL , Stiehl KA , Weber G. A systematic review on assessment instruments for dementia in persons with intellectual disabilities . Res Dev Disabil . 2013 ; 34 ( 11 ): 3962 - 77 . Epub 2013/09/13. https://doi. org/10.1016/j.ridd. 2013 . 08 .013 PMID: 24025441 . 25. Nieuwenhuis-Mark RE . Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions . Res Dev Disabil . 2009 ; 30 ( 5 ): 827 - 38 . Epub 2009/03/10. https://doi.org/10.1016/j.ridd. 2009 . 01 .010 PMID: 19269132 . 26. Temple V , Jozsvai E , Konstantareas MM , Hewitt TA . Alzheimer dementia in Down's syndrome: the relevance of cognitive ability . J Intellect Disabil Res . 2001 ; 45 (Pt 1): 47 - 55 . Epub 2001/02/13. PMID: 11168776 . 27. Carr J , Collins S. Ageing and dementia in a longitudinal study of a cohort with Down syndrome . Journal of applied research in intellectual disabilities: JARID . 2014 ; 27 ( 6 ): 555 - 63 . Epub 2014/04/02. https://doi. org/10.1111/jar.12093 PMID: 24687962 . 28. Adams D , Oliver C. The relationship between acquired impairments of executive function and behaviour change in adults with Down syndrome . J Intellect Disabil Res . 2010 ; 54 ( 5 ): 393 - 405 . Epub 2010/04/07. https://doi.org/10.1111/j.1365- 2788 . 2010 . 01271 . x PMID : 20367747 . 29. Margallo-Lana ML , Moore PB , Kay DW , Perry RH , Reid BE , Berney TP , et al. Fifteen-year follow-up of 92 hospitalized adults with Down's syndrome: incidence of cognitive decline, its relationship to age and neuropathology . J Intellect Disabil Res . 2007 ; 51 ( Pt . 6): 463 - 77 . Epub 2007/05/12. https://doi.org/10. 1111/j.1365- 2788 . 2006 . 00902 . x PMID : 17493029 . 30. Urv TK , Zigman WB , Silverman W. Maladaptive behaviors related to dementia status in adults with Down syndrome . Am J Ment Retard . 2008 ; 113 ( 2 ): 73 - 86 . Epub 2008/02/05. https://doi.org/10.1352/ 0895 - 8017 ( 2008 ) 113 [73:MBRTDS] 2.0 .CO; 2 PMID : 18240877 . 31. Makary AT , Testa R , Tonge BJ , Einfeld SL , Mohr C , Gray KM . Association between adaptive behaviour and age in adults with Down syndrome without dementia: examining the range and severity of adaptive behaviour problems . J Intellect Disabil Res . 2015 ; 59 ( 8 ): 689 - 702 . Epub 2014/11/22. https://doi.org/10. 1111/jir.12172 PMID: 25414060 . 32. Ghezzo A , Salvioli S , Solimando MC , Palmieri A , Chiostergi C , Scurti M , et al. Age-related changes of adaptive and neuropsychological features in persons with Down Syndrome . PLoS One . 2014 ; 9 ( 11 ): e113111 . Epub 2014 /11/25. https://doi.org/10.1371/journal.pone. 0113111 PMID: 25419980 mc4242614. 33. Elliott-King J , Shaw S , Bandelow S , Devshi R , Kassam S , Hogervorst E. A critical literature review of the effectiveness of various instruments in the diagnosis of dementia in adults with intellectual disabilities . Alzheimer's & dementia (Amsterdam , Netherlands). 2016 ; 4 : 126 - 48 . Epub 2016/10/19. https://doi. org/10.1016/j.dadm. 2016 . 06 . 002 mc5061450. 34. Bacioglu M , Maia LF , Preische O , Schelle J , Apel A , Kaeser SA , et al. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases . Neuron . 2016 ; 91 ( 1 ): 56 - 66 . Epub 2016/06/14. https://doi.org/10.1016/j.neuron. 2016 . 05 .018 PMID: 27292537 . 35. Disanto G , Barro C , Benkert P , Naegelin Y , Schadelin S , Giardiello A , et al. Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis . Ann Neurol . 2017 ; 81 ( 6 ): 857 - 70 . Epub 2017/05/ 18. https://doi.org/10.1002/ana.24954 PMID: 28512753 mc5519945. 36. Piehl F , Kockum I , Khademi M , Blennow K , Lycke J , Zetterberg H , et al. Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod . Mult Scler . 2018 ; 24 ( 8 ): 1046 - 54 . Epub 2017/06/20. https://doi.org/10.1177/1352458517715132 PMID: 28627962 .


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Makiko Shinomoto, Takashi Kasai, Harutsugu Tatebe, Masaki Kondo, Takuma Ohmichi, Masafumi Morimoto, Tomohiro Chiyonobu, Naoto Terada, David Allsop, Isao Yokota, Toshiki Mizuno, Takahiko Tokuda. Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients, PLOS ONE, 2019, DOI: 10.1371/journal.pone.0211575