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\begin{document}


\def\RunningAuthor{Yuvaraj Babu K et al.}
\firstPage{1546}
\articleType{Review Article}
\receivedDate{02 Sep 2020}
\acceptedDate{16 Oct 2020}
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\title{\textbf{White Matter Biomarkers - A Review}}
\author{Hemaanhini~Tamilmani\textsuperscript{1},  
            Yuvaraj~Babu~K\textsuperscript{*}\textsuperscript{2}, 
            Gayathri~R\textsuperscript{3}~\\[5pt]{\textsuperscript{1}Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-77, Tamil Nadu, India}~\\{\textsuperscript{2}Department of Anatomy, Saveetha Dental College and Hospitals,  Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-77, Tamil Nadu, India}~\\{\textsuperscript{3}Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-77, Tamil Nadu, India}}

\begin{abstract}
Biomarkers are indicators of a disease or the severity of a disease. For example, in the human body, antibodies can be termed as a biomarker. White matter is important to learn for understanding various topics such as the theory of mind, empathy, clinical disorders in terms of neuroscience. White matter can change depending upon traumatic experience. This research is seen as a scoping literature review. In seeking to identify the relevant literature from the past twenty years, we used common databases such as Pubmed, Google Scholars. Searches of the reference list from relevant review articles were also employed to identify further relevant studies. Search items included, 'white matter', 'biomarkers', 'white matter biomarkers', 'biomarkers used in neurology'. The obtained articles were later thoroughly read through and understood. A total of '45' articles have been selected and reviewed in this article. Biomarkers present in white matter help diagnose the various white matter related diseases which can help prevent further stages or increase of the disease. But accurate biomarkers for white matter disease are yet to be found. More research must be done in order to help prevent and treat white matter diseases. This study on white matter biomarkers still does not have an accurate answer and must be discovered in the future. There are many biomarkers that can serve for white matter, but none of them fulfils the desired features of a biomarker needed for diagnosing white matter diseases. Future studies are to be done for early prevention of diseases related to white matter and its complete use in humanity.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}White matter,\newline Biomarkers,\newline White matter biomarkers,\newline Neurology,\newline Alzheimer's disease
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Yuvaraj~Babu~K~\\ Phone:\ +91 9840210597~\\  Email:\ yuvarajbabu@saveetha.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{ Introduction}
Biomarkers are indicators of a disease or the severity of a disease. For example, in the human body, antibodies can be termed as a biomarker \unskip~\citep{901706:20486107}. If we see biomarkers related to coronary heart disease [CAD], an inflammatory biomarker such as fibrinogen or hs-CRP can be used or lipoprotein associated biomarker such as lipoprotein associated PA2 or lipoprotein a and even cystatin C which is an organ specific biomarker can be used. But an ideal biomarker for CAD is still yet to be found \unskip~\citep{901706:20486117,901706:20486107}. In the case of aging or age- related diseases, Micro RNAs, can be used which are detected by microarray and sequencing, and various other techniques \unskip~\citep{901706:20486113}. 

White matter is important to learn for understanding various topics such as the theory of mind. Empathy, clinical disorders in terms of neuroscience \unskip~\citep{901706:20486081}. It was noticed that white matter changes, but this change depends upon various traumatic experiences \unskip~\citep{901706:20486079}. Human behaviour can be changed if the white matter tract is distributed [in terms of cognition] \unskip~\citep{901706:20486089}.

In an article written by Hansen, they had mentioned that white matter tract integrity [WMTI] biomarkers show promising results in brain development studies. Still, currently, it is being used only in animal studies and slow progressing studies. The fast approach of WMTI can be used in pre-clinical trials and research before being used on patients \unskip~\citep{901706:20486118}. Cerebrospinal fluid [CSF] biomarkers had also been used to detect white matter lesions. But this research showed lack of association between white matter lesions and Alzheimer's disease [AD] in terms of CSF biomarkers \unskip~\citep{901706:20486091,901706:20486120}. In another research article, it was found that white matter hyperintensities [WMH] played the role of biomarkers in cerebrovascular diseases [CVD] \unskip~\citep{901706:20486121}.

Over the past years various research done by our team was on Osteology \unskip~\citep{901706:20486078,901706:20486077}, stature estimation \unskip~\citep{901706:20486094}, uses and ill effects of electronic gadgets \unskip~\citep{901706:20486110,901706:20486111}, on RNA \unskip~\citep{901706:20486080,901706:20486088}, animal studies \unskip~\citep{901706:20486115} and in few other fields \unskip~\citep{901706:20486084,901706:20486082}. There is a lack of information on the current topic of white matter biomarkers, hence the main aim of this study is to explore and review some detailed information on white matter biomarkers and its related topics\unskip~\citep{901706:20486086}.
    
\section{Materials and Methods}
 This research is seen as a scoping literature review. In seeking to identify the relevant literature from the past twenty years, we used common databases such as Pubmed, Google Scholars\unskip~\citep{901706:20486097,901706:20486093}. Searches of the reference list from relevant review articles were also employed to identify further relevant studies. Search items included, `white matter', `biomarkers', `white matter biomarkers', `biomarkers used in neurology'. The obtained articles were later thoroughly read through and understood. A total of `45' articles have been selected and reviewed in this article\unskip~\citep{901706:20486105,901706:20486087}. Quality of articles used was assessed using a quality assessment tool and graded as strong, moderate and weak.

\textbf{Biomarkers}

\textbf{Acute Kidney Injury}

Acute kidney injury [AKI] occurs usually based on serum creatinine change. Diagnosis of AKI, this was studied in a total of 31 studies, from which 25 studies out of the 31 studies had good quality. From these studies, it was found that serum cystatin C, urine IL- 18 and urine KIM- 1 gave better results for the diagnosis of AKI. 

These biomarkers have great potential but need more future study \unskip~\citep{901706:20486109}. Often in the case of AKI, renal replacement therapy [RRT]. But there is one problem, ideal circumstances of whether to or whether not to do this therapy is still unclear. In this study, a total of 63 studies was performed on 15,928 critically ill patients. 

Through this study, several biomarkers showed promising results, but this current evidence is not enough to prove the establishment of these biomarkers for clinical purposes \unskip~\citep{901706:20486118}. 

\textbf{Micro RNAs}

Micro RNAs [Mi RNAs] are important regulators. In this research article, they have mentioned that Mi RNAs have great potential to be biomarkers for prostate cancer management. But this review does not show any promising results and thus, more research and future clinical studies must be done \unskip~\citep{901706:20486122}. As seen in the introduction, Mi RNAs are found in biofluids [circulating]. 

Mi RNAs can act as a biomarker for aging and age related diseases. Mi RNAs are quite suitable in circulation and are detected by microarray and sequencing [a high- throughput technique] \unskip~\citep{901706:20486113}. 

\textbf{Coronary Heart Disease }

Coronary heart disease [CAD] is one of the most common reasons of death all around the world. Various biomarkers such as fibrinogen, lipid associated biomarkers and organ specific biomarkers have been used in this research article. 

These biomarkers fulfilled several qualities of an ideal biomarker for CAD. But none fulfilled all the qualities desired, hence further study is needed for this research \unskip~\citep{901706:20486117}.

\textbf{Osteoarthritis}

Several protein and non protein biomarkers have been found to diagnose osteoarthritis. But the improved quality of sample and testing, as well as more clinical trials are needed as they may help in identifying a suitable biomarker which may fulfil all the requirements of an ideal biomarker for osteoarthritis \unskip~\citep{901706:20486096}.

\textbf{Neonatal Sepsis}

There are many biomarkers such as CRP and PCT, but both have not fulfilled the ideal qualities of a biomarker for neonatal sepsis. Further study must be done so that with the help of the biomarker, neonatal sepsis can be identified in an early stage and appropriate measures can be taken \unskip~\citep{901706:20486101}. 

\textbf{White Matter}

White matter diseases are poorly understood. For understanding the radiological manifestations, we must understand the pathological view. Few of the previous research articles had made a systematic approach to the radiological findings \unskip~\citep{901706:20486100}. In another research article, white matter degeneration is related to vascular dementia and other age related diseases. It was also mentioned in this research that the preservation of axonal function and prevention of cognitive impairment is very important \unskip~\citep{901706:20486119}. The association between white matter and cognition has shown a lot of new scopes. But many are there to be discovered as one can face many challenges while trying for new opportunities \unskip~\citep{901706:20486089}. 

In a research article, it was seen that out of 792 cases, there were several cases which proved the association between neuroinflammation and white matter pathology in people with schizophrenia \unskip~\citep{901706:20486103} . It is also important to understand white matter injury and also its recovery after a hypersensitive intracerebral haemorrhage \unskip~\citep{901706:20486085}. It was also found that the white matter is damaged in early treated phenylketonuria [ETPKU] patients. But this study also did not show proper evidence and had poor control in various studies \unskip~\citep{901706:20486098}. 

\textbf{Neurology}

Biomarkers used in neurology are in need of greater study, to help in early diagnosis of CNS conditions. In an article, it was found out that saliva was used as a biomaterial, it is an alternative and also has several advantages. Its use has been studied from many perspectives and can also become an actual biomarker \unskip~\citep{901706:20486083}. Psychiatric disorders are disturbances of cognitive functions. The benefits of neurosciences and biomarkers can help solve mysteries of multiple regions of the brain, along with various features \unskip~\citep{901706:20486081,901706:20486116}. Computational neuroscience or psychiatry developments can allow simultaneous diagnosis as well as treatment of mental disorders using techniques such as neuroimaging, etc\unskip~\citep{901706:20486090}. 

\textbf{White Matter Biomarkers}

There are several white matter tract integrity biomarkers which showed promising results. When an axially symmetric diffusion kurtosis imaging [DKI] and conventional DKI were compared with each other, axially symmetric DKI showed faster protocols which may be useful for preclinical research \unskip~\citep{901706:20486118}. A continuous theta burst stimulation [cTBS] advanced the knowledge of white matter and showed different relations in individuals with stroke \unskip~\citep{901706:20486104}. 

\textbf{Parkinson'S Disease}

Quantitative Susceptibility Mapping [QSM], as well as Diffusion Tensor Imaging, was used to evaluate the white matter alterations. It was seen that both showed similar results. Further combination of QSM and DTI will provide a complete evaluation of the brain's diseased state \unskip~\citep{901706:20486108}. There is not even one clear biomarker which shows promising results for Parkinson's disease. A combinatorial and multimodal approach must be developed in the future \unskip~\citep{901706:20486106}. 

\textbf{Alzheimer's Disease}

It was noticed that A𝛃42 and tau had a lot of chances of becoming a future biomarker in saliva. And it was also noticed that lactoferrin and other selected metabolites also have the potential. Future researches must be done \unskip~\citep{901706:20486114,901706:20486092}. Lipid biomarkers had also shown various roles in being a biomarker for Alzheimer's disease \unskip~\citep{901706:20486099}.

\textbf{Dementia}

CSF and blood based biomarkers, diagnosed in vivo also showed a lot of potential of a biomarker in various stages of this research \unskip~\citep{901706:20486102,901706:20486112}. Different biomarkers showed various relations between aging, dementia and cognition impairment \unskip~\citep{901706:20486095} . 
    
\section{Results and Discussion}

\begin{table*}[!htbp]
\caption{\boldmath {Quality of study for articles used in review} }
\label{tw-907319b12a6f}
\def\arraystretch{1.1}
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\begin{tabulary}{\linewidth}{p{\dimexpr.05960000000000001\linewidth-2\tabcolsep}p{\dimexpr.2947999999999999\linewidth-2\tabcolsep}p{\dimexpr.06099999999999996\linewidth-2\tabcolsep}p{\dimexpr.082\linewidth-2\tabcolsep}p{\dimexpr.4031\linewidth-2\tabcolsep}p{\dimexpr.0995\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S. No & Author & Year & Type of Study & Key Points & Quality of Study\\
\tblmidrule 
1. &
  \unskip~\cite{901706:20486118} &
  2017 &
  Review  &
  Axially symmetric DKI &
  Strong\\
2. &
  \unskip~\cite{901706:20486104} &
  2019 &
  Review  &
  cTBS &
  Moderate \\
3. &
  \unskip~\cite{901706:20486121} &
  2014 &
  Review  &
  Cerebrovascular disease &
  Moderate \\
4. &
  \unskip~\cite{901706:20486120} &
  2014 &
  Review  &
  Cerebrovascular biomarker &
  Strong\\
5. &
  \unskip~\cite{901706:20486108} &
  2019 &
  Review  &
  Parkinson's disease &
  Moderate\\
6. &
  \unskip~\cite{901706:20486117} &
  2017 &
  Review  &
  Biomarker- CAD &
  Strong \\
7. &
  \unskip~\cite{901706:20486106} &
  2016 &
  Review  &
  Parkinson's disease- biomarker &
  Moderate\\
8. &
  \unskip~\cite{901706:20486109} &
  2008 &
  Review  &
  AKI- biomarker &
  Moderate\\
9. &
  \unskip~\cite{901706:20486092} &
  2016 &
  Review  &
  CSF and blood biomarker &
  Moderate\\
10. &
  \unskip~\cite{901706:20486096} &
  2017 &
  Review  &
  Osteoarthritis biomarker &
  Strong \\
11. &
  \unskip~\cite{901706:20486101} &
  2018 &
  Review  &
  Neonatal sepsis &
  Moderate \\
12. &
  \unskip~\cite{901706:20486100} &
  2016 &
  Review  &
  White matter disease &
  Strong\\
13. &
  \unskip~\cite{901706:20486119} &
  2018 &
  Review  &
  White matter degeneration, dementia &
  Moderate \\
14. &
  \unskip~\cite{901706:20486099} &
  2018 &
  Review  &
  Lipid biomarker- alzheimer's disease &
  Moderate\\
15. &
  \unskip~\cite{901706:20486112} &
  2014 &
  Review  &
  Dementia- biomarkers &
  Moderate \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
Biomarkers present in white matter help diagnose the various white matter related diseases, which can help prevent further stages or increase of the disease is yet to be found \unskip~\citep{901706:20486120}. Linda and Helena both did research on biomarkers, but both of them stated that they needed a larger and deeper future study for more evidence of the biomarker \unskip~\citep{901706:20486122,901706:20486114}. 

Helena and Bob found quite a few biomarkers for Parkinson's disease. But out of the few selected and analysed, none showed complete efficiency \unskip~\citep{901706:20486114,901706:20486092}. Maria and Xiaojun used MRI sequences and DTI techniques for diagnoses of white matter diseases \unskip~\citep{901706:20486098,901706:20486108}. 

Nicolae discussed various white matter diseases in a radiological approach which is poorly understood by many \unskip~\citep{901706:20486100}. Brian and Chutinet found biomarkers, but again none of them fulfilled the criteria and did not have the full potential to be a biomarker for white matter \unskip~\citep{901706:20486118,901706:20486109}. Jonsson diagnosed white matter biomarkers using MRI \unskip~\citep{901706:20486091} while Wadden used cTBS technique for diagnosing white matter biomarkers \unskip~\citep{901706:20486104}. 

Bob found three biomarkers for Alzheimer's disease. These were systematically reviewed and was found out that it can be used for future clinical use \unskip~\citep{901706:20486092}. Maria found cerebrovascular biomarkers such as NF-L, MBP, MMPs. TIMP for diagnosing white matter diseases \unskip~\citep{901706:20486120}. 

Few of the limitations which can be seen in this study are that a larger and deeper study is required as well as future studies of discovering white matter biomarkers for recognition of white matter diseases. There must be more future study done on this topic. The study on white matter biomarkers still does not have an accurate answer and must be discovered. 
    
\section{Conclusion}
There are many biomarkers that can serve for white matter, but none of them fulfils the desired features of a biomarker needed for diagnosing white matter diseases. This review concludes that further studies are to be done for early prevention of diseases related to white matter and its complete use in humanity.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.
    

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