\r\n\tDiagnostic tools are advancing: micro-and nano-diagnostics, advanced molecular genetics, and diagnosis of the aberrant clotting factor synthesis development and the options for the staging of the genetic abnormality - severe, moderate, and mild expression.
\r\n\tTreatment developments and advances start with prevention, intra-uterine approaches, genetic manipulation, genetic engineering, the high specificity of replacement factors, and recombinant technology.
\r\n\tIn addition to the above, the book will provide an update on the prevention of transmission of pathogens and potentially toxic substances used to stabilize and preserve treatment commodities. The role of big data and artificial intelligence through both machine learning and the application of deep learning and digital footprinting will also be addressed.
\r\n\tIn the developing world, there is an urgent need to collect, preserve and process plasma for the manufacturing of high yield, safe, and stabilized cryoprecipitate, or pharmaceutical fractionation of purified and specific clotting factors, as well as improvement on diagnostic and sociomedical approaches with an emphasis on patient and family care, and management of bleeding episodes.
Huntington’s disease (HD) is an inherited disease that causes breakdown of nerve cells in the brain. HD, resulting from gene mutation, affects different parts of the brain impacting movement, behavior, emotion regulation, and psychiatric disturbance. Eventually, the person will need full-time care, and death of the disease is inescapable. HD is caused by an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the huntingtin gene. HD is one of the rare neurodegenerative conditions for which predictive genetic testing is available for individuals with a known family history [1]. The identification of HD gene mutation carriers, while they are still healthy before manifestation (premanifest) of clinical signs of the disease has several benefits as this may help prevent the development or slowdown of the progression of the disease, hence, improved quality of life of the patient.
HD symptoms can develop at any time, but they often start at 30–50 years of age. If the condition develops earlier, before the age of 20, the symptoms start with behavioral disturbances and learning difficulties. Because of this, there is an urgent need to diagnose the disease as early as possible using biomarkers and assess the development of the disease. This can be achieved by identifying a number of biomarkers that are altered either premanifest or during the disease progression.
The unified Huntington’s Rating Scale (UHDRS) has been used as a clinical rating scale to assess four domains (motor function, cognitive function, behavioral abnormalities, and functional capacity) of clinical performance and capacity in HD patients. However, one of the main challenges in using this rating scale is the slow progression of HD, rendering the scale imperfect as a standalone tool [2] leading, in some cases, to limitations of clinical trials that aiming to assess the benefits of therapeutic agents in HD. In addition, there are several factors that could influence the clinical measures including the placebo effect and the clinical rater variability. This results in reduced ability indistinguishing between symptom relief and amelioration of the underlying disease process [3].
Finding biomarkers that change with clinical progression quickly and predictably with the use of a therapeutic agent could greatly facilitate future HD clinical trials by reducing the duration and number of patient volunteer required for such studies. This is especially important in premanifest HD mutation carriers, who may remain free from all clinical manifestations for decades. In addition, pharmacodynamic biomarkers can be utilized in preclinical trials and early phase clinical trials to predict if the therapeutic agent will have its intended effect and to assist in the decision-making process on whether to continue such trials or not.
Up to date biomarker research has included both focused small-scale and large studies. For instance, TRACK-HD (a prospective observational study of HD that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early-stage disease and those who have had it for 12 months or less) [4], and PREDICT-HD (a multicenter observational research study aimed to examine measures that may be associated with disease in the largest cohort ever recruited of pre-diagnosed individuals carrying the gene expansion for HD) [5], have afforded scientists in the field the opportunity to study many potential biomarkers for HD.
The term biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [6]. Therefore, a biomarker can be related to the disease itself or to the response to treatment. Hence, biomarkers can serve many different functions, such as diagnostic, prognostic, monitoring, response/pharmacodynamic, susceptibility/Risk Biomarker [7, 8]. In addition, most therapeutic clinical trials that aim to evaluate the efficacy of potential disease-modifying treatments during pre-manifest HD require biomarkers to serve as outcome measures. Some efficacy biomarkers may also function as ‘state biomarkers’ or ‘biomarkers of progression’, which are used as indicators of disease severity. These state biomarkers could very well reflect the underlying disease pathobiology and linearly track clinical progression of the disease (including during the pre-manifest stage) [1].
The biomarkers that have been used, hitherto, in HD are of types including, clinical biomarkers, wet biomarkers, and imaging biomarkers. Detailed discussion of these biomarkers and their subtypes is presented below.
Rather than relying on United Huntington’s Disease Rating Scale (UHDRS’s) dichotomous notion of ‘disease onset’, some researchers have proposed the use of continuous measures, such as clinical symptoms of the disease. Some UHDRS motor abnormalities can be objectively quantified, thereby improving accuracy and reducing inter-rater and intra-rater variability [1].
Tabrizi et al. have supported the hypothesis that neuronal dysfunction occurs many years before the development of motor signs that are diagnostic of HD. The motor alterations that have been described are most likely secondary to progressive neuronal loss or dysfunction. This could help define quantifiable endpoints for future therapeutic interventions [9]. Motor signs are amenable to quantitative assessment and may provide objective measures for disease onset and progression. Several quantitative motor tasks, including force-transducer-based assessments, detect deficits in premanifest gene carriers [10], for example, finger tapping precision and a problem task is evident even in pre-manifest HD and worsen with time. Another longitudinal study identified numerous cognitive task impairments in more than one variable, one of these variables is the Symbol Digit Modalities test which assesses visual attention and psychomotor speed [1, 10, 11] suggesting the limited use of clinical markers in preventive clinical trials.
Wet biomarkers also called biofluids, (those obtained from bodily fluids, such as blood, urine, saliva, and cerebrospinal fluids (CSF)) are another potential source of useful outcome measures if they reflect the pathophysiology of a disease and show the response for a therapeutic agent.
In HD, various pathologic mechanisms have been implicated and numerous potential molecular markers have been detected. Progression of the disease have been reported to be associated with detectable changes in inflammatory signals in peripheral blood which matched changes in peripheral and central processes such as immune activation, neuroinflammation, and metabolic markers [12, 13]. In some cases, substances that are released from dying neurons that can penetrate the blood-brain barrier can be detected in peripheral blood and could be used as a biomarker. Unfortunately, however, if these substances have peripheral sources, conflict in interpretation may occur [14]. Cerebrospinal fluid, which is enriched with brain-derived substances is of particular interest, however, other biofluids have the potential to yield relevant biomarkers if their composition reflects that of the CNS. Consequently, all biofluids, including CSF, may reflect peripheral as well as central disease-related changes [3].
Huntington’s disease (HD) is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT), which leads to the production of the mutant huntingtin (mHTT) protein. The degree of symptom severity, disease stage, and markers of neuronal damage have been shown to correlate with levels of mHTT protein in the CSF in patients with HD. This toxic mHTT protein production is believed to result in neurotoxicity, as normal cellular processes important for cellular survival are disrupted. Furthermore, decreased level of mHTT is an important measure of the response to the therapeutic agents. mHTT quantification has been achieved for the first time in 2015 using a `femtomolar` single molecule counting (SMC) immunoassay, and a combination of mHTT N-terminal-detecting 2B7 antibody and polyglutamine-binding MW1 antibody. mHTT was significantly higher in manifest HD and premanifest HD compared to controls with a roughly threefold difference seen between premanifest HD and manifest [3, 14].
mHTT detection is associated with disease onset and cognitive and motor function disability. mHTT quantification in CSF could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering therapies for HD [15]. mHTT levels also correlate with clinical manifestations as well as with two indicators of neuronal damage (CSF tau and neurofilament light chain) [14] suggesting that mHTT is released from damaged or dying neurons.
Neurofilament light protein (NfL, also known as NFL) is the smallest of three subunits that make up neurofilaments, which are major components of the neuronal cytoskeleton. NfL is released from damaged neurons. Its concentrations in CSF are elevated in people with neurodegenerative diseases.
Detection of NfL in the CSF using enzyme-linked immunosorbent assay (ELISA) reflects that NfL concentration is elevated in both premanifest and manifest HD. This elevation is associated with mHTT elevation in CSF, disease stage, motor and cognitive impairment, functional impairment and brain atrophy, as well as reduction in all brain volume measures [14, 16, 17, 18].
Also, NfL is detectable in blood plasma or serum using a single-molecule ‘Simoa’ assay. It has been shown to increase in blood of people with neurodegenerative diseases including HD [14, 16]. Quantification of NfL in plasma provides an accessible biomarker that has close links to diagnosis, progression of HD and the response to disease-modifying treatments. Also, NfL in both plasma and CSF is considered a better biomarker to differentiate between premanifest and manifest HD than CSF mHTT [3, 17, 18, 19].
Tau protein (a microtubule-associated protein, which aggregates abnormally under certain pathologic conditions) is another protein that is hypothesized to be associated withHD. It has been found that CSF tau concentration in HD gene mutation carriers is increased compared with that of healthy controls. It has also been reported that CSF tau concentrations are associated with phenotypic variability in HD. This report strengthens the case for CSF tau as a biomarker in HD [20].
Activation of glial cells has been reported in several neurodegenerative diseases including HD. Biomarkers reflecting these peripheral and/or central neuroinflammation could be useful to identify the disease onset, progression, and the therapeutic response. Proteomics screen of HD plasma identified immune proteins that are elevated in HD compared to healthy controls, including pro-inflammatory cytokine IL-6, acute-phase protein alpha-2-macroglobulin, complement factors, and a complement inhibitor clusterin. Additionally, it has been found that IL-6 levels were significantly increased in premanifest subjects with an estimated mean of 16 years before motor signs onset [8, 12, 16, 21].
Another marker that has also been studied as a CSF inflammatory marker in HD is YKL-40 (chitinase 3-like protein 1 (CHI3L1)), a member of the glycosyl hydrolase family 18 and a marker of microglial activation. The results about this marker are mixed [3, 14, 16].
Weight loss and muscle wasting are examples of some disorders that appear in patients with HD reflecting metabolic alterations in those patients. Several metabolites were tested as potential biomarkers for HD. In addition, several amino acids were tested as potential biomarkers. It has been reported that plasma levels of asparagine (Asn) and Serine (Ser) were significantly decreased suggesting a potential biomarker role for these two amino acids [22].
Studies conducted on the association of total cholesterol, HDL-cholesterol and LDL-cholesterol with HD revealed mixed, and in some cases, contradictory results. Whereas most studies showed that changes in cholesterol levels were insignificant, one study showed that reductions in cholesterol levels were significant in premanifest and manifest patients [23]. In another study, 24(S) hydroxycholesterol (24OHC), the brain-specific elimination product of cholesterol long considered a marker of brain cholesterol turnover, was significantly reduced in HD patients at all disease stages. This reduction was paralleled with a reduction of the caudate volume suggesting that the reduction of 24OHC may reflect progressive neuronal loss in HD patients. In addition, a decrease in the plasma concentration of cholesterol precursors` lanosterol and lathosterol was observed [8, 24, 25]. These results suggest the potential usefulness of these two cholesterol precursors as metabolic biomarkers in HD diagnosis and progression.
Patients with manifest HD display circadian rhythm abnormalities with disturbances in rest-activity profiles and abnormal day-night ratios associated with alterations in sleep-wake timing and melatonin and cortisol profiles [26].
Melatonin is a light-sensitive hormone secreted predominantly by the pineal gland and displays a circadian rhythm with maximum levels peaking at night. It has a key role in the sleep-wake cycle which is disrupted in the early stages of HD. A significant decrease in mean melatonin levels has been reported in manifest HD, with trends towards decreased melatonin levels in premanifest HD and temporal shift in melatonin release in mHTT carriers. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior of HD patients acting as a biomarker for this disease state [3, 26, 27, 28, 29]. While there were no differences in melatonin release when it was measured at a single time point in advanced HD, differences in melatonin release were detected when measured at multiple time points. This suggests the need to measure melatonin levels at points representing the whole circadian rhythmicity [8].
Cortisol is another substance that plays a role in circadian rhythm as it has been observed that increased cortisol levels lead to sleep disturbances, which are likely to potentiate neurodegeneration and associated changes in cognitive, motor deficits and mood disturbances in HD [27, 30].
With markers that have specific circadian rhythms, 24-hour sample collections could be the means to using these markers as pharmacodynamic markers to assess the response to the treatment rather than the progression of the disease [3].
Both human and animal studies have suggested the involvement of energy metabolism dysfunction and oxidative stress in HD pathogenesis as it has been shown that levels of oxidative damage products, free radical production are elevated in areas of degeneration in HD brain [31]. It is thought that impairment in the electron transport chain and mitochondrial dysfunction are behind the increased production of reactive oxygen species in HD [32, 33, 34]. Markers of oxidative stress have been investigated in HD blood plasma and brain tissue in the animal model, but few have been quantified in CSF.
Several studies have reported enhanced lipid peroxidation in individuals with HD with a correlation between lipid peroxidation products in plasma and the degree of severity in patients with HD. It has been reported that F2-isoprostanes are a marker for lipid peroxidation found to be elevated in HD [3, 8, 14].
The endogenous opioid peptides have been found to be implicated in the regulation of motor function as well as in the pathophysiology of abnormal movement disorders. Degeneration of opioid peptide-containing neurons in the basal ganglia has been demonstrated in some neurodegenerative diseases such as HD [35]. Recently, it has been found that CSF proenkephalin (PENK) levels were significantly decreased in manifest HD patients compared to premanifest. The decrease in PENK CSF levels in premanifest patients was insignificant when compared to controls. Moreover, levels of PENK in the CSF is inversely proportional to the progression of HD symptoms. This decrease in PENK levels reflects the degeneration or dysfunction of neurons that produce PENK, consequently, PENK levels may serve as marker for the state of medium spiny neurons (MSNs) in HD patients [36].
Prodynorphin (PDYN) is another endogenous opioid that has been studied in HD. It has been found that PDYN-derived peptide levels were significantly decreased in CSF of patients with HD. This decrease is unique to HD as a comparable decrease was not observed in the other neurodegenerative disorders studied. These results suggest that PDYN-derived peptides in CSF could be considered as strong biomarker candidates for HD [37].
The microRNAs (miRNAs) are involved in different biological processes including development, proliferation, inflammation and apoptosis. miRNA is an intracellular component but also can be detected in the peripheral circulation. The level, structure, type and sequence of miRNAs detected in blood will reflect the physiological status, the type and stage of the disease [38]. The detection of abnormal expression of different miRNAs in the HD mouse model provides further support regarding the importance of miRNA in HD pathogenesis and therapeutics [39], and the potential usefulness of miRNAs as biomarkers for diagnosis, prognosis, and therapeutic response [38].
In the central nervous system (CNS), exosomes play essential physiological roles in the cell-to-cell communication and homeostasis maintenance required for normal brain function [40]. Exosomes contain a variety of key bioactive substances reflecting the status of the intracellular environment. As exosomes can penetrate the blood-brain barrier they can be found in peripheral body fluids, and their contents will change with diseases [41]. Most cell types in the brain release extracellular vesicles (EVs) and these have been shown to contain neurodegenerative proteins. In HD, by using a model culture system with overexpression of HTT-exon 1 polyQ-GFP constructs in human 293 T cells, it has been found that the EVs did incorporate both the polyQ-GFP protein as well as the expanded repeat RNA. These findings support the role of EVs as delivery vehicles of toxic expanded trinucleotide repeat RNAs from one cell to another [42]. Exosomes have a huge potential as non-invasive diagnostic biomarkers of HD for their content of mHTT, its fragments, or other proteins reflect the conditions of exosomes producing CNS cells [40].
In HD, neuroimaging techniques have been extensively investigated and have aided in our understanding of the disease’s natural history. Imaging is attractive as a source of biomarkers because it is generally non-invasive; data collecting, processing, and quality control can be standardized, and data can be easily sent over great distances, which is advantageous for multi-site investigations. The ideal imaging biomarker would be widely available, reasonably priced, and repeatable across multiple sites using different scanner manufacturers and field strengths and have a reasonable acquisition time - especially since HD patients may not tolerate longer scanning protocols and movement that degrades image quality.
Structural MRI, diffusion imaging, functional MRI, and PET are just a few of the imaging modalities available. There are a variety of image processing algorithms for each modality, and the approach chosen can have a big impact on the output metrics that are used as biomarkers. Some automated procedures, for example, can generate mistake and systemic bias, especially in atrophic brains [43]. To avoid difficulties, extensive validation of the acquisition and processing technique is essential before such measures may be used as a biomarker, which has been absent in many imaging investigations to date.
Structural MRI (sMRI) is a non-invasive technique that provides information to describe the shape, size, and integrity of gray and white matter structures in the brain. MRI results emphasized that there are strong correlations between many gray and white matter regions and clinical tests, including recognition of negative emotions, metronome tapping precision, and measures of tongue force. The latest findings point of sMRI data enables to collect information from across the brain during the premanifest to manifest period in HD. The data show that no uniform atrophy occurs throughout the brain (Figure 1), where the largest changes (~18–22%) occurring in the striatum (caudate, pallidum, and putamen) and gradual changes (~7–16%) occurring across the four main brain regions (parietal, temporal, frontal, and occipital) over a period of ~11 years [44]. This timeframe is similar to prior studies of the timing of sMRI alterations in HD [45], according to which the rate of putamen and caudate atrophy becomes substantial roughly 9 and 11 years after estimated onset, respectively [44].
RACK-HD cohort. Average magnitude of change of ten regional volumes from genotype-positive trajectories in TRACK-HD [
When used as a clinical trial endpoint, the rate of change of a proposed biomarker can influence the length of the study and the number of participants required to identify a meaningful change. There is no agreement on whether the pace of striatal atrophy progression differs with disease stage. TRACK-HD found stepwise accelerated rates of change from the earliest premanifest stage to early-stage disease, with limited evidence that the acceleration diminishes after symptoms appear [4, 46]. After controlling for age, TRACK-HD found highly significant relationships between the rate of change and disease burden ratings in both the caudate and putamen. The PREDICT-HD study, on the other hand, did not discover that rates accelerated across its premanifest group, but this could be due to differences in longitudinal change assessment methodology [47].
Studies for regional Cortical found in HD patients reported a heterogeneous volume loss [4, 9, 46, 48, 49, 50], where the cortical thinning occurs early during the clinical stage of disease and seems to increase with disease progression. The reported thinning of the cortical gray was clear in posterior cortical regions, with increasing duration of symptoms, more anterior cortical regions were affected. The reported data suggest that the cortex undergoes degeneration, much of which occurs in the striatum particularly in the early premanifest stage of the disease [46, 48, 51]. Cortical thinning was distributed in many areas, even within gray regions. In some areas the thinning was as much as 0.4 mm which corresponds to approximately a 20% loss of thickness whereas in other areas, thinning was around 1 mm, corresponding to 30% loss of thickness (Figure 2) [49, 52, 53, 54, 55, 56].
(A) Mean thickness maps. The surface reconstruction demonstrates mean thickness differences of three different subjects with Huntington’s disease (HD) in differing stages of the disease. Darker gray areas correspond to sulci; lighter gray areas correspond to gyri [
The Cross-sectional studies have reported volume reductions in the corpus callosum [5] and frontal white matter (Figure 3) [9, 57, 58]. In premanifest HD, both TRACK-HD and PREDICT-HD showed progressive white matter atrophy, even in the groups farthest from anticipated onset [9, 46, 60]. In manifest disease, a similar picture has been observed, with cross-sectional reductions in white matter volume compared to controls [4, 9, 61, 62, 63], and elevated atrophy rates in longitudinal studies [57, 64]. White matter atrophy has been shown to correlate with motor function [47, 58, 65, 66], cognitive function [58, 65, 67] and total functional capacity (TFC) [47, 68]. White matter volume loss’ prognostic value for manifest HD conversion is less evident, with inconsistent findings in two large observational investigations [48, 69]. White matter atrophy, on the other hand, does track disease progression and is present from the earliest premanifest stage through established disease.
Tracts showing lower fractional anisotropy in Huntington’s disease gene carriers when compared with controls. Results (red-yellow [lower to higher statistical values]) are projected on a white matter skeleton (green), overlaid on a customized mean fractional anisotropy image [
There is mounting evidence that the severity of clinical manifestations in HD is influenced not just by neuronal loss but also by neuronal dysfunction and circuitry rearrangement, and that these processes can occur early in the disease, possibly even before neurodegeneration. By monitoring the hemodynamic response (blood flow) of neural activation, functional neuroimaging methods such as functional MRI (fMRI) produce dynamic images of the brain that aid in elucidating neural activity. Data from manifest HD patients revealed decreased task-activation in multiple subcortical and cortical regions, as well as increased task-activation in various cortical areas, which was interpreted as a compensatory mechanism for task performance [70, 71, 72, 73, 74, 75]. Interestingly, premanifest HD gene carriers who were further away from illness onset showed increased activation in multiple brain regions, whereas premanifest HD gene carriers who were closer to disease onset showed lower activation in the striatum [76, 77, 78, 79].
Both premanifest and manifest HD gene carriers have exhibited intrinsic deficits in functional connectivity in resting-state fMRI data [80, 81, 82]. Reduced blood-oxygen-level-dependent (BOLD) synchronization between the caudate and premotor cortex was reported in premanifest HD gene carriers [80]. A study found several abnormal networks in both premanifest and manifest HD subjects using a method that measures changes in synchrony in BOLD signal amplitude and across space. For example, it has been found that premanifest HD gene carriers had lower resting-state synchronization in the sensory-motor network and that this level of synchrony was related to motor performance as determined by speeded self-paced tapping [83]. Overall, these data demonstrate aberrant functional network connection in both premanifest and manifest HD, implying that resting state fMRI could be valuable for detecting early neural dysfunction and tracking disease progression.
Premanifest HD gene carriers have also been discovered to have neurovascular changes. Cortical arteriolar cerebral blood volume (CBVa) was significantly elevated in premanifest HD gene carriers compared to normal controls, which was connected with genetic parameters including the CAG-age product score and estimated years to onset [84].
Diffusion MRI assesses the microstructural integrity of white matter filaments, providing additional information to volumetric MRI. The diffusion of water in different directions within the brain is measured using this technique. Water diffusion in healthy white matter fibers is usually only in one direction, making them anisotropic. When white matter breaks down, for example, due to axonal injury or demyelination, diffusion increases in directions other than the axons. Diffusion MRI might, in theory, reveal neuronal injury or dysfunction that occurs before volumetric loss.
The most widely-studied diffusion technique in HD is diffusion tensor imaging (DTI). Across various neurodegenerative diseases, reductions in fractional anisotropy (FA) and increases in mean diffusivity (MD) are commonly observed [85, 86, 87] indicating their sensitivity but lack of specificity to the underlying neurodegenerative process. Axonal loss, demyelination, and less cohesive white matter tracts are thought to be the cause of these abnormalities, which would be expected to occur before volume loss.
A Diffusion metric change has been observed in premanifest HD in cross-sectional investigations, particularly in the corpus callosum, internal capsule, and thalamic radiations [88, 89, 90, 91]. These alterations in the white matter, particularly the frontal, parietal, and occipital white matter, become increasingly pronounced and extensive in manifest HD [92, 93, 94]. The results of longitudinal studies using diffusion metrics have proved inconclusive. Two studies in premanifest HD failed to find 12–30 month changes [89, 95], whereas two larger studies found progressive changes over 1–5 years in premanifest HD cohorts including those up to 10 years away from onset [90, 96]. In manifest-HD, longitudinal alterations in DTI measures have also been demonstrated [51].
Changes in regional DTI measurements have been linked to total motor score (TMS), timed finger tapping, executive function [80], apathy [97], and depression [98]. However, no research has looked into the effectiveness of DTI measurements in predicting clinical development. Furthermore, DTI measurements had smaller impact sizes than volumetric measures in a comparative investigation across periods of 6–15 months [99] limiting the use of DTI as a biomarker of HD progression.
Recent advances in diffusion acquisition and modeling techniques, such as the use of neurite orientation dispersion and density imaging (NODDI) methods (Figure 4), have the potential to improve the sensitivity of diffusion MRI measures in HD [100, 101, 102]. However, there is currently a lack of agreement on diffusion imaging acquisition parameters, processing, and analysis procedures, which accounts for some of the variance in findings to date.
White matter abnormalities: Neurite orientation dispersion and density imaging (NODDI) analysis [
The use of PET in the diagnosis and understanding of neurological pathologies is crucial. It is a non-invasive molecular imaging technology that uses radiopharmaceuticals to attach to a specific molecular target, such as a transporter or receptor, after crossing the blood–brain barrier, allowing accurate tracking of changes in their function. PET now has a wide range of radiolabeled biomarkers for neuroimaging in psychiatry and neurodegenerative diseases like Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD).
PET has been used in HD to investigate metabolic markers of hypo-metabolism, dopaminergic function, microglial activation, and the expression of the PDE10A enzyme [103]. However, similar research have been conducted in small numbers, with mixed results. PET scanning is also more expensive than volumetric or diffusion MRI, generally is less available for large multicenter studies, and is more invasive because it uses ionizing radiation. PET, on the other hand, has the advantage of being able to provide more detailed information about pathological processes, and a future use of PET as a biomarker for target engagement in smaller proof-of-concept or phase 1 trials is in the horizon. PET was recently used to demonstrate effective target engagement of a new PDE10A inhibitor after a single dosage, paving the way for continued clinical development into a phase 2 trial [104]. Amyloid PET has shown promise in both experimental and clinical studies of Alzheimer’s disease [105] and a ligand capable of binding a pathogenic form of mutant huntingtin protein could be a useful PET biomarker for relevant pathology and regional brain tissue target engagement in huntingtin lowering studies [106].
Computational methods such as machine learning techniques are very useful tools in helping and improving the diagnosis as well as the disease monitoring process. A recent review study [107] concentrated on artificial intelligence in neurodegenerative diseases such as Huntington’s disease and others in which the authors reviewed the available tools with focus on machine learning techniques. Many authors have concentrated on Huntington’s disease alone using artificial intelligence and machine learning techniques [108, 109, 110]. More details on using artificial intelligence and machine learning techniques in the diagnosis and monitoring of Huntington’s disease will be reviewed alone later in a future publication.
As Huntington’s disease is not a preventable or curative disease, the availability of a diagnostic, prognostic, or response biomarker will have significant importance either in premanifest or manifest stage. Reliable biomarkers are needed either to delay/prevent the appearance of symptoms, slow the progression of the disease, and/or to monitor response to the therapy.
The identification of imaging and other measurements that have the ability to monitor and predict disease progression and therapy response has recently progressed in HD biomarker research. The most promising of them appear to be suitable for providing target engagement and efficacy readouts in premanifest HD or at short intervals. Such biomarkers may be verified as surrogate endpoints or even in the clinical context to guide prognostic discussions and treatment decisions in HD in the future as viable medicines become available. This promise will be realized through ongoing efforts to standardize methodology and reproduce findings in large-scale cohorts.
The authors declare no conflict of interest.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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This chapter aims to redefine what identity is as a concept and the impact of globalization on contemporary architecture especially on regions with rich heritage and unique culture as the Arab World. To accomplish this, the chapter examines the emergence of “local identity” as a reaction to the globalization of cultural values, uniform architectural styles, and stereotype patterns through discussing sustainability as a motivation for identity in culture and architecture. The research methodology is based on conducting a qualitative analysis of literature review to the main concepts discussed in this chapter such as: identity, culture, vernacular architecture, and sustainability. 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This change influences one another at various temporal and spatial scales; however, improper land uses are the primary causal factor on climate change. It studies relevant literature and Nepal’s case to assess the relationship between land use and climate change. Similarly focuses on how land-use impacts climate change and vice versa. In recent centuries land-use change significant effects on ecological variables and climate change. 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Meanwhile, decision-making periods of location choice and determining areal densities are conducted without quantitative spatial/technical analyses. Those urban matters bring along new planning paradigms like smart growth (SG) and new urbanism. SG is a land use planning paradigm which indicates that traffic problems should be minimized by transit alternatives, effective demand management and providing a balance between land use and transportation planning. This study aims to apply SG strategies to the land use planning process and evaluate the accuracy of land use planning decisions in the perspective of sustainable transportation. In order to reveal the effects of land use planning decisions on the available transportation infrastructure, two scenarios are investigated for 2030. In the first scenario “do nothing” option is considered, while the residential area densities and trip generation rates are regulated based on SG strategies in the second scenario. 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She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/12955",hash:"",query:{},params:{id:"12955"},fullPath:"/chapters/12955",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()