matrix metalloproteinases ( mmps ) ( zinc - dependent proteinases ) play important roles in extracellular matrix ( ecm ) remodelling in physiological and pathological processes [ 16 ] . the ecm is not only a mechanical support for its constituent cells , but also participates in the regulation of metabolism and in the exchange of information with the environment . to accomplish these functions , the imbalance between decay and renewal of ecm is characteristic of most pathologies as their primary or secondary cause [ 7 , 8 ] . matrix metalloproteinases are not only able to cleave all the constituents of ecm proteins , but also to activate or deactivate other numerous  signalling  molecules , such as receptors , adhesion molecules and growth factors [ 1 , 5 , 9 , 10 ] . matrix metalloproteinase-9 ( mmp-9 ) , a typical ecm protease ( gelatinase ) , is characterized by a wide range of substrates in vitro [ 4 , 6 ] . recently , a convincing support for the involvement of mmp-9 in inflammation , autoimmune diseases , cancer metastases and physical injuries has been reported . recent studies have also focused on the relationship of mmp-9 with the neurological disorders in adults , and its possible role in the reorganisation of ecm after injuries of the nervous system . brain barrier [ 1115 ] , and its level can be assessed in the plasma [ 1719 ] . the data focus an potential association of mmp-9 with depression , schizophrenia and bipolar disorder in adults . many studies indicate that cognitive dysfunctions may be associated with changes in mmp-9 activity [ 11 , 17 , 2224 ] , and show the importance of mmp-9 in cognitive dysfunctions of adult patients with dementia [ 19 , 25 ] , cerebral ischemia [ 11 , 13 , 14 , 17 ] or neuropsychiatric symptoms in autoimmune diseases . so far , no studies have been conducted on the relationship of mmp-9 and cognitive function in children with attention deficit / hyperactivity disorder and hyperkinetic disorder ( adhd / hkd ) . cognitive deficits and behavioural symptoms in adhd have been studied intensely and are well documented [ 2634 ] . they are classified according to dsm - ivr   and dsm - v , or icd-10 . the cognitive symptoms of adhd cover two domains : inattention and hyperactivity / impulsivity . in the version of dsm - ivr or dsm - v , three subtypes have been proposed and evaluated : adhd predominately inattentive , predominately hyperactive / impulsive ( if symptoms involve only one domain ) or combined . according to icd-10 , hkd can be diagnosed when symptoms belonging to all the domains are observed , including inattention , hyperactivity and impulsivity . neuropsychological studies concerning adhd show a variety of cognitive deficits , altered level of motivational processes and irregularities in the stages of processing and storage of information in the brain [ 3033 , 3840 ] . intellectual and neuropsychological abilities in adhd have been investigated for many years [ 4143 ] . children with adhd exhibit a wide range of performance deficits across a range of neuropsychological domains , including response inhibition , working memory , planning , sense of time , sustained attention , and verbal learning [ 28 , 3133 , 4345 ] . many studies have attempted to determine the characteristic profiles of the intellectual capacity of children with adhd [ 27 , 42 , 46 , 47 ] . children with adhd have a lower overall level of intellectual ability than their healthy peers [ 27 , 32 , 43 , 47 ] , but a similar decrease is also observed in children with other neuropsychiatric disorders [ 42 , 46 ] . several studies also point to a difference between verbal and performance iq in children with adhd as compared with healthy children [ 27 , 40 , 46 , 47 ] , whereas others provide contradictory results regarding these cognitive aspects [ 40 , 42 , 48 ] . research to date could not fully explain neuropsychiatric deficits in the functioning of children with adhd and their response to treatment . differences in the research paradigms along with the heterogeneity of the disease phenotypes are , at least partly , responsible for the problem . despite of intense research in recent decades , the brain processes and mechanisms which underlie the cognitive deficits of adhd are unclear . it can be assumed , that the reorganization of the brain responsible for behavioural and cognitive symptoms of adhd / hkd , and changes in the activity of mmp-9 may be the result of ecm reconfiguration in this disorder . to date , serum mmp-9 levels in children with adhd / hkd have not been studied . therefore , the aim of this study was to evaluate associations between serum mmp-9 levels and the symptoms severity in children with adhd / hkd . we hypothesized that the activity of mmp-9 may be related to intensity of symptoms and the degree of cognitive dysfunction in children with adhd / hkd . the study group comprised 37 caucasian boys with combined adhd subtype and hkd , aged between 7 and 12  years ( median 9.2  years ; 25th percentile7 and 75th percentile 11  years ) . the study group was selected among patients with hyperactivity symptoms from primary care , who had been referred to the specialized psychiatric diagnosis and therapy at the child and adolescent psychiatry unit of the university children s hospital in bialystok ( poland ) . the presence of several inattentive or hyperactive , impulsive symptoms in two or more situation ( at home , school , in other activities ) is required for the diagnosis of adhd / hkd [ 3537 ] . attention deficit / hyperactivity disorder symptoms at study baseline were measured using the nichq vanderbilt assessment scale for parent ( vadprs ) and for teacher ( vadtrs ) , each of which being divided into two sections : symptoms and performance . the vadprs contains 47 items , and vadtrs includes 35 items of symptoms and 8 items of performance . the construction of the toolkit is based on the diagnostic and statistical manual of mental disorders , fourth edition ( dsm - iv ) , and includes the 18 adhd items ( 9inattention and 9hyperactive / impulsive symptoms ) , and as well as a screen for the following coexisting conditions : oppositional - defiant disorder , conduct disorder , anxiety and depression . =  never , 1  =  occasionally , 2  =  often , and 3  =  very often ) , whereas the 5-point likert scale assesses performance ( i.e. , 1  =  excellent , 2  =  above average , 3  =  average , 4  =  somewhat of a problem , 5  =  problematic ) . for combined inattention / hyperactivity subtype , at least six of nine items of inattention and at least six of nine items of hyperactive / impulsivity need to score two or three points , with at least one of performance questions scoring four or five points . the internal consistency and structure of the vanderbilt assessment scales are acceptable and consistent with dsm - iv and other accepted measures of adhd  [ 50 , 51 ] . this toolkit has recommendations of american academy of pediatrics as a framework for diagnostic decision making in a child 612  years old . the diagnosis of combined adhd subtype was ascertained using current dsm - iv criteria , stating that one must have at least six positive responses to either the inattentive nine and six out of nine items on hyperactive / impulsive nine core symptoms . the diagnosis of hkd was performed according to the criteria of icd-10 , requiring symptoms of three domains ( at least six of nine items of inattention , at least three of five items of hyperactive and at least one of four of impulsivity ) . in the study group , these symptoms were present before the child reached 7  years of age , in a number of situations , continued on regular basis for more than 6  months and significantly impaired the child s academic and social functioning . for the study , the 18 adhd items were examined by separating symptoms into subscales of inattention , hyperactivity and impulsivity . mean ( sd ) subscale scores were computed across each rate for each symptom domain . each examination comprised observation of the family and other informants , attention being paid to parents / guardians personality traits and attitudes to the child , relationships of parents , the child s behaviour towards his / her parents / guardians , the child s behaviour and spontaneous play and group functioning . exclusion criteria of the study were the coexistence of other psychiatric or neurodevelopmental disorders ( e.g. autistic spectrum , obsessive  compulsive , oppositional - defiant , conduct disorders , anxiety , depression , tics ) , epilepsy , mental retardation and somatic diseases . all participants in the study were administered the wechsler intelligence scale for children - revised ( wisc - r , polish adaptation ) . wechsler intelligence scale for children - revised includes verbal ( subtests : general information , similarities , arithmetic , vocabulary , understanding ) and performance ( subtests : picture completion , picture arrangement , block design , object assembly , coding - digit symbol ) scales . raw scores obtained in subtests results were restated for conversion in accordance with the standards of the corresponding age group . the sum of the results converted from individual subtests create an overall score for the verbal and performance scales . the values corresponded to the amount of iq results translated into verbal scales , wordless , and full of different age groups . in addition to the standard deviation scores of these subtests , verbal intelligence scale , performance scale , and full - scale iq coefficients were calculated . venous blood samples of each child with adhd were taken during the run psychiatric and psychological diagnosis . after centrifugation , the serum was frozen and stored at 70  c until the time of the signs . matrix metalloproteinase-9 activity in the serum was determined by elisa , using a kit human elisa system biotrak ( ge healthcare , amersham biosciences ) and expressed in g / l . to minimize assay variance , serum levels of mmp-9 from each subject the assay was based on a two - site elisa sandwich format using two antibodies directed against different epitopes of mmp-9 . protocols were performed according to the manufacturer s instructions . the sensitivity defined as two standard deviations above the zero dose binding was determined as 0.6  g / l , assay range 4128  g / l . all statistical analyses were performed using the statistica 10.0 pl ( statsoft ) . since many variables were not normally distributed according to the shapiro wallis test with post hoc test , mann  whitney u test and spearman s rank correlation . the values of the variables are presented as mean    sd or median , first and third quartile . the study was approved by the ethical committee of the medical university of bialystok , in accordance with the principles of guidelines for good clinical practice r - i/003/168 . the study group comprised 37 caucasian boys with combined adhd subtype and hkd , aged between 7 and 12  years ( median 9.2  years ; 25th percentile7 and 75th percentile 11  years ) . the study group was selected among patients with hyperactivity symptoms from primary care , who had been referred to the specialized psychiatric diagnosis and therapy at the child and adolescent psychiatry unit of the university children s hospital in bialystok ( poland ) . the presence of several inattentive or hyperactive , impulsive symptoms in two or more situation ( at home , school , in other activities ) is required for the diagnosis of adhd / hkd [ 3537 ] . attention deficit / hyperactivity disorder symptoms at study baseline were measured using the nichq vanderbilt assessment scale for parent ( vadprs ) and for teacher ( vadtrs ) , each of which being divided into two sections : symptoms and performance . the vadprs contains 47 items , and vadtrs includes 35 items of symptoms and 8 items of performance . the construction of the toolkit is based on the diagnostic and statistical manual of mental disorders , fourth edition ( dsm - iv ) , and includes the 18 adhd items ( 9inattention and 9hyperactive / impulsive symptoms ) , and as well as a screen for the following coexisting conditions : oppositional - defiant disorder , conduct disorder , anxiety and depression . =  never , 1  =  occasionally , 2  =  often , and 3  =  very often ) , whereas the 5-point likert scale assesses performance ( i.e. , 1  =  excellent , 2  =  above average , 3  =  average , 4  =  somewhat of a problem , 5  =  problematic ) . for combined inattention / hyperactivity subtype , at least six of nine items of inattention and at least six of nine items of hyperactive / impulsivity need to score two or three points , with at least one of performance questions scoring four or five points . the internal consistency and structure of the vanderbilt assessment scales are acceptable and consistent with dsm - iv and other accepted measures of adhd  [ 50 , 51 ] . this toolkit has recommendations of american academy of pediatrics as a framework for diagnostic decision making in a child 612  years old . the diagnosis of combined adhd subtype was ascertained using current dsm - iv criteria , stating that one must have at least six positive responses to either the inattentive nine and six out of nine items on hyperactive / impulsive nine core symptoms . the diagnosis of hkd was performed according to the criteria of icd-10 , requiring symptoms of three domains ( at least six of nine items of inattention , at least three of five items of hyperactive and at least one of four of impulsivity ) . in the study group , these symptoms were present before the child reached 7  years of age , in a number of situations , continued on regular basis for more than 6  months and significantly impaired the child s academic and social functioning . for the study , the 18 adhd items were examined by separating symptoms into subscales of inattention , hyperactivity and impulsivity . mean ( sd ) subscale scores were computed across each rate for each symptom domain . each examination comprised observation of the family and other informants , attention being paid to parents / guardians personality traits and attitudes to the child , relationships of parents , the child s behaviour towards his / her parents / guardians , the child s behaviour and spontaneous play and group functioning . exclusion criteria of the study were the coexistence of other psychiatric or neurodevelopmental disorders ( e.g. autistic spectrum , obsessive  compulsive , oppositional - defiant , conduct disorders , anxiety , depression , tics ) , epilepsy , mental retardation and somatic diseases . all participants in the study were administered the wechsler intelligence scale for children - revised ( wisc - r , polish adaptation ) . wechsler intelligence scale for children - revised includes verbal ( subtests : general information , similarities , arithmetic , vocabulary , understanding ) and performance ( subtests : picture completion , picture arrangement , block design , object assembly , coding - digit symbol ) scales . raw scores obtained in subtests results were restated for conversion in accordance with the standards of the corresponding age group . the sum of the results converted from individual subtests create an overall score for the verbal and performance scales . the values corresponded to the amount of iq results translated into verbal scales , wordless , and full of different age groups . in addition to the standard deviation scores of these subtests , verbal intelligence scale , performance scale , and full - scale iq coefficients were calculated . venous blood samples of each child with adhd were taken during the run psychiatric and psychological diagnosis . after centrifugation , the serum was frozen and stored at 70  c until the time of the signs . matrix metalloproteinase-9 activity in the serum was determined by elisa , using a kit human elisa system biotrak ( ge healthcare , amersham biosciences ) and expressed in g / l . to minimize assay variance , serum levels of mmp-9 from each subject the assay was based on a two - site elisa sandwich format using two antibodies directed against different epitopes of mmp-9 . protocols were performed according to the manufacturer s instructions . the sensitivity defined as two standard deviations above the zero dose binding was determined as 0.6  g / l , assay range 4128  g / l . all statistical analyses were performed using the statistica 10.0 pl ( statsoft ) . since many variables were not normally distributed according to the shapiro wilk test , the analysis used non - parametric tests : the kruskal  wallis test with post hoc test , mann  whitney u test and spearman s rank correlation . the values of the variables are presented as mean    sd or median , first and third quartile . the study was approved by the ethical committee of the medical university of bialystok , in accordance with the principles of guidelines for good clinical practice r - i/003/168 . both models ( hkd and combined adhd subtype ) were identified in every boy in the study group . total scores were similar for the clinical model of hkd ( mean    sd : 14.68    2.00 ; median 14 , first and third quartile:1416 ) and adhd ( mean    sd : 14.76    1.62 ; median 14 , first and third quartile:1416 ) . no significant differences were noted between the average values of vadprs ( mean    sd : 39.95    6.81 ) and vadtrs ( mean    sd : 38.14    6.14 ) in the study group . there were significant positive correlations between icd-10 and dsm - iv symptoms ( rs  =  0.95 ; p  <  0.001 ) and vadprs ( rs  =  0.69 ; p  =  0.001 ) ( table  1 ) . the number of hyperactivity symptoms of hkd correlated significantly with hyperactivity / impulsivity of adhd ( rs  =  0.76 ; p  <  0.001 ) , however the relationship between the impulsivity of hkd and adhd domain was not significant ( rs  =  0.32 ; p  =  0.06 ) . there was a highly significant correlation between inattention of hkd and inattention of adhd ( rs  =  0.98 ; p  <  0.001 ) ( table  1).table  1cognitive domains and intellectual functions in boys with hkdmean ( sd)hkd modelinattentionhyperactivityimpulsivity 
 r 
 s 

 p * * * 
 r 
 s 

 p * * * 
 r 
 s 

 p * * * icd ( total)14.68 ( 2.00)0.82**<0.0010.70**<0.0010.38 * 0.019inattention7.11 ( 1.17)10.320.24impulsivity3.16 ( 0.73)0.240.101hyperactivity4.43 ( 1.12)0.3210.10combined adhd subtype  dsm - iv ( total)14.76 ( 1.62)0.89**<0.0010.56**<0.0010.35 * 0.03  inattention7.03 ( 1.14)0.92**<0.0010.260.27  hyperactivity / impulsivity7.73 ( 0.87)0.76**<0.0010.32vadprs ( total)39.95 ( 6.81)0.73**<0.0010.35 * 0.030.26inattention19.29 ( 4.31)0.74**<0.0010.080.25hyperactivity / impulsivity20.68 ( 3.57)0.50**0.0010.61**<0.0010.20vadtrs ( total)38.14 ( 6.14)0.190.050.08inattention19.27 ( 3.68)0.230.040.09hyperactivity / impulsivity19.03 ( 3.81)0.220.060.10total iq98.43 ( 14.12)0.210.100.10verbal iq99.40 ( 15.31)0.110.130.02performance iq97.32 ( 14.41)0.060.010.30information10.38 ( 3.34)0.090.120.15similarities10.32 ( 2.68)0.010.150.06arithmetic8.95 ( 3.47)0.060.040.07vocabulary10.00 ( 3.59)0.42**0.010.210.15comprehension10.14 ( 2.18)0.49**0.0020.050.22picture completion10.49 ( 1.74)0.050.100.08picture arrangement10.57 ( 2.90)0.030.190.05block design9.27 ( 3.39)0.020.040.28object assembly9.32 ( 2.69)0.040.190.07coding - digit symbol8.05 ( 3.06)0.310.120.32the comparison of dsm - iv to icd-10 . statistical coherence of values was determined by spearman s rank correlation test . the statistical correlation between intellectual functions and domains of hkd was determined by spearman s rank correlation test 
 r 
 s spearman s rank correlation coefficient * significant correlation at the 0.05 level ( two - sided ) * * significant correlation at the 0.01 level ( two - sided ) cognitive domains and intellectual functions in boys with hkd the comparison of dsm - iv to icd-10 . statistical coherence of values was determined by spearman s rank correlation test . the statistical correlation between intellectual functions and domains of hkd was determined by spearman s rank correlation test 
 r 
 s spearman s rank correlation coefficient * significant correlation at the 0.05 level ( two - sided ) * * significant correlation at the 0.01 level ( two - sided ) the median values of the total iq-98 ( 25th75th percentile : 90106 ) , the verbal iq-102 ( 25th75th percentile : 91108 ) and the performance iq-90 ( 25th75th percentile : 87106 ) were determined in all the study subjects . the vocabulary subtest and the comprehension subtest with the inattention domain showed a negatively significant correlation ( rs  =  0.42 ; p  =  0.01 and 0.49 ; p  =  0.002 , respectively ) ( table  1 ) . the mean ( sd ) of mmp-9 levels 49.13 ( 15.86 )  g / l and median of mmp-9 levels 50.82  g / l ( 25th percentile43.14  g / l ; 75th percentile56.34  g the general regression models ( grm ) were used to assess the effect of mmp-9 on hkd / adhd symptoms ( table  2 ) . the mmp-9 levels were significantly associated with symptoms severity of hkd and of adhd (   =  0.34 ; p  =  0.037 and   =  0.33 ; p  =  0.043 , respectively ) ( fig . 1a , b ) . furthermore , serum mmp-9 concentrations correlated with increase impulsiveness (   =  0.38 ; p  =  0.019 ) ( fig .  2a , b).table  2mmp-9 levels in relation to cognitive domains of hkd / adhd 
 b 
 se95  % ci 
  

 p 
 hkd  mmp-90.0430.020.0030.084 
 0.34 * 

 0.037*inattention  mmp-90.0210.0120.0030.0450.290.085hyperactivity  mmp-90.0040.0120.0210.0280.050.770impulsivity  mmp-90.0180.0070.0030.032 
 0.38 * 

 0.019*adhd  mmp-90.0340.0160.0010.067 
 0.33 * 

 0.043*innatention  mmp-90.0210.0110.0020.0450.290.075hyperactivity / impulsivity  mmp-90.0120.0090.0050.0310.240.160 
 -standardized regression coefficient parameterization of sigma limits 
 b regression coefficient , se standard error , ci confidence intervals * regression model statistically significant p  <  0.05fig . 2mmp-9 levels and impulsivity mmp-9 levels in relation to cognitive domains of hkd / adhd 
 -standardized regression coefficient parameterization of sigma limits 
 b regression coefficient , se standard error , ci confidence intervals * regression model statistically significant p  <  0.05 the symptom severity and mmp-9 levels in boys with hkd / adhd mmp-9 levels and impulsivity analysis of the relationship between serum activity of mmp-9 and wisc - r subtests quotient measurements revealed no correlation . there was no relationship between age and the level of mmp-9 in the study group . to our best knowledge , this is the first study to assess the levels of mmp-9 in children with hkd / adhd , and to investigate the correlation of mmp-9 with the cognitive function and symptoms severity . a certain limitation of our study was small group size . however , our intention was to include children with a very similar phenotype of hkd / adhd . in our study , the increased serum mmp-9 levels was correlated with the severity of symptoms in the hkd / adhd clinical model . based on the data , elevated levels of serum mmp-9 in boys with hkd children with adhd / hkd are incapable of to the self - control , reveal rapid unplanned reactions and difficulty of postponing award [ 54 , 55 ] . the concept of impulsivity domain for hkd in accordance with the icd-10 includes four symptoms , whereas the impulsivity is not a separate domain for adhd in dsm iv or dsm v [ 3437 , 57 ] . one of the four impulsivity symptoms for hkd :  talks excessively  is categorized as a symptom of hyperactivity in dsm - iv and dsm - v [ 36 , 37 ] . unclear conceptualization of the impulsivity domain may have influenced the differences in the correlation between serum mmp-9 levels and hkd - model or adhd - model in the study group . we found a significant negative correlation between severity of inattention and the vocabulary and comprehension subtests , which form verbal conceptual thinking ( can shape account for social intelligence , verbalization , memory recall ) [ 33 , 58 ] . it has been proved that the attention deficit is most disturbing factor in the social functioning of children with adhd / hkd . symptoms of inattention hinder to establish social relationships through observation and focus on the social factors , that are essential for supporting interaction [ 30 , 31 , 59 ] . most authors agree that children with a diagnosis of combined adhd subtype present with difficulties in the largest number of areas of cognitive and psychosocial functioning [ 32 , 40 , 41 , 44 , 47 ] , but the reasons for the existence of cognitive deficits in children with adhd / hkd are still unclear . recent pet brain imaging studies revealed , that the most da deficits were evident in the ventral striatum ( modulation of reward and motivation ) and in the midbrain ( where most da neurons are located ) , which supports the da hypothesis of adhd [ 61 , 62 ] , although the specific details are not yet clear . dopamine transporter dat , which is located in dendrites and axonal membrane , or activation of dopamine receptors may be responsible for dopamine levels [ 62 , 63 ] . although most studies have been focused on the prefronto - striatal system , others , concerned with psychopharmacology and neuroimaging ( mri , fmri ) of brain processes , have pointed to many cortical and subcortical brain regions implicated in adhd [ 6567 ] . furthermore , it has been recently shown that many neural networks are involved in cognitive and behavioural symptoms of adhd [ 6871 ] . researchers who have defined the pattern for typical brain development suggest that some childhood onset cases may be disorders of neuroplasticity [ 7274 ] . the plasticity is a property of the nervous system that provides the capability for adaptation , self - healing , learning and memory . the extracellular proteolysis by mmp-9 is important for the functional and structural synaptic plasticity [ 1 , 2 , 57 , 9 , 10 ] . matrix metalloproteinase-9 is expressed in the hippocampus , striatum , diencephalon , midbrain , cerebellum and frontal cortex of the rat [ 3 , 6 , 76 , 78 ] , with the greatest activity in the hippocampus [ 14 , 15 , 24 , 77 ] . the contribution of mmp-9 in addictions to methamphetamine [ 79 , 80 ] or cocaine   may suggest its role in dopamine neurotransmission . this enzyme , located in dendritic spines is responsible for the structural changes in synapses and thereby may be partly responsible for the improper regulation of extracellular dopamine levels . matrix metalloproteinase-9 is required for the formation of abnormal synaptic connections between hippocampal granule cell axons and their dendrites in rodent brain , and is also related to immature dendritic spine morphology . the level of this enzyme is elevated in fragile x syndrome ( fxs ) , in which inattention , impulsivity and hyperactivity are manifested beside autism , and administration of minocycline ( mmp-9 inhibitor ) to mouse model of fxs results in normalization of behaviours and a decrease in anxiety . despite the absence of clinical symptoms of asd in our study boys , according to research , inadequate social behaviours in children with adhd may be phenomenologically and etiologically related to autism spectrum disorders [ 84 , 85 ] . the mmp-9 concentration increases in inflammation , hypoxia or injuries of brain , where the blood  brain barrier is damaged [ 1117 , 86 ] . this leads to the hypothesis that prenatal environmental risk factors for adhd , such as viral infections , asphyxia , neurotoxins , alcohol or nicotine can affect the expression of mmp-9 , and consequently the long - term alteration in blood brain barrier permeability to small - molecular - weight markers [ 12 , 75 ] . another hypothesis is related to continuous disturbances in mmp-9 gene transcription by unknown specific factors , which may be supported by the result of mutation in fmr1gene ( leading to autism ) , in which the fmpr protein , natural of mmp-9 translation inhibitor , is missing . in the animal model ( fmfr1ko mice ) , though the relevant scientific studies gained great interest in recent decades , the etiopathogenesis and underlying mechanism of adhd / hkd remain still unclear . so far , laboratory , psychological or biological studies that could be specific enough to allow explicit in diagnosis of adhd / hkd have been missing . the structuralised interview and either icd-10 or dsm - iv / dsm - v are the fundamental elements of diagnosis . however , some variation in the domain of impulsivity may suggest difficulty in understanding the place for cognitive deficits in the clinical diagnosis of adhd / hkd . therefore , a genetic defect determines a certain predisposition to adhd / hkd but environmental factors contribute largely to the phenotype of the disorder [ 72 , 87 ] . the mechanism of the impact of unexplained environmental factors is not clear , but mmp-9 may be associated with the severity of symptoms . to understand the processes engaged in cognitive dysfunction in adhd / hkd , it is necessary to unravel signalling pathways , complex interaction networks and metabolic alterations involving many anatomical components . however , we are aware that the role of mmp-9 in neurodevelopmental damage still remains unclear , and the present study is the first to show the elevated levels of serum mmp-9 in boys with hkd correlated with severity of the disorder . the results indicate that the increased levels of serum mmp-9 in boys with hkd are associated with the clinical domain of impulsivity .
the serum levels of matrix metalloproteinase-9 ( mmp-9 ) in neuropsychiatric disorders of adults have been widely investigated . 
 so far , no studies have been conducted on the relationship of mmp-9 and cognitive domains in children with two phenotype models , attention deficit / hyperactivity disorder and hyperkinetic disorder ( adhd / hkd ) . 
 the aim of this research was to evaluate and test the hypothesis that serum mmp-9 levels are associated with the severity of symptoms in children with adhd / hkd and to compare the results in two models of this disorder . 
 the study group comprised 37 caucasian boys aged 712  years with hkd , being a subset of the combined adhd subtype . 
 intellectual functions were measured using wechsler intelligence scale for children - revised . 
 the analysis of serum concentrations of mmp-9 was based on a quantitative sandwich elisa . 
 the statistical regression analysis revealed a correlation between increased serum mmp-9 levels and severity of symptoms in the adhd (   =  0.33 ; p  =  0.043 ) and hkd (   =  0.34 , p  =  0.037 ) model . according to the results , elevated levels of serum mmp-9 in boys with hkd 
 may be associated with clinical impulsivity domain (   =  0.38 ; p  =  0.019 ) .