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Curr Psychiatry Rep (2014) 16:497
DOI 10.1007/s11920-014-0497-1
Abstract The etiology and pathogenesis of attention-deficit/ Vigilance/sustained attention . Executive functions .
hyperactivity disorder (ADHD) are unclear and a more valid Working memory . EEG Theta/Beta ratio
diagnosis would certainly be welcomed. Starting from the
literature, we built an hypothetical pyramid representing a
putative set of biomarkers where, at the top, variants in Introduction
DAT1 and DRD4 genes are the best candidates for their
associations to neuropsychological tasks, activation in specific The aetiology and pathogenesis of attention-deficit/hyperac-
brain areas, methylphenidate response and gene expression tivity disorder (ADHD) is not yet fully understood [1, 2].
levels. Interesting data come from the noradrenergic system ADHD is also a highly heritable disease, with estimated
(norepinephrine transporter, norepinephrine, 3-methoxy-4- heritability rates of up to 80 % [3]. A recent review on genetics
hydroxyphenylglycol, monoamine oxidase, neuropeptide Y) of ADHD summarized that all variants associated with the
for their altered peripheral levels, their association with neu- pathology explain only a small fraction of heritability: pheno-
ropsychological tasks, symptomatology, drugs effect and type complexity and variants of small effect contribute to the
brain function. Other minor putative genetic biomarkers could missing heritability issue [4]. To gain more insight into the
be dopamine beta hydroxylase and catechol-O-methyltrans- mechanisms leading from a genetic/biological basis of the
ferase. In the bottom, we placed endophenotype biomarkers. disease to the full clinical phenotype, endophenotypes are a
A more deep integration of omics sciences along with more promising strategy [5].
accurate clinical profiles and new high-throughput computa- The DSM and ICD diagnoses of ADHD are based on a
tional methods will allow us to identify a better list of bio- consensus about clusters of clinical symptoms. However, this
markers useful for diagnosis and therapies. diagnostic procedure has been criticized for not allowing
sufficiently reliable and valid diagnoses [6]. NIMH recently
Keywords Biomarkers . Attention-deficit/hyperactivity has approved the Research Domain Criteria (RDoC) project
disorder . Dopaminergic pathway . Noradrenergic pathway . where a set of assumptions permit to found a new classifica-
Metabolism enzymes . CNS developmental network . tion system, by integrating genetics, imaging and cognitive
Environmental risk factors . Endophenotypes . SLC6A3 . information [6]. The RDoC approach suggests that a biomarker
DRD4 . DBH . COMT . Reaction time variability . approach to diagnosis may be a more valid way to classify
complex mental disorders such as ADHD. Biomarkers offer the
opportunity to standardize and improve diagnostic assessment
This article is part of the Topical Collection on Attention-Deficit Disorder while providing insights into etiological mechanisms.
S. V. Faraone
Department of Psychiatry, SUNY Upstate Medical University,
Syracuse, NY, USA What is a Biomarker?
S. V. Faraone
Department of Neuroscience and Physiology, SUNY Upstate The United States food and drug administration (FDA) de-
Medical University, Syracuse, NY, USA fines a biomarker as an objective measure of normal process-
es, pathological processes or pharmacological response [7].
C. Bonvicini : C. Scassellati (*)
For psychiatry, biomarkers could be used to screen for, diag-
Genetic Unit - IRCCS Centro S. Giovanni di Dio Fatebenefratelli,
Via Pilastroni 4, 25123 Brescia, Italy noses, or predict the development of, not only psychiatric
e-mail: cscassellati@fatebenefratelli.it disorders but also of personality or behavioral traits and
497, Page 2 of 20 Curr Psychiatry Rep (2014) 16:497
RDoC domains. Biomarkers could potentially be used to between the 10R allele and ADHD [13], although a reverse
inform treatment decisions. association has been seen for ADHD adults [72].
Because no single biomarker candidate may be sufficient Kebir and Joober and Barnes et al. summarized DAT1 studies
for accurate and reliable diagnosis, the current trend in psy- of neuropsychological tasks [21, 22]. As regards the association
chiatry has shifted towards identifying sets of biomarkers [8, between attention tasks and the 10R allele, some studies showed
9, 10, 11]. For example, Pies et al. defined a set of bio- higher commission errors, more impulsive responses and greater
markers for schizophrenia comprising:-neuregulin-1 muta- reaction time variability (RTV) using the continuous performance
tions; -abnormal smooth-pursuit eye movements; -reduced test (CPT) and sustained attention to response test (SART). Other
anterior cingulate volumes, enlarged lateral and third ventric- studies reported no association or opposite results [21]. Moreover
ular volumes and white matters abnormalities [12]. boys scoring high on a teacher-rated report of ADHD symptoms
Despite their promise, the search for biomarkers of psychiatric and who were homozygous for the 10R allele displayed poorer
disorders has largely proven elusive. In a comprehensive review response inhibition on the opposite word task. Concerning execu-
[10], the authors concluded that according to their stringent tive functions, the 10/10 genotype predicted better performance on
criteria, no biomarker is available for diagnosing ADHD. the Tower of London (TOL), the self-order pointing task, and the
The main goal of this review is to present evidence for a Wechsler Intelligence Scale for Children-III (WISC-III) arithmetic
putative signature set of biomarkers for ADHD using geno- and digit span subtests. Associations between a neurocognitive
mic, neurophysiological/neuropsychological, neuroimaging, phenotype-spatial attentional bias and 10R allele was reported in
pharmacogenomic and proteomic knowledge to diagnose children with ADHD [73, 74]. The attentional phenotype (left-
ADHD. In Table 1 we report data from genomics and meta- sided inattention) was related to higher symptom severity [74].
bolomics classified according to neurophysiological/neuro- Several studies have been conducted on neuroimaging and 3
psychological, neuroimaging, pharmacogenomic, biochemi- UTR VNTR variant in ADHD. Genotype 10/10 individuals
cal and gene expression findings. Table 2 presents data from were found to generate more activations corresponding to inhi-
endophenotypes studies to define a further potential signature bition tasks, showing also its interaction with diagnostic status
set of biomarkers useful for ADHD diagnosis. (ADHD vs. controls) [15]. Moreover on non-ADHD siblings of
ADHD probands and controls, an influence was observed be-
tween the variant and the activation in striatum and cerebellum
Potential Dopaminergic Biomarkers for ADHD vermis, with its interaction with familial risk for ADHD [18].
Similarly in another study, 10/10 individuals were more activat-
Genomics ed in left striatum, right dorsal premotor cortex, and bilateral
temporoparietal junction [20]. In contrast, Congdon et al. ob-
Deficiencies of dopaminergic and noradrenergic neurotrans- served greater neural activation associated with carriers of the 9R
mitter systems have been associated with ADHD and the main [23]. Finally caudate volumes were overall smaller in 10/10 than
symptoms of ADHD, but the dopamine system has been the 9/10 children, particularly in the left than right hemisphere [14].
main focus of genomic research [69]. Positron emission tomography (PET) and single photon
emission tomography (SPECT) have been used to determine
Dopamine Transporter Gene (DAT1, SLC6A3) if ADHD patients show abnormal activity of the DAT in
striatum. In a meta-analysis of these studies, Fusar-Poli et al.
There are at least four main reasons for a central role of DAT1 in concluded that DAT activity was 14 % higher in ADHD
ADHD genetics: 1) dopaminergic neurotransmission is con- patients compared with controls [24]. A meta-analysis of neu-
trolled by the DAT1 protein; 2) the DAT1 protein is the main roimaging studies of humans found that the 9R allele was
target for two ADHD medications: methylphenidate (MPH) and associated with increased DAT activity in striatum [75]. This
amphetamine (AMP); 3) knockout mice for DAT1 show hyper- study was conducted considering different neuropsychiatric
activity and deficits in inhibitory behavior [69]; 4) DAT1 has illnesses and this strengths the issue that VNTR polymorphism
been mapped near to a susceptibility locus for ADHD, 5p13 [70]. regulates dopamine activity in the striatal brain regions not only
The most studied DAT1 variant is a variable number of tandem in presence of ADHD but also of other disorders
repeats (VNTR) of 40 base pairs located at the 3-untranslated A recent review on neuroimaging and pharmacogenetics
region (3-UTR) of the gene. The ten repeat (10R) and nine reported some studies on DAT1 [25]. In particular an asso-
repeat (9R) alleles are the most common. It has been demon- ciation with 10R was found with higher regional cerebral
strated that the DAT density measured in vivo using neuroimag- blood flow in medial frontal and left basal ganglia regions,
ing was significantly higher in ADHD children with homozy- and with poorer treatment response, in children with ADHD
gosity for the 10R in basal ganglia, a brain area participating in receiving MPH for 4 days before SPECT imaging session.
inhibitory behaviors. This suggests a functional effect of the 10R Moreover this allele was associated with greater DAT avail-
allele [71]. A recent meta-analysis demonstrated an association ability in basal ganglia following treatment and poorer
Table 1 Data from genomic and metabolomic studies classified according to neurophysiological/neuropsychological, neuroimaging, pharmacogenomic, biochemical and gene expression findings
Systems Potential biomarker Gene function/rationale Location, polymorphism, Meta-analysis (OR, 2, GWAS/ Neuropsychological
risk allele, functionality p value) CNVs endophenotypes
studies
Genomics Dopaminergic system Dopamine transporter 3-UTR, VNTR, 10R, 1.12, 3.66, 0.028 [13] -Sustained Attention: some
(DAT1, SLC6A3) higher expression levels studies showed association
of the transporter 10R and higher commission
errors, more impulsive
responses, greater RTV on
CPT, SART. Other studies
Curr Psychiatry Rep (2014) 16:497
reported no association or
opposite results.
Encodes a transmembrane -Executive functions:
transport protein mediating association 10R with
the active reuptake of DA good performance on
from the synapse and serves TOL, SOPT, WISC-III,
as a critical regulator of digit span subtests.
dopaminergic
neurotransmission in the
brain.
1) dopaminergic neurotransmission -Response inhibition:
is controlled by the DAT1; association 10R allele and
2) it is the main target for MPH; poorer response inhibition
on the Opposite Word Task;
3) DAT1 knockout mice lead to -Association 10R and spatial
suggestive behavior of attentional bias [reviews 21,
ADHD; 22].
4) maps near a susceptibility Intron VIII, VNTR, 3R 1.25, 3.35, 0.034 [13]
locus . Intron, rs403636, Intron, -Association haplotype
rs463379, Intron, rs403636 (G)/rs463379 (C)/
rs393795, Intron, rs393795 (C)/rs37020 (G)
rs37020 and spatial working memory
[28].
Exon, rs6350 -Association with alerting and
executive control
performance [29].
Dopamine D4 receptor A member of the dopamine D2- Exon III, VNTR, 7R, less 1.35, 5.10, <0.0001 -Association 7R with speed of
(DRD4) like receptor family inhibiting responsive to DA. [13, 30] processing, set shifting, and
adenylyl cyclase. Expressed cognitive impulsiveness ;
in frontal lobe regions
(orbitofrontal cortex and
anterior cingulated regions).
It was the first associated with -Association absence 7R with
novelty-seeking personality high RTV ;
trait - no effect on response
inhibition [reviews 21, 22].
Dopamine D2 receptor A member of the dopamine D2- 3Flank, rs18000497 (TaqI), 1.65, 2.56, 0.11 [13]; [34]
(DRD2) like receptor family. T (A1 allele), reduced
Expressed in neostriatum, DRD2 expression. 1.65, 2.18, 0.03 [30]
olfactory tubercle, substantia
Page 3 of 20, 497
Table 1 (continued)
Systems Potential biomarker Gene function/rationale Location, polymorphism, Meta-analysis (OR, 2, GWAS/ Neuropsychological
risk allele, functionality p value) CNVs endophenotypes
studies
497, Page 4 of 20
Systems Potential biomarker Gene function/rationale Location, polymorphism, Meta-analysis (OR, 2, GWAS/ Neuropsychological
risk allele, functionality p value) CNVs endophenotypes
studies
receptor (ADRA2A) Encodes alpha-2A-adrenergic G, functional 1.077, 0.20, 0.65 [45] TMT, RTVon different tasks
receptors regulating [review 21].
neurotransmitter release from
sympathetic nerves and from
adrenergic neurons.
Metabolomics Influences executive functions 3-UTR, rs553668 (DraI), 0.94, 0.12, 0.638 [13] -Association with performance
in the prefrontal cortex. T in TMT [review 21].
Epinephrine (EPI) Neuroimaging and animal
studies support alteration in
EPI in ADHD.
Metanephrine (M) Main metabolite of EPI.
Metabolism enzymes Catechol-O- Enzyme catalyzing the Exon IV, rs4680 (158Val/ -, 1.02, 0.7267 [48] -interaction: COMT(val/val)-
methyltransferase inactivation of DA within the Met), valine, higher MAOA(3R) and high
(COMT) PFC. Expressed in frontal activity intelligence [49].
lobe regions of brain.
It regulates synaptic DA levels.
Genomics/ Monoamine oxidase A Encodes a protein involved in Promoter, 30-bp VNTR, 2- 1.02, 0.01, 0.464 [13] -Association 4- and 5R alleles
metabolomics (MAOA) the metabolism of DA, 5-HT, and 3-R are considered with more commission
and NE. low-activity alleles errors [54];
-Interaction: COMT(val/val)-
MAOA(3R) and high
intelligence [49].
It is associated to impulsive, Intron, rs12843268, A, -Gender-specific association ATT
aggressive behavior. haplotype and poor motor
MAOA knockout mouse Intron, rs3027400, T, control (boys), visuo-spatial
showed increased levels of Exon, rs1137070, T working memory (girls) [55];
aggressive behavior and -Association of rs12843268
monoaminergic and symptoms and reward
neurotransmitter levels. deficiency or insufficient
response inhibition [56].
Dopamine Beta Catalyzes the conversion of DA Intron V, rs2519152 (TaqI), 1.12, 0.43, 0.206 [13] -Association A2/T allele with
Hydroxylase (DBH) into NE. T/A2 allele, associated poorer performances on
with reduced DBH temporal order judgment
activity task, more commission and
omission errors and greater
RTV (on the SART), more
errors on the WCST
(problem-solving) and the
Page 5 of 20, 497
MFFT (cognitive
impulsiveness).
Table 1 (continued)
Systems Potential biomarker Gene function/rationale Location, polymorphism, Meta-analysis (OR, 2, GWAS/ Neuropsychological
risk allele, functionality p value) CNVs endophenotypes
studies
497, Page 6 of 20
Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes
Dopamine transporter -Association 10R with -Association 10R and more -Association 10R and increased
(DAT1, SLC6A3) smaller caudate volumes activations corresponding to MPH response, but also
particularly in the left inhibition tasks [15]; contrasting results [reviews
than right hemisphere 16, 17];
[14]. -Association 10R and activation -No association 10R and MPH
in striatum and cerebellum response [meta-analysis
vermis [18]; [19].
-Association 10R and activation
Curr Psychiatry Rep (2014) 16:497
Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes
Dopamine D4 receptor -Association 7R with - lower mRNA expression - Association 7R and increased
(DRD4) thinner prefrontal and levels [31]. MPH response, but also
parietal cortex; contrasting results;
-Association 7R with a -Association 4R and positive
delay in cerebral cortical linear improvement on
maturation [32, 33]. mathematics test outcomes
with increasing MPH dose,
absence 4R decreased
responses to higher MPH
doses;
-Association 4R and picking
behaviors, 7R with social
Page 7 of 20, 497
Table 1 (continued)
Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes
MPH doses.
[reviews 16, 17].
Dopamine D2 receptor -No association with MPH
(DRD2) response [35].
Dopamine D5 receptor
(DRD5) -No association with MPH
response [37].
Phenylethylamine (PEA) -Reduced urine levels in ADHD -Normalization after AMP and
[meta-analysis 39]. MPH [39].
Dopamine (DA) -No alteration in urine levels in
ADHD [meta-analysis 39].
Homovanillic acid (HVA) -No alteration in urine levels in
ADHD [meta-analysis 39].
Norepinephrine -Small influence on MPH
transporter protein 1 response [review 17];
NET (SLC6A2) -Association G allele with
greater decrease in mean
omission error scores after
MPH administration
compared to A allele carriers
[40, 41].
Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes
non-remission of ADHD
symptoms with atomoxetine
treatment [47].
Epinephrine (EPI) -No peripheral alterations in
ADHD [meta-analysis 39].
Metanephrine (M) -Higher urinary levels in
ADHD, lost after bonferroni
correction [meta-analysis
39].
Catechol-O- -Association with -Association Val allele and MPH
methyltransferase antisocial and response [52, 53].
(COMT) aggressive
behaviors of
ADHD [50, 51].
Monoamine oxidase A -Reduced platelet levels in -Normalization after MPH
(MAOA) ADHD [meta-analysis [39]. treatment [39].
Brain-Derived -Higher plasma levels in ADHD -Association Val allele and MPH
Neurotrophic Factor [58]; response [59].
(BDNF) -no alteration in serum levels in
ADHD [60].
Synaptosomal-associated -Association T allele with
protein 25 (SNAP-25) improved MPH responses;
-Association G allele with sleep
difficulties and irritability
[37].
-Association T allele and poorer
MPH response;
-Association C allele with tics
and other abnormal
movements [37].
Ferritin (iron store) -Reported reduced serum levels
in ADHD, lost after
Page 9 of 20, 497
497, Page 10 of 20 Curr Psychiatry Rep (2014) 16:497
Note: ADHD: Attention-deficit/hyperactivity disorder; OR: Odd Ratio; 2 : chi-square; VNTR: Variable number tandem repeat; UTR: Untranslated region; MPH: methylphenidate; DA: Dopamine;
SART: Sustained attention to response test; TOL: Tower of London test; WISC-III: Wechsler intelligence scale for children-III; SOPT: Self ordered pointing Test; FDI: Freedom from distractibility index;
WGAS: Genome Wide Association study; CNVs: Copy number variations; MRI: Magnetic resonance imaging; TMT: Trail making test; RTV: Reaction time variability; CPT: Continuous performance test;
Pharmacogenetics/drugs effect
treatment response in children with ADHD who completed 8 weeks
of MPH treatment. In particular only a 28.6% of the subjects with
10/10 genotype showed good response to MPH treatment [71].
Pharmacogenetic studies have demonstrated increased re-
sponse to MPH among homozygous 10R, but there are conflict-
ing results [16, 17]. However a recent meta-analysis [19]
shows that there is no significant association between this
VNTR and response to MPH treatment. The meta-analysis also
found no effects on dimensions of hyperactivity/impulsivity and
inattention. Thus this finding suggests that VNTR polymor-
phism is not a reliable predictor of MPH treatment success in
Gene expression
[meta-analysis 39].
two DAT1 variants: the 10/6 haplotype (formed by the 10R allele
of the 3UTR VNTR and the 6R allele of the intron 8 VNTR) is
analysis 39].
analysis 61].
endophenotypes
Potential biomarker
Potential biomarker Rationale Meta-analysis Review Neuropsychological Neurophysiological Variations in brain anatomy Variations in brain function
endophenotypes endophenotypes (structural MRI finding) (functional MRI finding)
EEG Theta/Beta ratio (TBR) Elevated Theta/Beta ratio [62] [63] -Prognostic
(TBR) in ADHD. measure [62];
-potential
biomarker [63].
Reaction time variability (RTV) Increased RTV in ADHD. [100] Stable feature of ADHD
Curr Psychiatry Rep (2014) 16:497
but no specific.
Selective attention and vigilance/ Attention impairment in [6466]. [10] -Robust findings [10];
sustained attention ADHD. -No association [6466].
Verbal and visuo-spatial Anomalies in prefrontal [6467] [10] -Robust findings
working memory cortical regiones and [10, 67, 68];
the basal ganglia in -No association [6466]
ADHD. Alterations in
dopaminergic,
noradrenergic and
fronto-striatal systems.
Caudate Neuroimaging studies [102] Reduced gray matter volume Reduced activity and
supported dysfunction of functional connectivity
Thalamus several areas of the brain. Reduced gray matter volume Reduced activity and
functional connectivity
Anterior cingulated Reduced gray matter volume, Reduced activity and
reduced white matter integrity functional connectivity
Prefrontal cortex Reduced gray matter volume, Reduced activity and
reduced white matter integrity functional connectivity
Premotor and SMA cortex Reduced gray matter volume Reduced activity and
functional connectivity
Superior parietal cortex Reduced gray matter volume Reduced activity and
functional connectivity
Precuneus, posterior cingulate, Reduced activity and
lateral parietal cortex, medial functional connectivity
frontal cortex (default-mode
network)
Cerebellum (posterior inferior Reduced gray matter volume, Reduced activity and
vermis) reduced white matter integrity functional connectivity
Corpus callosum (splenium/ Reduced white matter integrity
isthmus)
Fasciculus longitudinalis Reduced white matter integrity
superior
Anterior corona radiate Reduced white matter integrity
Note: ADHD: Attention-deficit/hyperactivity disorder; MRI: Magnetic resonance imaging; SMA: Supplementary motor area
Page 11 of 20, 497
497, Page 12 of 20 Curr Psychiatry Rep (2014) 16:497
in noradrenergic and dopaminergic reuptake [80]. A frequent- Potential Adrenergic Biomarkers for ADHD
ly studied SNP (rs5569 or G1287A) located in exon 9 was not
significant in a meta-analysis of candidate gene studies [13], Genomics
but a nominal association was observed in a genome-wide
association study [34]. No association was found between this Alpha-2A-adrenergic receptor (ADRA2A)
variant and CPT performance [21]. A recent review on phar-
macogenetics concluded that NET1 influence on response to ADRA2A in the prefrontal cortex influences executive func-
MPH is small [17], although a recent genome-wide associ- tions impaired in ADHD [83]. It is also a target for two ADHD
ation study found two SNPs in SLC6A2 gene associated with medications: guanfacine and clonidine. A-1291 C>G creates
MPH response [81]. In a study rs3785143 was associated with an MspI site in the promoter region and it is a functional
atomoxetine response [47]. polymorphism. Two meta-analyses confirmed no association
Moreover children with the G/G genotype at G1287A showed with ADHD [13, 45]. However the C allele was associated
a greater decrease in mean omission error scores after MPH with TOL, trail making test (TMT), and RTV on the stop-
administration compared to A allele carriers. Another polymor- signal task as well as the CC genotype was associated with
phism A-3081T at 5flank, demonstrated to be functional, was high RTV on the CPT test [21]. A recent pharmacogenetic
associated with T allele with greater decrease in mean commis- review [17] summarized some studies reporting that G allele
sion errors scores, meaning improved impulsive behavior [40, is associated with greater reduction of inattentive symptoms
41]. Other variants such as rs998424 and rs3785157 were linked over time. Froehlich et al. also found a main effect of this
to high performance on the similarities subtest of the WISCIII, genetic variant on MPH response [46]. However, the G allele
but not with the cerebral volume or thickness of the cortex [42]. was associated with hyperactive-impulsive symptoms on pla-
Another SNP rs3785155 was associated to RTV [43]. cebo and across doses.
Another variant rs553668, for which the disorder meta-
Metabolomics analysis was negative [13], was associated with the perfor-
mance on TMT suggesting an involvement of this gene on
Norepinephrine (NE) executive functions [21]. Yang et al. described an association
between GG haplotype (rs1800544/rs553668) and non-
Concerning NE levels, a meta-analysis [39] indicated higher remission of ADHD symptoms with atomoxetine treatment
urinary levels in ADHD compared with controls, and a nor- [47].
malization of NE concentrations has been observed after
treatment with polyphenol complex and with fenfluramine Metabolomics
and AMP [39].
Epinephrine (EPI) and Metanephrine (M)
3-Methoxy-4-Hydroxyphenylglycol (MHPG)
EPI and its main metabolite M levels, according to a recent
MHPG is the main metabolite of NE. Its urinary levels meta-analysis [39], were respectively no different or higher
were lower in ADHD patients and stimulant trials in ADHD patients. The difference for M was lost after
showed that decreases in ADHD symptoms with treat- Bonferroni correction.
ment were associated with greater reductions in urinary
MHPG excretion [39].
Potential Metabolism Enzymes as Biomarkers for ADHD
Neuropeptide Y (NPY)
Genomics/Metabolomics
NPY frequently colocalizes with catecholamine systems. It
participates in the regulation of feeding, circadian rhythms, Catechol-O-Methyltransferase (COMT)
reproduction, and thermoregulation. Oades et al. found in-
creased plasma NPY concentrations in ADHD children com- COMT is an enzyme responsible for the degradation of DA
pared with controls [82]. Moreover a recent genome-wide and NE. It is highly expressed in frontal lobe where it regu-
copy number variation analysis [44] found that NPY was lates synaptic DA levels [84]. Studies examining the associa-
included in a rare 3 Mb duplication on chromosome 7p15.2 tion between COMT and ADHD have largely focused on a
to 15.3 and an association of this duplication was found with functional SNP in exon 4 that creates an amino acid substitu-
increased NPY plasma concentrations. Moreover an associa- tion (valine/methionine). This variant affects COMT enzyme
tion was observed between gene dose-dependent increases in activity, such that homozygotes for the valine allele shows 34
NPY and emotion processing [44]. times greater activity than homozygotes for the methionine
497, Page 14 of 20 Curr Psychiatry Rep (2014) 16:497
allele. However meta-analysis [48] indicates no association temporal order judgment task, more commission and omission
between ADHD and the 158Val/Met. errors and greater RTV on the SART, more errors on the
A review summarized studies on 158Val/Met and neuropsy- Wisconsin Card Sorting Test (WCST) (problem-solving) and
chological endophenotypes [21]. While no association was the Matching Familiar Figures Test (MFFT) (cognitive
observed between this variant and performance on cognitive impulsiveness).
tasks, a significant finding was reported between the Met allele Finally an association between neuropsychological mea-
and impairment in sustained attention and fewer commission sures of executive function in children with ADHD and the
errors. In the neurophysiological studies, this variant was asso- 1021C/T variant has been reported [57].
ciated with antisocial and aggressive behaviors of ADHD [50, A meta-analysis [39] found that ADHD patients showed
51]. Pharmacogenetic studies reported a positive association lower activities of DBH in serum and urine and it was sug-
between Val allele and response to MPH [52, 53]. gested that decreased DBH levels correlate with ADHD
symptoms [39, 89, 90].
Monoamine Oxidase A (MAOA)
Potential Biomarkers for Environmental Risk factors EEG Theta/Beta Ratio (TBR)
Zinc is another essential cofactor for neurotransmitter me- Reaction Time Variability (RTV)
tabolism which affects DA metabolism. Zinc deficiency is
associated with behavior problems in children with ADHD Individuals with ADHD are described frequently as ubiqui-
[review 90]. Although a systematic review of randomized tously slower and more variable than their unaffected peers,
controlled clinical trials demonstrated that using zinc, either and ADHD-related RTV is considered by many to reflect a
alone or in combination with stimulants, did not improve unique, stable, and etiologically important characteristic of the
ADHD symptoms [93], a meta-analysis reported reduced disorder. Results of a recent meta-analysis indicate that, con-
serum/plasma/urine levels in ADHD [39]. trary to contemporary characterizations of individuals with
ADHD as slower and more variable, ADHD individuals
Oxidative Stress may be better characterized as more variable but not slower
after accounting for their increased response variability.
The normal oxidation-reduction reactions that create energy in the However RTV lacks specificity among clinical disorders,
cell create toxic oxidants or reactive oxygen species. These by- and thus is not a viable diagnostic marker of ADHD [100].
products of normal oxidation-reduction reactions are highly un-
stable. Antioxidants counteract the effects of oxidants. When Selective Attention and Vigilance/Sustained Attention
antioxidants are not sufficient, oxidative stress occurs and dam-
ages cellular proteins, lipids, carbohydrates, and nucleic acids. A prominent multidimensional model of attention differentiates
Brain tissue is especially susceptible to oxidative stress. Indirect between alertness, divided attention, selective attention,
evidence for oxidative stress in ADHD comes from studies show- vigilance/sustained attention and shifting. According to
ing some treatment efficacy for anti-oxidant compounds such as Thome et al. the most robust findings indicated that children
omega-3 fatty acids, pycnogenol and N-acetylcysteine [9497]. with ADHD displayed difficulties in measures of selective
A meta-analysis of oxidative stress in ADHD suggested attention and vigilance/sustained attention [10]. Impairments
that patients with ADHD have normal levels of anti-oxidant of vigilance/sustained attention are the most replicated neuro-
production but that their response to oxidative stress is insuf- psychological finding in ADHD. However a considerable num-
ficient, leading to oxidative damage [61]. ber of investigations were unable to find difference between
ADHD patients and controls [6466]. In addition effect sizes
indicated only small to moderate differences between ADHD
patients and controls.
Potential Endophenotypes as Biomarkers for ADHD
Executive Functions
Besides indentifying a genetic marker involved in neurophysio-
logical/neuropsychological, neuroimaging, pharmacogenetics, They are an umbrella term encompassing various functions of
biochemical features, a putative signature set of biomarkers higher cognitive functioning including planning, problem
could be integrated with a research on endophenotypes solving, concept formation, fluency, cognitive flexibility, and
(Table 2). working memory. The most consistent finding in the domain
497, Page 16 of 20 Curr Psychiatry Rep (2014) 16:497
Fig. 1 Hypothetical pyramid representation of possible signature sets of Catechol-O-methyltransferase. In the bottom, we placed endophenotype
biomarkers for ADHD diagnosis. Starting from the literature, we built an biomarkers. In particular working memory, selective attention vigilance/
hypothetical pyramid describing a putative set of biomarkers where, at sustained attention, Theta/beta ratio, Reaction Time Variability and
the top, variants in DAT1 and DRD4 genes are the best candidates as neuropsychological endophenotypes are, in this order, probably not
useful biomarkers, for their associations to neuropsychological tasks, useful biomarkers for ADHD diagnosis. Notes: Dopamine Transporter
activation in specific brain areas, methylphenidate response and gene gene (DAT1, SLC6A3); Dopamine D4 receptor (DRD4);
expression levels. A further level is represented by the noradrenergic Norepinephrine transporter (NET1, SLC6A2); Norepinephrine (NE);
system (Norepinephrine transporter, Norepinephrine, 3-methoxy-4- 3-methoxy-4-hydroxyphenylglycol (MHPG); Monoamine oxidase
hydroxyphenylglycol, Monoamine Oxidase, Neuropeptide Y) for their (MAO); Neuropeptide Y (NPY); Dopamine beta hydroxylase (DBH);
altered peripheral levels, their association with neuropsychological Catechol-O-methyltransferase (COMT); Theta/beta ratio (TBR);
tasks, symptomatology, drugs effect and brain function. Other minor Reaction time variability (RTV)
putative genetic biomarkers could be Dopamine Beta Hydroxylase and
Curr Psychiatry Rep (2014) 16:497 Page 17 of 20, 497
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