Johanna Krause

Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography.

Ten previously untreated adults with attention deficit hyperactivity disorder (ADHD) were investigated before and after 4 weeks of treatment with a dose of 3x5 mg methylphenidate/d by single photon emission computed tomography (SPECT) with [Tc-99m]TRODAT-1, the first Tc-99m labelled SPECT ligand specifically binding to the dopamine transporter (DAT). For semiquantitative evaluation of the DAT, specific binding ([STR-BKG]/BKG) was calculated in the striatum (STR) with the cerebellum used as background (BKG). The patients with ADHD presented with increased specific binding of Tc-99m-TRODAT-1 to the DAT as compared with age and sex matched controls ([STR-BKG]/BKG 1.43+/-0.18 vs. 1.22+/-0.05, P<0.001). After treatment with methylphenidate specific binding decreased in all patients ([STR-BKG]/BKG 1.02+/-0.23, P<0.001). Thus, for the first time it could be demonstrated using SPECT that methylphenidate lowers increased striatal DAT availability in adults suffering from ADHD.

The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder.

There is evidence that abnormalities within the dopamine system in the brain play a major role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). For instance, dopaminergic psychostimulants, the drugs of first choice in ADHD, interact directly with the dopamine transporter (DAT). Molecular genetic studies suggest involvement of a polymorphism of the DAT gene in ADHD. More recent imaging studies show abnormalities in various brain structures, but particularly in striatal regions. In the current paper we review recent studies in this area. First in vivo measurements of DAT with single photon emission computed tomography (SPECT) in ADHD patients revealed an elevation of striatal DAT density. No differences in DAT density between the left and right side and between putamen and caudate nucleus have been found in [99mTc]TRODAT-1 SPECT of ADHD patients. Patients with ADHD and with a history of nicotine abuse both displayed lower values of DAT density in [99mTc]TRODAT-1 SPECT than non-smokers with ADHD. DAT seem to be elevated in non-smoking ADHD patients suffering from the purely inattentive subtype of ADHD as well as in those with the combined or purely hyperactive/impulsive subtype.

Stimulant-like action of nicotine on striatal dopamine transporter in the brain of adults with attention deficit hyperactivity disorder

Eleven adult patients with attention deficit hyperactivity disorder (ADHD) without medication, consuming 7-40 cigarettes per day, showed statistically significant lower values for striatal dopamine transporter (DAT) measured by [99mTc]TRODAT-1 SPECT compared to 11 non-smoking drug-naive patients with ADHD, matched for sex and age, despite higher ADHD scores for the smokers. Because stimulants have been shown to reduce primarily elevated DAT density in adults with ADHD, it can be suggested that nicotine acts in a similar way on striatal DAT as do stimulants.

Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD

AbstractIn this study, we investigated whether availability of striatal dopamine transporter (DAT) may have an influence on the response of adult patients with attention deficit hyperactivity disorder (ADHD) on methylphenidate (MPH). In 18 non–smoking and non–medicated adult patients with ADHD, availability of DAT was measured with [99mTc] TRODAT–1 SPECT. Then, the patients received methylphenidate (MPH), individually titrated up to 60 mg per day. Ten weeks later, clinical improvement was rated by Clinical Global Impressions scale. In all, 6 patients were classified as non–responders, and 12 responded to MPH. From the non–responders, 5 presented with a DAT availability below that of normal controls of the same age, whereas in the group of responders all patients had elevated DAT availability. There was a significant negative correlation between values for global clinical improvement and striatal DAT availability. In conclusion, ADHD patients with low DAT availability seem not to respond to therapy with MPH.

Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: no higher DAT availability in patients with homozygosity for the 10-repeat allele

In 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability was assessed by [99mTc]TRODAT-1 SPECT and correlated with 3′ VNTR polymorphism of the DAT gene on chromosome 5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 were heterozygous (9–10). No statistically significant difference in DAT availability was found between patients with 10–10 carriers (DAT 1.28±0.34) and with at least one 9 allele (DAT 1.31±0.27); when smokers were excluded, DAT availability was 1.38±0.28 in the 10–10 carriers (n=12) and 1.42±0.19 in the 9–10 and 9–9 carriers (n=7). In conclusion, no higher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These results differ from a study in 11 Korean children with ADHD, in which 10–10 carriers showed higher DAT availability in [123I]IPT SPECT. Discrepancies may be explained by differences in patients age, ethnical differences, different imaging techniques or the limited number of patients included in both studies.

Elevated striatal dopamine transporter in a drug naive patient with Tourette syndrome and attention deficit/ hyperactivity disorder: positive effect of methylphenidate.

Sirs: Until recently prescription of methylphenidate (MPH) was thought to be contraindicated in patients with tic disorders such as Tourette syndrome (TS). Now this belief is being questioned, since some investigators have found positive effects of MPH in children with comorbidity of attention deficit hyperactivity disorder (ADHD) and TS. In these studies only a small number of patients deteriorated under MPH treatment[3, 6]. There was no predictor whether an individual patient would profit from the drug or not. Here, we report on a female patient suffering from both ADHD and TS, presenting with elevation of striatal dopamine transporters (DAT) as measured by SPECT prior to treatment. MPH treatment clearly reduced striatal DAT and correlated well with clinical improvement. A 38-year-old woman showed symptoms of ADHD such as inattention and impulsivity since childhood (high scores of 74 in Wender Utah Rating Scale[13] and of 94 in Brown ADD Scales[1]). Additionally the patient suffered from TS with motor (blinking, eye rolling, neck twisting and shoulder shrugging) and sonic (grunting, snorting, chirping and fizzling) tics since childhood with marked distress and impairment in her daily life activities. The symptoms diminished in adolescence, but persisted during adulthood. The patient was not treated for either ADHD or TS. After written informed consent had been given by the patient, a SPECT examination with [Tc–99m]TRODAT–1, a selective marker for the dopamine transporter (DAT)[5] was performed, showing a 24 % elevation of striatal DAT density (specific binding [STR-BKG]/BKG = 1.51, calculated in the striatum [STR] with the cerebellum as background [BKG], see Figure) compared with controls (mean ± s. d. in 14 adult controls = 1.22 ± 0.06[2]). When the patient was given a dose of 10 mg MPH daily, symptoms of ADHD significantly improved, but symptoms of TS deteriorated slightly. Consecutively the MPH dose was reduced to 2.5 mg three times per day (total daily dose 7.5 mg), which clearly improved symptoms of both disorders. A second SPECT scan using [Tc–99m]TRODAT–1 revealed a reduction of striatal DAT of 40 % (Figure) after 5 months of low dose MPH therapy with intake of the third dose of 2.5 mg on the day of examination one hour before SPECT. The D2 receptor density, measured simultaneously in the second examination by [I–123]IBZM SPECT was normal. The good clinical effect of low dose MPH on both conditions, ADHD and TS, remained impressive. The pathophysiology of ADHD and TS still remains unclear as is the reason for the high incidence of comorbidity of these conditions. It has been suggested, that in both diseases abnormalities of dopamine pathways may play an important role. In a post mortem study elevated striatal dopamine uptake sites in patients with TS have been reported[11] and in two studies using [I–123]beta-CIT SPECT some adult patients with TS revealed higher DAT ligand binding than in controls[7, 9]. However, no significant differences have been found between patients with TS and controls in striatal vesicular monoamine transporter type–2 binding, measured by PET[8]. This led to the hypothesis that increased DAT binding might result from medication effects or a primary abnormality in the regulation of DAT expression. A similar conclusion was drawn from a recent [I–123]beta-CIT SPECT study of 15 untreated adult TS patients, where no changes in striatal dopamine reuptake site density was seen[12]. D2 dopamine receptor antagonists like haloperidol and pimozide show effectiveness in suppressing tics of most of TS patients. Stimulants like MPH used for therapy of ADHD may have the opposite effect on striatal dopamine system. In patients with ADHD it has been shown recently, that MPH reduces primarly elevated striatal DAT binding[2, 4]; this normalization of binding of a ligand if interpreted as a normalization of elevated DAT sites by competing of MPH with DAT ligands could result in increasing dopamine levels in the synaptic cleft. Thus, it would be conceivable, that under MPH tics may worsen in comorbid ADHD and TS patients. It also has to be in mind that MPH might interact with presynaptic dopamine D2 receptors, which regulate DAT activity. Whereas no direct influence of MPH has been found on the postsynaptic D2 receptor function in spontaneously hypertensive rats, used as a model for ADHD, presynaptic mechanisms controlling dopamine release had been altered, LETTER TO THE EDITORS