Positron Emission Tomography Shows Reduced Striatal Dopamine D1 but not D2 Receptors in Juvenile Neuronal Ceroid Lipofuscinosis

Abstract

We studied striatal dopamine D1 and D2 receptors in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) with positron emission tomography (PET) using a dopamine D1 receptor antagonist [11C]NNC 756 and a dopamine D2 receptor antagonist [11C]raclopride as ligands. The mean [11C]NNC 756 uptake value in JNCL was reduced by 15 % from the mean control value in the putamen (p < 0.01) and by 13 % in the caudate nucleus (p < 0.01). The mean [11C]raclopride uptake in JNCL patients was not significantly different from the mean of the control group either in the putamen or the caudate nucleus. Our results show a mild reduction in striatal dopamine D1 but not in D2 receptors in JNCL, indicating slightly impaired striatal neuronal function. The contribution of these changes to the extrapyramidal symptoms of the patients and their treatment deserves further studies.

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

“…Over time, this is likely to lead to an accumulation of undegraded, unsequestered dopamine which auto-oxidizes, initiating an increase in oxidative damage as we demonstrated by an increased carbonyl burden. Eventually, this cellular stress could progress to the down regulation of the D1α receptor that we see that is similar to that seen in the striatum of JNCL patients (Rinne et al, 2002).…”

“…The D1α and D2 receptors are the post-synaptic dopaminergic receptors and establish the direct and indirect pathway between the striatum and output nuclei of the basal ganglia (Kandel et al, 2000). Patients with Batten disease have a down-regulation in the expression of D1α receptor of the medium spiny striatal neurons (Rinne et al, 2002). To address whether a similar decrease in receptor levels occurs in the Cln3 -/-mice, western blot analysis was performed on cortical and striatal samples at three and nine months of age.…”

“…Recent attempts to elucidate the events leading up to cell loss and microglial activation in the Cln3 -/-mice have demonstrated elevated oxidative burden in different anatomical compartments, often with activated microglial located immediately adjacent to neurons reactive for potent antioxidant markers (Benedict et al, 2007). Elevated oxidative stress within the striatum could result from or trigger the previously reported inflammatory response (Pontikis et al, 2004), subsequently leading to restricted cellular changes, including the post-synaptic receptor down regulation reported in JNCL (Rinne et al, 2002). Indeed, we saw a marked increase in oxidized proteins and the down regulation of D1α receptors in the Cln3 -/-striatum by nine months of age, paralleling the increase in glial activation.…”

“…Once released into the synaptic cleft, dopamine activates either the D1 or D2 class of receptors. PET studies of JNCL patients showed a reduction in the striatal D1, but not D2 receptors (Rinne et al, 2002). In this study, we have investigated these basal ganglia deficits in Cln3 knockout mice (Cln3 -/-), a mouse model of Batten disease.…”

A clinical rating scale for Batten disease

“…[3][4][5] A number of studies have focused on specific clinical features [6][7][8][9][10][11][12][13][14][15][16] or correlated such features with molecular, pathologic, or imaging characteristics. [17][18][19][20][21][22][23] Therapeutic studies have targeted specific symptoms rather than overall disease progression. [24][25][26][27][28] A scoring system has been used to characterize a small number of patients, but no data are published regarding its interrater reliability.…”