Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Deficiency of glutathione S-transferases T1 and M1 as heritable factors of increased cutaneous UV sensitivity.

Glutathione S-transferases (GSTs) play a primary role in cellular defense against electrophilic chemical species and radical oxygen species. Because free radical attack is one mechanism of UV irradiation-caused skin damage, we investigated whether genetic variation at the GST loci GST T1 and GST M1 influences individual UVB sensitivity. In a double-blind clinical trial, 50 healthy volunteers were evaluated for minimal erythema dose of UVB irradiation, MED (J/cm2), skin types were assigned, and internal standard-controlled polymerase chain reaction (PCR) was used to identify their GST T1 and GST M1 genotypes. The five homozygous carriers of the GST T1 deletion (GST T1*0/0) presented with the most intensive inflammatory reactions after irradiation; they were significantly overrepresented among the highly UVB-sensitive subgroups (p = 0.006). Lack of GST M1 (GST M1*0/0, n = 27) tended to be more frequent only in UVB-sensitive subjects, and the proportion of the active GST M1 allelic variants *A and *B was similar in all UVB sensitivity subgroups. Three subjects with deficiencies in GST T1 and GST M1 had the most intense inflammatory responses. No effect of gender or genetic variations at the MC1R gene locus was established. Thus, heritable GST T1 deficiency may be a genetic determinant of individual skin sensitivity toward UV irradiation.

Unilateral fetal mesencephalic grafts in intact rats reduce amphetamine-induced dopamine release in both striata. An in vivo voltammetric study.

This study investigated amphetamine-induced striatal dopamine release after intraventricular unilateral fetal mesencephalic grafts in otherwise intact rats. Dopamine was monitored in vivo by differential pulse voltammetry. In grafted animals, amphetamine-induced dopamine release was decreased compared to sham-grafted, age-matched controls. This decrease was observed in the grafted as well as in the contralateral striatum five months after intraventricular grafting. There was no measurable effect of the graft on the amphetamine-induced rotational behaviour. Our results exceed former observations reporting decreased amphetamine-induced dopamine release in the contralateral striatum of 6-hydroxydopamine-lesioned and unilaterally-grafted rats which had been attributed to a reduction of dopamine transporters. Furthermore, it was shown that concerning this effect ventral mesencephalic grafts are independent of a previous 6-hydroxydopamine lesion.

Graft-induced reduction in [3H]dopamine uptake into the non-lesioned striatum.

The effect of intraventricular fetal mesencephalic grafts placed in the 6-hydroxydopamine (6-OHDA) lesioned striatum on [3H]dopamine (DA) uptake into synaptosomes was studied. Apomorphine (APO)- and amphetamine (AMPH)-induced rotational behaviour was continuously reduced by the grafts over 7 months. After this time, a non-significant increase in [3H]DA uptake into synaptosomes of the lesioned striatum and an approximately 40% decrease in [3H]DA uptake into synaptosomes of the non-lesioned striatum were found. Grafts placed in the non-lesioned striatum did not significantly change both rotational behaviour or [3H]DA uptake. The results show that unilateral fetal mesencephalic grafts producing behavioural improvement in the unilateral 6-OHDA lesioned rat induce changes in dopaminergic structures in the non-lesioned striatum.

Grafts modulate dopamine transporters of the non-lesioned striatum.

The effect of intraventricular fetal mesencephalic grafts placed in the previously 6-hydroxydopamine (6-OHDA) lesioned striatum on the kinetics of [3H]dopamine (DA) uptake into striatal synaptosomes prepared from the non-lesioned (contralateral) striatum was studied in rats. Using WIN 35,065 as specific [3H]DA uptake inhibitor, the equilibrium dissociation constant (Km) of [3H]DA uptake into synaptosomes of the non-lesioned (contralateral) striatum did not differ between grafted and nongrafted controls 7 months after grafting. However, the maximal rate of specific [3H]DA uptake (Vmax) was markedly decreased in the non-lesioned striatum of grafted animals. This result indicates that fetal mesencephalic grafts reduce the [3H]DNA uptake in the non-lesioned (contralateral) striatum by reducing the number of functional DA transporters.

High frequency stimulation of the subthalamic nucleus influences striatal dopaminergic metabolism in the naive rat.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) can partially alleviate motor symptoms in patients with Parkinson's disease (PD). However, the mechanism of action of HFS is incompletely understood. We investigated the effect of HFS (130 Hz) and low frequency stimulation (LFS, 20 Hz) of the STN on striatal dopaminergic transmission and metabolism using in vivo microdialysis in anaesthetized and freely moving rats. While LFS had no effect, HFS of the STN produced a delayed, stable and intensity-dependent increase of extracellular dopamine metabolites. Striatal extracellular levels of dopamine and 5-HIAA were not influenced by HFS or LFS in the present experimental paradigm. We conclude that HFS of the STN influences striatal dopaminergic metabolism in naive, nonlesioned rats.

Extracellular dopamine in the anterior nucleus accumbens is distinctly affected by ventral tegmental area administration of cholecystokinin and apomorphine: data from in vivo voltammetry.

The interaction of cholecystokinin (CCK) and dopamine (DA) in the mesolimbic system was investigated. The study focused on DAergic cells not containing colocalized CCK projecting from the ventral tegmental area (VTA) to the anterior nucleus accumbens (NA). Differential pulse voltammetry in pargyline pretreated and anesthetized rats was used to measure extracellular DA in the anterior NA following microinjection of apomorphine either alone or in combination with CCK-8s into the VTA. In agreement with an earlier study there was a dose-dependent increase in the DA signal in the anterior NA after microinjection of CCK-8s into the VTA. Apomorphine microinjected into the VTA produced a biphasic effect on extracellular DA in the anterior NA with an increase from basal levels of approximately 50% by 1 ng, whereas 10 ng was ineffective and 100 ng apomorphine caused a slight decrease in the DA signal. Apomorphine (1 ng) microinjected together with 1 ng CCK-8s produced an increase in the DA signal to approximately 180% of the baseline value, whereas the combination of 1 ng apomorphine and 100 ng CCK-8s was ineffective. When 100 ng apomorphine were microinjected in combination with either 1 ng or 100 ng CCK-8s, the DA signal in the anterior NA was unchanged. These results suggest that low doses of apomorphine injected into the VTA synergistically influence the effects of CCK-8s on extracellular DA in the anterior NA, whereas higher doses of apomorphine suppress the effect of CCK-8s on DAergic cells projecting to the anterior NA.

Cholecystokinin increases extracellular dopamine overflow in the anterior nucleus accumbens via CCK(B) receptors in the VTA assessed by in vivo voltammetry.

Differential pulse voltammetry was used to investigate the extracellular dopamine (DA) and DOPAC signal in the anterior part of nucleus accumbens (N.acc.) after microinjection of cholecystokinin (CCK) derivatives into the ventral tegmental area (VTA). Both the mixed CCK(A)/CCK(B) receptor agonist CCK-8s and the selective CCK(B) receptor agonist CCK-4 caused a dose-dependent increase in the DA signal after doses of 10 ng and 100 ng while CCK-8s had no effect on the DOPAC signal. The CCK(A) receptor antagonist L 364,718 (25 microg/kg i.p.) as well as the CCK(B) receptor antagonist L 365,260 (25 microg/kg i.p.) were administered prior to microinjection of 100 ng CCK-8s and L 365,260, but not L 364,718, completely inhibiting the DA increase produced by CCK-8s. Analysis of the tissue levels of DA and its main metabolites in the anterior part of N.acc. revealed no changes after CCK-8s microapplication into VTA. The presented data indicate a CCK(B) receptor-mediated increase in extracellular DA in the anterior N.acc. after microapplication of CCK derivatives into the VTA.

Comparison by microdialysis of striatal L-DOPA after its systemic administration in rats with probes implanted acutely or through a guide cannula.

Different methods of microdialysis probe implantation are utilized according to the purpose and needs of each particular study. However, very few experiments have systematically examined whether these different techniques have an impact on the obtained data. In the present study we examined the influence of two different microdialysis methods - acute probe implantation vs. insertion into a preimplanted guide cannula - on the striatal extracellular availability of systemically administered L-DOPA. Furthermore, we monitored the effects of L-DOPA administration on dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). In rats that received a guide cannula 4 days prior to probe insertion and microdialysis, extracellular L-DOPA concentrations increased to concentrations that were about nine times higher than in rats with acute implantation of a microdialysis probe. Extracellular DOPAC concentrations were also higher in the chronic preparations but dopamine concentrations showed no differences between groups. Our results suggest that the observed differences may be due to inflammatory disruption of the BBB following chronic implantation of a guide cannula.

Modelling constant potential amperometry for investigations of dopaminergic neurotransmission kinetics in vivo.

Constant potential amperometry (CPA) was used for in vivo recording of extracellular dopamine (DA) after electrical stimulation of the medial forebrain bundle (MFB) (4 pulses, 2 mA, 20 or 100 Hz) in the striatum of the rat brain. CPA signals were analysed in the absence and presence of the DA uptake inhibitor nomifensine with the help of a mathematical model which considered both the influence of DA diffusion after its stimulated release and the Michaelis-Menten kinetics of cellular DA uptake from the extracellular space. We found an excellent conformity of experimentally obtained CPA signals and calculated curves. Mathematical analysis revealed that CPA signals were strongly influenced by DA diffusion. The kinetic parameters calculated from CPA signals in this study were in agreement with experimental determinations of Vmax and Km of extracellular DA uptake in other studies and reflect the particular pharmacological properties of nomifensine. CPA is a useful and efficient method for in vivo estimation of individual changes of DA kinetic parameters by pharmacological treatment.