Concepció Marin

The Basal Ganglia in Parkinson's Disease: Current Concepts and Unexplained Observations

The pathophysiology of Parkinsons disease is reviewed in light of recent advances in the understanding of the functional organization of the basal ganglia (BG). Current emphasis is placed on the parallel interactions between corticostriatal and corticosubthalamic afferents on the one hand, and internal feedback circuits modulating BG output through the globus pallidus pars interna and substantia nigra pars reticulata on the other. In the normal BG network, the globus pallidus pars externa emerges as a main regulatory station of output activity. In the parkinsonian state, dopamine depletion shifts the BG toward inhibiting cortically generated movements by increasing the gain in the globus pallidus pars externa‐subthalamic nucleus‐globus pallidus pars interna network and reducing activity in “direct” cortico‐putaminal‐globus pallidus pars interna projections. Standard pharmacological treatments do not mimic the normal physiology of the dopaminergic system and, therefore, fail to restore a functional balance between corticostriatal afferents in the so‐called direct and indirect pathways, leading to the development of motor complications. This review emphasizes the concept that the BG can no longer be understood as a “go‐through” station in the control of movement, behavior, and emotions. The growing understanding of the complexity of the normal BG and the changes induced by DA depletion should guide the development of more efficacious therapies for Parkinsons disease. Ann Neurol 2008;64 (suppl):S30–S46

Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease

We studied an autoantibody (called anti-Tr), found in the serum and CSF of five patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkins disease (HD). Anti-Tr antibodies labelled the cytoplasm of Purkinje cells of human and rat cerebellum. The molecular layer of rat cerebellum showed a characteristic dotted pattern suggestive of immunoreactivity of dendritic spines of Purkinje cells. Patients with cerebellar disorders without HD (159) or HD without PCD (30) did not harbor anti-Tr antibodies. Immunoblots of human Purkinje cells or rat and mouse cerebellum were negative. Anti-Tr antibodies, as defined in this study, appear specific for HD-associated PCD. The immunohistochemical pattern described in the rat cerebellum coupled with the absence of reactivity in the immunoblot may be used to identify anti-Tr antibodies.

Metabolic effects of nigrostriatal denervation in basal ganglia

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinsons disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.

MK-801 prevents levodopa-induced motor response alterations in parkinsonian rats.

The systemic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) , has previously been found to reverse the motor response alterations that develop during long-term levodopa treatment of parkinsonian rats. To determine whether co-administration of MK801 with levodopa might prevent the initial appearance of these response changes, rats, rendered parkinsonian by a 6-hydroxydopamine lesion of the medial forebrain bundle, received either levodopa alone or levodopa with the NMDA receptor antagonist. After four weeks of treatment with levodopa alone, the duration of the turning response declined by 37% (P < 0.05) and the number of ineffectual levodopa injections had more than doubled (P < 0.05). MK801 co-treatment completely blocked the shortening in response duration and prevented the frequency of ineffectual levodopa injection from exceeding baseline levels in animals receiving levodopa alone. The total magnitude of the turning response to levodopa was not affected. These results suggest that NMDA receptor blockade may act prophylactically to prevent the appearance of motor response alterations in levodopa-treated parkinsonian rodents that resemble those occurring in levodopa-treated patients with Parkinsons disease.

Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders.

The detection of 14‐3‐3 protein in cerebrospinal fluid by immunoblotting is useful for the diagnosis of Creutzfeldt‐Jakob disease (CJD). We found 14‐3‐3 protein in 10 of 80 (12.5%) patients with paraneoplastic neurological disorders (PNDs), whose presenting symptoms may mimic those of CJD. In 47 of 48 CJD patients, the 14‐3‐3 protein was detected as a single band, and it was detected as a double band in 1 patient. The double‐band pattern was observed in 9 of the 10 14‐3‐3 protein–positive patients with PNDs. The 14‐3‐3 protein assay may be positive in PND patients, but the immunoblotting pattern distinguishes most PND samples from those of CJD.

Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in parkinsonian rats

Chronic dopaminomimetic administration to parkinsonian animal models or Parkinsons disease patients leads to characteristic alteration in motor response. Previous studies suggested that the nonphysiologic stimulation of dopaminergic receptors on striatal medium spiny neurons enhances the synaptic efficacy of juxtaposed glutamate receptors of the N‐methyl‐D‐aspartate (NMDA) subtype. Resultant NMDA receptor sensitization due to differential changes in subunit phosphorylation appears to favor alterations in striatal output in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional changes might develop in α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptors, the effects of selective antagonist of AMPA receptors (6‐nitro‐7‐sulfamoyl‐benzo[f]‐quinoxaline‐2,3 (1H,4H)‐dione sodium salt, NBQX, 10 mg/kg) on levodopa‐induced response alterations in 6‐hydroxydopamine (6‐OHDA) lesioned rats were compared with drugs which act competitively (3‐(±)‐2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonicacid, CPP, 6.25 mg/kg) or noncompetitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a nonselective inhibitor of glutamatergic transmission (2‐amino‐6‐trifluoromethoxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing‐off fluctuations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4–6) but dextromethorphan did not. These observations strengthen the possibility that a reduction in levodopa‐associated changes in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding‐sites may relate to their ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an enhanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa‐treated parkinsonian rats. Synapse 36:267–274, 2000.

Furthering the understanding of olfaction, prevalence of loss of smell and risk factors: a population-based survey (OLFACAT study)

Objectives To investigate olfaction in general population, prevalence of olfactory dysfunction and related risk factors. Design Cross-sectional population-based survey, distributing four microencapsulated odorants (rose, banana, musk and gas) and two self-administered questionnaires (odour description; epidemiology/health status). Setting The survey was distributed to general population through a bilingual (Catalan, Spanish) newspaper in Catalonia (Spain), on December 2003. Participants Newspaper readers of all ages and gender; 9348 surveys were analysed from the 10 783 returned. Main outcome measures Characteristics of surveyed population, olfaction by age and gender, smell self-perception and smell impairment risk factors. Terms normosmia, hyposmia and anosmia were used when participants detected, recognised or identified all four, one to three or none of the odours, respectively. Results Survey profile was a 43-year-old woman with medium–high educational level, living in a city. Olfaction was considered normal in 80.6% (detection), 56% (recognition/memory) and 50.7% (identification). Prevalence of smell dysfunction was 19.4% for detection (0.3% anosmia, 19.1% hyposmia), 43.5% for recognition (0.2% anosmia, 43.3% hyposmia) and 48.8% for identification (0.8% anosmia, 48% hyposmia). Olfaction was worse (p<0.0001) in men than in women through all ages. There was a significant age-related smell detection decline however smell recognition and identification increased up to fourth decade and declined after the sixth decade of life. Risk factors for anosmia were: male gender, loss of smell history and poor olfactory self-perception for detection; low educational level, poor self-perception and pregnancy for recognition; and older age, poor self-perception and history of head trauma and loss of smell for identification. Smoking and exposure to noxious substances were mild protective factors for smell recognition. Conclusions Sense of smell in women is better than in men suggesting a learning process during life with deterioration in older ages. Poor self-perception, history of smell loss, head trauma and pregnancy are potential risk factors for olfactory disorders.

What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity.

One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinsons disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state.

Biochemical and Molecular Effects of Chronic Haloperidol Administration on Brain and Muscle Mitochondria of Rats

The objectives of the current study were to evaluate (1) the respiratory rates and enzyme activities of brain and muscle mitochondria from rats chronically treated with haloperidol, (2) the protective role of dopamine (DA) D‐1 (SKF38393) and D‐2 (quinpirole) receptor agonists, and (3) the effect of haloperidol on the mitochondrial DNA (mtDNA) and protein synthesis. Thirty male Sprague‐Dawley rats were subdivided into the following five groups: controls, haloperidol, haloperidol plus SKF38393, haloperidol plus quinpirole, and haloperidol plus SKF38393 and quinpirole. We compared the respiratory rates and enzymatic activities of brain and muscle mitochondria from controls with other groups. We finally analyzed the mitochondrial protein synthesis and mtDNA alterations (deletions, point mutations, and depletion) in two rats from each group. In brain but not in muscle from haloperidol‐treated rats, we found a decrease of oxygen consumption rates using glutamate plus malate (−68 ± 35%, P < 0.05) and succinate (−78 ± 20%, P < 0.05) as substrates as well as low complex I, II, and V activities (−35 ± 15%, P < 0.05; −54 ± 13%, P < 0.05; and −60 ± 33%, P < 0.01; respectively). The administration of SKF38393 alone or together with quinpirole prevented most of haloperidol‐induced effects, whereas the protective effects of quinpirole alone were lower. Brain mitochondrial protein synthesis was decreased in haloperidol‐treated rats and was not prevented by SKF38393, quinpirole, or both. We did not find mtDNA abnormalities in brain or muscle mitochondria from haloperidol‐treated rats. Chronic administration of haloperidol in rats is associated with a nonspecific deleterious effect in the activity of electron transport chain of brain, and this effect is only partially prevented by DA D‐1 agonists. These results suggest that other mechanisms different from DA receptors pathway can contribute to the expression of behavioral supersensitivity. J. Neurosci. Res. 53:475–481, 1998.

In vivo magnetic resonance imaging characterization of bilateral structural changes in experimental Parkinson's disease: a T2 relaxometry study combined with longitudinal diffusion tensor imaging and manganese-enhanced magnetic resonance imaging in the 6-hydroxydopamine rat model

The neuropathological hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNc). The degenerative process starts unilaterally and spreads to the dopaminergic system of both hemispheres. However, the complete characterization of the nigra lesion and the subsequent changes in basal ganglia nuclei activity has not yet been achieved in vivo. The aim of this study was to characterize the time course of the nigral lesion in vivo, using longitudinal T2 relaxometry and diffusion tensor imaging, and the changes in basal ganglia nuclei activity, using manganese‐enhanced magnetic resonance imaging, in 6‐hydroxydopamine (6‐OHDA)‐lesioned rats. Our results showed that a unilateral SNc lesion induces bilateral alterations, as indicated by the enhancement of magnetic resonance imaging T2 relaxation times in both the ipsilateral and contralateral SNc. Moreover, axial and radial diffusivities demonstrated bilateral changes at 3 and 14 days after 6‐OHDA injection in the pars reticulata of the substantia nigra and cortex, respectively, in comparison to the sham group, suggesting bilateral microstructural alterations in these regions. Unexpectedly, manganese‐enhanced magnetic resonance imaging showed decreased axonal transport from the ipsilateral subthalamic nucleus to the ventral pallidum in 6‐OHDA‐lesioned animals compared with the sham group. These findings demonstrate, for the first time in vivo, the temporal pattern of bilateral alteration induced by the 6‐OHDA model of Parkinson’s disease, and indicate decreased axonal transport in the ipsilateral hemisphere.