Multicenter Validation of Metabolic Abnormalities Related to PSP According to the MDS-PSP Criteria.

It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross-validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP-Richardson's syndrome, n = 47; PSP-parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP-related pattern that was cross-validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP-related pattern obtained confirmed the regions described above. At the individual level, the PSP-related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%) and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP-Richardson's syndrome and PSP-parkinsonian variant patients showed significantly more PSP-related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP-Richardson's syndrome and PSP-parkinsonian variant. © 2020 International Parkinson and Movement Disorder Society.

Clinical and neuroimaging characteristics of 14 patients with prionopathy: a descriptive study.

INTRODUCTION: Prionopathy is the cause of 62% of the rapidly progressive dementias (RPD) in which a definitive diagnosis is reached. The variability of symptoms and signs exhibited by the patients, as well as its different presentation, sometimes makes an early diagnosis difficult. METHODS: Patients withdiagnosis of definite or probable prionopathy during the period 1999-2012 at our hospital were retrospectively reviewed.The clinical features and the results of the complementary tests (14-3-3 protein, EEG, MRI, FDG-PET, and genetic analysis) were evaluated in order to identify some factors that may enable an earlier diagnosis to be made. RESULTS: A total of 14 patients are described: 6 with definite sporadic Creutzfeldt-Jakob (sCJD) disease, 3 with probable sCJD, 4 with fatal familial insomnia, and 1 with the new variant. The median age at diagnosis was 54 years old. The mean survival was 9.5 months. Mood disorder was the most common feature, followed by instability and cognitive impairment. 14-3-3 protein content in the cerebrospinal fluid was positive in 7 of 11 patients, and the EEG showed typical signs in 2 of 12 patients. Neuroimaging (FDG-PET, MRI) studies suggested the diagnosis in 13 of the 14 patients included. CONCLUSIONS: Most patients presenting with RPD suffer from a prion disease. In our series the most useful complementary tests were MRI and FDG-PET, being positive in 13 of the 14 patients studied.

Structural and functional neuroimaging in human prion diseases.

INTRODUCTION: Prion diseases are neurodegenerative disorders resulting from the accumulation of a misfolded isoform of the cellular prion protein (PrPc). They can occur as acquired, sporadic, or hereditary forms. Although prion diseases show a wide range of phenotypic variations, pathological features and clinical evolution, they are all characterised by a common unfavourable course and a fatal outcome. REVIEW SUMMARY: Some variants, such as kuru, have practically disappeared, while others, for example the variant Creutzfeldt-Jakob (vCJD) or those attributable to iatrogenic causes, are still in force and pose a challenge to current medicine. There are no definitive pre-mortem diagnostic tests, except for vCJD, where a tonsil biopsy detects 100% of the cases. For this reason, diagnostic criteria dependent on statistical probability have had to be created. These require complementary examinations, such as an electroencephalogram (EEG) or the detection of 14-3-3 protein in cerebrospinal fluid (CSF). Only the pulvinar sign in magnetic resonance imaging (MRI) has been included as a vCJD diagnostic criterion. The present review discusses neuroimaging findings for each type of prion disease in patients with a definitive histopathological diagnosis. CONCLUSIONS: The aim is to define the usefulness of these complementary examinations as a tool for the diagnosis of this family of neurodegenerative diseases.

Advanced Parkinson's disease: clinical characteristics and treatment. Part II.

INTRODUCTION: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa. OBJECTIVE: To define the indications and results for the 3 available therapies for advanced PD. DEVELOPMENT: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. CONCLUSIONS: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique.

[Advanced Parkinson's disease: clinical characteristics and treatment (part 1)]. / Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I).

INTRODUCTION: A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson's disease. OBJECTIVE: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. DEVELOPMENT: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). CONCLUSIONS: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD.

Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population.

BACKGROUND AND PURPOSE: Linkage analysis in familial Parkinson's disease (PD) identified a locus in 2q36-37 (PARK11). Sequencing of GIGYF2 identified several variants only present amongst PD individuals. METHODS: We analyzed the presence of disease-associated GIGYF2 variants in familial and sporadic PD from Spanish origin by sequencing of 147 PD individuals. The entire GIGYF2 coding sequence was analyzed in 122 familial PD individuals and exons 2, 4, 8-11, 14 and 25-26 were sequenced in 25 sporadic PD to identify disease-associated variants. RESULTS: We found no variants associated with PD and failed to identify any of previously PD-associated GIGYF2 variants in our sample. We identified four novel missense changes in GIGYF2. p.Met48Ile was found in a PD individual who also was a carrier of two PARKIN mutations. p.Q1244_Q1247del variant was present only in one PD individual but not found in 70 controls. However, its location in the highly polymorphic GIGYF2 glutamine/proline-rich region does not support a role in PD. Two variants (p.P1238insAGC and p.Q1249del) were present both in PD subjects and in controls. Additionally, the p.L1230_Q1237del variant, which was previously considered as a PD-associated change, was found in one control. CONCLUSION: Our findings suggest that GIGYF2 mutations are not a frequent cause of PD in the Spanish population, since we found no clearly segregating variants. We propose further analyses in PD subjects from different populations to define the role of GIGYF2. A clear pathogenic mutation in other gene at 2q36-37 in the PARK11-linked PD families would definitively disprove GIGYF2 as the responsible gene.

New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification.

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of (18)F-DOPA and (11)C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, (18)F-DOPA and (11)C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of (11)C-DTBZ PET. A symmetric reduction in striatal (11)C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings.

OBJECTIVE: To describe the clinical, biochemical, and neuropathological findings of an autosomal dominant globular glial tauopathy caused by the P301T mutation at the MAPT gene. METHODS: Five patients from two unrelated pedigrees underwent clinical evaluation. Genetic analysis, brain pathological examination, and biochemical analysis of tau were performed. RESULTS: The patients studied were 3 men and 2 women with a mean age at onset of 52.2 years and mean disease duration of 5.2 years. Three patients presented a corticobasal syndrome, one patient an asymmetric pyramidal syndrome compatible with primary lateral sclerosis, and one patient a frontotemporal dementia. In both pedigrees (4 patients) Sanger sequencing showed the p.P301T mutation in exon 10 of the MAPT gene. Neuropathological findings consisted of atrophy of frontal and temporal lobes with marked spongiosis and astrogliosis, and abundant phosphorylated tau protein deposits in the frontal and temporal cortex, limbic area, basal ganglia, and brain stem. The most striking finding was the presence of oligodendroglial 4R phospho-tau globular positive inclusions in the white matter and cortex. Globose-type neurofibrillary neuronal tangles, and in particular astrocytic globular inclusions and coarse tufts, were present in the grey matter. Biochemical analysis of sarkosyl-insoluble fractions revealed two tau bands of 64 and 68 kDa and case-dependent bands of lower molecular weight. CONCLUSION: This is the first pathological and biochemical study of the MAPT p.P301T mutation showing variable clinical manifestation and neuropathological phenotype of globular glial tauopathy not only among different families but also within families.

Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen.

We have studied the effect of unilateral autografts of carotid body cell aggregates into the putamen of MPTP-treated monkeys with chronic parkinsonism. Two to four weeks after transplantation, the monkeys initiated a progressive recovery of mobility with reduction of tremor and bradykinesia and restoration of fine motor abilities on the contralateral side. Apomorphine injections induced rotations toward the side of the transplant. Functional recovery was accompanied by the survival of tyrosine hydroxylase-positive (TH-positive) grafted glomus cells. A high density of TH-immunoreactive fibers was seen reinnervating broad regions of the ipsilateral putamen and caudate nucleus. The nongrafted, contralateral striatum remained deafferented. Intrastriatal autografting of carotid body tissue is a feasible technique with beneficial effects on parkinsonian monkeys; thus, this therapeutic approach could also be applied to treat patients with Parkinson's disease.

Immunohistochemical characterization of the rat carotid body.

We studied the histochemical phenotype of carotid body (CB) cells in the adult rat. In addition to tyrosine hydroxylase (TH), type I cells expressed numerous growth factors such as glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), as well as the receptors p75, Ret, epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-alpha (PDGFR-alpha). Type II cells expressed the glial fibrillary acid protein (GFAP), vimentin, the trophic factor bFGF and receptors p75, EGFR and PDGFR-alpha. Both types I and II cells exhibited a positive immunoreaction to markers of neural progenitor cells such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) and nestin, respectively, suggesting that CB contain some immature cells even at the adult stage. The possibility that these cells can be expanded and differentiated into mature neurons should be explored.

Modification of the number and phenotype of striatal dopaminergic cells by carotid body graft.

In non-human primates, striatal tyrosine hydroxylase-immunoreactive (TH-ir) cells are increased in number after dopamine depletion and in response to trophic factor delivery. As carotid body cells contain the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF), we evaluated the number, morphology and neurochemistry of these TH-ir cells, in the anterior and posterior striatum of five monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which received a graft of carotid body cell aggregates (CBCA) (n = 3) or sham surgery (n = 2), and six MPTP-monkeys that were sacrificed 6 months and 3 years after the last MPTP dose [MPTP I (n = 3) and MPTP II (n = 3), respectively]. Three intact monkeys served as controls. A disability rating scale was used for the assessment of parkinsonism in all lesioned animals, both before and after surgery. For the neurochemical examination, tissue sections were double-labelled with antibodies to TH, dopamine transporter, dopa decarboxylase-67, vesicular monoamine transporter 2, glutamic acid decarboxylase -67, calbindin, parvalbumin, calretinin, neuronal nitric oxide synthase and GDNF. Only animals receiving CBCA graft showed a moderate but significant recovery of parkinsonism that persisted 12 months after the graft. The grafted striatum contained the greatest TH-ir cell density (120.4 +/- 10.3 cells/100 mm2), while the control striatum displayed the lowest (15.4 +/- 6.8 cells/100 mm2), and MPTP I, MPTP II and sham-operated monkeys showed a similar intermediate value (66.1 +/- 6.2, 58.3 +/- 17.2 and 57.7 +/- 7.0 cells/100 mm2, respectively). In addition, in the post-commissural striatum, only CBCA graft induced a significant increase in the TH-ir cell density compared to control animals (47.9 +/- 15.9 and 7.9 +/- 3.2, respectively). Phenotypically, TH-ir cells were striatal dopaminergic interneurons. However, in the grafted animals, the phenotype was different from that in control, MPTP and sham-operated monkeys, with the appearance of TH/GDNF-ir cells and the emergence of two TH-ir subpopulations of different size as the two main differentiating features. Our data confirm and extend previous studies demonstrating that striatal CBCA grafts produce a long-lasting motor recovery of MPTP-monkeys along with an increase in the number and phenotype changes of the striatal TH-ir interneurons, probably by the action of the trophic factors contained in carotid body cells. The increased number of striatal TH-ir cells observed in the grafted striatum may contribute to the improvement of parkinsonism observed after the graft.

[Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia]. / Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.

INTRODUCTION: Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. AIM: To analyze and summarize different questions about the use of BTA in our clinical practice. DEVELOPMENT: A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. CONCLUSION: This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.

TITLE: Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.Introduccion. La toxina botulinica de tipo A (TBA) ha supuesto una verdadera revolucion terapeutica en neurologia, y en la actualidad es el tratamiento rutinario en las distonias focales y la espasticidad. Objetivo. Plantear, revisar y responder cuestiones controvertidas en relacion con la neurofarmacologia de la TBA y su uso en las distonias en la practica clinica habitual. Desarrollo. Un grupo de expertos en trastornos del movimiento reviso una lista de temas controvertidos relacionados con la farmacologia de la TBA y su uso en las distonias. Revisamos la bibliografia e incluimos articulos relevantes especialmente en ingles, pero tambien, si su importancia lo merece, en castellano y en frances, hasta junio de 2016. El documento se estructuro como un cuestionario que incluyo las preguntas que podrian generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. Incluimos preguntas sobre diferentes aspectos de la neurofarmacologia, especialmente el mecanismo de accion, la bioequivalencia de los diferentes preparados y la inmunogenicidad. En relacion con el subapartado de las distonias, se incluyeron aspectos sobre la evaluacion y el tratamiento de las distonias focales. Conclusiones. Esta revision no pretende ser una guia, sino una herramienta practica destinada a neurologos y medicos internos residentes interesados en esta area, dentro de diferentes ambitos especificos del manejo de la TBA.

Neutral-red reaction is related to virulence and cell wall methyl-branched lipids in Mycobacterium tuberculosis.

Searching for virulence marking tests for Mycobacterium tuberculosis, Dubos and Middlebrook reported in 1948 that in an alkaline aqueous solution of neutral-red, the cells of the virulent H37Rv M. tuberculosis strain fixed the dye and became red in color, whereas the cells of the avirulent H37Ra M. tuberculosis strain remained unstained. In the 1950 and 1960s, fresh isolates of M. tuberculosis were tested for this neutral-red cytochemical reaction and it was reported that they were neutral-red positive, whereas other mycobacteria of diverse environmental origins that were non-pathogenic for guinea pigs were neutral-red negative. However, neutral-red has not really been proven to be a virulence marker. To test if virulence is in fact correlated to neutral-red, we studied a clinical isolate of M. tuberculosis that was originally neutral-red positive but, after more than 1 year passing through culture mediums, turned neutral-red negative. We found that, in comparison to the original neutral-red positive strain, this neutral-red negative variant was attenuated in two murine models of experimental tuberculosis. Lipid analysis showed that this neutral-red negative natural mutant lost the capacity to synthesize pthiocerol dimycocerosates, a cell wall methyl-branched lipid that has been related to virulence in M. tuberculosis. We also studied the neutral-red of different gene-targeted M. tuberculosis mutants unable to produce pthiocerol dimycocerosates or other cell wall methyl-branched lipids such as sulfolipids, and polyacyltrehaloses. We found a negative neutral-red reaction in mutants that were deficient in more than one type of methyl-branched lipids. We conclude that neutral-red is indeed a marker of virulence and it indicates important perturbations in the external surface of M. tuberculosis cells.

Brain aging and Parkinson's disease: New therapeutic approaches using drug delivery systems.

The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.

Development and characterization of polo-like kinase 2 loaded nanoparticles-A novel strategy for (serine-129) phosphorylation of alpha-synuclein.

Polo like kinase 2 (PLK2), a serine/threonine serum inducible kinase, has been proposed to be the major factor responsible for phosphorylating alpha-synuclein (α-syn) at Serine-129 (Ser-129) in Parkinson's disease (PD). A suitable strategy to gain insights into PLK2's biological effects might be to increase PLK2 intracellular levels with the aim of reproducing the slow progressive neuronal changes that occur in PD. The goal of this study was to develop and characterize a novel drug delivery system (DDS) for PLK2 cytosolic delivery using Total recirculating one machine system (TROMS), a technique capable of encapsulating fragile molecules while maintaining their native properties. A protocol for nanoparticle (NP) preparation using TROMS was set up. NPs showed a mean diameter of 257±15.61nm and zeta potential of -16±2mV, suitable for cell internalization. TEM and SEM images showed individual, spherical, dispersed NPs. The drug entrapment efficacy was 61.86±3.9%. PLK2-NPs were able to enter SH-SY5Y cells and phosphorylate α-syn at Ser-129, demonstrating that the enzyme retained its activity after the NP manufacturing process. This is the first study to develop a DDS for continuous intracellular delivery of PLK2. These promising results indicate that this novel nanotechnology approach could be used to elucidate the biological effects of PLK2 on dopaminergic neurons.

[Neuropsychological profile of frontotemporal lobar degeneration]. / Perfil neuropsicológico de la degeneración lobar frontotemporal.

Frontotemporal lobar degeneration encompasses three different syndromes, with clinical and pathologic commonalities, making diagnosis difficult in early stages. Three subtypes are recognized: frontotemporal dementia and its three variants, corticobasal syndrome and supranuclear palsy syndrome. The objective of this study is to review the neuropsychological features of each syndrome in order to differentiate amongst subtypes as well as from other forms of dementia. We review multiple studies from the literature, highlighting the main clinical features, neuropathology and changes in brain imaging of each syndrome. Subsequently, we describe the neuropsychological profile compared to other dementias, and how it progresses over time. Although there is an overlap amongst the different subtypes of frontotemporal lobar degeneration, neuropsychological profiles can help identify subtypes and discriminate frontotemporal lobar degeneration from other forms of dementia.

Gangliosides and parkinsonism.

The protective effect of GM1 ganglioside against nerve cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was analyzed in monkey mesencephalon. Administration of GM1 before and during MPTP treatment improved motor performances compared with MPTP-treated animals that received saline rather than GM1. Postmortem analysis revealed that GM1 did not protect dopaminergic cell bodies from MPTP intoxication but resulted in an increased immunoreactivity of tyrosine hydroxylase in the perikarya and processes of the surviving neurons. These data suggest that GM1 may be potentially used as a palliative rather than a curative therapy in Parkinson's disease.

Motor complications associated with chronic levodopa therapy in Parkinson's disease.

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.

Consequences of nigrostriatal denervation on the gamma-aminobutyric acidic neurons of substantia nigra pars reticulata and superior colliculus in parkinsonian syndromes.

To examine the effects of nigrostriatal denervation on the substantia nigra pars reticulata (SNpr), one of the main outputs of the basal ganglia, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the SNpr neurons from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), and their respective controls. In MPTP-intoxicated monkeys, the expression of GAD67 mRNA was increased in the SNpr neurons, and the increase was reversed by L-dopa treatment. There were no differences in the level of GAD67 mRNA between PD patients who had been treated with L-dopa and control subjects. Combined with the previously reported increased expression of GAD67 mRNA in the internal segment of the pallidum of MPTP-intoxicated monkeys, these data suggest that the gamma-aminobutyric acid (GABAergic) activity of the output system of the basal ganglia is globally increased by nigrostriatal denervation. We also analyzed the level of GAD67 mRNA expression in the superior colliculus, a structure that receives the inhibitory influence of the GABAergic neurons of the SNpr and that is involved in eye movement control. GAD67 mRNA expression was reduced in both MPTP-intoxicated monkeys, whether or not they received L-dopa therapy, and PD patients, compared to their respective controls. This decrease may result from the hyperactivity of the inhibitory nigrotectal pathway, but also from other influences since it was not corrected by L-dopa therapy. These changes may account for the slight ocular motor and visuospatial cognitive impairment occurring in PD, even after L-dopa therapy.

Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum.

To examine the consequences of nigrostriatal denervation and L-dopa treatment on the basal ganglia output system, we analyzed, by quantitative in situ hybridization, the messenger RNA coding for glutamic acid decarboxylase (Mr 67,000) (GAD67 mRNA) in pallidal cells from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) receiving or not receiving L-dopa, and their respective control subjects. In MPTP-treated monkeys, the expression of GAD67 mRNA was increased in cells from the internal pallidum, and this effect was abolished by L-dopa treatment. There were no differences in the levels of GAD67 mRNA between patients with PD, who were all treated with L-dopa, and control subjects. These results indicate that the level of GAD67 mRNA is increased in the cells of the internal pallidum after nigrostriatal dopaminergic denervation and that this increase can be reversed by L-dopa therapy.