Parkinson’s disease (PD) is characterized by the loss of dopamine in the basal ganglia and leads to paucity of movements, rigidity of the limbs, and rest tremor. Synaptic plasticity was characterized in the substantia nigra pars reticulata (SNr), a basal ganglia output structure, in 18 PD patients undergoing implantation of deep brain stimulating electrodes. Field evoked potentials (fEPs) in SNr were measured with one microelectrode using single pulses from a second microelectrode ~ 1 mm away. High frequency stimulation (HFS – 4 trains of 2s at 100Hz) in the SNr failed to induce a lasting change in test fEPs amplitudes in patients OFF medication. Following L-Dopa, HFS induced a potentiation of the fEPs that lasted more than 150s. Our findings suggest that extrastriatal dopamine modulates activity dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of PD.

Darmstadt, Techn. Univ., Diss., 2002. / Dateien im PDF-Format

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23070号 / 医博第4697号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 溝脇 尚志, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Hintergrund: Bei erwachsenen Patient*innen mit Erkrankungen aus dem Schizophrenie-Spektrum konnte im transkraniellen Ultraschall im Vergleich zu gesunden Proband*innen eine signifikant erhöhte Echogenität der Substantia Nigra (SN) nachgewiesen werden. Zudem bestand ein Zusammenhang zwischen der SN-Fläche und stärker ausgeprägten extrapyramidalmotorischen Bewegungsstörungen unter Antipsychotikatherapie. In der vorliegenden Arbeit wurde überprüft, inwiefern die Echogenität der SN auch bei Jugendlichen und jungen Erwachsenen als Biomarker für Erkrankungen aus dem psychotischen Formenkreis und als Korrelat psychopharmakologischer Nebenwirkungen herangezogen werden kann. Des Weiteren wurde der Einfluss von Alter, Krankheitsdauer sowie Antipsychotika-Lebenszeitdosis auf die SN-Echogenität untersucht sowie Zusammenhänge mit peripheren Eisenparametern. Methoden: Hierfür wurden insgesamt 16 stationär behandelte Patient*innen zwischen 14 – 22 Jahren mit Erkrankungen aus dem schizophrenen Formenkreis sowie nach Alter und Geschlecht gematchte gesunde Kontrollen mittels TCS untersucht. Aus peripher entnommenem Blut wurden Parameter des Eisenhaushalts bestimmt. Ergebnisse: Es konnten entgegen der Hypothese keine signifikanten Unterschiede in Bezug auf die Echogenität der SN im Vergleich zur gesunden Kontrollgruppe festgestellt werden. Bezüglich der Schwere der beobachteten EPMS ergab sich entgegen der Hypothese und im Kontrast zu Befunden bei Erwachsenen kein Zusammenhang mit der SN-Echogenität. Das Alter der Proband*innen, die Krankheitsdauer sowie die Dosis der eingenommenen Antipsychotika zeigten keine Zusammenhänge mit der SN-Echogenität. Interessanterweise zeigte sich eine signifikant negative Korrelation zwischen der echogenen Fläche der SN und Eisen sowie Transferrin. Schlussfolgerung: Im Jugend- und jungen Erwachsenenalter eignet sich die SN-Echogenität vermutlich nicht als Biomarker für Erkrankungen aus dem Schizophrenie-Spektrum oder für die Prädiktion von Nebenwirkungen antipsychotischer Medikation. Möglicherweise manifestiert sich eine erhöhte Echogenität der SN, welche als Zeichen für eine Schädigung der dopaminergen Neurone gesehen wird, bei schizophrenen Psychosen erst im Verlauf der Krankheit. Da wir die Studienteilnehmer*innen nur zu einem einzigen Zeitpunkt im Laufe ihrer Krankheitsgeschichte untersuchten, kann keine Aussage über den weiteren Verlauf der SN-Echogenität getroffen werden. Hierfür wären longitudinale Untersuchungen zielführend, da nur so mögliche entwicklungsbedingte Veränderungen festgestellt werden können. / Background: Adult patients with schizophrenic spectrum disorders showed a significantly larger mean echogenic area of the subtantia nigra (SN) in transcranial sonography compared to healthy controls. Also, patients showing larger echogenic SN developed more severe neuroleptic-induced extrapyramidal side-effects. In this study, we examined if SN echogenicity can function as a biomarker for schizophrenic spectrum disorders and as a predictor of neuroleptic-induced extrapyramidal side-effects in adolescents and young adults. Furthermore, we investigated the correlation of age, disease duration, lifetime neuroleptic dose and iron parameters with SN echogenicity. Methods: 16 hospitalized patients who had been diagnosed with schizophrenic spectrum disorders and 16 healthy controls between the ages of 14 – 22 years were examined via transcranial sonography. We also assessed the concentration of iron parameters in peripheral blood samples. Results: In contradiction to our hypothesis, no significant differences regarding SN echogenicity could be found when comparing the two groups. There also was no correlation of severity of extrapyramidal side-effects, age, disease duration or lifetime neuroleptic dose with echogenicity of the SN. Interestingly, we found a significant negative correlation of SN echogenicity with serum iron as well as serum transferrin levels. Conclusion: SN echogenicity apparently cannot be used as a biomarker for schizophrenic spectrum disorders or a predictor of neuroleptic-induced extrapyramidal side-effects in adolescents and young adults. Increased SN echogenicity, which is assumed to be an indicator of nigrostriatal injury, presumably evolves much later in the course of schizophrenic disorders. As our probands underwent examination only once in the course of their disease, we cannot draw conclusions regarding the development of SN echogenicity. Longitudinal studies are needed to shed more light on possible developmental changes in this regard.

Melatonin has a neuroprotective function, which is mediated via its G-protein-coupled MT1 and MT2 receptors. When activated, various downstream pathways are triggered promoting cell protection and survival. By utilizing this function of melatonin, studies have shown positive effects in animal models of neurodegenerative disorders such as Parkinson’s disease (PD). In our previous studies, a physiological dose of melatonin was shown to have neuroprotective effects in the nigrostriatal pathway, as indicated by preservation of tyrosine hydroxylase (TH) immunoreactivity in a 6-hydroxydopamine (6-OHDA) model of PD. We also have reported that transplantation of MT1 receptor-expressing mouse neural stem cells (C17.2) along with melatonin treatment, preserved TH immunoreactivity in a similar PD model. Moreover, others have reported an increase in striatal melatonin levels in 6-OHDA-induced hemiparkinsonian rats. Based on these implications of a close relationship between the dopaminergic and melatonergic systems, we hypothesize that degeneration of dopaminergic neurons induced by 6-OHDA will affect the melatonergic system in the nigrostriatal pathway. In this study, 6-hydroxydopamine was unilaterally injected in the rat striatum or medial forebrain bundle. An apomorphine rotation test showed significant increases in net contralateral rotations (p<0.01) in lesioned animals as compared to sham. Also, a loss of TH immunoreactivity in the striatum and substantia nigra was seen in striatum lesioned groups, confirming lesion-induced degeneration of dopaminergic neurons in the nigrostriatal pathway. There were no significant differences in MT1 receptor protein expression in the striatum and substantia nigra, between all intrastriatal lesioned groups and the sham group. However, 6-OHDA lesions in the medial forebrain bundle caused a significant increase in MT1 receptor mRNA expression on the lesioned side (right) of the ventral midbrain as compared with the contralateral side. These results suggest that MT1 receptors are upregulated in the ventral midbrain following lesion-induced dopaminergic neurodegeneration, and may be involved in an endogenous neuroprotective mechanism. / Thesis / Master of Science (MSc)

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Over 15 million contact sports players and military veterans are at risk for the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) that sometimes presents with parkinsonian motor symptoms, although very little is understood about how these individuals develop parkinsonism. CTE is characterized by accumulation of hyperphosphorylated tau protein (p-tau), and diagnosis requires the presence of neuronal tau in the form of neurofibrillary tangles at the depth of cortical sulci. We performed quantitative immunoassays for markers of neurovascular inflammation within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers were increased in CTE compared to RHI-exposed and -naïve controls. Markers increased with RHI exposure duration and were associated with increased microglial density and tau pathology. Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity. We next performed a cross-sectional analysis of all brain donors with CTE and without comorbid neurodegenerative disease (n=495) in the UNITE Brain Bank. Participants with parkinsonism (CTE-p, n=119) had a higher mean age at death (71.5 years (y)) than participants without parkinsonism (CTE-np, n=362, 54.1 y) and exhibited a higher rate of dementia than CTE-np participants. CTE-p participants had a more severe CTE stage and nigral pathology (NFTs, neuronal loss, and more frequent Lewy bodies), though the majority of cases were negative for nigral Lewy bodies. In American football players, simultaneous regression analysis demonstrated that nigral NFTs and neuronal loss mediate a connection between years of play and parkinsonism in CTE. In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation was associated with SN proteinopathy and neuronal loss, and these pathologies were associated with parkinsonism. Finally, in a postmortem cohort (n=392) of brain donors with CTE without comorbid neurodegenerative disease, we used linear regression modelling to analyze the associations between isodendritic core nuclei pathology (semiquantitative neurofibrillary tangles (NFTs), neurites, and neuronal loss scores) and CTE disease severity, RHI exposure duration (years of contact sport play), and informant-reported cognitive and daily function as assessed by the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ), respectively. Overall, isodendritic core (IC) NFT scores increase with disease stage, Initially in the locus coeruleus and finally in the median raphe nuclei. Neuronal loss occurred at later disease stages than NFT accumulation. RHI exposure was associated with p-tau pathology for all IC regions. NFTs and neuronal loss in the substantial nigra were associated with increased CDS scores (i.e., worse cognitive function), and neuronal loss in the substantia nigra and locus coeruleus were associated with increased FAQ scores (i.e., worse daily function). We are able to show CTE is similar in distribution of p-tau pathology to progressive supranuclear palsy (PSP), a disease that is thought to primarily affect subcortical regions, especially by end stage disease. These results demonstrate the vulnerability of the isodendritic core nuclei to p-tau pathology and neuronal loss in CTE, and suggest that their involvement contributes to cognitive and functional symptoms during life. This work highlights the possible linkage between neuroinflammation leading to nigral p-tau accumulation and neuron loss which likely underlies the development and progression of parkinsonian motor symptoms in CTE.

No / Nursing has reciprocal benefits for both mother and infant, helping to promote maternal behavior and bonding. To test the "rewarding" nature of nursing, functional magnetic resonance imaging was used to map brain activity in lactating dams exposed to their suckling pups versus cocaine. Suckling stimulation in lactating dams and cocaine exposure in virgin females activated the dopamine reward system. In contrast, lactating dams exposed to cocaine instead of pups showed a suppression of brain activity in the reward system. These data support the notion that pup stimulation is more reinforcing than cocaine, underscoring the importance of pup seeking over other rewarding stimuli during lactation

Thesis (M.Sc.)--Memorial University of Newfoundland, 2003. / Restricted until October 2004. Bibliography: leaves 90-116.

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