Neuropsychiatric symptoms and brain dopamine transporter imaging in Parkinson's disease

Parkinson’s disease (PD) is a common neurodegenerative movement disorder. The motor symptoms of PD are linked to the degeneration of dopaminergic neurons of the substantia nigra, which leads to dopamine depletion in the striatum. Non-motor symptoms (NMSs), such as depression, hallucinations and impulse control disorders (ICDs), are important manifestations of PD. The role of dopamine in the pathophysiology of these symptoms is less clear. This thesis investigated NMSs in PD and their association with brain dopamine function using dopamine transporter (DAT) single-photon emission computed tomography (SPECT) imaging. Furthermore, factors that predict the DAT imaging outcome were investigated. The results suggest that ICDs of PD are associated with multiple other psychiatric symptoms. Furthermore, an older age, longer motor symptom duration and asymmetric motor symptoms are associated with an abnormal DAT imaging outcome. The results also demonstrate that lower DAT binding in the limbic striatum is associated with the development of hallucinations in PD. Finally, although PD patients suffer from multiple NMSs, the total burden of these symptoms does not differentiate PD patients from parkinsonism patients with normal DAT binding. The results demonstrate that the total NMS burden is not a specific manifestation for Parkinson’s disease and is unrelated to brain dopamine function. Clinical factors, such as patient age, motor symptom duration and motor symptom asymmetry, may be useful for selecting which patients should undergo DAT SPECT imaging. Moreover, DAT imaging may be useful in predicting subsequent NMS manifestations, such as visual hallucinations; however, further studies are required.Neuropsykiatriset oireet ja aivojen dopamiinitransportterikuvantaminen parkinsonin taudissa Parkinsonin tauti on yleinen neurodegeneratiivinen liikehäiriö. Parkinsonin taudin motoristen oireiden ajatellaan johtuvan keskiaivojen mustatumakkeen dopaminergisten hermosolujen tuhoutumisesta. Motoristen oireiden lisäksi ei-motoriset oireet, kuten masennus, hallusinaatiot ja impulssikontrollihäiriöt, ovat tärkeitä Parkinsonin taudin ilmentymiä. Dopamiinin merkitys Parkinsonin taudin ei-motoristen oireiden patofysiologiassa on vielä epäselvä. Tässä väitöskirjassa tutkittiin Parkinsonin taudin ei-motorisia oireita sekä niiden yhteyttä aivojen dopamiinitoimintaan käyttäen aivojen dopamiinitransportterien yksifotoniemissiotomografiakuvausta. Lisäksi tutkittiin kliinisiä tekijöitä, jotka ennustavat dopamiinitransportterikuvauksen tulosta. Tämän tutkimuksen kohteina olleilla henkilöillä Parkinsonin taudin impulssikontrollihäiriöt esiintyivät usein yhdessä muiden psykiatristen oireiden kanssa. Epänormaaliin löydökseen dopamiinitransportterikuvauksessa liittyivät korkea ikä, pitkä motoristen oireiden kesto sekä epäsymmetriset oireet. Tulokset osoittavat myös, että aivojen alentunut dopamiinitransportterisitoutuminen limbisessä aivojuoviossa liittyy Parkinsonin tautia sairastavilla hallusinaatioiden kehittymiseen. Lisäksi, vaikka Parkinsonin tautia sairastavat potilaat kärsivät monista ei-motorisista oireista, näiden oireiden kokonaismäärä ei näyttäisi erottavan Parkinsonin tautia sairastavia potilaita niistä potilaista, joilla esiintyy parkinsonismia mutta joiden aivojen dopamiinitransportterisitoutuminen on normaalia. Tulokset osoittavat, että ei-motoristen oireiden kokonaismäärä ei ole spesifinen ilmentymä Parkinsonin taudille, eikä se liity aivojen dopamiinitoimintaan. Kliiniset tekijät, kuten potilaan ikä, oireiden kesto ja motoristen oireiden epäsymmetria, voivat olla avuksi, kun valitaan tutkittaviksi potilaita, jotka hyötyvät aivojen dopamiinitransportterikuvauksesta. Vaikka aihetta on tutkittava vielä lisää, tulosten perusteella dopamiinitransportterikuvaus voi olla hyödyksi, kun ennustetaan ei-motoristen oireiden, kuten hallusinaatioiden, kehittymisiä Parkinson-potilailla

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) [FP7-242003], from the Medical Research Council (MRC) [MR/P025870/1] and from Parkinson’s UK [J-1204]. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) and NIHR Imperial CRF at Imperial College healthcare NHS trust. The views expressed are those of the authors and not necessarily those of the funder, the NHS, the NIHR, or the Department of Health. This work was also supported financially by a PhD studentship awarded to N.P.L-K from Parkinson’s UK

PET studies on the aetiology of Parkinson's disease and on the efficacy of cell transplantation therapy

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Volume increases in putamen associated with positive symptom reduction in previously drug-naive schizophrenia after 6 weeks antipsychotic treatment

Background Brain structure appears to alter after antipsychotic administration, but it is unknown whether these alterations are associated with improvement of psychopathology in patients with schizophrenia. In this study, the authors explore this relationship.Method Altogether, 66 first-episode, drug-naive patients with schizophrenia and 23 well-matched healthy controls underwent brain magnetic resonance imaging scans at baseline. All 23 healthy controls and 42 of the patients were rescanned after 6 weeks follow-up. The patients received regular antipsychotic treatment during the 6-week period and their psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and 6 weeks. The difference in PANSS scores between baseline and 6 weeks was expressed as a ratio of the scores at baseline a- a PANSS reduction ratio. A modified tensor-based morphometry procedure was applied to analyse longitudinal images. Correlations between regional volume changes, PANSS reduction ratio and antipsychotic drug dosages were explored.Results Compared with healthy controls, there was a significant increase in grey-matter volume of the right putamen in patients after 6 weeks treatment. This volume change was positively correlated with a positive PANSS reduction score but not related to drug dosages.Conclusions Putaminal volume increased after 6 weeks antipsychotic treatment in first-episode schizophrenia. The increased volume was closely correlated with improved psychopathology, suggesting the putamen might be a biomarker to predict the treatment response in schizophrenia. © 2011 Cambridge University Press.published_or_final_versio

Molecular Imaging of Central Dopamine in Obesity : A Qualitative Review across Substrates and Radiotracers

Dopamine is a neurotransmitter that plays a crucial role in adaptive behavior. A wealth of studies suggests obesity-related alterations in the central dopamine system. The most direct evidence for such differences in humans comes from molecular neuroimaging studies using positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The aim of the current review is to give a comprehensive overview of molecular neuroimaging studies that investigated the relation between BMI or weight status and any dopamine target in the striatal and midbrain regions of the human brain. A structured literature search was performed and a summary of the extracted findings are presented for each of the four available domains: (1) D2/D3 receptors, (2) dopamine release, (3) dopamine synthesis, and (4) dopamine transporters. Recent proposals of a nonlinear relationship between severity of obesity and dopamine imbalances are described while integrating findings within and across domains, after which limitations of the review are discussed. We conclude that despite many observed associations between obesity and substrates of the dopamine system in humans, it is unlikely that obesity can be traced back to a single dopaminergic cause or consequence. For effective personalized prevention and treatment of obesity, it will be crucial to identify possible dopamine (and non-dopamine) profiles and their functional characteristics.Peer reviewe

An Initial Analysis of a Long-Term Ketogenic Diet’s Impact on Motor Behavior, Brain Purine Systems, and Nigral Dopamine Neurons in a New Genetic Rodent Model of Parkinson’s Disease

A growing body of research suggests that dopaminergic cell death seen in Parkinson’s disease is caused by mitochondrial dysfunction. Oxidative stress, with subsequent generation of reactive oxygen species, is the hallmark biochemical product of mitochondrial dysfunction. The ketogenic diet has been found to enhance mitochondrial energy production, protect against reactive oxygen species-generated cell death, and increase adenosine, a purine that modulates dopamine activity. The current study evaluates the effects of a long-term (5-month) ketogenic diet on behavioral, neurochemical, and neuroanatomical measures in PINK1-KO rats, a new animal model of Parkinson’s disease. Both wild-type and PINK1-KO animals fed a ketogenic diet exhibited significantly higher blood beta-hydroxybutyrate levels. PINK1-KO animals fed a normal diet experienced a decrease in stride length and an increase in stride frequency over time which was absent in PINK1-KO animals fed a ketogenic diet. Animals fed the ketogenic diet had decreased tissue content of both adenosine and inosine in the nucleus accumbens, posterior caudate, hippocampus, and substantia nigra. Finally, immunohistochemical staining for tyrosine hydroxylase-positive cells in the substantia nigra suggest a ketogenic diet-induced protection of dopaminergic cell death. The results of the present study indicate that a long-term ketogenic diet may positively impact both motor and neuroanatomical correlates and alter neurochemical systems in a genetic rodent model of Parkinson’s disease

An Initial Analysis of a Long-Term Ketogenic Diet’s Impact on Motor Behavior, Brain Purine Systems, and Nigral Dopamine Neurons in a New Genetic Rodent Model of Parkinson’s Disease

A growing body of research suggests that dopaminergic cell death seen in Parkinson’s disease is caused by mitochondrial dysfunction. Oxidative stress, with subsequent generation of reactive oxygen species, is the hallmark biochemical product of mitochondrial dysfunction. The ketogenic diet has been found to enhance mitochondrial energy production, protect against reactive oxygen species-generated cell death, and increase adenosine, a purine that modulates dopamine activity. The current study evaluates the effects of a long-term (5-month) ketogenic diet on behavioral, neurochemical, and neuroanatomical measures in PINK1-KO rats, a new animal model of Parkinson’s disease. Both wild-type and PINK1-KO animals fed a ketogenic diet exhibited significantly higher blood beta-hydroxybutyrate levels. PINK1-KO animals fed a normal diet experienced a decrease in stride length and an increase in stride frequency over time which was absent in PINK1-KO animals fed a ketogenic diet. Animals fed the ketogenic diet had decreased tissue content of both adenosine and inosine in the nucleus accumbens, posterior caudate, hippocampus, and substantia nigra. Finally, immunohistochemical staining for tyrosine hydroxylase-positive cells in the substantia nigra suggest a ketogenic diet-induced protection of dopaminergic cell death. The results of the present study indicate that a long-term ketogenic diet may positively impact both motor and neuroanatomical correlates and alter neurochemical systems in a genetic rodent model of Parkinson’s disease

Quantification of striatal dopaminergic uptake in Parkinson's disease: a new multimodal method combining SPECT DaT and MPRAGE

Parkinson's disease (PD) is a neurodegenerative disease that causes degeneration of nigral dopaminergic terminals in the caudate and the putamen regions of the striatum in the basal ganglia. According to current practice, when an unequivocal clinical diagnosis of PD cannot be made, a single-photon emission computed tomography scan using the DaTscan radionuclide (SPECT DaT scan) is ordered. However, the assessment of SPECT DaT scans in the diagnosis of PD depends on the subjective judgment of a radiologist, which can pose problems for the accuracy of the diagnosis. Furthermore, as research studies generally do not quantify SPECT DaT scans when using them, their conclusions are not based on standardized data. The aim of this paper is to propose a method of quantification for SPECT DaT scans, to be employed in diagnostic and research environments. The methodology proposed in this thesis project will eventually be used for a much larger multimodal imaging project investigating the connectivity changes in the brain related to cognitive and affective symptoms in PD patients. Each of the 4 subjects in this project underwent a SPECT DaT scan and an MPRAGE scan (Magnetization Prepared Rapid Gradient Echo), an anatomical MRI (magnetic resonance image). The SPECT DaT scans and the MPRAGEs were coregistered, and then a voxel-based quantification of the caudate and the putamen in the left and the right hemispheres was performed in every subject. First, the percentages of voxels with intensities exceeding various pericalcarine baselines were calculated. A pericalcarine baseline was used because the pericalcarine gyrus in the occipital lobe has been shown to have little to no dopaminergic activity, particularly on SPECT DaT scans. Next, asymmetry indices (AI) were calculated for two of the thresholds whereby the ratio of the percentage of voxels in the right to the left hemispheric region was taken. Wilcoxon Signed-Rank tests and bootstrapping analyses were performed on both the caudate and the putamen in all four subjects to determine the significance of any detected asymmetry. The quantification of the data and the AI values revealed asymmetries in the voxel intensities between the left and right hemispheres. This asymmetry was consistent with each subject's side of physical symptom onset. According to the bootstrapping analyses, this asymmetry was significant in five of the eight comparisons. In summary, this methodology has potential to bring greater objectivity to the use of SPECT DaT scans in the diagnosis of PD and in research through its anatomically accurate, voxel-based quantification