Mapping track density changes in nigrostriatal and extranigral pathways in Parkinson's disease

peer reviewedHighlights First whole-brain probabilistic tractography study in Parkinson's disease High quality diffusion-weighted images (120 gradient directions, b = 2500 s/mm2) Voxel-based group analysis comparing early-stage patients and controls Abnormal reconstructed track density in the nigrostriatal pathway and brainstem Track density also increased in limbic and cognitive circuits

LRRK2 genetics and expression in the Parkinsonian brain

Mutations in LRRK2 have been established as a common genetic cause of Parkinson’s disease (PD). Variation in gene expression of PARK loci has previously been demonstrated in PD pathogenesis, although it has not been described in detail for LRRK2 expression in the human brain. This study further elucidates the role of LRRK2 in development of PD by describing an investigation into the role of LRRK2 genetics and expression in the human brain. The G2019S mutation is a common LRRK2 mutation that exhibits a clinical and pathological phenotype indistinguishable from idiopathic PD. Thus, the study of G2019S mutation is a recurrent theme. The frequency of G2019S was estimated in unaffected subjects that lived or shared a cultural heritage to the predicted founding populations of the mutation, and was found not to be common in these populations. Morphological analysis revealed a ubiquitous expression for LRRK2 mRNA and protein in the human brain. In-situ hybridisation data suggests that LRRK2 mRNA is present as a low copy number mRNA in the human brain. A semi-quantitative analysis of LRRK2 immunohistochemistry revealed extensive regional variation in the LRRK2 protein levels, although the weakest immunoreactivity was consistently identified in the nigrostriatal dopamine region. No difference was observed in the morphological localisation of LRRK2 mRNA and protein in unaffected, IPD or G2019S positive PD subjects. Dysregulation of LRRK2 mRNA expression and the effects of cis- acting genetic variation on these levels were demonstrated. A widespread decrease of LRRK2 mRNA was observed in IPD and G2019S positive PD subjects in comparison to unaffected controls. Furthermore, non-coding genetic variation was also demonstrated to have an effect on the LRRK2 transcriptional activity in PD subjects. Collectively, these findings suggest that LRRK2 has an important physiological role, and a dysregulation in its levels could affect auxiliary mechanisms that contribute to PD pathogenesis. This data also supports the possibility of a shared mechanism contributing to the identical phenotype of IPD and G2019S linked PD

Brain connectivity analysis of patients with Parkinson’s disease

Mestrado em Radiações Aplicadas às Tecnologias da Saúde - Ramo de especialização: Ressonância MagnéticaAtualmente existe um debate sobre “Scans Without Evidence for Dopaminergic Deficit" (SWEDD) de ser uma patologia independente ou um subtipo benigno da doença de Parkinson (DP). Neste estudo analisou-se a conectividade estrutural cerebral de 30 indivíduos saudáveis, 29 doentes com SWEDD e 29 doentes com DP, utilizando diversos softwares especializados e a teoria dos grafos para caracterizar 96 regiões de interesse. Diferentes métricas de imagem e de conectividade foram obtidas a partir de dados de imagem em ponderação T1 e de tensor de difusão. Em relação aos dados demográficos dos grupos, observaram-se diferenças estatísticas na Unified Parkinson Disease Rating Scale entre os indivíduos saudáveis (Controlo) e os doentes com DP (p=0,000) e com SWEDD (p=0,000). Na comparação Controlo vs DP, várias diferenças foram observadas em relação às métricas de imagem e de conectividade, particularmente nos núcleos da base de ambos os hemisférios. No Controlo vs SWEDD, as regiões dos lobos frontal e parietal mostraram alterações nas métricas de conectividade, particularmente o giro marginal superior e o giro parietal superior de ambos os hemisférios. Na DP vs SWEDD, foram observadas alterações de métricas de imagem e de conectividade, particularmente no polo frontal e no córtex pré-frontal anterior. Todos os resultados observados neste estudo estão de acordo com a literatura sobre mudanças observadas nas regiões relacionadas com as, mesolímbica mesocortical e nigroestriatal. Estes achados sugerem que o estudo da conectividade estrutural é um importante método para distinguir SWEDD e DP.ABSTRACT - Currently, there is an ongoing controversy about Scans Without Evidence of Dopaminergic deficit (SWEDD) being a Parkinson’s Disease (PD) lookalike disease or a benign subtype of PD. In this study the brain structural connectivity of 30 healthy subjects, 29 patients with SWEDD and 29 patients with PD was analysed, using various specialized software and graph theory to characterize the structural connectivity of 96 regions of interest. Different imaging metrics and connectivities were obtained from diffusion tensor imaging and T1 weighted data. With regard to group data, statistical differences in Unified Parkinson Disease Rating Scale (UPDRS) scores were observed between healthy subjects (Control) and PD (p=0.000) and SWEDD (p=0.000) patients. In comparing Control vs PD, several differences were observed regarding various imaging and connectivity metrics, particularly in the basal ganglia of both hemispheres. In comparing Control vs SWEDD, regions of the frontal and parietal lobes showed various connectivity metrics changes, particularly in the superior marginal gyrus and superior parietal gyrus of both hemispheres. In comparing SWEDD vs PD, various DTI-based imaging and connectivity metrics changes were observed, particularly in the frontal pole and rostral middle frontal gyrus. All results observed in this study are in agreement with the literature regarding observed changes in regions related to the nigrostriatal, mesocortical and mesolimbic pathways. These findings suggest that the study of SC is an important method in distinguishing between SWEDD and PD.info:eu-repo/semantics/publishedVersio

AN EXPLORATIVE ASSESSMENT OF POTENTIAL NOVEL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS FOR IDENTIFICATION OF PRODROMAL PARKINSON¿S DISEASE

ABSTRACT Background - Parkinson\u2019s disease (PD) is the second most common neurodegenerative disorder after Alzheimer, primarily affecting about 6 million people worldwide. An early identification of PD is one of the main challenges in neurological research because to date, its diagnosis is still largely based on the clinical assessment of cardinal motor signs (bradykinesia, rigidity, resting tremor and postural instability) resulting by a progressive degeneration of dopaminergic neurons of the substantia nigra and locus coeruleus. However, impaired motor function appears when over 60% of the dopaminergic neurons are degenerated in the brain. In recent years, several evidence indicates that the onset of PD happens years to decades before the occurrence of classic motor symptoms. Pathological and imaging studies, for example, suggest that signs of nigrostriatal lesion can be detected 5\u201310 years before this clinical stage, and various observational prospective studies reveal that several non-motor symptoms (NMS) occur in this pre-diagnostic phase. Actually NMS such as olfactory impairment, cardiovascular dysautonomia such as orthostatic hypotension (OH) and rapid eye movement (REM) behaviour disorder (RBD) are currently being studied as features of prodromal PD and seem to be correlated to the early neuropathological process of disease. Beside these clinical manifestations, other biological alterations such as elevated oxidative stress and pro-inflammatory response have been involved in the cascade of events leading to degeneration of dopaminergic neurons. Recently, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of PD-related gene expression. Consequently, the characterization of several NMS together with the assessment of molecular biomarkers linked to inflammation and oxidative damage, could be a potential methodological approach for the early identification of PD patients. Objectives - The main objective of my study was to explore potential novel diagnostic and prognostic biomarkers of PD. Specific study aims were, in patients with prodromal and established PD: a) to evaluate clinical markers such as olfactory and cardiovascular autonomic functions; b) to measure circulating mediators of oxidative stress and inflammatory response as early biomarkers of organ failure; c) to correlate biological findings with clinical functional alterations; d) to characterize specific circulating miRNA profiles in plasma samples. Methods - For this purpose, we recruited 15 patients with overt PD (Hoehn and Yahr stage I-III, on L-DOPA and dopamine agonists combination therapy), 11 subjects diagnosed with idiopathic RBD (iRBD) confirmed by lack of atonia during the REM sleep phase on polysomnography and 12 age- and gender-matched controls (CTRL). All enrolled subjects underwent the following assessments: total olfactory score (TOS) using Sniffin' Sticks Extended Test; autonomic function by measuring heart rate variability during deep breathing (DB) test, which expresses parasympathetic function, lying to standing (LS) test and the Valsalva manoeuvre (VM), that gives information about both sympathetic and parasympathetic function; antioxidant/oxidative stress mediators [glutathione (GSH), the most important endogenous scavenger, assessed in total and reduced form and in plasma and blood samples according to a high performance liquid chromatographic (HPLC) method; plasma malondialdehyde (MDA), a marker of lipid peroxidation, assayed by HPLC with fluorescence detection; 8-hydroxy-2-deoxyguanosine (8-OHdG), index of oxidative DNA damage, and 3-nitrotyrosine (3-NT), a stable end product of peroxynitrite oxidation, analyzed by commercial ELISA kits]; inflammatory response [plasma concentrations of tumor necrosis factor alpha (TNF\uf061) and interleukin 1-beta (IL1\uf062), the most important inflammatory cytokines, by ELISA commercial kits, while urine neopterin levels, a sensitive marker of cellular-mediated inflammation, were measured by an isocratic HPLC method]. Biochemical parameters were than correlated with clinical functional results. The miRNA profiling was performed in a subpopulation of the enrolled subjects (4 PD, 4 iRBD and 4 CTRL) by small RNA Sequencing, using Miseq sequencer (Illumina). The differentially expressed (DE) miRNAs analysis, based on the negative binomial distribution, was performed with DE Seq2 by performing three comparisons:1) iRBD versus CTRL; 2) PD versus iRBD; 3) PD versus CTRL. Subsequently, the relative expressions of specific miRNAs were validated in all study population by quantitative real-time (qRT) PCR using miScript PCR System kit (Qiagen). Results - A significant worsening trend was observed in total olfactory score, blood reduced GSH, LS and VM ratio and neopterin from the reference controls to iRBD and PD groups. In the multivariable ordinal logistic regression model, only low blood reduced GSH levels (p=0.037, OR=0.994; 95% CI 0.988 \u2013 1.000), adjusted by history of hypertension, total olfactory score, LS ratio and VM ratio, were associated to PD status. Functional anosmia was similarly prevalent in iRBD (36%) and PD (33%) patients, but was absent in CTRL (p= 0.097). OH was more common among iRBD (73%) and PD (60%) than in controls (25%) (p=0.055), independently of antihypertensive treatment. A direct correlation was observed between total olfactory score and blood reduced GSH concentrations (R=0.034, p=0.037) and with VM ratio (R=0.43 p=0.015). Conversely, an inverse relation was found between total olfactory score and urine neopterin levels (R=-0.39 p=0.016). The results on circulating miRNA profiles found about 889 thousand sequenced reads mapped to mature miRNA sequences annotated in miRBase v21, by small RNA sequencing analysis. After data processing, no statistically significant DE miRNA was observed in the PD versus CTRL, whereas we found 33 DE miRNAs (18 downregulated, 15 upregulated, p-value <0.005) in the comparison between PD and iRBD and 6 (3 downregulated, 3 upregulated, p-value <0.005) in iRBD versus CTRL. Four common DE miRNAs (miR-101, miR-1260a, miR-142, miR15a) were dysregulated between the two different comparisons. In the PD patients, three miRNAs (miR-101, mir-142 and miR15a) were downregulated (Fold Change 0.5) with respect to iRBD. Conversely, miR-101, miR-142 and miR15a were upregulated and miR-1260a downregulated in iRBD compared to CTRL. The NGS results have not been validated by RT-PCR analysis till now because these miRNAs are poorly expressed in plasma. This condition makes very difficult, from a methodological point of view, their extraction. Discussion - The main findings of the present study are that reduced systemic antioxidant capacity is independently associated to overt PD and iRBD, a condition now established as prodromal PD, and correlates with olfactory and sympathetic dysfunction. Moreover, progressive cardiovascular autonomic dysfunction, expressed as altered sympathetic (VM ratio, OH) or parasympathetic (LS ratio) response to testing, is found from prodromal state to overt disease and correlates with olfactory dysfunction. Increased concentrations of neopterin, an inflammatory biomarker, are associated with worse olfactory dysfunction. The NGS analysis highlights a miRNA profiling in PD and iRBD subjects that needs to be verify, by changing and modifying the methodological approach for miRNA quantification. Conclusions - Reduced systemic antioxidant capacity is found in prodromal and overt PD and may represent, in association with olfactory loss and cardiovascular autonomic dysfunction, a useful additive biomarker of disease. Our pilot findings need to be confirmed in a larger population to establish their actual clinical value for an early diagnosis of PD

Apparent propagator anisotropy from single-shell diffusion MRI acquisitions

Purpose The apparent propagator anisotropy (APA) is a new diffusion MRI metric that, while drawing on the benefits of the ensemble averaged propagator anisotropy (PA) compared to the fractional anisotropy (FA), can be estimated from single‐shell data. Theory and Methods Computation of the full PA requires acquisition of large datasets with many diffusion directions and different b‐values, and results in extremely long processing times. This has hindered adoption of the PA by the community, despite evidence that it provides meaningful information beyond the FA. Calculation of the complete propagator can be avoided under the hypothesis that a similar sensitivity/specificity may be achieved from apparent measurements at a given shell. Assuming that diffusion anisotropy (DiA) is nondependent on the b‐value, a closed‐form expression using information from one single shell (ie, b‐value) is reported. Results Publicly available databases with healthy and diseased subjects are used to compare the APA against other anisotropy measures. The structural information provided by the APA correlates with that provided by the PA for healthy subjects, while it also reveals statistically relevant differences in white matter regions for two pathologies, with a higher reliability than the FA. Additionally, APA has a computational complexity similar to the FA, with processing‐times several orders of magnitude below the PA. Conclusions The APA can extract more relevant white matter information than the FA, without any additional demands on data acquisition. This makes APA an attractive option for adoption into existing diffusion MRI analysis pipelines

The crossed mesostriatal pathway and circling behaviour in rats

Bibliography: pages 326-345.Rats with unilateral 6-OHDA lesions of the nigrostriatal (NS) projection display motor asymmetry in the form of rotational behaviour. The rotation is in the direction ipsilateral with respect to the lesioned side (Ungerstedt 1979). The nett ipsilateral rotations decrease with time, from 1 week to about a month. This decrease has been interpreted as recovery from the lesion-induced motor asymmetry (Glick and Cox 1978). Pritzel et al. (1983) have ascribed the recovery from motor asymmetry to increased activity of a crossed NS projection, which is spared by the ipsilateral lesion. The present study has defined the size and anatomical path of this crossed projection, and has examined its involvement in the behavioural recovery of rats from lesion-induced motor asymmetry. The anatomy of the crossed projection was investigated in male Long-Evans rats using retrograde HRP tract tracing from deposition sites in the striatum

Diagnosis and Treatment of Parkinson's Disease

Parkinson's disease is diagnosed by history and physical examination and there are no laboratory investigations available to aid the diagnosis of Parkinson's disease. Confirmation of diagnosis of Parkinson's disease thus remains a difficulty. This book brings forth an update of most recent developments made in terms of biomarkers and various imaging techniques with potential use for diagnosing Parkinson's disease. A detailed discussion about the differential diagnosis of Parkinson's disease also follows as Parkinson's disease may be difficult to differentiate from other mimicking conditions at times. As Parkinson's disease affects many systems of human body, a multimodality treatment of this condition is necessary to improve the quality of life of patients. This book provides detailed information on the currently available variety of treatments for Parkinson's disease including pharmacotherapy, physical therapy and surgical treatments of Parkinson's disease. Postoperative care of patients of Parkinson's disease has also been discussed in an organized manner in this text. Clinicians dealing with day to day problems caused by Parkinson's disease as well as other healthcare workers can use beneficial treatment outlines provided in this book

A clinicopathological study of the neuropsychiatric features of Parkinson's disease

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