37 research outputs found

    Evaluation of the effect of training using auditory stimulation on rhythmic movement in Parkinsonian patients—a combined motor and [18F]-FDG PET study

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    [Abstract] Introduction: A programme of rehabilitation using auditory cues has previously been shown to decrease movement variability in the gait of Parkinsonian patients. Objective and methods: We studied the temporal variability of finger-tapping and gait in 9 patients with Parkinson's disease (PD) before and after they undertook a physical rehabilitation programme. Positron Emission Tomography (PET) using 2-deoxy-2[18F]fluoro-d-glucose (FDG) was performed in these subjects to look for changes in metabolic brain activity after completion of the rehabilitation program. Results: The reduction of variability was seen not only in gait but also other repetitive movements such as finger tapping. Furthermore, here we show differences in resting regional cerebral glucose utilisation in these patients compared to healthy controls (significant hypometabolism—p<0.001—for the PD group in the right parietal and temporal lobes, left temporal and frontal lobes and a hypermetabolism in the left cerebellum) and specific changes following the improvements in repetitive movement abilities (significant metabolic increment—p<0.001—in the PD group in the right cerebellum and in the right parietal and temporal lobes). Conclusions: Although our study does not allow us to draw firm conclusions, it provides new information on the neural basis of auditory stimulation in PD. Our results extend those from previous studies to show improvement in the temporal variability of two types of rhythmic movements after participation by PD patients in a physical rehabilitation programme, along with changes in glucose uptake in several brain areas involved in sensorimotor processing.Xunta de Galicia; PGIDIT02BTF13701P

    Tremor severity in Parkinson’s disease and cortical changes of areas controlling movement sequencing: a preliminary study.

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    . There remains much to learn about the changes in cortical anatomy that are associated with tremor severity in Parkinson’s disease (PD). For this reason, we used a combination of structural neuroimaging to measure cortical thickness and neurophysiological studies to analyze whether PD tremor was associated with cortex integrity. Magnetic resonance imaging and neurophysiological assessment were performed in 13 nondemented PD patients (9 women, 69.2%) with a clearly tremor-dominant phenotype. Cortical reconstruction and volumetric segmentation was performed with the Freesurfer image analysis software. Assessment of tremor was performed by means of high-density surface electromyography (hdEMG) and inertial measurement units (IMUs). Individual motor unit discharge patterns were identified from surface hdEMG and tremor metrics quantifying motor unit synchronization from IMUs were defined. Increased motor unit synchronization (i.e., more severe tremor) was associated with cortical changes (i.e., atrophy) in dorsal premotor cortices, left posterior parietal cortex, left lateral orbitofrontal cortex, cingulate cortex bilaterally, left posterior and transverse temporal cortex, and left occipital lobe, as well as reduced left middle temporal volume. Given that the majority of these areas are involved in controlling movement sequencing, our results support Albert’s classic hypothesis that PD tremor may be the result of an involuntary activation of a program of motor behavior used in the genesis of rapid voluntary alternating movements.pre-print670 K

    In vivo assessment of non-dopaminergic systems in Parkinson’s disease with Positron Emission Tomography

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    Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Non-dopaminergic neurotransmission is also impaired. Intraneuronal Lewy bodies, the pathological hallmark of PD, have been observed in serotoninergic, noradrenergic, and cholinergic neurons. Dysfunction of these systems could play a role in the occurrence of non-motor symptoms including fatigue. However, the extent of non-dopaminergic degeneration in PD, rates of its progression, and its contribution to the development of non-motor symptoms is unclear. First, I used 18F-dopa Positron Emission Tomography (PET), a marker of monoaminergic terminal function, to assess the involvement of dopaminergic, noradrenergic, and serotoninergic pathways in PD and in parkin-linked parkinsonism, a genetic form of PD. I found that parkin patients and PD patients have distinct patterns of monoaminergic involvement, with more widespread dysfunction in PD. In a second study, I used serial 18F-dopa PET to assess longitudinal changes in tracer uptake in brain monoaminergic structures over a 3-year period in a group of PD patients. I also assessed the relationship between striatal function decline and dysfunction in extra-striatal areas in the same patients. I found that the degeneration in extrastriatal monoaminergic structures in PD occurs independently from nigrostriatal degeneration and at a slower rate. Brain compensatory mechanisms disappear within the first years of disease. I then used 18F-dopa and 11C-DASB PET to investigate whether fatigue in PD is associated with dysfunction of dopaminergic/serotoninergic innervation. I found that PD patients with fatigue show severe loss of serotoninergic innervation in basal ganglia and limbic areas. Finally, I assessed the relationship between 18F-dopa uptake and measurements of serotonin transporter availability by 11C-DASB PET within brain serotoninergic structures and I provided evidence for the hypothesis that 18F-dopa PET can be used to evaluate the distribution and the function of serotoninergic systems in the brain of PD patients

    Altered intrinsic functional coupling between core neurocognitive networks in Parkinson\u27s disease

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    Parkinson3s disease (PD) is largely attributed to disruptions in the nigrostriatal dopamine system. These neurodegenerative changes may also have a more global effect on intrinsic brain organization at the cortical level. Functional brain connectivity between neurocognitive systems related to cognitive processing is critical for effective neural communication, and is disrupted across neurological disorders. Three core neurocognitive networks have been established as playing a critical role in the pathophysiology of many neurological disorders: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). In healthy adults, DMN–CEN interactions are anti-correlated while SN–CEN interactions are strongly positively correlated even at rest, when individuals are not engaging in any task. These intrinsic between-network interactions at rest are necessary for efficient suppression of the DMN and activation of the CEN during a range of cognitive tasks. To identify whether these network interactions are disrupted in individuals with PD, we used resting state functional magnetic resonance imaging (rsfMRI) to compare between-network connectivity between 24 PD participants and 20 age-matched controls (MC). In comparison to the MC, individuals with PD showed significantly less SN–CEN coupling and greater DMN–CEN coupling during rest. Disease severity, an index of striatal dysfunction, was related to reduced functional coupling between the striatum and SN. These results demonstrate that individuals with PD have a dysfunctional pattern of interaction between core neurocognitive networks compared to what is found in healthy individuals, and that interaction between the SN and the striatum is even more profoundly disrupted in those with greater disease severity

    Targeting the Progression of Parkinson’s Disease

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    By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease

    Dissecting the Genetic Basis of Parkinson Disease, Dystonia and Chorea

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    In this thesis I used of a range of genetic methodologies and strategies to unravel the genetic bases of Parkinson disease (PD), myoclonus-dystonia (M-D), and chorea. First, I detail the work I performed in PD, including (1) the screening of GBA in a cohort of early-onset PD cases, which led to the identification of the allele E326K (p.Glu365Lys) as the single most frequent, clinically relevant, risk variant for PD; (2) a detailed genetic analysis in a large cohort of PD cases who underwent deep-brain stimulation treatment and a longitudinal comparison of the phenotypic features of carriers of mutations in different genes; (3) the observation that rare GCH1 coding variants, known to be responsible for the childhood-onset disorder DOPA-responsive dystonia, are a novel risk factor for PD. Then, I describe the work I performed to identify novel causes of M-D, including (1) the discovery of the missense p.Arg145His mutation in KCTD17 as a novel cause of autosomal dominant M-D; (2) the identification of tyrosine hydroxylase deficiency as a novel treatable cause of recessive M-D; and (3) the conclusive disproof of the pathogenic role of the p.Arg1389His variant in CACNA1B as a cause of M-D. Finally, I detail my work in the field of choreic syndromes, including (1) the genetic screening of NKX2-1 in the Queen Square cohort of benign hereditary chorea (BHC) cases; (2) the identification of ADCY5 mutations, the gene thought to be responsible for the condition familial dyskinesias with facial myokymia, as an important cause of BHC; and (3) the identification of de novo mutations in PDE10A as a novel genetic cause of chorea. These findings are discussed in light of the recent literature. Following my analysis, I suggest future directions for the identification of novel genetic causes of movement disorders, in light of my recent findings and ongoing research

    Dietary Plant Lectins May be an ‘Unknown Etiology’ in Parkinson’s Disease and Dietary Bioactive Compounds Affect Lifespan and Fat Storage Aspects of Caenorhabditis Elegans

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    Dietary bioactive compounds benefit health while some might induce pathological processes. Parkinson’s disease (PD) is the second most common neurodegenerative disease. Braak and Hawkes hypothesized that the gastrointestinal tract may be a potential site of neuronal invasion by an “unknown pathogen” leading to some Parkinsonism. Neurotoxin botulinum or ricin can trans-synaptically transport in nervous system. Our hypothesis 1: dietary plant lectins might be responsible for the “unknown pathogen” causing PD. Pomegranate juice (PJ) have antioxidant and anti-obesity effects. Our hypothesis 2: PJ increases lifespan in C. elegans and reduces fat storage. Study 1: Post-feeding rhodamine or TRITC tagged dietary lectins was tracked from gut to dopaminergic (DAergic) neurons in C. elegans BZ555 (egIs1[Pdat-1::GFP]) that has Green Fluorescent Protein (GFP) gene fused to a dopamine transport protein gene labeling DAergic neurons. Although this observation was tested with specific inhibiting sugars (SIS), supplemented with Escherichia coli, the high concentrations of monosaccharides necessary may have their own side effects. Results showed that Amaranthus caudatus agglutinin, Euonymus europaeus agglutinin and Arachis hypogaea agglutinin co- localized with DAergic neurons. Lectins affected the number, size or intensity of DAergic neurons, reduced the mobility and affected the lifespan of C. elegans to different extents, with the SIS either augmenting or mitigating the effects. Our observations are a tantalizing possible explanation for why dietary plants have been linked to a risk of developing PD. Study 2: Lifespan of C. elegans was increased by PJ treatment in wild type (N2, 56%) and daf-16 mutant (daf-16(mgDf50)I) (GR1307, 18%), by POMx in N2 (28%) and in GR1307 (10%), or by EA (11%). PJ reduced intestinal fat deposition (IFD) in N2 (-68%) or in GR1307 (-33%). The IFD was increased by POMx in N2 (137%) and in GR1307 (26%), by EA in N2 (66%) and in GR1307 (74%), or by UA in N2 (57%) and in GR1307 (43%). Both lectins and PJ are bioactive compounds, playing important roles in life. These studies may provide useful information for an alternative etiology of PD and offer solutions of using PJ to delay aging and prevent obesity in humans

    Parkinson hastalığındaki psikotik süreçlerde florodeoksiglukoz pozitron emisyon tomografi bulguları

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    Parkinson hastalığı (PH) sık görülen nörodejeneratif hastalıklardan biridir. Primer bulguları olan motor bulguların ön planda olması dışında non-motor (otonomik, davranışsal, bilişsel ve duysal) bulgular da birey hayatında etkilidir. Bu çalışmada, psikotik belirtileri olan ve olmayan PH olgularında metabolik olarak etkilenen beyin bölgelerini tespit etmek ve bunların klinik ve demografik özellikler ile ilişkilerini saptamak amaçlandı. Başkent Üniversitesi Dr. Turgut Noyan Adana Uygulama ve Araştırma Merkezi Nöroloji kliniğine Ocak 2014- Mayıs 2016 tarihleri arasında başvuran PH tanısı almış olgulardan psikoz bulguları olan 13, psikozu olmayan 15 olgu alındı. Nörolojik muayene, Standardize Mini Mental Test (SMMT), Montreal Bilişsel Değerlendirme Ölçeği (MOBİD), Birleşik Parkinson Hastalığı Değerlendirme Ölçeği (BPHDÖ) ve Hoehn&Yahr bulguları kaydedildi. Psikotik belirtiler psikiyatri uzmanı tarafından varsanı, sanrı, davranış bozukluğu, düşünce ve duygudurum bozukluğu şekilde sınıflandırıldı. F18-FDG PET/BT bulguları psikozu olan ve olmayan hastalarda, psikozu olanlarda ise belirti durumuna göre karşılaştırıldı. Sonuçlar değerlendirildiğinde demografik verilerde psikoz grubu ile kontrol grubu arasında anlamlı fark saptanmadı. Görme varsanısı varlığı ile hastalık süresi arasında pozitif ilişki bulundu. MOBİD toplam puan ve alt gruplarında lisan, dikkat ve yönelim puanları, BPHDÖ toplam ve alt gruplarından mental durum, günlük aktivite, motor bölümleri, anksiyete ve depresyon ölçekleri artan puanları ile psikoz varlığı ilişkili bulundu. Parkinson hastalığı tanısı daha uzun süredir olan hastalarda nörodejenerasyonun artması tüm bu motor ve non-motor belirti ve bulguların artmış olarak ortaya çıkmasının sebebi olarak değerlendirilebilir. Psikoz belirtileri olan ve olmayan hastaların PET/BT bulgularının karşılaştırmasında tespit edilen fark anlamlı düzeye ulaşmadı. Bu bulguların görsel değerlendirmeden ziyade sayısal değerlendirme ile işlenmesi halinde anlamlılık düzeyine ulaşacağı düşünülmektedir. Parkinson’s disease (PD) is one of the frequently seen neurodegenerative diseases. Besides its motor symptoms which are the primary findings and more apparent, also non-motor symptoms (autonomic, behavioral, cognitive and sensory) are effective on the individual’s life. In the present study, locating the metabolically affected brain regions in PD patients with and without psychotic symptoms, and determining the relation of these with the clinical and demographic characteristics. From the patients who presented to the Neurology Clinic of Başkent University, Dr. Turgut Noyan Adana Research and Application Center between January 2014 and May 2016 and were diagnosed with PD, 13 patients with psychotic symptoms and 15 patients without psychosis were included. Neurological examination, Standardized Mini Mental Test (SMMT), Montreal Cognitive Assessment Scale (MOCA), Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn&Yahr results were recorded. Psychotic symptoms were classified by a psychiatrist as hallucination, delusion, behavioral disorder, and thought and mood disorders. The F18-FDG PET/CT findings were compared between the patients with and without psychosis and by symptoms within those with psychosis. An assessment of the results showed no significant difference between the psychotic group and the control group with respect to demographic data. A positive correlation was found between visual hallucination and duration of disease. Positive correlation between presence of psychosis and the MOCA overall score and its language, attention and orientation subgroup scores, the UPDRS overall score and its increasing mental status, daily activities, motor sections subgroup scores, anxiety and depression scores were found. Increased neurodegeneration in patients who had a diagnosis of PD for a longer time might be estimated as a cause of worsening of all these motor and non-motor symptoms. The difference found in the comparison of the PET/CT findings of the patients with and without psychotic symptoms did not reach the level of significance. We think that the level of significance can be reached if these findings are processed numerical rather than visual

    Perception and cognition in Parkinson's disease: a neural network perspective

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    Parkinson’s disease (PD) is a neurodegenerative disorder commonly presenting with perceptual and cognitive dysfunction. Whereas previous work in PD suggests that abnormal basal ganglia activity has profound effects on integrated functioning of widespread cortical networks, the relation of specific network functions to the perceptual and cognitive impairments is still poorly understood. Here, I present a series of fMRI investigations of network-level functioning in non-demented individuals with PD with the aim of elucidating these associations. Study 1 examined the neural correlates of optic flow processing in 23 individuals with PD and 17 age-matched control participants (MC). An optic flow network comprising visual motion areas V6, V3A, MT+ and visuo-vestibular areas PIVC and CSv is known to be important for parsing egomotion depth cues in humans. The hypothesis was that individuals with PD would show less activation in these regions than MC when processing optic flow. While MC participants showed robust activation in this network, PD participants showed diminished activity within MT+ and CSv. Diminished CSv activity also correlated with greater disease severity. Study 2 investigated intrinsic network organization in PD with a focus on the functional coupling among three neurocognitive networks: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). Twenty-four individuals with PD and 20 MC participants were scanned at rest. The hypothesis was that PD participants would demonstrate dysfunctional SN coupling with the DMN and CEN. Relative to MC, in PD the CEN was less positively coupled with the SN and less anti-correlated with the DMN. Study 3 investigated the association between functional coupling and cognition in the same group that participated in Study 2. As hypothesized, anti-correlated functional coupling between the SN and DMN was related to successful performance on tests of executive function, psychomotor speed, and memory retrieval in MC but not in PD, suggesting that dysfunction within these networks could underlie early cognitive deficits in PD. Together, the results from the three studies suggest that dysfunctional activity in cortical networks important for visual motion processing and neurocognitive efficiency may underlie aspects of perceptual and cognitive impairment in PD.2017-12-06T00:00:00

    Neuropsychiatric and cognitive symptoms in Parkinson’s disease: the contribution to subtype classification, to differential diagnosis, their clinical and instrumental correlations

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    Il piano di ricerca è volto ad approfondire il contributo dei sintomi neuropsichiatrici e cognitivi nelle diverse fasi della Malattia di Parkinson (MP). In particolare, l’argomento di studio è focalizzato sull’analisi dei sintomi cognitivi e neuropsichiatrici nella MP, affrontando queste tematiche anche mediante l’utilizzo di tecniche di neuroimaging, in pazienti drug-naïve, in fase precoce di malattia ed in fase avanzata. Nei pazienti drug-naïve, la ricerca è stata finalizzata alla caratterizzazione dei sintomi neuropsichiatrici e cognitivi nei sottotipi motori (i.e., tremorigeni vs acinetico-rigidi) e rispetto alla lateralità di esordio degli stessi (i.e., lateralità destra vs lateralità sinistra). Nei pazienti in fase precoce di malattia, è stato indagato il contributo dei sintomi neuropsichiatrici e cognitivi nella diagnosi differenziale tra MP e Paralisi Sopranucleare Progressiva (PSP) in pazienti valutati entro i 24 mesi dall’esordio motorio, finestra temporale in cui spesso si assiste ad un overlapping dei sintomi motori. Nei pazienti in fase avanzata di malattia, la ricerca è stata finalizzata alla caratterizzazione, mediante i sintomi neuropsichiatrici e cognitivi, del Gioco D’Azzardo Patologico (gambling) rispetto agli altri tipi di Disturbi del controllo degli Impulsi (ICDs). Ancora nell’ambito dell’ICDs, è stato sviluppato uno studio di neuroimaging, volto ad identificare i correlati morfostrutturali (spessori corticali e volumi dei nuclei sottocorticali) di tali disturbi. Infine, si sono identificati i sintomi neuropsichiatrici e cognitivi che possono impedire l’esecuzione di un esame di Risonanza Magnetica (RM), al fine, in ambito clinico, di preparare adeguatamente all’esame i pazienti più a rischio di mancato svolgimento e con l’intento di indagare, in ambito di ricerca, la reale rappresentatività campionaria dei pazienti inseriti in studi di RM
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