scholarly journals In vivo locus coeruleus imaging in Alzheimer’s and Parkinson’s disease

2020 ◽  
Vol 16 (S5) ◽  
Author(s):  
Matthew J. Betts ◽  
Johanna Pape ◽  
Annika Spottke ◽  
Stefan J. Teipel ◽  
Ingo Kilimann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locus Coeruleus

scholarly journals Locus Coeruleus Degeneration Correlated with Levodopa Resistance in Parkinson’s Disease: A Retrospective Analysis

2021 ◽  
pp. 1-10
Author(s):  
Cheng Zhou ◽  
Tao Guo ◽  
JingJing Wu ◽  
Linbo Wang ◽  
Xueqin Bai ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locus Coeruleus ◽  
Rating Scale ◽  
Linear Regression Analysis ◽  
Animal Experiments ◽  
Network Synchronization ◽  
Clinical Issue ◽  
The Relationship

Background: The widely divergent responsiveness of Parkinson’s disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment. Objective: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo. Methods: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was evaluated by the rates of change of the Unified Parkinson’s Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness. Results: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R = 0.421, p = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R = –0.323, p = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration. Conclusion: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa.

scholarly journals Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes

2021 ◽  
Author(s):  
Frank Hubert Hezemans ◽  
Noham Wolpe ◽  
Claire O'Callaghan ◽  
Rong Ye ◽  
Catarina Rua ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locus Coeruleus ◽  
Prior Beliefs ◽  
Double Blind ◽  
Visuomotor Task ◽  
Noradrenaline Reuptake ◽  
Magnetisation Transfer Imaging ◽  
Psychophysical Analysis

Apathy is a debilitating feature of many diseases, including Parkinson's disease. We tested the hypothesis that degeneration of the locus coeruleus-noradrenaline system contributes to apathy by modulating the relative weighting of prior beliefs about action outcomes. Participants with mild-to-moderate idiopathic Parkinson's disease (N=17) completed a double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity.

scholarly journals Locus Coeruleus Integrity from 7T MRI Relates to Apathy and Cognition in Parkinson’s Disease and Progressive Supranuclear Palsy

2021 ◽  
Author(s):  
Rong Ye ◽  
Claire O’Callaghan ◽  
Catarina Rua ◽  
Frank H. Hezemans ◽  
Negin Holland ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Spatial Pattern ◽  
Locus Coeruleus ◽  
Progressive Supranuclear Palsy ◽  
Neuropsychiatric Symptoms ◽  
Test Group ◽  
Cross Sectional ◽  
Richardson’S Syndrome

AbstractBackground and ObjectivesThe loss of noradrenergic neurons in the locus coeruleus (LC) contributes to various cognitive and neuropsychiatric symptoms in Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). The spatial precision of in vivo LC imaging is improved using a magnetisation transfer sequence combined with ultra-high field 7T MRI. This study aimed to test the sensitivity of LC imaging in PD and PSP, to characterise the spatial pattern of LC atrophy in patients, and its relationship to cognition and apathy.MethodsThis cross-sectional observational study recruited patients with idiopathic PD, probable PSP-Richardson’s syndrome and age-matched healthy controls (HC) via specialist clinics and volunteer registries. All participants underwent clinical assessments for cognition and apathy, and high-resolution (0.08 mm3) LC scans. To quantify LC integrity, the contrast-to-noise ratio (CNR) relative to a pons reference region was calculated and extracted using a probabilistic atlas. Subregional mean CNRs were summarised to test group differences and to correlate LC integrity with apathy and cognition scores. LC clusters were identified to confirm the spatial pattern of the effect (threshold free cluster enhancement, 10000 permutations, p<0.05, corrected for family-wise error).ResultsTwenty-five patients with PD, 14 with PSP and 24 controls with completed dataset were included in the study. Patients with PSP were more impaired on global cognition and apathy scores, compared to controls and PD. Clusters with reduced contrast were observed in the caudal LC for both PD and PSP patients relative to controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels). PSP and PD patients showed similar levels of LC degeneration, but this was more extensive in PSP. Across both disease groups, LC integrity was associated with cognitive performance (MoCA: F(1,37)=5.339, p=0.027, bilateral LC, 200 voxels; ACE-R: F(1,37)=4.297, p=0.045, left LC, 70 voxels) and apathy (Apathy Scale: F(1,37)=4.335, p=0.044, left LC, 99 voxels).DiscussionWe confirm the sensitivity of 7T LC imaging to detect sub-regional LC changes in PD and PSP. The relationship between LC integrity and non-motor symptoms highlights the potential for noradrenergic therapeutic strategies to ameliorate cognitive and behavioural features of PD and PSP.

In vivo multimodal (MRI, SPECT) imaging of the 6-OHDA rat model for Parkinson's disease correlated with behavior and histology

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S392-S392
Author(s):  
Nadja Van Camp ◽  
Koen Van Laere ◽  
Ruth Vreys ◽  
Marleen Verhoye ◽  
Erwin Lauwers ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Spect Imaging ◽  
Multimodal Mri

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies

2016 ◽  
Vol 55 (01) ◽  
pp. 21-28 ◽  
Author(s):  
C. Antke ◽  
H. Hautzel ◽  
H.-W. Mueller ◽  
S. Nikolaus
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Sites ◽  
Human Subjects ◽  
Synaptic Cleft ◽  
Presynaptic Terminal ◽  
Imaging Studies ◽  
Psychiatric Conditions ◽  
Da Release

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

scholarly journals Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jarrin ◽  
Abrar Hakami ◽  
Ben Newland ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Growth Factors ◽  
Growth Factor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Delivery Systems ◽  
Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

Comparison of Locus Coeruleus Pathology with Nigral and Forebrain Pathology in Parkinson's Disease

2021 ◽  
Author(s):  
Benjamin Huynh ◽  
Yuhong Fu ◽  
Deniz Kirik ◽  
James M. Shine ◽  
Glenda M. Halliday
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locus Coeruleus

scholarly journals Effectiveness and mechanisms of adipose-derived stem cell therapy in animal models of Parkinson’s disease: a systematic review and meta-analysis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Keya Li ◽  
Xinyue Li ◽  
Guiying Shi ◽  
Xuepei Lei ◽  
Yiying Huang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Therapeutic Option ◽  
Meta Analysis ◽  
Future Application ◽  
Neuroprotective Effects ◽  
Standard Mean Difference ◽  
Study Characteristics

AbstractAnimal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells (ADSCs). Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease (PD). Here, eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention. Quality assessment was conducted using a 10-item risk of bias tool. For the subsequent meta-analysis, study characteristics were extracted and effect sizes were computed. Ten out of 2324 published articles (n = 169 animals) were selected for further meta-analysis. After ADSC therapy, the rotation behavior (10 experiments, n = 156 animals) and rotarod performance (3 experiments, n = 54 animals) were improved (P < 0.000 01 and P = 0.000 3, respectively). The rotation behavior test reflected functional recovery, which may be due to the neurogenesis from neuronally differentiated ADSCs, resulting in a higher pooled effect size of standard mean difference (SMD) (− 2.59; 95% CI, − 3.57 to − 1.61) when compared to that of primitive cells (− 2.18; 95% CI, − 3.29 to − 1.07). Stratified analyses by different time intervals indicated that ADSC intervention exhibited a long-term effect. Following the transplantation of ADSCs, tyrosine hydroxylase-positive neurons recovered in the lesion area with pooled SMD of 13.36 [6.85, 19.86]. Transplantation of ADSCs is a therapeutic option that shows long-lasting effects in animal models of PD. The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects. The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.

scholarly journals Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson’s Disease

2020 ◽  
pp. 1-14
Author(s):  
Shelby Shrigley ◽  
Fredrik Nilsson ◽  
Bengt Mattsson ◽  
Alessandro Fiorenzano ◽  
Janitha Mudannayake ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Functional Recovery ◽  
Embryonic Stem ◽  
Hesc Line ◽  
Alternative Source ◽  
And Function

Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

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