scholarly journals Fiber-specific white matter alterations in early-stage tremor-dominant Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Christina Andica ◽  
Koji Kamagata ◽  
Yuya Saito ◽  
Wataru Uchida ◽  
Shohei Fujita ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
White Matter ◽  
Cross Section ◽  
Corticospinal Tract ◽  
Early Stage ◽  
Brain Regions ◽  
Fiber Density ◽  
Compensation Mechanisms ◽  
Progression Markers

AbstractUsing a fixel-based analysis (FBA), we assessed the fiber-specific white matter (WM) alterations in nonmedicated patients with early-stage Parkinson’s disease (PD) with tremor-dominant (TD; n = 53; mean age, 61.7 ± 8.7 years) and postural instability and gait disorder (PIGD; n = 27; mean age, 57.8 ± 8.1 years) motor subtypes and age- and sex-matched healthy controls (HC; n = 43; mean age, 61.6 ± 9.2 years) from Parkinson’s Progression Markers Initiative dataset. FBA revealed significantly increased macrostructural fiber cross section and a combination of fiber density and cross section metrics within the corticospinal tract in patients with TD-PD compared with HC. Nonetheless, no significant changes in FBA-derived metrics were found in patients with PIGD-PD compared with HC or patients with TD-PD. Our results may provide evidence of WM neural compensation mechanisms in patients with TD-PD marked by increases in fiber bundle size and the ability to relay information between brain regions.

Olfactory Function and Diffusion Tensor Imaging as Markers of Mild Cognitive Impairment in Early Stages of Parkinson's Disease

2021 ◽  
pp. 155005942110582
Author(s):  
Sophie A. Stewart ◽  
Laura Pimer ◽  
John D. Fisk ◽  
Benjamin Rusak ◽  
Ron A. Leslie ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Diffusion Tensor Imaging ◽  
Mild Cognitive Impairment ◽  
White Matter ◽  
Neurodegenerative Disorder ◽  
Diffusion Tensor ◽  
Early Stage ◽  
White Matter Integrity

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to established groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

scholarly journals Pervasive White Matter Fiber Degeneration in Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (5) ◽  
pp. 1507-1513 ◽  
Author(s):  
Natalia Egorova ◽  
Thijs Dhollander ◽  
Mohamed Salah Khlif ◽  
Wasim Khan ◽  
Emilio Werden ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Cross Section ◽  
Corticospinal Tract ◽  
Brain Volume ◽  
Morphological Changes ◽  
Axonal Loss ◽  
Fiber Density ◽  
Whole Brain ◽  
Brain Volume Loss

Background and Purpose— We examined if ischemic stroke is associated with white matter degeneration predominantly confined to the ipsi-lesional tracts or with widespread bilateral axonal loss independent of lesion laterality. Methods— We applied a novel fixel-based analysis, sensitive to fiber tract–specific differences within a voxel, to assess axonal loss in stroke (N=104, 32 women) compared to control participants (N=40, 15 women) across the whole brain. We studied microstructural differences in fiber density and macrostructural (morphological) changes in fiber cross-section. Results— In participants with stroke, we observed significantly lower fiber density and cross-section in areas adjacent, or connected, to the lesions (eg, ipsi-lesional corticospinal tract). In addition, the changes extended beyond directly connected tracts, independent of the lesion laterality (eg, corpus callosum, bilateral inferior fronto-occipital fasciculus, right superior longitudinal fasciculus). Conclusions— We conclude that ischemic stroke is associated with extensive neurodegeneration that significantly affects white matter integrity across the whole brain. These findings expand our understanding of the mechanisms of brain volume loss and delayed cognitive decline in stroke.

scholarly journals The role of brain perivascular space burden in early-stage Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ting Shen ◽  
Yumei Yue ◽  
Shuai Zhao ◽  
Juanjuan Xie ◽  
Yanxing Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
White Matter ◽  
Early Stage ◽  
Mean Diffusivity ◽  
Perivascular Space ◽  
Motor Symptom ◽  
Imaging Features ◽  
Subcortical Nuclei ◽  
The Difference

AbstractPerivascular space (PVS) is associated with neurodegenerative diseases, while its effect on Parkinson’s disease (PD) remains unclear. We aimed to investigate the clinical and neuroimaging significance of PVS in basal ganglia (BG) and midbrain in early-stage PD. We recruited 40 early-stage PD patients and 41 healthy controls (HCs). Both PVS number and volume were calculated to evaluate PVS burden on 7 T magnetic resonance imaging images. We compared PVS burden between PD and HC, and conducted partial correlation analysis between PVS burden and clinical and imaging features. PD patients had a significantly more serious PVS burden in BG and midbrain, and the PVS number in BG was significantly correlated to the PD disease severity and L-dopa equivalent dosage. The fractional anisotropy and mean diffusivity values of certain subcortical nuclei and white matter fibers within or nearby the BG and midbrain were significantly correlated with the ipsilateral PVS burden indexes. Regarding to the midbrain, the difference between bilateral PVS burden was, respectively, correlated to the difference between fiber counts of white fiber tract passing through bilateral substantia nigra in PD. Our study suggests that PVS burden indexes in BG are candidate biomarkers to evaluate PD motor symptom severity and aid in predicting medication dosage. And our findings also highlight the potential correlations between PVS burden and both grey and white matter microstructures.

scholarly journals P.015 Long-term progression and prognosis in different subtypes of Parkinson’s disease: validation of a new multi-domain subtyping method

2019 ◽  
Vol 46 (s1) ◽  
pp. S17
Author(s):  
S Fereshtehnejad ◽  
Y Zeighami ◽  
A Dagher ◽  
RB Postuma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Early Stage ◽  
Real Life ◽  
Clinical Manifestations ◽  
Personalized Care ◽  
Autonomic Disturbance ◽  
Progression Markers

Background: Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods: Data on 421 individuals with de novo early-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results: Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions: This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.

scholarly journals Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

2020 ◽  
Author(s):  
Johannes Burtscher ◽  
Jean-Christophe Copin ◽  
Carmen Sandi ◽  
Hilal A. Lashuel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Early Stage ◽  
Relevant Literature ◽  
Brain Regions ◽  
Substantia Nigra Pars Compacta ◽  
Ros Generation

AbstractIncreasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

scholarly journals Motor Progression in Early-Stage Parkinson's Disease: A Clinical Prediction Model and the Role of Cerebrospinal Fluid Biomarkers

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling-Yan Ma ◽  
Yu Tian ◽  
Chang-Rong Pan ◽  
Zhong-Lue Chen ◽  
Yun Ling ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dynamic Models ◽  
Rating Scale ◽  
Early Stage ◽  
Neurovascular Unit ◽  
Progression Model ◽  
Progression Markers ◽  
Updrs Part ◽  
Threshold Range

Background: The substantial heterogeneity of clinical symptoms and lack of reliable progression markers in Parkinson's disease (PD) present a major challenge in predicting accurate progression and prognoses. Increasing evidence indicates that each component of the neurovascular unit (NVU) and blood-brain barrier (BBB) disruption may take part in many neurodegenerative diseases. Since some portions of CSF are eliminated along the neurovascular unit and across the BBB, disturbing the pathways may result in changes of these substances.Methods: Four hundred seventy-four participants from the Parkinson's Progression Markers Initiative (PPMI) study (NCT01141023) were included in the study. Thirty-six initial features, including general information, brief clinical characteristics and the current year's classical scale scores, were used to build five regression models to predict PD motor progression represented by the coming year's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score after redundancy removal and recursive feature elimination (RFE)-based feature selection. Then, a threshold range was added to the predicted value for more convenient model application. Finally, we evaluated the CSF and blood biomarkers' influence on the disease progression model.Results: Eight hundred forty-nine cases were included in the study. The adjusted R2 values of three different categories of regression model, linear, Bayesian and ensemble, all reached 0.75. Models of the same category shared similar feature combinations. The common features selected among the categories were the MDS-UPDRS Part III score, Montreal Cognitive Assessment (MOCA) and Rapid Eye Movement Sleep Behavior Disorder Questionnaire (RBDSQ) score. It can be seen more intuitively that the model can achieve certain prediction effect through threshold range. Biomarkers had no significant impact on the progression model within the data in the study.Conclusions: By using machine learning and routinely gathered assessments from the current year, we developed multiple dynamic models to predict the following year's motor progression in the early stage of PD. These methods will allow clinicians to tailor medical management to the individual and identify at-risk patients for future clinical trials examining disease-modifying therapies.

scholarly journals Correlation of Dopaminergic Denervation and the Progression of Autonomic Dysfunctions in Different Clinical Subtypes of Parkinson’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Eun Hye Jeong ◽  
Mun Kyung Sunwoo ◽  
Sung Wook Hyung ◽  
Sun-Ku Han ◽  
Jae Yong Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Positive Relationship ◽  
Early Stage ◽  
Gait Disorder ◽  
Autonomic Dysfunctions ◽  
Progression Markers ◽  
Spect Images

Background. Autonomic dysfunctions occur in the early stage of Parkinson’s disease (PD) and impact the quality of life during the progression of the disease. In this study, we evaluated the serial progression of autonomic dysfunctions between different subtypes of a prospective PD cohort. Materials and Methods. From the Parkinson’s Progression Markers Initiative (PPMI) database, 325 PD patients (age: 61.2 ± 9.7, M : F = 215 : 110) were enrolled. Patients were subgrouped into tremor-dominant (TD), indeterminate, and postural instability and gait disorder (PIGD) subtypes. The progression of autonomic dysfunctions and dopaminergic denervation from I-123 FP-CIT SPECT images of each group were analyzed and compared at baseline, 12 months, 24 months, and 48 months of follow-up periods. Results. The SCOPA-AUT score of the indeterminate subtype was significantly higher than that of the TD subtype ( P < 0.05 ) at baseline and was significantly higher than that of both TD and PIGD subtypes ( P < 0.05 ) at 48 months. The indeterminate subtype had the most significant correlation between the aggravation of dopaminergic denervation in I-123 FP-CIT SPECT images and the increase of SCOPA-AUT scores during 48 months of follow-up (r = 0.56, P < 0.01 ). Conclusions. Autonomic dysfunctions were most severe in the indeterminate subtype throughout the 48 months of the follow-up period, with a significant correlation with dopaminergic denervation. We suggest a positive relationship between dopaminergic denervation and autonomic dysfunctions of the indeterminate subtype, beginning from the early stage of PD.

scholarly journals An Integrative Nomogram for Identifying Early-Stage Parkinson's Disease Using Non-motor Symptoms and White Matter-Based Radiomics Biomarkers From Whole-Brain MRI

2020 ◽  
Vol 12 ◽  
Author(s):  
Zhenyu Shu ◽  
Peipei Pang ◽  
Xiao Wu ◽  
Sijia Cui ◽  
Yuyun Xu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
White Matter ◽  
Risk Group ◽  
Early Stage ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Nonmotor Symptoms ◽  
Number Of Patients ◽  
Significant Difference

Purpose: To develop and validate an integrative nomogram based on white matter (WM) radiomics biomarkers and nonmotor symptoms for the identification of early-stage Parkinson's disease (PD).Methods: The brain magnetic resonance imaging (MRI) and clinical characteristics of 336 subjects, including 168 patients with PD, were collected from the Parkinson's Progress Markers Initiative (PPMI) database. All subjects were randomly divided into training and test sets. According to the baseline MRI scans of patients in the training set, the WM was segmented to extract the radiomic features of each patient and develop radiomics biomarkers, which were then combined with nonmotor symptoms to build an integrative nomogram using machine learning. Finally, the diagnostic accuracy and reliability of the nomogram were evaluated using a receiver operating characteristic curve and test data, respectively. In addition, we investigated 58 patients with atypical PD who had imaging scans without evidence of dopaminergic deficit (SWEDD) to verify whether the nomogram was able to distinguish patients with typical PD from patients with SWEDD. A decision curve analysis was also performed to validate the clinical practicality of the nomogram.Results: The area under the curve values of the integrative nomogram for the training, testing and verification sets were 0.937, 0.922, and 0.836, respectively; the specificity values were 83.8, 88.2, and 91.38%, respectively; and the sensitivity values were 84.6, 82.4, and 70.69%, respectively. A significant difference in the number of patients with PD was observed between the high-risk group and the low-risk group based on the nomogram (P &lt; 0.05).Conclusion: This integrative nomogram is a new potential method to identify patients with early-stage PD.

Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1541-1549
Author(s):  
Seok Jong Chung ◽  
Sangwon Lee ◽  
Han Soo Yoo ◽  
Yang Hyun Lee ◽  
Hye Sun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Early Stage ◽  
Striatal Dopamine ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Severe Motor ◽  
Severe Group ◽  
Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

Gene expression analysis in modeling Parkinson’s disease

2020 ◽  
pp. 103-104
Author(s):  
М.М. Руденок ◽  
А.Х. Алиева ◽  
А.А. Колачева ◽  
М.В. Угрюмов ◽  
П.А. Сломинский ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Stage ◽  
Systemic Disease ◽  
Molecular Genetic ◽  
Presymptomatic Stage ◽  
Whole Transcriptome Analysis ◽  
Whole Transcriptome ◽  
The Brain ◽  
Transcriptome Level

Несмотря на очевидный прогресс, достигнутый в изучении молекулярно-генетических факторов и механизмов патогенеза болезни Паркинсона (БП), в настоящее время стало ясно, что нарушения в структуре ДНК не описывают весь спектр патологических изменений, наблюдаемых при развитии заболевания. В настоящее время показано, что существенное влияние на патогенез БП могут оказывать изменения на уровне транскриптома. В работе были использованы мышиные модели досимптомной стадии БП, поздней досимптомной и ранней симптомной (РСС) стадиями БП. Для полнотранскриптомного анализа пулов РНК тканей черной субстанции и стриатума мозга мышей использовались микрочипы MouseRef-8 v2.0 Expression BeadChip Kit («Illumina», США). Полученные данные указывают на последовательное вовлечение транскриптома в патогенез БП, а также на то, что изменения на транскриптомном уровне процессов транспорта и митохондриального биогенеза могут играть важную роль в нейродегенерации при БП уже на самых ранних этапах. Parkinson’s disease (PD) is a complex systemic disease, mainly associated with the death of dopaminergic neurons. Despite the obvious progress made in the study of molecular genetic factors and mechanisms of PD pathogenesis, it has now become clear that violations in the DNA structure do not describe the entire spectrum of pathological changes observed during the development of the disease. It has now been shown that changes at the transcriptome level can have a significant effect on the pathogenesis of PD. The authors used models of the presymptomatic stage of PD with mice decapitation after 6 hours (6 h-PSS), presymptomatic stage with decapitation after 24 hours (24 h-PSS), advanced presymptomatic (Adv-PSS) and early symptomatic (ESS) stages of PD. For whole transcriptome analysis of RNA pools of the substantia nigra and mouse striatum, the MouseRef-8 v2.0 Expression BeadChip Kit microchips (Illumina, USA) were used. As a result of the analysis of whole transcriptome data, it was shown that, there are a greater number of statistically significant changes in the tissues of the brain and peripheral blood of mice with Adv-PSS and ESS models of PD compared to 6 h-PSS and 24 h-PSS models. In general, the obtained data indicate the sequential involvement of the transcriptome in the pathogenesis of PD, as well as the fact that changes at the transcriptome level of the processes of transport and mitochondrial biogenesis can play an important role in neurodegeneration in PD at an early stage.

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