Abstract:Parkinson’s disease (PD) is typically considered an age-related disease, but the age at disease onset can vary by decades between patients. Aging and aging-associated diseases can affect the movement system independently of PD, and advanced age has previously been proposed to be associated with a more severe PD phenotype with accelerated progression. In this work, we investigated how interactions between PD progression and aging affect a wide range of outcomes related to PD motor and nonmotor symptoms as well … Show more
“…Therefore, the current study aimed to use the modified DTI‐ALPS method to explore the glymphatic activity and its related factors, including the severity of motor and non‐motor symptoms in PD patients. Age has been reported to be associated with different PD phenotypes by previous studies, 6,7 underpins which we hypothesized that glymphatic function plays different roles in the pathogenesis and progression of PD among patients of different age groups. So, associations between ALPS index and disease severity in PD patients of different age groups were also explored.…”
Section: Introductionmentioning
confidence: 93%
“…And it has been reported that the accumulation of α‐syn in the brain is greatly related to age 5 . However, the underlying mechanism between aging and the pathogenesis and progression of PD is poorly understood 6–8 …”
Aims
The aim of the study was to evaluate the glymphatic function and its related factors in patients with Parkinson's disease (PD) and patients with PD of different ages using the diffusion tensor image analysis along the perivascular space (DTI‐ALPS) method.
Methods
Medical records and imaging data of 93 patients with idiopathic PD and 42 age‐ and sex‐matched healthy controls (HCs) were retrospectively reviewed and analyzed. The diffusivity along the perivascular spaces, projection fibers, and association fibers were calculated on diffusion tensor imaging (DTI) to acquire the analysis along the perivascular space (ALPS) index.
Results
PD patients exhibited a reduced ALPS index compared with the HCs. Negative correlations between the ALPS index and clinical information including age, age at disease onset, Parkinson's disease sleep scale 2nd version (PDSS‐2) scores, and history of diabetes mellitus were revealed in the PD group. Besides, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup aged 65 and above, rather than in the younger ones.
Conclusions
The results demonstrate that reduced ALPS index, a potential noninvasive measure of compromised glymphatic activity, is involved in the pathophysiology of PD, especially in the aged ones and those with sleep disorders.
“…Therefore, the current study aimed to use the modified DTI‐ALPS method to explore the glymphatic activity and its related factors, including the severity of motor and non‐motor symptoms in PD patients. Age has been reported to be associated with different PD phenotypes by previous studies, 6,7 underpins which we hypothesized that glymphatic function plays different roles in the pathogenesis and progression of PD among patients of different age groups. So, associations between ALPS index and disease severity in PD patients of different age groups were also explored.…”
Section: Introductionmentioning
confidence: 93%
“…And it has been reported that the accumulation of α‐syn in the brain is greatly related to age 5 . However, the underlying mechanism between aging and the pathogenesis and progression of PD is poorly understood 6–8 …”
Aims
The aim of the study was to evaluate the glymphatic function and its related factors in patients with Parkinson's disease (PD) and patients with PD of different ages using the diffusion tensor image analysis along the perivascular space (DTI‐ALPS) method.
Methods
Medical records and imaging data of 93 patients with idiopathic PD and 42 age‐ and sex‐matched healthy controls (HCs) were retrospectively reviewed and analyzed. The diffusivity along the perivascular spaces, projection fibers, and association fibers were calculated on diffusion tensor imaging (DTI) to acquire the analysis along the perivascular space (ALPS) index.
Results
PD patients exhibited a reduced ALPS index compared with the HCs. Negative correlations between the ALPS index and clinical information including age, age at disease onset, Parkinson's disease sleep scale 2nd version (PDSS‐2) scores, and history of diabetes mellitus were revealed in the PD group. Besides, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup aged 65 and above, rather than in the younger ones.
Conclusions
The results demonstrate that reduced ALPS index, a potential noninvasive measure of compromised glymphatic activity, is involved in the pathophysiology of PD, especially in the aged ones and those with sleep disorders.
“…Aging is a well known factor for PD [53][54][55][56] . Hence, it is common to detect gene modules associated with PD diagnosis and their age simultaneously (see results).…”
Section: Gene Segregation Based On Covariatesmentioning
Motivation: gene co-expression networks have been widely applied to identify critical genes and pathways for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Now, with the advent of single-cell RNA-sequencing, we have the opportunity to create cell-type specific gene co-expression networks. However, single-cell RNA-sequencing data is characterized by its sparsity, amongst some other issues raised by this new type of data. Results: We present scCoExpNets, a framework for the discovery and analysis of cell-type specific gene coexpression networks (GCNs) from single-cell RNA-seq data. We propose a new strategy to address the problem of sparsity, named iterative pseudo-cell identification. It consists of adding the gene expression of pairs of cells that belong to the same individual and the same cell-type while the number of cells is over 200, thus creating multiple matrices and multiple scGCNs for the same cell-type, all of them seen as alternative and complementary views of the same phenomena. We applied this new tool on a snRNA-seq dataset human post-mortem substantia nigra pars compacta tissue of 13 controls and 14 Parkinson's disease (PD) cases (18 males and 9 females) with 30-99 years. We show that one of the hypotheses that support the selective vulnerability of dopaminergic neurons in PD, the iron accumulation, is sustained in our dopaminergic neurons network models. Moreover, after successive pseudo-celluling iterations, the gene groups sustaining this hypothesis remain intact. At the same time, this pseudo-celulling strategy also allows us to discover genes whose grouping changes considerably throughout the iterations and provides new insights. Finally, since some of our models were correlated with diagnosis and age at the same time, we also developed our own framework to create covariate-specific GCNs, called CovCoExpNets. We applied this new software to our snRNA-seq dataset and we identified 11 age-specific genes and 5 diagnosis-specific genes which do not overlap. Availability and implementation: The CoExpNets implementations are available as R packages, scCoExpNets package, for creating single-cell GCNs and CovCoExpNets, for creating covariate-specific GCNs. Users can either download the development version via github https://github.com/aliciagp/scCoExpNets and https://github.com/aliciagp/CovCoExpNets Contact: alicia.gomez1@um.es Supplementary information: supplementary data is available online. Keywords: weighted gene co-expression networks, single-nucleus RNA-sequencing, sparsity, pseudo-cells, Parkinson's disease, selective vulnerability, dopaminergic neurons, lasso regression
“…There have been recent efforts to better define the different forms of the disease based on specifics of motor and non-motor features, age of disease onset and pathology. This has been explored extensively elsewhere ( Greenland et al, 2019 ; Raket et al, 2022 ), but, pertinent to this Review, many of the clinical transplantation studies ( Table 1 ) occurred prior to any clear differentiation of specific PD phenotypes. Box 1.…”
First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD.
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