Pathophysiology Of PD Research Articles

The role of inflammation in neurological disorders: a brief overview of multiple sclerosis, Alzheimer’s, and Parkinson’s disease’

Neuroinflammation is a central feature in the pathophysiology of several neurodegenerative diseases, including MS, AD, and PD. This review aims to synthesize current research on the role of inflammation in these conditions, emphasizing the potential of inflammatory biomarkers for diagnosis and treatment. We highlight recent findings on the mechanisms of neuroinflammation, the utility of biomarkers in disease differentiation, and the implications for therapeutic strategies. Advances in understanding inflammatory pathways offer promising avenues for developing targeted interventions to improve patient outcomes. Future research should focus on validating these biomarkers in larger cohorts and integrating them into clinical practice to enhance diagnostic accuracy and therapeutic efficacy.

A comprehensive review and recent advancement in the application of tannins for treating Parkinson disease

IntroductionParkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Despite extensive research, the etiology of PD remains elusive, and current treatments focus primarily on symptomatic relief rather than disease modification. MethodsThe papers were searched in Web of Science, Scopus, PubMed, PubMed Prime, Cochrane library, Sciencedirect and Google Scholar as web resources. This article includes information about tannins research and reviews in the treatment of PD. However, other paper related to CNS have been avoided. ResultsIn recent years, there has been growing interest in exploring the therapeutic potential of natural compounds, such as tannins, for the management of PD. Tannins, polyphenolic compounds found abundantly in various plant species, have demonstrated neuroprotective effects through their antioxidant, anti-inflammatory, and metal chelating properties. This review provides a comprehensive overview of the current understanding of PD pathophysiology, existing treatment modalities, and the potential role of tannins in PD management. Additionally, recent advancements in the application of tannins, including in vitro and in vivo studies, clinical trials, and novel delivery systems, are discussed. Furthermore, challenges and future perspectives regarding the translation of tannin-based therapies into clinical practice are addressed. DiscussionOverall, this review highlights the promising therapeutic potential of tannins in the treatment of Parkinson's disease and underscores the need for further research to elucidate their mechanisms of action and optimize their clinical efficacy.

Orthogonal analysis of mitochondrial function in Parkinson’s disease patients

The etiopathology of Parkinson’s disease has been associated with mitochondrial defects at genetic, laboratory, epidemiological, and clinical levels. These converging lines of evidence suggest that mitochondrial defects are systemic and causative factors in the pathophysiology of PD, rather than being mere correlates. Understanding mitochondrial biology in PD at a granular level is therefore crucial from both basic science and translational perspectives. In a recent study, we investigated mitochondrial alterations in fibroblasts obtained from PD patients assessing mitochondrial function in relation to clinical measures. Our findings demonstrated that the magnitude of mitochondrial alterations parallels disease severity. In this study, we extend these investigations to blood cells and dopamine neurons derived from induced pluripotent stem cells reprogrammed from PD patients. To overcome the inherent metabolic heterogeneity of blood cells, we focused our analyses on metabolically homogeneous, accessible, and expandable erythroblasts. Our results confirm the presence of mitochondrial anomalies in erythroblasts and induced dopamine neurons. Consistent with our previous findings in fibroblasts, we observed that mitochondrial alterations are reversible, as evidenced by enhanced mitochondrial respiration when PD erythroblasts were cultured in a galactose medium that restricts glycolysis. This observation indicates that suppression of mitochondrial respiration may constitute a protective, adaptive response in PD pathogenesis. Notably, this effect was not observed in induced dopamine neurons, suggesting their distinct bioenergetic behavior. In summary, we provide additional evidence for the involvement of mitochondria in the disease process by demonstrating mitochondrial abnormalities in additional cell types relevant to PD. These findings contribute to our understanding of PD pathophysiology and may have implications for the development of novel biomarkers and therapeutic strategies.

(258) Agatston Calcium Score Assessment of Plaque Calcification in Peyronie’s Disease

Abstract Introduction Peyronie’s disease (PD) is characterized by penile pain, penile deformation and curvature, sexual dysfunction, and psychological implications. Fibrosis and plaque formation are often part of PD pathophysiology. Calcified plaques can alter treatment planning. Penile ultrasound with Doppler (PUS) is used to exclude erectile dysfunction and identify plaques. However, plaque extent and distribution can be obscured by acoustic shadowing, limiting complete plaque characterization. Non-contrast pelvis computed tomography (CT) provides a noninvasive method to identify plaques in 3 dimensions and quantify plaque Ca burden. Objective Our objective was to utilize Agatston Ca scoring measure Ca burden in patients with Peyronie's disease. Methods A retrospective database from 1/1/2017 and 6/30/2021 identified 25 men with calcified plaques on CT after PUS performed by a single urologist. Two abdominal radiologists reviewed CTs in consensus to measure calcified plaque size and distribution on Visage PACS. Semiautomated Agatston Ca scoring values were obtained with Syngo.via. Total Ca volume (mm3), total Ca score were correlated with hourglass deformity on clinical exam, plaque complexity on CT (>2 discrete calcified plaques, circumferential corpus cavernosum involvement, septal involvement), and surgical management using descriptive statistics and t-test. Results Mean Ca volume was 1417 mm3 (range 1.4-5425.7, standard deviation (SD) 1570); mean Ca score was 1691 (range 1.6-6048; SD 1862) with significantly higher Ca volume in patients with complex plaques (265 mm3 vs 472 mm3, p<0.05), and significantly longer plaque dimension for longest plaque dimension measured by CT vs US (31 vs 23, p<0.05). There was no significant difference in Ca volume for nonsurgical vs surgical (1791 vs 893, p=0.06) or for no hourglass vs hourglass deformity (1173 vs 1904, p=0.19). Conclusions CT scan and calcium scoring are useful tools in the assessment of PD. Semiautomated Ca scoring may help noninvasively identify complex calcified penile plaques to guide medical and surgical therapy for Peyronie’s disease. Disclosure No

The Relationship between Rem Sleep Behaviour Disorder and Parkinson’s Disease Revisited – Are They One and the Same?

This paper reviews the relationship between RBD and PD and the pathophysiology. Most RBD patients develop PD within 14 years. PD pathophysiology is α-synucleinopathy with dopamine degeneration in nigrostriatal pathways. RBD pathology is poorly understood. Anomalies suggest RBD and PD are different, evidenced by smoking. RBD and PD are associated with glucocerebrosidase gene mutations (GBA gene), suggesting RDB with GBA gene mutation predicts PD. PET imaging, assessing vesicular monoamine transporter 2 (VMAT2), indexing nigrostriatal dopamine innervation, is lower in PD and RBD, in the putamen, ventral striatum and globus pallidus but not substantia nigra or subthalamus, compared with controls. VMAT2 may not contribute to pathophysiology of RBD in PD. Treatments for RBD and PD differ. PD with RBD had more depression, compared to PD without RBD. Only PD with RBD had statistically significant increased depression, compared with controls, and non-significant lowered cognition. PD patients, with and without RBD, had decreased ligand binding, compared to healthy controls, indicating no difference in VMAT2 within the caudate and putamen. Research showed differences in cholinergic levels, noradrenaline and glucose metabolism for PD with and without RBD. RBD with PD, is multi-systematic, affecting regions beyond dopaminergic pathways. Treatment of RBD does not affects PD neurodegeneration. Researchers continue to search for neuro-protective intervention. There is a relationship between PD and RBD but it is not absolute. PD nigrostriatal degeneration is independent of RBD. Pathophysiological differences may explain why treatment of RBD does not alter its natural history.

Propolis induces cardiac metabolism changes in 6-hydroxydopamine animal model: A dietary intervention as a potential cardioprotective approach in Parkinson's disease.

While there is sustained growth of the older population worldwide, ageing is a consistent risk factor for neurodegenerative diseases, such as Parkinson’s-disease (PD). Considered an emblematic movement disorder, PD comprises a miscellany of non-motor symptoms, for which effective management remains an unfulfilled need in clinical practice. Highlighted are the cardiovascular abnormalities, that cause significant burden in PD patients. Evidence suggests that key biological processes underlying PD pathophysiology can be modulated by diet-derived bioactive compounds, such as green propolis, a natural functional food with biological and pharmacological properties. The effects of propolis on cardiac affection associated to PD have received little coverage. In this study, a metabolomics approach and Positron Emission Tomography (PET) imaging were used to assess the metabolic response to diet supplementation with green propolis on heart outcomes of rats with Parkinsonism induced by 6-hydroxydopamine (6-OHDA rats). Untargeted metabolomics approach revealed four cardiac metabolites (2-hydroxybutyric acid, 3-hydroxybutyric acid, monoacylglycerol and alanine) that were significantly modified between animal groups (6-OHDA, 6-OHDA + Propolis and sham). Propolis-induced changes in the level of these cardiac metabolites suggest beneficial effects of diet intervention. From the metabolites affected, functional analysis identified changes in propanoate metabolism (a key carbohydrate metabolism related metabolic pathway), glucose-alanine cycle, protein and fatty acid biosynthesis, energy metabolism, glutathione metabolism and urea cycle. PET imaging detected higher glucose metabolism in the 17 areas of the left ventricle of all rats treated with propolis, substantially contrasting from those rats that did not consume propolis. Our results bring new insights into cardiac metabolic substrates and pathways involved in the mechanisms of the effects of propolis in experimental PD and provide potential novel targets for research in the quest for future therapeutic strategies.

Adenosine A2A receptor availability in patients with early- and moderate-stage Parkinson’s disease

IntroductionAdenosine 2A (A2A) receptors co-localize with dopamine D2 receptors in striatopallidal medium spiny neurons of the indirect pathway. A2A receptor activation in the striatum or pallidum decreases D2 signaling. In contrast, A2A receptor antagonism may help potentiate it. Furthermore, previous PET studies have shown increased A2A receptor availability in striatum of late-stage PD patients with dyskinesia. However, human in vivo evidence for striatal A2A receptor availability in early-stage PD is limited. This study aimed to investigate possible differences in A2A receptor availability in the striatum and pallidum of early- and moderate-stage PD patients without dyskinesias.MethodsBrain MRI and PET with [11C]TMSX radioligand, targeting A2A receptors, was performed in 9 patients with early- and 9 with moderate-stage PD without dyskinesia and in 6 healthy controls. Distribution volume ratios (DVR) were calculated to assess specific [11C]TMSX binding in caudate, putamen and pallidum.ResultsA2A receptor availability (DVR) was decreased in the bilateral caudate of early-stage PD patients when compared with healthy controls (P = 0.02). Conversely, DVR was increased bilaterally in the pallidum of moderate-stage PD patients compared to healthy controls (P = 0.03). Increased mean striatal DVR correlated with higher motor symptom severity (rho = 0.47, P = 0.02).ConclusionOur results imply regional and disease stage-dependent changes in A2A receptor signaling in PD pathophysiology and in response to dopaminergic medication.

Homozygous mutation of the LRRK2 ROC domain as a novel genetic model of parkinsonism

BackgroundParkinson’s disease (PD) is one of the most important neurodegenerative disorders in elderly people. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in a large proportion of the patients with sporadic and familial PD. Mutations can occur at different locations in the LRRK2. Patients with LRRK2 ROC-COR mutations face an increased risk of typical motor symptoms of PD, along with cognitive decline. An animal model with a monogenic LRRK2 gene mutation is a suitable model for exploring the pathophysiology of PD and identifying potential drug therapies. However, the effect of homozygous (HOM) LRRK2 in PD pathophysiology is unclear.MethodsWe established human LRRK2 (hLRRK2) R1441G HOM transgenic (Tg) mice to explore the phenotype and pathological features that are associated with hLRRK2 R1441G Tg mouse models and discuss the potential clinical relevance. The open field test (OFT) was performed to examine motor and nonmotor behaviors. A CatWalk analysis system was used to study gait function. [18F]FDOPA PET was used to investigate functional changes in the nigrostriatal pathway in vivo. Transmission electron microscopy was used to examine the morphological changes in mitochondria and lysosomes in the substantia nigra.ResultsThe R1441G HOM Tg mice demonstrated gait disturbance and exhibited less anxiety-related behavior and exploratory behavior than mice with hLRRK2 at 12 months old. Additionally, [18F]FDOPA PET showed a reduction in FDOPA uptake in the striatum of the HOM Tg mice. Notably, there was significant lysosome and autophagosome accumulation in the cytoplasm of dopaminergic neurons in R1441G hemizygous (HEM) and HOM mice. Moreover, it was observed using transmission electron microscopy (TEM) that the mitochondria of R1441G Tg mice were smaller than those of hLRRK2 mice.ConclusionThis animal provides a novel HOM hLRRK2 R1441G Tg mouse model that reproduces some phenotype of Parkinsonism in terms of both motor and behavioral dysfunction. There is an increased level of mitochondrial fission and no change in the fusion process in the group of HOM hLRRK2 R1441G Tg mouse. This mutant animal model of PD might be used to study the mechanisms of mitochondrial dysfunction and explore potential new drug targets.

Complementary and Alternative Medicines in Parkinson's Disease.

Epidemiological studies reviewed in 2016, suggest that 6.1 million people in the world had PD. There is currently no cure for PD. For now, currently, the treatment of PD includes drugs, general measures to control symptoms (ie, physical and occupational therapy), and surgery. Because dysfunction of the basal ganglia system for dopamine depletion occurs in the pathophysiology of PD, the key therapeutic strategy is the use of drugs that increase the amount of dopamine in the affected brain areas. PD is a progressive disease, despite pharmacotherapy or surgical treatments. The progression of symptoms and movement disorders in PD is so severe that patients resort to complementary and alternative medicine (CAM), even without knowing their effectiveness and adverse reactions.

What Do Randomized Controlled Trials Inform Us About Potential Disease-Modifying Strategies for Parkinson's Disease?

Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. In this review, we made a broad survey of the published literature that report possible disease-modifying effects on PD. While there are many studies that demonstrate benefits for various therapies for PD in animal and human studies, we confined our search to human "randomised controlled trials" and with the key words "neuroprotection" or "disease-modifying". It is hoped that through studying the results of these trials, we might clarify possible mechanisms that underlie idiopathic PD. This contrasts with studying the effect of pathophysiology of familial PD, which could be carried out by gene knockouts and animal models. Randomised controlled trials indicate promising effects of MAO-B inhibitors, dopamine agonists, NMDA receptorantagonists, metabotropic glutamate receptor antagonists, therapies related to improving glucose utilization and energy production, therapies related to reduction of excitotoxicity andoxidative stress, statin use, therapies related to iron chelation, therapies related to the use of phytochemicals, and therapies related to physical exercise and brain reward pathwayon slowing PD progression. Cumulatively, these approaches fall into two categories: direct enhancement of dopaminergic signalling, and reduction of neurodegeneration. Overlaps between the two categories result in challenges in distinguishing between symptomatic versus disease-modifying effects with current clinical trial designs. Nevertheless, a broad-based approach allows us to consider all possible therapeutic avenues which may be neuroprotective. While the traditional standard of care focuses on symptomatic management with dopaminergic drugs, more recent approaches suggest ways to preserve dopaminergic neurons by attenuating excitotoxicity and oxidative stress.

GUT-MICROBIOME-BRAIN AXIS AND ITS INFLUENCE ON PARKINSON'S DISEASE (Review Article)

The relationship between the nervous system and microbiota opened up research opportunities that can significantly change the management of several neurological disorders. The discovery of the microbiota-gut-brain axis helped us understand how the information is relayed between the brain and the enteric nervous system. This connection demonstrated how, in Parkinson’s disease, the alpha- synuclein accumulates in different organs, resulting in a wide array of symptoms. Moreover, pathways such as the hypothalamic-pituitary axis, the neuroinflammatory pathway, and neuroactive molecules are associated with the pathophysiology of PD. The manifestation of gastrointestinal symptoms and altered gut microbiota have been noted in patients several years before other significant clinical symptoms appeared. The role of alpha-synuclein accumulation and environmental factors that disrupt the natural flora of the gut in the overall progression of PD has been observed through well documented clinical studies on mice. With the current knowledge that has been established, the alteration of gut microbiota using recently explored treatment options such as probiotics, fecal microbiota transplantation, dietary changes, and certain antibiotics can prevent the progressive symptoms of Parkinson's disease.

Dysautonomia in Parkinson's Disease: Impact of Glucocerebrosidase Gene Mutations on Cardiovascular Autonomic Control.

Evidence from clinical practice suggests that PD patients with the Glucocerebrosidase gene mutations (GBA-PD) are characterized by more severe dysautonomic symptoms than patients with idiopathic PD (iPD). Therefore, an accurate assessment of cardiovascular autonomic control (CAC) is necessary to clarify the role of GBA mutations in the pathophysiology of PD. We evaluated the CAC at rest and during orthostatic challenge of 15 iPD, 15 GBA-PD and 15 healthy controls (CTR). ECG and respiration were recorded in supine position and during active standing. The analysis of Heart Rate Variability (HRV) was performed on ECG recordings using two different approaches, linear spectral analysis and non-linear symbolic analysis. GBA-PD patients presented more frequently an akinetic-rigid phenotype and cognitive dysfunction than iPD patients. Both iPD and GBA-PD group were characterized by a lower spectral HRV than CTR group. At rest, the GBA-PD group was characterized by a lower parasympathetic modulation and a shift of the sympathovagal balance toward a sympathetic predominance compared to the CTR group. Moreover, the GBA-PD patients presented a lower HR increment and a lower or absent reduction of the vagal modulation in response to the active standing than iPD patients. Lastly, the cardiovascular autonomic dysfunction in PD patients was associated with longer disease duration, and with the occurrence of REM sleep behavior disorder and constipation. Our findings suggest a more severe impairment of the CAC in PD patients with GBA mutations. These results and further studies on the role of GBA mutations could allow a stratification based on cardiovascular risk in PD patients and the implementation of specific prevention programs.

Multi-omic landscaping of human midbrains identifies disease-relevant molecular targets and pathways in advanced-stage Parkinson's disease.

BackgroundParkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease‐mediated alterations, we investigated the molecular landscape of PD in human post‐mortem midbrains, a region that is highly affected during the disease process.MethodsTissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi‐omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole‐time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies.ResultsOur analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real‐time polymerase chain reaction/western blotting) several PD‐deregulated molecular candidates, including miR‐539‐3p, miR‐376a‐5p, miR‐218‐5p and miR‐369‐3p, the valid miRNA‐mRNA interacting pairs miR‐218‐5p/RAB6C and miR‐369‐3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi‐omic analyses allowed validating disease‐mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function.ConclusionsThis comprehensive assessment of PD‐affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD.

Resting-State Low-Frequency Cerebellar Oscillations Can Be Abnormal in Parkinson's Disease.

Recent anatomical studies have shown connections between the basal ganglia and the cerebellum. The basal ganglia and cerebellum are major subcortical structures that influence motor and cognitive functions. Recent neuroimaging and animal studies have suggested the role of the cerebellum in the pathophysiology of Parkinson's disease. However, the role of cerebellar oscillations in PD has not been studied. Here, we recruited 75 PD and 39 healthy control subjects to collect cerebellar EEG during a resting-state condition. We followed the recently published protocols to collect cerebellar oscillations. Relative spectral power was computed in the delta, theta, beta, and gamma frequency bands. Further, we performed classifier methods to differentiate PD subjects from controls. We observed significantly increased theta-band (4-7Hz) relative power in the cerebellar electrodes in PD subjects compared to controls. We also found differences in different frequency bands between mid-cerebellar and nearby mid-occipital EEG signals. Classification analysis using mid-cerebellartheta relative power showed differentiation between PD and control groups. Our results demonstrate that in addition to established cortical and basal ganglia oscillations, abnormal cerebellar oscillations in the theta-band may also participate in the underlying pathophysiology of PD. We suggest that low-frequency cerebellar oscillations may be a potential target for non-invasive neuromodulation to improve PD symptoms.

Gut microbiota in Parkinson\u2019s disease patients: hospital-based study

BackgroundParkinson’s disease (PD) is one of the most common neurodegenerative diseases. There is accumulating evidence that link gut microbiota to symptomatology and pathophysiology of PD. The aim of this study was to describe the pattern of gut microbiota and its association with PD and identify the effect of environmental factors on gut microbiota. This case–control study included 46 patients diagnosed as Parkinson’s disease (PD) and 31 healthy volunteers age and sex matched. Detailed history including age of onset, duration of disease, environmental risk factors, diet data, treatment, Unified Parkinson’s Disease Rating Scale (UPDRS), and gastrointestinal tract (GIT) domain of Non‐Motor Symptoms Scale (NMSS) were assessed. After extraction of bacterial DNA from the fecal samples, bacterial abundance was quantified by qPCR using 16S rRNA group-specific primers.ResultsSignificant high abundance of Clostridium cluster IV, Akkermansia, Bifidobacterium, and lactic acid bacteria were found in the PD group compared with the control group (P < 0.001, 0.04, 0.02 and < 0.001, respectively), while Firmicutes were significantly less abundant in the PD group (P < 0.001) compared with the control group. The naive PD patients had significant abundance of Bifidobacterium, and lactic acid compared with control group. Interestingly, Akkermansia was more abundant in treated than untreated patients. There were significant associations between pesticide exposure and Bifidobacterium (P = 0.002), while no significant correlations between different gut microbiota and demographic, environment data, different rating scores or dominant type of PD. There was a significant negative correlation between the Bifidobacterium with the duration of illness (P = 0.012). ConclusionThe present study highlighted a significant connection between PD and levels of certain types of gut microbiota, in support of a possible link between gut microbiota and a neurodegenerative cascade of PD.

Different resting-state network disruptions in newly diagnosed drug-na\xefve Parkinson\u2019s disease patients with mild cognitive impairment

BackgroundCognitive impairment is a common non-motor symptom in patients with Parkinson’s disease (PD). Mild cognitive impairment (MCI) is also prevalent in nondemented PD patients, even in newly diagnosed PD patients. The possible impacts of MCI on brain function activities for PD patients need more investigation, and the potential of emerging technologies for detecting underlying pathophysiology of cognitive signs in PD can be further improved.MethodForty-seven newly diagnosed drug-naïve PD patients (28 PD-MCI patients and 19 PD patients with cognitively unimpaired (PD-CU)) and 28 healthy controls (HCs) underwent resting-state functional MRI. The connectivity patterns of specific networks were investigated through the independent component analysis among PD-MCI, PD-CU and HCs groups.ResultsThe independent component analysis revealed significantly decreased functional connectivity (FC) of the default mode network, visual network and sensorimotor network in the PD-MCI subgroup compared with the HC group. Furthermore, FC of the default mode network was positively correlated with memory scores from the brief visuospatial memory test-revised, and FC of the visual network was positively correlated with visuospatial scores from the clock copying test in the PD-MCI group. In all patients with PD, FC of the sensorimotor network negatively correlated with motor severity scores from the Unified PD Rating Scale (UPDRS) part III. On the other hand, the potential damage was more likely to occur in FC between the sensorimotor network and limbic network, and between the ventral attention network and visual network in all PD patients.ConclusionsNewly diagnosed drug-naïve PD-MCI patients showed characteristic damage of FC within the default mode network, visual network and sensorimotor network, and all PD patients presented impaired FC between the sensorimotor network and limbic network, and FC between the ventral attention network and visual network. These network-wide functional aberrations may underline the pathophysiology of PD.

Therapeutic Indications of NAAG Peptidase Inhibitors for Parkinson’s Disease

Current studies of NAAG Peptidase Inhibitors show their potential for neuroprotection of dopaminergic cells and result in a reduction in Glutamate excitotoxicity. These results reveal that NAAG Peptidase Inhibitors could assist clinicians in understanding the pathophysiology of PD leading to a more effective treatment of patients’ symptoms. They underscored some of the most historical attempts in experimental therapeutics of PD in the past decade. The futility of some of the studies should be examined in the context of the current science as discussed in our paper. A deeper understanding of NAAG Peptidase inhibition could potentially accelerate early stages of PD interventions.

Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson\u2019s disease brain

BackgroundParkinson’s disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved.MethodsWe studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression.ResultsImmunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts.ConclusionsOur findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease.

Single-cell Transcriptomics Uncover a Novel Role of Myeloid Cells and T-lymphocytes in the Fibrotic Microenvironment in Peyronie’s Disease

BackgroundPeyronie’s disease (PD) is an acquired fibrotic disease affecting the penile tunica albuginea that can lead to curvature and deformities, shortening, and erectile dysfunction. Although immunological mechanisms have been suggested for the pathophysiology of PD, these have not been investigated using single-cell transcriptomics. ObjectiveTo investigate the immunological signature of plaques from PD patients using immunohistochemistry (IHC) and single-cell RNA sequencing (scRNA-Seq). Design, setting, and participantsTunica albuginea biopsy was performed in patients undergoing penile surgery for either PD (n = 12) or plication or penile cancer (control, n = 6). The inclusion criteria for PD patients were stable chronic disease (≥12 mo in duration) and no previous penile surgery or intralesional injection therapy. Outcome measurements and statistical analysisIHC was performed on surgical samples from ten patients with PD and five control subjects. An additional two PD and one control sample were used for scRNA-Seq (droplet-based; 10X Genomics). Cell clusters were visualised using heatmaps and t-distributed stochastic neighbour embedding plots (BioTuring v2.7.5). Results and limitationsIHC revealed the presence of myeloid dendritic cells (DCs; CD68+, TLR4+, CD206+), cytotoxic T lymphocytes (CTLs; CD3+, CD8+), and B lymphocytes (CD20+) in PD plaques, which were absent in controls. scRNA-Seq yielded results for 3312 PD and 5658 control cells. Cell clusters contained fibroblasts (COL1A2+), myofibroblasts (COL1A2+, ACTA2+), smooth muscle cells (ACTA2+, DES+), endothelial cells (VWF+), myeloid cells (CD14+), T lymphocytes (CD3D+), and neutrophils (ALPL+). Myeloid cell subclustering showed infiltration of monocyte-derived cells; control tissue contained classical DCs and resident macrophages. Lymphocyte subclustering revealed mucosal-associated invariant T (MAIT) cells and CTLs in PD. Differential gene expression suggests an increase in inflammatory and immune responses in chronic PD. The study is limited by the small scRNA-seq sample size (n = 3) for IHC, mitigated by a larger cohort of historic paraffin-embedded samples (n = 15), which showed largely parallel findings. Owing to tissue stiffness and extracellular matrix adhesion, our single-cell yield was lower for PD than for the control sample. ConclusionsOur data suggest that even in the chronic PD stage (painless and stable curvature) there is a sustained inflammatory reaction. While vascularisation and collagen production are elevated, the inflammation is driven by specialised monocyte-derived CTL and MAIT cells. These findings could uncover new avenues for medical treatment of PD. Patient summaryWe looked at the role of the immune system in patients suffering from Peyronie’s disease, a condition causing shortening and curvature of the penis. We found that even in a stable, chronic stage of the disease, there is activation of the immune system. Our results suggest that there is potential for novel treatments for this condition.

Objective sleep data as predictors of cognitive decline in dementia with Lewy Bodies and Parkinson's disease

IntroductionParkinson's disease (PD) and Dementia with Lewy Bodies (DLB) prognosis depends on cognitive function evolution. Sleep disorders, as objectivated by polysomnography (PSG), are intimately connected with PD and DLB pathophysiology, but have seldomly been used to predict cognitive decline. Methods20 DLB and 49 PD patients underwent one-night in-lab video-PSG. Sleep variables were defined, including REM sleep motor events, Tonic and phasic REM sleep muscular tone and RBD diagnosis. Cognitive state (assessed with the Global Deterioration Scale (GDS) was collected from case files for 6 months intervals, for a maximum period of 3.5 years or until death/drop-out.). The relation between PSG data at baseline and variation of GDS scores over time was tested with mixed linear regression analysis. ResultsGDS scores were higher in DLB, than in PD. We confirmed significant cognitive decline in both disorders, but no significant differences in progression between them. There were no significant interactions between PSG data and GDS variation for the entire group and DLB separately. In PD patients, there was a significant interaction between RBD diagnosis and tonic excessive muscular tone and GDS increase. ConclusionOur data suggests that PSG data can be useful in predicting cognitive decline in PD but not in DLB patients. In PD patients, an RBD diagnosis is predictive of cognitive deterioration, confirming the notion that this non-motor symptom relates to a malignant sub-type. Tonic excessive muscular activity, but not other RBD features, had predictive value in this group, pointing to a specific relation with the disease pathophysiology.