Imaging Parkinson’s disease below the neck

Borghammer, Per; Knudsen, Karen A.; Fedorova, Tatyana D.; Brooks, David J.

doi:10.1038/s41531-017-0017-1

Cited by 21 publications

(15 citation statements)

References 148 publications

(163 reference statements)

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“…In addition to such epidemiological studies, novel lab analytical research approaches for the examination of PD patients or biological sample materials from them might shed further light on the neural gut–brain axis in PD. In vivo imaging using radiotracers and positron emission tomography (PET) provided an innovative approach to demonstrate a loss of sympathetic and parasympathetic nerve terminal function in Parkinson’s disease [ 111 ], but this examination method did not track αSyn PD itself. Here, the development of specific ligands for in vivo monitoring of the distribution of pathological αSyn PD species and its evolution over time, for example by longitudinal PET imaging, would provide a further advanced but technically very challenging approach [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

The Neural Gut–Brain Axis of Pathological Protein Aggregation in Parkinson’s Disease and Its Counterpart in Peroral Prion Infections

Beekes

2021

Viruses

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A neuropathological hallmark of Parkinson’s disease (PD) is the cerebral deposition of abnormally aggregated α-synuclein (αSyn). PD-associated αSyn (αSynPD) aggregates are assumed to act, in a prion-like manner, as proteinaceous nuclei (“seeds”) capable of self-templated propagation. Braak and colleagues put forward the idea of a neural gut-brain axis mediating the centripetal spread of αSynPD pathology from the enteric nervous system (ENS) to the brain in PD. This has sparked great interest and initiated passionate discussions both in support of and opposing the suggested hypothesis. A precedent for the spread of protein seeds or seeding from the gastro-intestinal (GI) tract to the central nervous system (CNS) had been previously revealed for pathological prion protein in peroral prion infections. This article scrutinizes the similarities and dissimilarities between the pathophysiological spread of disease-associated protein aggregation along the neural gut–brain axis in peroral prion infections and PD. On this basis, evidence supporting the proposed neural gut–brain axis in PD is concluded to be not as robust as that established for peroral prion infections. New tools for the ultrasensitive detection of αSynPD-associated seeding activity in archived or fresh human tissue samples such as real-time quaking induced conversion (RT-QuIC) or protein misfolding cyclic amplification (PMCA) assays can possibly help to address this deficit in the future.

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Section: Discussionmentioning

confidence: 99%

The Neural Gut–Brain Axis of Pathological Protein Aggregation in Parkinson’s Disease and Its Counterpart in Peroral Prion Infections

Beekes

2021

Viruses

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“…Gastrointestinal and urinary autonomic symptoms often predate PD diagnosis by several years 24 . In our study, the impaired gastrointestinal and urinary functions were also associated with FoG occurrence as disease proceeded.…”

Section: Discussionmentioning

confidence: 99%

Predicting the onset of freezing of gait in de novo Parkinson’s disease

Wang

Pan

Zhang

et al. 2021

Preprint

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Freezing of gait (FoG) is a debilitating symptom of Parkinson's disease (PD) related to higher risks of falls and poor quality of life. In this study, we predicted the onset of FoG in PD patients using a battery of risk factors from patients enrolled in the Parkinson's Progression Markers Initiative (PPMI) cohort. The endpoint was the presence of FoG, which was assessed every year during the five-year follow-up visit. Overall, 212 PD patients were included in analysis. Seventy patients (33.0%) developed FoG during the visit (pre-FoG group). Age, bradykinesia, TD/PIGD classification, fatigue, cognitive impairment, impaired autonomic functions and sleep disorder were found to be significantly different in patients from pre-FoG and non-FoG groups at baseline. The logistic regression model showed that motor factors such as TD/PIGD classification (OR = 2.67, 95% CI = 1.41-5.09), MDS-UPDRS part III score (OR = 1.05, 95% CI = 1.01-1.09) were associated with FoG occurrence. Several indicators representing non-motor symptoms such as SDMT total score (OR = 0.95, 95% CI = 0.91-0.98), HVLT immediate/Total recall (OR = 0.91, 95% CI = 0.86-0.97), MOCA (OR = 0.87, 95% CI = 0.76-0.99), Epworth Sleepiness Scale (OR = 1.13, 95% CI = 1.03-1.24), fatigue(OR = 1.98, 95% CI = 1.32-3.06), SCOPA-AUT gastrointestinal score (OR = 1.27, 95% CI = 1.09-1.49) and SCOPA-AUT urinary score (OR = 1.18, 95% CI = 1.06-1.32) were found to have the predictive value. PD patients that developed FoG showed a significant reduction of DAT uptake in the striatum. However, no difference at baseline was observed in genetic characteristics and CSF biomarkers between the two patient sets. Our model indicated that TD/PIGD classification, MDS-UPDRS total score, and Symbol Digit Modalities score were independent risk factors for the onset of FoG in PD patients. In conclusion, the combination of motor and non-motor features including the akinetic subtype and poor cognitive functions should be considered in identifying PD patients with high risks of FoG onset.

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“…Although PD is considered a degenerative disease of the brain, it has become apparent that dysfunction and or alpha-synuclein pathology is observed in non-CNS tissues of PD patients [13][14][15] . Our spatial eQTL analysis included an assessment of the tissue distribution of the effects of the identified eQTLs within 13 CNS and 36 peripheral tissues.…”

Section: The Regulatory Impact Of Pd-snps Extends Beyond the Cnsmentioning

confidence: 99%

“…Although PD is defined as a neurodegenerative disease, mounting evidence demonstrates the role of non-central nervous system (CNS) tissues in the development and presentation of such disorders (i.e. Huntington's 11 and PD 12,13 ). Both alpha-synuclein (αSyn) protein pathology and modulation of PD-related genes have been identified in peripheral tissues (e.g.…”

Section: Introductionmentioning

confidence: 99%

Establishing gene regulatory networks from Parkinson’s disease risk loci

Farrow

Schierding

Gokuladhas

et al. 2021

Preprint

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The latest meta-analysis of genome wide association studies (GWAS) identified 90 independent single nucleotide polymorphisms (SNPs) across 78 genomic regions associated with Parkinson's disease (PD), yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with PD-SNPs, we utilised an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci; eQTL) data. We identified 518 genes subject to regulation by 76 PD-SNPs across 49 tissues, that encompass 36 peripheral and 13 CNS tissues. Notably, one third of these genes were regulated via trans- acting mechanisms (distal; risk locus-gene separated by > 1Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-eQTL-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and PD GWAS loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neuro-development specific eQTL-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of PD. Through utilising Louvain clustering we extracted nine significant and highly intra-connected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with PD. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of PD-SNPs, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of PD.

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Imaging Parkinson’s disease below the neck

Cited by 21 publications

References 148 publications

The Neural Gut–Brain Axis of Pathological Protein Aggregation in Parkinson’s Disease and Its Counterpart in Peroral Prion Infections

The Neural Gut–Brain Axis of Pathological Protein Aggregation in Parkinson’s Disease and Its Counterpart in Peroral Prion Infections

Predicting the onset of freezing of gait in de novo Parkinson’s disease

Establishing gene regulatory networks from Parkinson’s disease risk loci

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