Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Sprenger, Fabienne; Stefanova, Nadia; Gelpí, Ellen; Seppi, Klaus; Navarro‐Otano, Judith; Offner, Felix; Vilas, Dolores; Valldeoriola, Francesc; Pont‐Sunyer, Claustre; Aldecoa, Ibán; Gaig, Carles; Ginés, Àngels; Cuatrecasas, Míriam; Högl, Birgit; Frauscher, Birgit; Iranzo, Álex; Wenning, Gregor K.; Vogel, Wolfgang; Tolosa, Eduardo; Poewe, Werner

doi:10.1212/wnl.0000000000002126

Cited by 127 publications

(96 citation statements)

References 32 publications

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“…Results were inconsistent with moderate sensitivity and low specificity in the study on prodromal PD [35] and low sensitivity but high specificity in the study on RBD patients [32], thus not allowing any conclusion on the usefulness of enteric biopsies as a stratification tool for RBD patients. A recent study evaluating p-alpha-syn deposition in submandibular salivary gland biopsies of RBD patients showed a promising high sensitivity and specificity of p-alpha-syn detection, but also had a procedural limitation as less than half of the biopsies of the RBD patients contained glandular parenchyma [39].…”

Section: Discussionmentioning

confidence: 99%

Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease

et al. 2017

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Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson’s disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT (ρ = −0.377, p = 0.048), with olfactory function (ρ = −0.668, p = 0.002), and positively correlated with the total LR for RBD to present prodromal PD (ρ = 0.531, p = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1684-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease

et al. 2017

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“…121–123 Lastly, autopsy series of patients with RBD have found underlying synucleinopathy in 94% of patients, 25,97,124,125 and tissues from living patients with idiopathic RBD have exhibited abnormal α-synuclein immunoreactivity in peripheral tissues such as the submandibular gland 126 and colonic submucosal nerve fibers or ganglia. 127 Other neurodegenerative pathologies have been reported, sometimes intermingling with typical synucleinopathy pathology of Lewy bodies and neurites with neuronal loss, including Alzheimer disease pathology of amyloid beta and tau proteins, progressive supranuclear palsy, neuronal brain iron accumulation type 1, other neurodegenerative pathologies, or brain lesions. However, the implication from converging evidence from cohort outcome studies, clinical neurodegenerative biomarker studies, and pathological series is that in most cases, particularly in older adults with symptom onset after the age of 50 years, RBD is associated with underlying synucleinopathy pathology.…”

Section: Clinical Implications Of Rbdmentioning

confidence: 99%

REM Sleep Behavior Disorder: Diagnosis, Clinical Implications, and Future Directions

Louis

Boeve

2017

Mayo Clinic Proceedings

161

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Rapid eye movement sleep behavior disorder (RBD) is diagnosed by a clinical history of dream enactment accompanied by polysomnographic rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia). Rapid eye movement sleep behavior disorder is strongly associated with neurodegenerative disease, especially synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. A history of RBD may begin several years to decades before onset of any clear daytime symptoms of motor, cognitive, or autonomic impairments, suggesting that RBD is the presenting manifestation of a neurodegenerative process. Evidence that RBD is a synlucleinopathy includes the frequent presence of subtle prodromal neurodegenerative abnormalities including hyposmia, constipation, and orthostatic hypotension, as well as abnormalities on various neuroimaging, neurophysiological, and autonomic tests. Up to 90.9% of patients with idiopathic RBD ultimately develop a defined neurodegenerative disease over longitudinal follow-up, although the prognosis for younger patients and antidepressant-associated RBD is less clear. Patients with RBD should be treated with either melatonin 3 to 12 mg or clonazepam 0.5 to 2.0 mg to reduce injury potential. Prospective outcome and treatment studies of RBD are necessary to enable accurate prognosis and better evidence for symptomatic therapy and future neuroprotective strategies.

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“…Some studies suggest that aSyn pathology may start and be detectable in the GI tract in the prodromal phase of PD perhaps before affecting the brain 4, 5, 6, 7, suggesting that GI aSyn detection could be used as a predictive biomarker. According to a recent popular hypothesis, the misfolding of aSyn initially occurs in the ENS as a result of some environmental or genetic insult that then further spreads to CNS via vagal preganglionic innervation of the gut 8.…”

Section: Introductionmentioning

confidence: 99%

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Ruffmann

Bengoa-Vergniory

Poggiolini

et al. 2018

Neuropathology Appl Neurobio

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AimsGastrointestinal (GI) α‐synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well‐characterized cohort of PD patients and healthy controls (HC).MethodsWith immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS‐PLA), we targeted oligomeric aSyn species specifically; and with paraffin‐embedded tissue blot (AS‐PET‐blot) we aimed to detect fibrillary, synaptic aSyn.ResultsA total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS‐PLA (cellular and diffuse signal) and with AS‐PET‐blot (aSyn‐localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC.ConclusionsOur study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.

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Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Cited by 127 publications

References 32 publications

Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease

Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease

REM Sleep Behavior Disorder: Diagnosis, Clinical Implications, and Future Directions

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

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