<i>α</i>‐synuclein RT‐QuIC in cerebrospinal fluid of <scp>LRRK</scp>2‐linked Parkinson's disease

Garrido, Alícia; Fairfoul, Graham; Tolosa, Eduardo; Martı́, Marı́a José; Green, Alison

doi:10.1002/acn3.772

Cited by 71 publications

(59 citation statements)

References 51 publications

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“…The number of submandibular glands with pAS positivity among aLRRK2 was low (25%). Of interest, the percentage of positive cases is close to the proportion of aLRRK2 reported to have misfolded synuclein in the cerebrospinal uid (18.8%) assessed by RT-QuIC 17 . Factors such the relatively young age of the patients may also in uence these results since parkinsonism appears generally late in LRRK2-PD.…”

Section: Discussionmentioning

confidence: 52%

“…The absence of pAS positivity in manifest LRRK2-PD was not expected, since pAS accumulation in the peripheral autonomic nervous system is thought to re ect an ongoing synucleinopathy, which occurs in the majority of, but not all, LRRK2-G2019S-PD cases. Still, in a study of alpha-synuclein aggregation in cerebrospinal uid by real-time quaking-induced conversion (RT-QuIC) 17 the percentage of positive cases in LRRK2-PD was also much lower than in iPD (40% vs 90%). The pleiomorphic pathology of LRRK2-PD linked to the p.G2019S mutation may in part explain the results.…”

Section: Discussionmentioning

confidence: 96%

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Alpha-Synuclein Pathology in the Submandibular Gland of LRRK2 p.G2019S Mutation Carriers.

Vilas

Tolosa

Aldecoa

et al. 2020

Preprint

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Background. The presence of intraneuronal aggregates of phosphorylated alpha-synuclein (pAS), the histological hallmark of Parkinson disease (PD), has been already demonstrated to be present in the autonomic nerve fibres that innervate the submandibular gland in approximately 75% of living PD patients. The presence of pAS in the peripheral autonomic nervous system in carriers of LRRK2 mutations has not been studied so far. The objective of the current study is to evaluate the presence of abnormal pAS aggregates in the submandibular gland tissue of LRRK2 p.G2019S mutations carriers.Methods. This is a prospective observational study conducted between 2014 and 2015 at Hospital Clínic de Barcelona, Spain. A random sample of nine asymptomatic LRRK2 (aLRRK2) and 11 LRRK2 associated PD (LRRK2-PD) patients were recruited among a cohort of LRRK2-PD patients and their relatives already identified at our centre. All the participants underwent transcutaneous needle core biopsy of the submandibular gland under ultrasound guidance. The presence of pAS was assessed in all the participants by immunohistochemistry using anti-Serine 129-phosphorylated AS antibody.Results. Submandibular biopsy material containing glandular parenchyma was obtained in 4 (44.44%) aLRRK2 and in 6 (54.55%) LRRK2-PD patients. Aggregates of pAS were detected in the glandular parenchyma in one of the four (25%) aLRRK2 subjects and in none (0%) of the LRRK2-PD patients. Conclusions. Our study shows that pAS aggregates obtained by needle core biopsy of the submandibular gland are infrequent in LRRK2 mutation carriers but may be detected in asymptomatic mutation carriers. The low rate of pAS positive biopsies suggests either a different physiopathology between LRRK2-related and idiopathic PD or that a one-time unilateral submandibular gland biopsy is not the optimal procedure for the study of synuclein aggregation in LRRK2 mutation carriers.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 96%

Alpha-Synuclein Pathology in the Submandibular Gland of LRRK2 p.G2019S Mutation Carriers.

Vilas

Tolosa

Aldecoa

et al. 2020

Preprint

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“… Ref. WT Hu (commercial) 0,1 g/L substrate, 15 μL seed, 100 mmol/L PB 37 zirconia/silica bead, 1 min double orbital shaking 200 rpm, 14 min rest, 30 °C cohort 1 (definite cases): [ 27 ] 12 pure DLB 92% 17 mixed DLB + AD 65% 13 AD+incidental LB 15% 20 ctrl, 30 AD 100% cohort 2: 20 PD 95% 15 ctrl 100% 53 PD 84% [ 89 ] 17 MSA 35% 14 other synucleinopathies 86% 26 non α-syn parkinsonism 89% 52 ctrl 98% 10 PD 90% [ 32 ] 15 PD-LRRK2 40% 16 LRRK2 carriers 19% 10 ctrl 80% 105 PD 96% [ 44 ] 79 ctrl 82% 52 iRBD 90% [ 42 ]a 9 ctrl 78% K23Q Hu (home-made) 0,1 g/L substrate, 15 μL seed, 0,0015% SDS 6 silica beads (0.8 mm diameter), 1 min double orbital shaking 400 rpm, 1 min rest, 42 °C 17 DLB 94% [ 37 ] 12 PD 92% 16 AD 100% 12 ctrl ...…”

Section: Main Textmentioning

confidence: 99%

“…In another study, the RT-QuIC was used to detect α-syn seeding activity in patients carrying mutations in LRRK2 (Leucine-rich repeat kinase 2 gene) [ 32 ], the most common cause of genetic PD. In a blind analysis that compared these carriers (LRRK2-PD, n = 15; asymptomatic carriers, n = 16) with either idiopathic PD or healthy controls, the assay sensitivity was surprisingly rather low (40% in LRRK2-PD, 19% in the asymptomatic carriers) in the former group, whereas it was comparable to previous studies (90%) in the idiopathic (non-genetic) PD group.…”

Section: Main Textmentioning

confidence: 99%

Towards an improved early diagnosis of neurodegenerative diseases: the emerging role of in vitro conversion assays for protein amyloids

Candelise

Baiardi

Franceschini

et al. 2020

acta neuropathol commun

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Tissue accumulation of abnormal aggregates of amyloidogenic proteins such as prion protein, α-synuclein, and tau represents the hallmark of most common neurodegenerative disorders and precedes the onset of symptoms by years. As a consequence, the sensitive and specific detection of abnormal forms of these proteins in patients' accessible tissues or fluids as biomarkers may have a significant impact on the clinical diagnosis of these disorders. By exploiting seeded polymerization propagation mechanisms to obtain cell-free reactions that allow highly amplified detection of these amyloid proteins, novel emerging in vitro techniques, such as the real-time quakinginduced conversion assay (RT-QuIC) have paved the way towards this important goal. Given its high accuracy in identifying misfolded forms of prion protein from Creutzfeldt-Jakob disease (CJD) CSF, RT-QuIC has already been included in the diagnostic criteria for the clinical diagnosis of sporadic CJD, the most common human prion disease. By showing that this assay may also accurately discriminate between Lewy body disorders and other forms of parkinsonisms or dementias, more recent studies strongly suggested that CSF RT-QuIC can also be successfully applied to synucleinopathies. Finally, preliminary encouraging data also suggested that CSF RT-QuIC might also work for tau protein, and accurately distinguish between 3R-and 4R tauopathies, including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Here we will review the state of the art of cell-free aggregation assays, their current diagnostic value and putative limitations, and the future perspectives for their expanded use in clinical practice.

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“…Real-Time Quaking Induced Conversion (RT-QuIC) is a novel assay based on the socalled "prion replication principle" implying that pathologic misfolded proteins (seeds) serve as template for imparting their conformation to normal isoform (substrate). Tissue samples such as cerebrospinal fluid and olfactory mucosa (OM) containing α-syn aggregates initiate amyloid fibril formation by converting the recombinant α-syn which, in turn, enhances the fluorescence of thioflavin T (ThT) (Fairfoul et al, 2016;De Luca et al, 2019;Garrido et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Alpha-synuclein seeds in olfactory mucosa of patients with isolated rapid-eye-movement sleep behaviour disorder

Stefani

Iranzo

Holzknecht

et al. 2020

Preprint

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Isolated REM sleep behaviour disorder is an early-stage alpha-synucleinopathy in most, if not all, affected subjects. Detection of pathological alpha-synuclein in peripheral tissues of isolated REM sleep behaviour disorder patients may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-Time Quaking-Induced Conversion provided evidence of alpha-synuclein seeding activity in cerebrospinal fluid and olfactory mucosa of patients with alpha-synucleinopathies. Aim of this study was to explore Real-Time Quaking-Induced Conversion detection of alpha-synuclein aggregates in olfactory mucosa of large cohort of subjects with isolated REM sleep behavior disorder compared to Parkinson's disease and controls. This prospective bicentric case-control study was performed between October 2017 and December 2018 at the Medical University of Innsbruck, Austria, and the Hospital Clinic de Barcelona, Spain. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated REM sleep behavior disorder, 31 matched Parkinson's disease patients and 59 matched controls were analysed by alpha-synuclein Real-Time Quaking-Induced Conversion in a blinded fashion at the University of Verona, Italy. Median age of isolated REM sleep behavior disorder patients was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was alpha-synuclein Real-Time Quaking-Induced Conversion positive in 44.4% isolated REM sleep behavior disorder patients, 41.9% Parkinson's disease and 10.2% controls. While the sensitivity for isolated REM sleep behavior disorder plus Parkinson's disease versus controls was 40.9%, specificity was high (89.8%). Among isolated REM sleep behavior disorder patients with positive alpha-synuclein Real-Time Quaking-Induced Conversion, 78.6% had olfactory dysfunction as compared to 21.4% with negative alpha-synuclein Real-Time Quaking-Induced Conversion, p<0.001. The extent of olfactory dysfunction was more severe in positive than in negative alpha-synuclein Real-Time Quaking-Induced Conversion olfactory mucosa isolated REM sleep behavior disorder patients (p<0.001). We provide evidence that alpha-synuclein Real-Time Quaking-Induced Conversion assay enables the molecular detection of neuronal alpha-synuclein aggregates in olfactory mucosa of patients with isolated REM sleep behavior disorder and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as simple, non-invasive test, with a potential of use as screening test to identify subjects in the prodromal stages of alpha-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of alpha-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated REM sleep behavior disorder to overt alpha-synucleinopathy.

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α‐synuclein RT‐QuIC in cerebrospinal fluid of LRRK2‐linked Parkinson's disease

Cited by 71 publications

References 51 publications

Alpha-Synuclein Pathology in the Submandibular Gland of LRRK2 p.G2019S Mutation Carriers.

Alpha-Synuclein Pathology in the Submandibular Gland of LRRK2 p.G2019S Mutation Carriers.

Towards an improved early diagnosis of neurodegenerative diseases: the emerging role of in vitro conversion assays for protein amyloids

Alpha-synuclein seeds in olfactory mucosa of patients with isolated rapid-eye-movement sleep behaviour disorder

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