Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study

Iranzo, Álex; Fairfoul, Graham; Ayudhaya, Anutra Chumbala Na; Serradell, Mónica; Gelpí, Ellen; Vilaseca, Isabel; Sánchez‐Valle, Raquel; Gaig, Carles; Santamaría, Joan; Tolosa, Eduard; Riha, Renata L.; Green, Alison J E

doi:10.1016/s1474-4422(20)30449-x

Cited by 223 publications

(239 citation statements)

References 37 publications

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“…Other sleep disorders have also been associated with subsequent onset of cognitive or neurodegenerative disorders. For example, periodic limb movements (PLMS), which precede dysexecutive impairment and REM sleep behavior disorder (RBD), has been shown to predict the development of Parkinson’s Disease [ 58 , 59 ]. Further investigations are required to understand the relationship between neurodegenerative processes and various sleep disorders, including PLMS, RBD, and now insomnia.…”

Section: Discussionmentioning

confidence: 99%

Specific cortical and subcortical grey matter regions are associated with insomnia severity

et al. 2021

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Background There is an increasing awareness that sleep disturbances are a risk factor for dementia. Prior case-control studies suggested that brain grey matter (GM) changes involving cortical (i.e, prefrontal areas) and subcortical structures (i.e, putamen, thalamus) could be associated with insomnia status. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia in older adults who could be at risk for dementia. Since depressive symptoms and sleep apnea can both feature insomnia-related factors, can impact brain health and are frequently present in older populations, it is important to include them when studying insomnia. Therefore, our goal was to investigate GM changes associated with insomnia severity in a cohort of healthy older adults, taking into account the potential effect of depression and sleep apnea as well. We hypothesized that insomnia severity is correlated with 1) cortical regions responsible for regulation of sleep and emotion, such as the orbitofrontal cortex and, 2) subcortical regions, such as the putamen. Methods 120 healthy subjects (age 74.8±5.7 years old, 55.7% female) were recruited from the Hillblom Healthy Aging Network at the Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), Geriatric Depression Scale (GDS) and Berlin Sleep Questionnaire (BA) to assess sleep apnea. Cortical thickness (CTh) and subcortical volumes were obtained by the CAT12 toolbox within SPM12. We studied the correlation of CTh and subcortical volumes with ISI using multiple regressions adjusted by age, sex, handedness and MRI scan type. Additional models adjusting by GDS and BA were also performed. Results ISI and GDS were predominantly mild (4.9±4.2 and 2.5±2.9, respectively) and BA was mostly low risk (80%). Higher ISI correlated with lower CTh of the right orbitofrontal, right superior and caudal middle frontal areas, right temporo-parietal junction and left anterior cingulate cortex (p<0.001, uncorrected FWE). When adjusting by GDS, right ventral orbitofrontal and temporo-parietal junction remained significant, and left insula became significant (p<0.001, uncorrected FWE). Conversely, BA showed no effect. The results were no longer significant following FWE multiple comparisons. Regarding subcortical areas, higher putamen volumes were associated with higher ISI (p<0.01). Conclusions Our findings highlight a relationship between insomnia severity and brain health, even with relatively mild insomnia, and independent of depression and likelihood of sleep apnea. The results extend the previous literature showing the association of specific GM areas (i.e, orbitofrontal, insular and temporo-parietal junction) not just with the presence of insomnia, but across the spectrum of severity itself. Moreover, our results suggest subcortical structures (i.e., putamen) are involved as well. Longitudinal studies are needed to clarify how these insomnia-related brain changes in healthy subjects align with an increased risk of dementia.

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Section: Discussionmentioning

confidence: 99%

Specific cortical and subcortical grey matter regions are associated with insomnia severity

et al. 2021

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“…Despite being developed in the last five years, αSyn RT-QuIC assays have been adapted for a range of diagnostically relevant human biospecimens, including the brain and CSF, olfactory mucosa, submandibular gland, and skin. (Table 2) It has previously been shown that α-synuclein can be detected in the brain and biological fluids such as CSF and serum [44][45][46][47][48][49][50][51][52][53][54][55]. The first successful use of α-syn RT-QuIC was applied to detect α-synuclein aggregation in the brain and CSF from dementia with LB and PD patients.…”

Section: Human Prion Diseasementioning

confidence: 99%

“…With 52 isolate REM sleep behavior disorder (iRBD) and 9 controls, the results showed that the sensitivity was 90% and the specificity was 78%. During follow-up, 32 (61.5%) patients were diagnosed with PD or DLB 3.4 ± 2.6 years after LP, and 31 (96.9%) of these were positive for CSF α-synuclein in the RT-QuIC, while none of the controls developed synucleinopathy [55].…”

Section: Human Prion Diseasementioning

confidence: 99%

The Latest Research on RT-QuIC Assays—A Literature Review

Dong

Satoh

2021

Pathogens

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The misfolding of proteins such as the prion protein, α-synuclein, and tau represents a key initiating event for pathogenesis of most common neurodegenerative disorders, and its presence correlates with infectivity. To date, the diagnosis of these disorders mainly relied on the recognition of clinical symptoms when neurodegeneration was already at an advanced phase. In recent years, several efforts have been made to develop new diagnostic tools for the early diagnosis of prion diseases. The real-time quaking-induced conversion (RT–QuIC) assay, an in vitro assay that can indirectly detect very low amounts of PrPSc aggregates, has provided a very promising tool to improve the early diagnosis of human prion diseases. Over the decade since RT–QuIC was introduced, the diagnosis of not only prion diseases but also synucleinopathies and tauopathies has greatly improved. Therefore, in our study, we summarize the current trends and knowledge of RT–QuIC assays, as well as discuss the diagnosis of neurodegenerative diseases using RT–QuIC assays, which have been updated in recent years.

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“…Pathological α-syn aggregates are also known to appear in the GI tract in PD patients even decades prior to the onset of motor impairments, but multiple IHC-based studies using GI biopsies have produced conflicting results regarding diagnostic accuracy [ 15 , 16 , 17 , 19 , 20 ]. Therefore, it is of interest whether the α-syn RT-QuIC assay that has demonstrated its diagnostic potential in multiple studies [ 43 , 44 , 45 , 46 , 49 , 58 ] could detect pathological α-syn aggregates in GI biopsies of PD patients, particularly at the prodromal phase. While the application of α-syn RT-QuIC into GI biopsies has not yet, to the best of our knowledge, been reported, our successful results in detecting α-syn seeding activity in the colon of presymptomatic G2-3 mice strongly support the diagnostic potential of this approach.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, based on the prion-like properties of misfolded α-syn aggregates [ 37 , 38 , 39 , 40 ], RT-QuIC was successfully adapted to synucleinopathies [ 41 , 42 ]. Subsequently, a number of studies employing this assay successfully detected α-syn seeding activity with high sensitivity and specificity in CSF or peripheral tissues from patients affected by a variety of synucleinopathies [ 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Detection of Alpha-Synuclein Seeding Activity in the Colon of a Transgenic Mouse Model of Synucleinopathy by RT-QuIC

Han

Shin

Choi

2021

Viruses

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In synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy body (DLB), pathological alpha-synuclein (α-syn) aggregates are found in the gastrointestinal (GI) tract as well as in the brain. In this study, using real-time quaking-induced conversion (RT-QuIC), we investigated the presence of α-syn seeding activity in the brain and colon tissue of G2-3 transgenic mice expressing human A53T α-syn. Here we show that pathological α-syn aggregates with seeding activity were present in the colon of G2-3 mice as early as 3 months old, which is in the presymptomatic stage prior to the observation of any neurological abnormalities. In contrast, α-syn seeding activity was not detectable in 3 month-old mouse brains and only identified at 6 months of age in one of three mice. In the symptomatic stage of 12 months of age, RT-QuIC seeding activity was consistently detectable in both the brain and colon of G2-3 mice. Our results indicate that the RT-QuIC assay can presymptomatically detect pathological α-syn aggregates in the colon of G2-3 mice several months prior to their detection in brain tissue.

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Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study

Cited by 223 publications

References 37 publications

Specific cortical and subcortical grey matter regions are associated with insomnia severity

Specific cortical and subcortical grey matter regions are associated with insomnia severity

The Latest Research on RT-QuIC Assays—A Literature Review

Preclinical Detection of Alpha-Synuclein Seeding Activity in the Colon of a Transgenic Mouse Model of Synucleinopathy by RT-QuIC

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