<scp>RT‐QuIC</scp> Detection of Pathological α‐Synuclein in Skin Punches of Patients with Lewy Body Disease

Mammana, Angela; Baiardi, Simone; Quadalti, Corinne; Rossi, Marcello; Donadio, Vincenzo; Capellari, Sabina; Liguori, Rocco; Parchi, Piero

doi:10.1002/mds.28651

Cited by 67 publications

(77 citation statements)

References 22 publications

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“…Neuropathology was available for only two patients, one with MSA as described above, and another (#3076) who had mixed Lewy body and Alzheimer pathology and that was detected as αSyn-SAA-positive by all three groups. There have been several important studies by other groups of αSyn-SAA of CSF [ 6 , 24 , 45 ] or skin [ 12 , 17 , 45 ] of autopsy-confirmed patient cohorts, with comparable diagnostic performance. We had sought to validate SAAs within an early PD cohort, which has correspondingly limited neuropathologic data from autopsy.…”

Section: Discussionmentioning

confidence: 99%

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

Russo

Orrú

Concha‐Marambio

et al. 2021

acta neuropathol commun

119

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Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods.

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Section: Discussionmentioning

confidence: 99%

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

Russo

Orrú

Concha‐Marambio

et al. 2021

acta neuropathol commun

119

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“…A potential biochemical marker for detecting DLB is α-synuclein. RT-QuIC measures that detect α-synuclein aggregates capable of seeding fibril formation have high accuracy when measured in CSF or skin biopsy samples but are not yet detectable in plasma [ 10 , 24 , 34 ]. Unfortunately, no specific biochemical marker for HS or LATE is available at present.…”

Section: Discussionmentioning

confidence: 99%

Plasma biomarkers for Alzheimer’s Disease in relation to neuropathology and cognitive change

et al. 2022

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Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer’s Disease (AD) as shown by recent clinical studies and selected autopsy studies. We have evaluated ATN plasma biomarkers in a series of 312 well-characterized longitudinally followed research subjects with plasma available within 5 years or less before autopsy and examined these biomarkers in relation to a spectrum of AD and related pathologies. Plasma Aβ42, Aβ40, total Tau, P-tau181, P-tau231 and neurofilament light (NfL) were measured using Single molecule array (Simoa) assays. Neuropathological findings were assessed using standard research protocols. Comparing plasma biomarkers with pathology diagnoses and ratings, we found that P-tau181 (AUC = 0.856) and P-tau231 (AUC = 0.773) showed the strongest overall sensitivity and specificity for AD neuropathological change (ADNC). Plasma P-tau231 showed increases at earlier ADNC stages than other biomarkers. Plasma Aβ42/40 was decreased in relation to amyloid and AD pathology, with modest diagnostic accuracy (AUC = 0.601). NfL was increased in non-AD cases and in a subset of those with ADNC. Plasma biomarkers did not show changes in Lewy body disease (LBD), hippocampal sclerosis of aging (HS) or limbic-predominant age-related TDP-43 encephalopathy (LATE) unless ADNC was present. Higher levels of P-tau181, 231 and NfL predicted faster cognitive decline, as early as 10 years prior to autopsy, even among people with normal cognition or mild cognitive impairment. These results support plasma P-tau181 and 231 as diagnostic biomarkers related to ADNC that also can help to predict future cognitive decline, even in predementia stages. Although NfL was not consistently increased in plasma in AD and shows increases in several neurological disorders, it had utility to predict cognitive decline. Plasma Aβ42/40 as measured in this study was a relatively weak predictor of amyloid pathology, and different assay methods may be needed to improve on this. Additional plasma biomarkers are needed to detect the presence and impact of LBD and LATE pathology.

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“…In 2017, researchers published findings showing that skin biopsies from proximal (cervical) and distal (thigh and distal leg) sites demonstrated phosphorylated α-synuclein in the cutaneous nerves of individuals with DLB ( n = 18) versus individuals with other dementias ( n = 23) and healthy controls ( n = 25). 41 Using skin biopsies to identify pathological α-synuclein continues to be an area of active research in DLB, PD, and other synucleinopathies, 42 – 45 including prodromal states (RBD). 44 Immunofluorescence and RT-QuIC approaches to detecting α-synuclein in skin biopsies show comparable efficacy 46 and one study showed similar diagnostic accuracy when comparing RT-QuIC assays using CSF versus skin samples.…”

Section: Biomarkersmentioning

confidence: 99%

“… 44 Immunofluorescence and RT-QuIC approaches to detecting α-synuclein in skin biopsies show comparable efficacy 46 and one study showed similar diagnostic accuracy when comparing RT-QuIC assays using CSF versus skin samples. 45 Commercial testing for synucleinopathies using skin punch biopsies is now available in the United States. As with CSF α-synuclein testing, the role that skin biopsy plays in routine clinical diagnosis of DLB is yet to be established.…”

Section: Biomarkersmentioning

confidence: 99%

Advances in dementia with Lewy bodies

Armstrong

2021

Ther Adv Neurol Disord

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Dementia with Lewy bodies (DLB) is a clinical diagnosis representing a specific presentation of a pathological α-synucleinopathy (Lewy body disease). DLB is one entity under the broader term Lewy body dementia, which also includes Parkinson’s disease dementia. Recent advances in DLB include publication of updated diagnostic criteria and recognition of prodromal DLB states, including mild cognitive impairment, delirium-onset, and psychiatric-onset forms. Research criteria for the mild cognitive impairment form of DLB were published in 2020. Increasing research shows that concomitant Alzheimer’s disease pathology in individuals with DLB is common in addition to the α-synucleinopathy pathology. This has implications for biomarker use and expected progression. Identifying biomarkers for DLB is an area of active research. Cerebrospinal fluid and skin biopsy tests are now commercially available in the United States, but their role in routine clinical care is not yet established. Additional research and biomarkers are needed. Research suggests that median survival after DLB diagnosis is 3–4 years, but there are rapidly and slowly progressive forms. Most individuals with DLB die of complications of the disease. Clinical trials for individuals with DLB have increased over the last 5 years, targeting both symptoms and underlying pathology. Effective therapies remain an unmet need, however. This review focuses on recent advances with an emphasis on literature that informs clinical care.

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RT‐QuIC Detection of Pathological α‐Synuclein in Skin Punches of Patients with Lewy Body Disease

Cited by 67 publications

References 22 publications

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

Plasma biomarkers for Alzheimer’s Disease in relation to neuropathology and cognitive change

Advances in dementia with Lewy bodies

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