Application of the Movement Disorder Society prodromal criteria in healthy <i>G2019S</i>‐<i>LRRK2</i> carriers

Mirelman, Anat; Saunders‐Pullman, Rachel; Alcalay, Roy N.; Shustak, Shiran; Thaler, Avner; Gurevich, Tanya; Raymond, Deborah; Mejia‐Santana, Helen; Reilly, Martha Orbe; Ozelius, Laurie J.; Clark, Lorraine N.; Gana‐Weisz, Mali; Bar‐Shira, Anat; Orr-Utreger, Avi; Bressman, Susan; Marder, Karen; Giladi, Nir

doi:10.1002/mds.27342

Cited by 45 publications

(57 citation statements)

References 30 publications

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“…The greater frequency of altered DaT‐SPECT uptake among the RTQuIC‐positive cases is in line with the interpretation that these asymptomatic carriers are possibly those that will eventually evolve into manifest PD. The higher proportion of probable prodromal PD based on the MDS prodromal criteria in those subjects with a positive RTQuIC reaction, also supports this hypothesis.…”

Section: Discussionsupporting

confidence: 57%

“…If a unilateral or bilateral reduction was observed in the striatal tracer uptake, the DAT‐SPECT was considered as abnormal . We also calculated the likelihood ratio and posttest probability for conversion to manifest PD for each LRRK2‐NMC, based on the MDS research criteria for prodromal PD as described elsewhere . We included the available risk markers (age, sex, genetic status, and habits) and prodromal markers (subtle motor and nonmotor symptoms with the previously published cutoffs and DaT SPECT results) for each subject.…”

Section: Methodsmentioning

confidence: 99%

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

Garrido

Fairfoul

Tolosa

et al. 2019

Ann Clin Transl Neurol

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Background Leucine‐rich kinase 2 (LRRK2)‐linked Parkinson's disease (PD) is clinically indistinguishable from idiopathic PD (IPD). A pleiotropic neuropathology has been recognized but the majority of studies in LRRK2 p.G2019S patients reveal Lewy‐type synucleinopathy as its principal histological substrate. To date no in vivo biomarkers of synucleinopathy have been found in LRRK2 mutation carriers. Objectives We used real‐time quaking‐induced conversion (RT‐QuIC) technique to assess the presence of alpha‐synuclein (a‐syn) aggregates in cerebrospinal fluid (CSF) of LRRK2 p.G2019S carriers. Methods CSF samples of 51 subjects were analyzed: 15 LRRK2 p.G2019S PD, 10 IPD, 16 LRRK2 p.G2019S nonmanifesting carriers (NMC) and 10 healthy controls. The presence of parkinsonism and prodromal symptoms was assessed in all study subjects. Results Forty percent (n = 6) LRRK2‐PD, and 18.8% (n = 3) LRRK2‐NMC had a positive a‐syn RT‐QuIC response. RT‐QuIC detected IPD with 90% sensitivity and 80% specificity. No clinical differences were detected between LRRK2‐PD patients with positive and negative RT‐QuIC. A positive RT‐QuIC result in LRRK2‐NMC occurred in a higher proportion of subjects meeting the Movement Disorder Society research criteria for prodromal PD. Interpretation RT‐QuIC detects a‐syn aggregation in CSF in a significant number of patients with LRRK2‐PD, but less frequently than in IPD. A small percentage of LRRK2‐NMC tested also positive. If appropriately validated in long‐term studies with large number of mutation carriers, and hopefully, postmortem or in vivo confirmation of histopathology, RT‐QuIC could contribute to the selection of candidates to receive disease modifying drugs, in particular treatments targeting a‐syn deposition.

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Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

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

Garrido

Fairfoul

Tolosa

et al. 2019

Ann Clin Transl Neurol

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“…The criteria have now been validated in prospective cohort studies of the general population, 2 REM sleep behavior disorder (RBD) patients, 3 and LRRK2 mutation carriers. 4 These studies show relatively high specificity and positive predictive values for conversion from probable prodromal PD to clinical PD, with variable sensitivity of detecting prodromal PD that depends on the depth of marker assessment and the time from marker assessments to PD diagnosis. 5 To improve the accuracy of prodromal PD diagnosis, the framework was designed to integrate new prospective ---------------------------------------------------------evidence of predictive values of prodromal and risk markers.…”

mentioning

confidence: 90%

Update of the MDS research criteria for prodromal Parkinson's disease

et al. 2019

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The MDS Research Criteria for Prodromal PD allow the diagnosis of prodromal Parkinson's disease using an evidence‐based conceptual framework, which was designed to be updated as new evidence becomes available. New prospective evidence of predictive values of risk and prodromal markers published since 2015 was reviewed and integrated into the criteria. Many of the predictive values (likelihood ratios, LR) remain unchanged. The positive likelihood ratio notably increase for olfactory loss and decreased for substantia nigra hyperechogenicity. Negative likelihood ratio remained largely unchanged for all markers. New levels of diagnostic certainty for neurogenic and symptomatic orthostatic hypotension have been added, which substantially differ in positive likelihood ratio from the original publication. For intermediate strength genetic variants, their age‐related penetrance is now incorporated in the calculation of the positive likelihood ratio. Moreover, apart from prospective studies, evidence from cross‐sectional case‐control genome‐wide association studies is also considered (given their likely lack of confounding and reverse causation), and to account for the effect of multiple low‐penetrance genetic variants polygenic risk scores are added to the model. Diabetes, global cognitive deficit, physical inactivity, and low plasma urate levels in men enter the criteria as new markers. A web‐based prodromal PD risk calculator allows the calculation of probabilities of prodromal PD for individuals. Several promising candidate markers may improve the diagnostic accuracy of prodromal PD in the future. © 2019 International Parkinson and Movement Disorder Society

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“…In contrast, the MDS prodromal PD diagnostic criteria failed to make a diagnosis of prodromal PD, implying that the MDS criteria lack the sensitivity to detect prodromal PD changes in this population. There is some evidence to suggest a more variable clinical prodrome of GBA1 PD, which may also explain the poor performance of the MDS criteria …”

Section: Discussionmentioning

confidence: 99%

“…There is some evidence to suggest a more variable clinical prodrome of GBA1 PD, which may also explain the poor performance of the MDS criteria. 21 A recent study in a large cohort of leucine-rich repeat kinase 2 (LRRK2) to whom the MDS prodromal PD criteria was applied showed 92% diagnostic specificity and 80% sensitivity. 22 Conversely, in cohort studies in elderly populations, although specificity was very high, sensitivity was estimated at only 14%, 18%, and 54%.…”

Section: Discussionmentioning

confidence: 99%

Evolution and clustering of prodromal parkinsonian features in GBA1 carriers

et al. 2019

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Background Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease‐modifying therapies. Objective Cross‐sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers. Design Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features. Results At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6–28.2; P < 0.05) and mild cognitive impairment (odds ratio: 4.2; 95% confidence interval: 1.1–16.6; P < 0.05) were more rapid compared to controls. Those with worse olfaction also had worse cognition (OR, 1.5; 95% CI: 0.0–2.8; P < 0.05) and depression (OR, 1.3; 95% CI: 0.6–2.8; P < 0.05). No participants reached the MDS prodromal PD diagnostic criteria before PD diagnosis. One participant developed PD. He did not fulfill the International Parkinson and Movement Disorder Society prodromal PD criteria before diagnosis. Conclusion Assessment of individual and clustered PD prodromal features may serve as a useful tool to identify high‐risk subjects for conversion to PD. As a result of the low conversion rate in our glucocerebrosidase mutation carriers to date, prospective validation is needed in larger cohorts to establish the profile of these features in PD convertors. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Application of the Movement Disorder Society prodromal criteria in healthy G2019S‐LRRK2 carriers

Cited by 45 publications

References 30 publications

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

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

Update of the MDS research criteria for prodromal Parkinson's disease

Evolution and clustering of prodromal parkinsonian features in GBA1 carriers

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