Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP)

Sturchio, Andrea; Marsili, Luca; Vizcarra, Joaquín A.; Dwivedi, Alok; Kauffman, Marcelo; Duker, Andrew P.; Lu, Peixin; Pauciulo, Michael W.; Wissel, Benjamin D.; Hill, Emily J.; Stecher, Benjamin; Keeling, Elizabeth; Vagal, Achala; Wang, Lily; Robson, Matthew J.; Tanner, Caroline M.; Hagey, Daniel W.; Andaloussi, Samir El; Ezzat, Kariem; Fleming, Ronan M. T.; Lu, Long; Little, Max A.; Espay, Alberto J.

doi:10.3389/fnagi.2020.553635

Cited by 26 publications

(18 citation statements)

References 89 publications

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“…Recent initiatives (e.g. PREDICT-PD 74 and the Cincinnati Cohort Biomarker Program (CCBP) 75 ) that incorporate discovery-based analyses of prospective cohorts are seeking to address this by defining PD developmental pathways and biomarkers. Furthermore, we contend that it is time to consider systematic n-of-1 76 – 78 approaches (see box 1 ) in PD research, to identify the combinations and relative contributions of the genetic, pathological and environmental factors in each unique circumstance 3 , 79 , for individuals within a heterogeneous population.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Redefining the hypotheses driving Parkinson’s diseases research

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Cooper

O’Sullivan

2022

npj Parkinsons Dis.

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Parkinson’s disease (PD) research has largely focused on the disease as a single entity centred on the development of neuronal pathology within the central nervous system. However, there is growing recognition that PD is not a single entity but instead reflects multiple diseases, in which different combinations of environmental, genetic and potential comorbid factors interact to direct individual disease trajectories. Moreover, an increasing body of recent research implicates peripheral tissues and non-neuronal cell types in the development of PD. These observations are consistent with the hypothesis that the initial causative changes for PD development need not occur in the central nervous system. Here, we discuss how the use of neuronal pathology as a shared, qualitative phenotype minimises insights into the possibility of multiple origins and aetiologies of PD. Furthermore, we discuss how considering PD as a single entity potentially impairs our understanding of the causative molecular mechanisms, approaches for patient stratification, identification of biomarkers, and the development of therapeutic approaches to PD. The clear consequence of there being distinct diseases that collectively form PD, is that there is no single biomarker or treatment for PD development or progression. We propose that diagnosis should shift away from the clinical definitions, towards biologically defined diseases that collectively form PD, to enable informative patient stratification. N-of-one type, clinical designs offer an unbiased, and agnostic approach to re-defining PD in terms of a group of many individual diseases.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Redefining the hypotheses driving Parkinson’s diseases research

Farrow

Cooper

O’Sullivan

2022

npj Parkinsons Dis.

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show abstract

“…39 However, subtyping using clinical or imaging features in PD has not shown alignment with the underlying biology. With one recent exception, 40 biomarker discovery cohorts have aimed at determining which biological signals statistically cluster within a given clinical subtype rather than which clinical subtypes cluster within a given biological abnormality of interest. A reversal in the direction of development from biology to phenotype stands to assist future precisionmedicine applications.…”

Section: Why Subtyping At All?mentioning

confidence: 99%

The Logic and Pitfalls of Parkinson's Disease as “Brain‐First” Versus “Body‐First” Subtypes

2021

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“…The potential of LRS technologies may get us closer to elucidating the underlying genetic mechanisms of molecular subsets of ET on the road to precision medicine ( 102 ). While this approach can only be phenotype-driven at the outset, we envision a data driven, unbiased analytic approach as of higher hierarchical order in the future ( 116 ). This unique approach will allow a reverse biology-to-phenotype direction of research development in which clinical and imaging data are subordinate to genetic and biological signals of interest ( 116 ).…”

Section: Discussionmentioning

confidence: 99%

“…While this approach can only be phenotype-driven at the outset, we envision a data driven, unbiased analytic approach as of higher hierarchical order in the future ( 116 ). This unique approach will allow a reverse biology-to-phenotype direction of research development in which clinical and imaging data are subordinate to genetic and biological signals of interest ( 116 ). A hypothesis free, causally- and data driven-based analyses, with an inclusive recruitment of patients with different phenotypes of neurodegenerative disorders, formed the foundations of the ongoing Cincinnati Cohort Biomarker Program (CCBP) study ( 116 ).…”

Section: Discussionmentioning

confidence: 99%

Uncovering Essential Tremor Genetics: The Promise of Long-Read Sequencing

et al. 2022

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Long-read sequencing (LRS) technologies have been recently introduced to overcome intrinsic limitations of widely-used next-generation sequencing (NGS) technologies, namely the sequencing limited to short-read fragments (150–300 base pairs). Since its introduction, LRS has permitted many successes in unraveling hidden mutational mechanisms. One area in clinical neurology in need of rethinking as it applies to genetic mechanisms is essential tremor (ET). This disorder, among the most common in neurology, is a syndrome often exhibiting an autosomal dominant pattern of inheritance whose large phenotypic spectrum suggest a multitude of genetic etiologies. Exome sequencing has revealed the genetic etiology only in rare ET families (FUS, SORT1, SCN4A, NOS3, KCNS2, HAPLN4/BRAL2, and USP46). We hypothesize that a reason for this shortcoming may be non-classical genetic mechanism(s) underpinning ET, among them trinucleotide, tetranucleotide, or pentanucleotide repeat disorders. In support of this hypothesis, trinucleotide (e.g., GGC repeats in NOTCH2NLC) and pentanucleotide repeat disorders (e.g., ATTTC repeats in STARD7) have been revealed as pathogenic in patients with a past history of what has come to be referred to as “ET plus,” bilateral hand tremor associated with epilepsy and/or leukoencephalopathy. A systematic review of LRS in neurodegenerative disorders showed that 10 of the 22 (45%) genetic etiologies ascertained by LRS include tremor in their phenotypic spectrum, suggesting that future clinical applications of LRS for tremor disorders may uncover genetic subtypes of familial ET that have eluded NGS, particularly those with associated leukoencephalopathy or family history of epilepsy. LRS provides a pathway for potentially uncovering novel genes and genetic mechanisms, helping narrow the large proportion of “idiopathic” ET.

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Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP)

Cited by 26 publications

References 89 publications

Redefining the hypotheses driving Parkinson’s diseases research

Redefining the hypotheses driving Parkinson’s diseases research

The Logic and Pitfalls of Parkinson's Disease as “Brain‐First” Versus “Body‐First” Subtypes

Uncovering Essential Tremor Genetics: The Promise of Long-Read Sequencing

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