Dataset Information

Multimodal phenotypic axes of Parkinson's disease.

ABSTRACT: Individuals with Parkinson's disease present with a complex clinical phenotype, encompassing sleep, motor, cognitive, and affective disturbances. However, characterizations of PD are typically made for the "average" patient, ignoring patient heterogeneity and obscuring important individual differences. Modern large-scale data sharing efforts provide a unique opportunity to precisely investigate individual patient characteristics, but there exists no analytic framework for comprehensively integrating data modalities. Here we apply an unsupervised learning method-similarity network fusion-to objectively integrate MRI morphometry, dopamine active transporter binding, protein assays, and clinical measurements from n?=?186 individuals with de novo Parkinson's disease from the Parkinson's Progression Markers Initiative. We show that multimodal fusion captures inter-dependencies among data modalities that would otherwise be overlooked by field standard techniques like data concatenation. We then examine how patient subgroups derived from the fused data map onto clinical phenotypes, and how neuroimaging data is critical to this delineation. Finally, we identify a compact set of phenotypic axes that span the patient population, demonstrating that this continuous, low-dimensional projection of individual patients presents a more parsimonious representation of heterogeneity in the sample compared to discrete biotypes. Altogether, these findings showcase the potential of similarity network fusion for combining multimodal data in heterogeneous patient populations.

SUBMITTER: Markello RD

PROVIDER: S-EPMC7785730 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Multimodal phenotypic axes of Parkinson's disease.

Markello Ross D RD Shafiei Golia G Tremblay Christina C Postuma Ronald B RB Dagher Alain A Misic Bratislav B

NPJ Parkinson's disease 20210105 1

Individuals with Parkinson's disease present with a complex clinical phenotype, encompassing sleep, motor, cognitive, and affective disturbances. However, characterizations of PD are typically made for the "average" patient, ignoring patient heterogeneity and obscuring important individual differences. Modern large-scale data sharing efforts provide a unique opportunity to precisely investigate individual patient characteristics, but there exists no analytic framework for comprehensively integra ...[more]

PMID: 33402689

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Project description:The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r = -0.72, P < 0.0001) and higher lysosomal counts (r = -0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = -0.52, P = 0.0016) and long (r = -0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.

Project description:Parkinson's disease (PD) is a multisystem neurological condition affecting different neurotransmitter pathways characterized by aberrant functional connectivity (FC) and perfusion alteration. Since the FC, measuring neuronal activity, and cerebral blood flow (CBF) are closely related through the neurovascular coupling (NVC) mechanism, we aim to assess whether FC changes found in PD mirror perfusion ones. A multimodal MRI study was implemented by acquiring resting state functional MRI (rsfMRI) and arterial spin labeling (ASL) datasets on a group of 26 early PD (66.8 ± 8 years, 22 males, median [interquartile range] Hoehn and Yahr = 1.5 [1]) and 18 age- and sex-matched healthy controls (HCs). In addition, a T1-weighted MPRAGE was also acquired in the same scan session. After a standard preprocessing, resting state networks (RSNs) and CBF maps were extracted from rsfMRI and ASL dataset, respectively. Then, by means of a dual regression algorithm performed on RSNs, a cluster of FC differences between groups was obtained and used to mask CBF maps in the subsequent voxel-wise group comparison. Furthermore, a gray matter (GM) volumetric assessment was performed within the FC cluster in order to exclude tissue atrophy as a source of functional changes. Reduced FC for a PD patient with respect to HC group was found within a sensory-motor network (SMN, pFWE = 0.01) and visual networks (VNs, primary pFWE = 0.022 and lateral pFWE = 0.01). The latter was accompanied by a decreased CBF (primary pFWE = 0.037, lateral pFWE = 0.014 VNs), while no GM atrophy was detected instead. The FC alteration found in the SMN of PD might be likely due to a dopaminergic denervation of the striatal pathways causing a functional disconnection. On the other hand, the changes in connectivity depicted in VNs might be related to an altered non-dopaminergic system, since perfusion was also reduced, revealing a compromised NVC. Finally, the absence of GM volume loss might imply that functional changes may potentially anticipate neurodegeneration. In this framework, FC and CBF might be proposed as early functional biomarkers providing meaningful insights in evaluating both disease progression and therapeutic/rehabilitation treatment outcome.

Dataset Information

Multimodal phenotypic axes of Parkinson's disease.

Publications

Multimodal phenotypic axes of Parkinson's disease.

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