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Abstract
Background and Objectives Mean diffusivity (MD) of diffusion MRI (dMRI) has been used to measure cortical and subcortical microstructural properties. This study investigated relationships of cortical and subcortical MD, clinical progression, and fluid biomarkers in Parkinson disease (PD).
Methods This longitudinal study using data from the Parkinson's Progression Markers Initiative was collected from April 2011 to July 2022. Clinical symptoms were assessed with Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS) and Montreal Cognitive Assessment (MoCA) scores. Clinical assessments were followed up to 5 years. Linear mixed-effects (LME) models were performed to examine associations of MD and the annual rate of changes in clinical scores. Partial correlation analysis was conducted to examine the associations of MD and fluid biomarker levels.
Results A total of 174 patients with PD (age 61.9 ± 9.7 years, 63% male) with baseline dMRI and at least 2 years of clinical follow-up were included. Results of LME models revealed a significant association between MD values, predominantly in subcortical regions, temporal lobe, occipital lobe, and frontal lobe, and annual rate of changes in clinical scores (UPDRS-Part-I, standardized β > 2.35; UPDRS-Part-II, standardized β > 2.34; postural instability and gait disorder score, standardized β > 2.47; MoCA, standardized β < −2.42; all p < 0.05, false discovery rate [FDR] corrected). In addition, MD was associated with the levels of neurofilament light chain in serum (r > 0.22) and α-synuclein (right putamen r = 0.31), β-amyloid 1–42 (left hippocampus r = −0.30), phosphorylated tau at 181 threonine position (r > 0.26), and total tau (r > 0.23) in CSF at baseline (all p < 0.05, FDR corrected). Furthermore, the β coefficients derived from MD and annual rate of changes in the clinical score recapitulated the spatial distribution of dopamine (DAT, D1, and D2), glutamate (mGluR5 and NMDA), serotonin (5-HT1a and 5-HT2a), cannabinoid (CB1), and γ-amino butyric acid A receptor neurotransmitter receptors/transporters (p < 0.05, FDR corrected) derived from PET scans in the brain of healthy volunteers.
Discussion In this cohort study, cortical and subcortical MD values at baseline were associated with clinical progression and baseline fluid biomarkers, suggesting that microstructural properties could be useful for stratification of patients with fast clinical progression.
Glossary
- 3D=
- 3 dimensional;
- 5-HT1a=
- 5-hydroxytryptamine receptor subtype 1a;
- Aβ42=
- β-amyloid 1–42;
- CB1=
- cannabinoid type 1 receptor;
- dMRI=
- diffusion tensor MRI;
- D1=
- dopamine receptor 1;
- D2=
- dopamine receptor 2;
- DAT=
- dopamine transporter;
- FDR=
- false discovery rate;
- GABA=
- γ-amino butyric acid A receptor;
- GO=
- gene ontology;
- GSEA=
- gene set enrichment analysis;
- H3=
- histamine H3 receptors;
- LEDD=
- levodopa equivalent daily dose;
- LME=
- linear mixed effects;
- MD=
- mean diffusivity;
- UPDRS=
- Unified Parkinson's Disease Rating Scale;
- MNI=
- Montreal Neurological Institute;
- MoCA=
- Montreal Cognitive Assessment;
- MOR=
- mu opioid receptor;
- mRNA=
- messenger RNA;
- NET=
- noradrenaline transporter;
- NfL=
- neurofilament light;
- NMDA=
- N-methyl D-aspartate receptor;
- PAP=
- progression-associated pattern;
- PD=
- Parkinson disease;
- PIGD=
- postural instability and gait disorder;
- PPMI=
- Parkinson's Progression Markers Initiative;
- p-tau181=
- phosphorylated tau at 181 threonine position;
- SNc=
- substantia nigra pars compacta;
- SOMAmers=
- slow off-rate modified aptamers;
- TE=
- time to echo;
- TR=
- repetition time;
- t-tau=
- total tau;
- VAChT=
- vesicular acetylcholine transporter
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Associate Editor Peter Hedera, MD, PhD.
- Received August 9, 2022.
- Accepted in final form March 28, 2023.
- © 2023 American Academy of Neurology
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