Sule Tinaz

Purpose: Dynamic [ ¹¹ C]UCB-J PET can simultaneously provide information about synaptic density and relative perfusion in Parkinson’s disease (PD). We investigated whether these complementary biomarkers could explain a higher percentage of motor symptom severity variation in PD and inform other PD-specific physiological alterations and symptomatology. Methods: Binding potential ( BP _ND ) and relative perfusion ( R ₁ ) images were derived 30 PD and 30 controls imaged with [ ¹¹ C]UCB-J PET. A spatial covariance analysis was used on R ₁ to derive PDRP-a known metabolic network alteration in PD. Linear models related PD-motor symptom severity to PDRP expression and nigral synaptic losses. Next, whole-brain cluster analyses identified physiological correlates for PD-tremor severity, a prominent motor symptom that does not correlate with dopaminergic losses. Lastly, inter-individual regional correlation alterations in PD were examined for both BP _ND and R ₁ . Results: PDRP was identified from R ₁ , with higher expression in PD ( p =1.7×10 ^-5 , Cohen’s d =1.2), and its expression correlated with MDS-UPDRS III ( r =0.57, p =0.0009). Combining PDRP expression scores with synaptic density in the substantia nigra explained 48% of the total variation in MDS-UPDRS Part III, twice as much as previously reported using nigral synaptic density alone. Two significant large clusters ( p _k -6 ) were identified in the occipital-parietal areas where R ₁ was negatively correlated with tremor severity ( r ∼ -0.65, p 11 C]UCB-J PET explains more physiological alterations associated with PD.

Parkinson's Disease (PD) Motor Scores (MDS-UPDRS Part III) are quite noisy. This paper proposes a new methodology for processing these scores by first denoising the scores to enhance the underlying progression signal, and then conducting a high-dimensional analysis which does not sum the scores into a total movement score. The analysis gives novel insights into PD progression heterogeneity: it reveals that the heterogeneity is continuously variable rather than clustered into "subtypes" and that the variability is along two easily understood axes. This analysis also resolves some of the discrepancies in previously reported progression subtypes. Finally, the analysis reveals that patient-specific progression cannot be predicted from baseline using only MDS-UPDRS Part III scores.

Cognitive impairment is a debilitating problem in Parkinson's disease (PD) with no effective treatment. This pilot randomized controlled trial (ClinicalTrials.gov identifier NCT05495997) tested the feasibility of a personalized mental imagery (MI) intervention focusing on goal-directed activities of daily living in people with PD. We screened 51 and randomized 30 nondemented people with PD. During the six-week training period delivered remotely, PD-MI group practiced MI and PD-Control group received psychoeducation on cognitive health in PD. The primary objective was testing protocol feasibility. We also collected cognitive and functional MRI data at baseline, six weeks, and 18 weeks, specifically, to assess the feasibility of using the Neuro-QoL Cognitive Function (CF) self-report survey and brain functional connectivity as potential efficacy outcome measures in a future definitive trial. Retention and participant compliance with study procedures were 100% during six weeks. There were (1) group differences in the Neuro-QoL-CF T-scores at six and 18 weeks, driven by a reduction in the control group scores, (2) stronger frontoparietal connectivity at six weeks, and (3) weaker visuospatial-motor connectivity at 18 weeks during MI tasks in the PD-MI compared to the PD-Control group. These cognitive and brain connectivity changes should be tested in a fully powered trial.

Background: ¹⁸ F‐FE‐PE2I is a highly selective dopamine transporter (DAT) positron emission tomography (PET) radioligand, whereas ¹¹ C‐UCB‐J targets synaptic vesicle glycoprotein 2A (SV2A), enabling the assessment of synaptic density. Both tracers show significant alterations in Parkinson's disease (PD) in nigrostriatal regions. However, the extent of overlap between overall synaptic loss and dopaminergic denervation across different disease stages remains unclear. Objective: To evaluate similarities and differences between patterns of DAT and SV2A binding in healthy controls (HC) and PD patients at different disease stages. Methods: Thirty patients with PD (12 women, age: 65.8 ± 7.1 years) and thirteen HCs (7 women, age: 57.8 ± 5.4 years) underwent PET imaging with ¹⁸ F‐FE‐PE2I and ¹¹ C‐UCB‐J on separate days. Patients with PD were also stratified by disease duration into two subgroups (6 years, n = 11). Binding potentials ( BP _ND ) were quantified in four regions of interest (ROIs): caudate, putamen, ventral striatum (VS), and substantia nigra (SN). Between‐group differences in BP _ND were evaluated against HCs for each tracer, and correlations between ¹⁸ F‐FE‐PE2I and ¹¹ C‐UCB‐J BP _ND were evaluated. Results: In HCs, significant correlations were observed between caudate ¹⁸ F‐FE‐PE2I and striatal ¹¹ C‐UCB‐J BP _ND (caudate, putamen, VS). In PD (full cohort and longer‐duration subgroup), significant correlations emerged between SN ¹¹ C‐UCB‐J and striatal ¹⁸ F‐FE‐PE2I. Percent differences between patients with PD and HCs with ¹⁸ F‐FE‐PE2I and ¹¹ C‐UCB‐J were similar only in the SN. Conclusions: This study examined the relationship between DAT and overall synaptic density in nigrostriatal ROIs in PD using dual‐tracer PET imaging, and there were distinct patterns that vary across disease stages. Understanding the interplay between dopaminergic and presynaptic degeneration in PD could enhance our knowledge of its pathophysiology and contribute to improve diagnosis. © 2025 International Parkinson and Movement Disorder Society.

Background: Skin punch biopsy has been investigated as a minimally invasive tool to aid in the diagnosis of idiopathic Parkinson's disease (IPD) via detection of cutaneous phosphorylated α‐synuclein. The use and impact of this tool in clinical practice has not been well‐characterized. Objective: To understand the utilization of skin punch biopsies for diagnosis and management of α‐synucleinopathy within a large medical system. Methods: Three hundred charts of patients who underwent skin punch biopsy were reviewed. Of these, 149 (49.7%) met criteria for analysis (concern for α‐synucleinopathy, age over 40). Demographic data, outpatient neurology and primary care notes, and imaging results were reviewed alongside biopsy results. Results: Of 149 biopsies, 70% (N = 105) were positive in at least one skin sample. There was no statistically significant relationship between any pre‐biopsy symptom and a positive result. Most patients identified as white (N = 124, 83%) and non‐Hispanic (N = 131, 88%). The sex distribution was roughly equal (52% male, 48% female). While most tests were ordered for IPD or an unspecified primary parkinsonism, other clinical concerns included dementia with Lewy bodies (N = 41, 28%) and multiple system atrophy (N = 6, 4%). Only 4% of biopsies (N = 6) were ordered by movement disorders specialists. Results changed or strengthened diagnosis in 52% of cases and changed management in 60% of cases. Conclusions: Skin punch biopsies are being used broadly with impactful results. However, there appears to be potential disparity in access to this test. Further research is required to inform clinical guidelines and promote equity in the use of this novel biomarker.

Cognitive impairment is a debilitating problem in Parkinson’s disease (PD) with no effective treatment. We developed a personalized mental imagery (MI) intervention focusing on goal-directed activities and examined its effect on everyday cognitive functioning and brain functional connectivity in people with PD in a pilot randomized controlled trial ( ClinicalTrials.gov identifier NCT05495997 ). Thirty nondemented people with PD were randomized to PD-MI and PD-Control groups. During the six-week training period, PD-MI received MI training and PD-Control received psychoeducation on cognitive health in PD. Participants underwent cognitive and functional MRI assessments at baseline, six weeks, and 18 weeks. The primary outcomes included changes in Neuro-QoL Cognitive Function (CF) survey scores and functional connectivity. The PD-MI compared to the PD-Control group showed (1) significant difference in Neuro-QoL-CF scores (F(1,26) = 6.802, p = 0.015) at six weeks which was not sustained at 18 weeks, (2) stronger connectivity between frontoparietal regions (T = 4.1, p = 0.009) during MI tasks at six weeks, and (3) weaker connectivity between visuospatial and motor regions at 18 weeks. Personalized MI training can be effective in facilitating cognitive preparedness for everyday tasks in people with PD. Its long-term effects and feasibility in cognitively impaired PD cohorts need further investigation.

Levodopa-induced dyskinesia (LID) is a significant treatment complication that affects a substantial proportion of Parkinson’s disease (PD) patients. Our understanding of the neural basis of LID remains limited, partly due to the small sample sizes in existing neuroimaging studies. In this study, we utilized structural MRI data from the Parkinson’s Progression Markers Initiative (PPMI) database, including de novo PD patients (104 non-dyskinetic for a least 3 years after diagnosis and 120 who developed dyskinesia) and 100 age- and sex-matched healthy controls. Additionally, we analyzed resting-state functional MRI data from a subset of these participants to investigate connectivity differences among the groups. Our analysis revealed no significant baseline volumetric differences between dyskinetic and non-dyskinetic PD patients. However, the thickness of frontal and sensorimotor cortices were significantly greater in dyskinetic patients. In the subcortical regions, vertex-based shape analysis identified localized surface growth in the left caudate and left pallidum, as well as surface morphology changes in the bilateral pallidum in dyskinetics. Resting-state functional connectivity analysis revealed stronger connectivity between the putamen, inferior frontal gyrus, and sensory cortex in dyskinetic PD patients compared to non-dyskinetics. These findings suggest that specific morphological and functional changes in the motor cortical-basal ganglia circuitry of de novo PD patients may predispose them to LID over time. Additionally, the altered functional connectivity patterns reinstate the role of the inferior frontal gyrus in the pathophysiology of dyskinesia and suggest that it might be a suitable target for neuromodulatory interventions, consistent with previous reports.

Idiopathic Parkinson’s disease (PD) is a neurodegenerative disorder that affects multiple systems in the body and is characterized by a variety of motor and non-motor (e.g., psychiatric, autonomic) symptoms. As the fastest growing neurological disorder expected to affect over 12 million people globally by 2040 (Dorsey, Bloem JAMA Neurol 75(1):9–10. https://doi.org/10.1001/jamaneurol.2017.3299. PMID: 29131880, 2018), PD poses an enormous individual and public health burden. Currently, there are no therapies that can slow down the disease progression in PD, and existing therapies are limited to symptomatic treatment. Importantly, people in the prodromal phase who are at high risk of developing PD can now be identified, which makes disease prevention an achievable goal. An in-depth understanding of the pathological processes in PD is crucial for prevention and treatment development. Advanced multimodal neuroimaging techniques provide unique biomarkers that can further our understanding of PD at multiple levels ranging from neurotransmitters to neural networks. These neuroimaging biomarkers also have value in clinical application, for example, in the differential diagnosis of PD. As the field continues to advance, neuroimaging biomarkers are expected to become more specific, more widely accessible, and can be readily incorporated into translational research for treatment development in PD.