Early Parkinson's Disease Patients Research Articles

Olfactory dysfunction and long-term trajectories of sleep disorders among early Parkinson's disease: findings from a longitudinal cohort.

Previous studies have suggested a connection between impaired olfactory function and an increased risk of rapid eye movement sleep behavior disorder (RBD) in individuals diagnosed with Parkinson's disease (PD). However, there is a gap in knowledge regarding the potential impact of olfactory dysfunction on the long-term patterns of sleep disorders among early PD patients. Data from the Parkinson's Progression Markers Initiative program included 589 participants with assessments of sleep disorders using the Epworth Sleepiness Scale (ESS) and RBD Screening Questionnaire (RBDSQ). Olfactory dysfunction at baseline was measured using the University of Pennsylvania Smell Identification Test. Trajectories of sleep disorders over a 5-year follow-up were identified using group-based trajectory modeling, and the relationship between olfactory dysfunction and sleep disorder trajectories was examined through binomial logistic regression. Two distinct trajectories of sleep disorders over the 5-year follow-up period were identified, characterized by maintaining a low or high ESS score and a low or high RBDSQ score. An inversion association was observed between olfactory function measures and trajectories of excessive daytime sleepiness (EDS) (odds ratio [OR]=0.97, 95% confidence interval [CI] 0.95, 1.00, P=0.038), after controlling for potential covariates. Similarly, olfactory function showed a significant association with lower trajectories of probable RBD (pRBD) (OR=0.96, 95% CI 0.94, 0.98, P=0.001) among early PD individuals. Consistent findings were replicated across alternative analytical models. Our findings indicated that olfactory dysfunction was associated with unfavorable long-term trajectories of sleep disorders among early Parkinson's disease.

Energetic dysfunction and iron overload in early Parkinson's disease: Two distinct mechanisms?

IntroductionIdentifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD. MethodsWe prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1H and 23Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R2*, qT1, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction. ResultsRelative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001). ConclusionIn ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.

ATST-Net: A method to identify early symptoms in the upper and lower extremities of PD

Bradykinesia, a core symptom of motor disorders in Parkinson's disease (PD), is a major criterion for screening early PD patients in clinical practice. Currently, many studies have proposed automatic assessment schemes for bradykinesia in PD. However, existing schemes suffer from problems such as dependence on professional equipment, single evaluation tasks, difficulty in obtaining samples and low accuracy. This paper proposes a manual feature extraction- and neural network-based method to evaluate bradykinesia, effectively solving the problem of a small sample size. This method can automatically assess finger tapping (FT), hand movement (HM), toe tapping (TT) and bilateral foot sensitivity tasks (LA) through a unified model. Data were obtained from 120 individuals, including 93 patients with Parkinson's disease and 27 age- and sex-matched normal controls (NCs). Manual feature extraction and Attention Time Series Two-stream Networks (ATST-Net) were used for classification. Accuracy rates of 0.844, 0.819, 0.728, and 0.768 were achieved for FT, HM, TT, and LA, respectively. To our knowledge, this study is the first to simultaneously evaluate the upper and lower limbs using a unified model that has significant advantages in both model training and transfer learning.

Parkinson's Disease Risk Variant rs9638616 is Non-Specifically Associated with Altered Brain Structure and Function.

A genome-wide association study (GWAS) variant associated with Parkinson's disease (PD) risk in Asians, rs9638616, was recently reported, and maps to WBSCR17/GALNT17, which is involved in synaptic transmission and neurite development. To test the association of the rs9638616 T allele with imaging-derived measures of brain microstructure and function. We analyzed 3-Tesla MRI and genotyping data from 116 early PD patients (aged 66.8±9.0 years; 39% female; disease duration 1.25±0.71 years) and 57 controls (aged 68.7±7.4 years; 54% female), of Chinese ethnicity. We performed voxelwise analyses for imaging-genetic association of rs9638616 T allele with white matter tract fractional anisotropy (FA), grey matter volume and resting-state network functional connectivity. The rs9638616 T allele was associated with widespread lower white matter FA (t = -1.75, p = 0.042) and lower functional connectivity of the supplementary motor area (SMA) (t = -5.05, p = 0.001), in both PD and control groups. Interaction analysis comparing the association of rs9638616 and FA between PD and controls was non-significant. These imaging-derived phenotypes mediated the association of rs9638616 to digit span (indirect effect: β= -0.21 [-0.42,-0.05], p = 0.031) and motor severity (indirect effect: β= 0.15 [0.04,0.26], p = 0.045). We have shown that a novel GWAS variant which is biologically linked to synaptic transmission is associated with white matter tract and functional connectivity dysfunction in the SMA, supported by changes in clinical motor scores. This provides pathophysiologic clues linking rs9638616 to PD risk and might contribute to future risk stratification models.

Nonlinear Relationship Between Homocysteine and Mild Cognitive Impairment in Early Parkinson's Disease: A Cross-Sectional Study.

Cognitive impairment, a prevalent non-motor symptom in advanced Parkinson's disease (PD), has been associated with hyperhomocysteinemia, an important risk factor for PD progression and cognitive decline in PD. However, evidence regarding the association between homocysteine (Hcy) and cognitive function during early PD remains insufficient. Therefore, this study aims to examine the correlation between Hcy levels and cognitive function in the early stage of PD. The study included 218 individuals in the early stages of PD who were consecutively admitted to the Suining Central Hospital Neurology Department. All the individuals completed the Parkinson's Disease Cognitive Rating Scale (PD-CDR). The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) was employed for measuring the severity of motor symptoms, while the Hoehn-Yahr scale was used to measure the clinical symptom stage. Fasting venous blood samples were also drawn to measure the Hcy concentration, red blood cell folate, and vitamin B12. In this cross-sectional study, 47 (21.5%) patients with PD showed cognitive dysfunction. The serum Hcy levels were significantly higher in the cognitive impairment PD (PDCI) group compared with the cognitive normal PD group (P<0.001). The Generalized Additive Model (GAM) analysis revealed a nonlinear relationship between Hcy and the risk of PDCI. Multiple logistic regression analyses demonstrated a positive relationship between elevated Hcy and the risk of PDCI in the fully adjusted model ([OR]:3.1, 95% CI, 1.1-8.5, P=0.028). Segmented linear regression analysis showed that when Hcy levels were above 17.7 umol/l, the risk of PDCI increased by 1.6 times for every 1 unit elevated in Hcy (95% CI:1.1-2.2, P=0.008). This study revealed a nonlinear positive correlation between the risk of PDCI and elevated serum Hcy levels in early PD patients, suggesting hyperhomocysteinemia as one of the treatable factors for cognitive impairment in the early stages of PD.

A New Wrist-Worn Tool Supporting the Diagnosis of Parkinsonian Motor Syndromes.

To date, clinical expert opinion is the gold standard diagnostic technique for Parkinson's disease (PD), and continuous monitoring is a promising candidate marker. This study assesses the feasibility and performance of a new wearable tool for supporting the diagnosis of Parkinsonian motor syndromes. The proposed method is based on the use of a wrist-worn measuring system, the execution of a passive, continuous recording session, and a computation of two digital biomarkers (i.e., motor activity and rest tremor index). Based on the execution of some motor tests, a second step is provided for the confirmation of the results of passive recording. In this study, fifty-nine early PD patients and forty-one healthy controls were recruited. The results of this study show that: (a) motor activity was higher in controls than in PD with slight tremors at rest and did not significantly differ between controls and PD with mild-to-moderate tremor rest; (b) the tremor index was smaller in controls than in PD with mild-to-moderate tremor rest and did not significantly differ between controls and PD patients with slight tremor rest; (c) the combination of the said two motor parameters improved the performances in differentiating controls from PD. These preliminary findings demonstrate that the combination of said two digital biomarkers allowed us to differentiate controls from early PD.

Morphometric similarity differences in drug-naive Parkinson's disease correlate with transcriptomic signatures.

Differences in cortical morphology have been reported in individuals with Parkinson's disease (PD). However, the pathophysiological mechanism of transcriptomic vulnerability in local brain regions remains unclear. This study aimed to characterize the morphometric changes of brain regions in early drug-naive PD patients and uncover the brain-wide gene expression correlates. The morphometric similarity (MS) network analysis was used to quantify the interregional structural similarity from multiple magnetic resonance imaging anatomical indices measured in each brain region of 170 early drug-naive PD patients and 123 controls. Then, we applied partial least squares regression to determine the relationship between regional changes in MS and spatial transcriptional signatures from the Allen Human Brain Atlas dataset, and identified the specific genes related to MS differences in PD. We further investigated the biological processes by which the PD-related genes were enriched and the cellular characterization of these genes. Our results showed that MS was mainly decreased in cingulate, frontal, and temporal cortical areas and increased in parietal and occipital cortical areas in early drug-naive PD patients. In addition, genes whose expression patterns were associated with regional MS changes in PD were involved in astrocytes, excitatory, and inhibitory neurons and were functionally enriched in neuron-specific biological processes related to trans-synaptic signaling and nervous system development. These findings advance our understanding of the microscale genetic and cellular mechanisms driving macroscale morphological abnormalities in early drug-naive PD patients and provide potential targets for future therapeutic trials.

Anatomical correlates of apathy and impulsivity co-occurrence in early Parkinson’s disease

BackgroundAlthough apathy and impulse control disorders (ICDs) are considered to represent opposite extremes of a continuum of motivated behavior (i.e., hypo- and hyperdopaminergic behaviors), they may also co-occur in Parkinson’s disease (PD).ObjectivesWe aimed to explore the co-occurrence of ICDs and apathy and its neural correlates analyzing gray matter (GM) changes in early untreated PD patients. Moreover, we aimed to investigate the possible longitudinal relationship between ICDs and apathy and their putative impact on cognition during the first five years of PD.MethodsWe used the Parkinson’s Progression Markers Initiative (PPMI) database to identify the co-occurrence of apathy and ICDs in 423 early drug-naïve PD patients at baseline and at 5-year follow-up. Baseline MRI volumes and gray matter changes were analyzed between groups using voxel-based morphometry. Multi-level models assessed the longitudinal relationship (across five years) between apathy and ICDs and cognitive functioning.ResultsAt baseline, co-occurrence of apathy and ICDs was observed in 23 patients (5.4%). This finding was related to anatomical GM reduction along the cortical regions involved in the limbic circuit and cognitive control systems. Longitudinal analyses indicated that apathy and ICDs were related to each other as well as to the combined use of levodopa and dopamine agonists. Worse apathetic and ICDs states were associated with poorer executive functions.ConclusionsApathy and ICDs are joint non-exclusive neuropsychiatric disorders also in the early stages of PD and their co-occurrence was associated with GM decrease in several cortical regions of the limbic circuit and cognitive control systems.

FABP2 is Involved in Intestinal α-Synuclein Pathologies.

Recently, the hypothesis that pathological α-Synuclein propagates from the gut to the brain has gained attention. Although results from animal studies support this hypothesis, the specific mechanism remains unclear. This study focused on the intestinal fatty acid-binding protein (FABP2), which is one of the subtypes of fatty acid binding proteins localizing in the gut, with the hypothesis that FABP2 is involved in the gut-to-brain propagation of α-synuclein. The aim of this study was to clarify the pathological significance of FABP2 in the pathogenesis and progression of synucleinopathy. We examined the relationship between FABP2 and α-Synuclein in the uptake of α-Synuclein into enteric neurons using primary cultured neurons derived from mouse small intestinal myenteric plexus. We also quantified disease-related protein concentrations in the plasma of patients with synucleinopathy and related diseases, and analyzed the relationship between plasma FABP2 level and progression of the disease. Experiments on α-Synuclein uptake in primary cultured enteric neurons showed that following uptake, α-Synuclein was concentrated in areas where FABP2 was localized. Moreover, analysis of the plasma protein levels of patients with Parkinson's disease revealed that the plasma FABP2 and α-Synuclein levels fluctuate with disease duration. The FABP2/α-Synuclein ratio fluctuated more markedly than either FABP2 or α-Synuclein alone, depending on the duration of disease, indicating a higher discriminant ability of early Parkinson's disease patients from healthy patients. These results suggest that FABP2 potentially contributes to the pathogenesis and progression of α-synucleinopathies. Thus, FABP2 is an important molecule that has the potential to elucidate the consistent mechanisms that lead from the prodromal phase to the onset and subsequent progression of synucleinopathies.

The Dubousset Functional Test: a reliable and valid test in early stage Parkinson's disease patients.

Dubousset Functional Test (DFT) is an assessment test evaluating the functional capacity and dynamic balance. The study aimed to examine the reliability, validity, and responsiveness of the DFT in early stage Parkinson's disease (PD) patients. This was a cross-sectional study. Thirty-three early stage PD patients were recruited. The DFT was performed along with the Timed Up and Go (TUG) test, dual-task TUG, Functional Reach Test (FRT), 3-m backward walk test (3MBWT), Tinetti Performance-Oriented Mobility Assessment (POMA), and Berg Balance Scale (BBS). The test-retest reliability of the subcomponents of the DFT was excellent. The ICCs were as follows: 0.952, 0.955, 0.917, and 0.919, respectively. The correlation with subcomponents of DFT and TUG, dual-task TUG, FRT, 3MBWT, BBS, and POMA was found to be statistically significant (p < 0.05). The standard measurement errors of the subcomponents of the DFT were 1.45, 1.39, 1.70, and 1.57, respectively. The minimal clinically important difference (MCID) of the subcomponents was 2.05, 1.97, 2.41, and 2.22, respectively. The DFT is a reliable, valid, and easy-to-administer tool in assessing the balance and physical function of early stage PD patients.

Reorganization of intrinsic functional connectivity in early-stage Parkinson’s disease patients with probable REM sleep behavior disorder

REM sleep behavior disorder (RBD) symptoms in Parkinson’s disease (PD) suggest both a clinically and pathologically malignant subtype. However, whether RBD symptoms are associated with alterations in the organization of whole-brain intrinsic functional networks in PD, especially at early disease stages, remains unclear. Here we use resting-state functional MRI, coupled with graph-theoretical approaches and network-based statistics analyses, and validated with large-scale network analyses, to characterize functional brain networks and their relationship with clinical measures in early PD patients with probable RBD (PD+pRBD), early PD patients without probable RBD (PD-pRBD) and healthy controls. Thirty-six PD+pRBD, 57 PD-pRBD and 71 healthy controls were included in the final analyses. The PD+pRBD group demonstrated decreased global efficiency (t = -2.036, P = 0.0432) compared to PD-pRBD, and decreased network efficiency, as well as comprehensively disrupted nodal efficiency and whole-brain networks (all eight networks, but especially in the sensorimotor, default mode and visual networks) compared to healthy controls. The PD-pRBD group showed decreased nodal degree in right ventral frontal cortex and more affected edges in the frontoparietal and ventral attention networks compared to healthy controls. Furthermore, the assortativity coefficient was negatively correlated with Montreal cognitive assessment scores in the PD+pRBD group (r = -0.365, P = 0.026, d = 0.154). The observation of altered whole-brain functional networks and its correlation with cognitive function in PD+pRBD suggest reorganization of the intrinsic functional connectivity to maintain the brain function in the early stage of the disease. Future longitudinal studies following these alterations along disease progression are warranted.

Increased iron in the substantia nigra pars compacta identifies patients with early Parkinson’s disease: A 3T and 7T MRI study

Degeneration in the substantia nigra (SN) pars compacta (SNc) underlies motor symptoms in Parkinson’s disease (PD). Currently, there are no neuroimaging biomarkers that are sufficiently sensitive, specific, reproducible, and accessible for routine diagnosis or staging of PD. Although iron is essential for cellular processes, it also mediates neurodegeneration. MRI can localize and quantify brain iron using magnetic susceptibility, which could potentially provide biomarkers of PD.We measured iron in the SNc, SN pars reticulata (SNr), total SN, and ventral tegmental area (VTA), using quantitative susceptibility mapping (QSM) and R2* relaxometry, in PD patients and age-matched healthy controls (HCs). PD patients, diagnosed within five years of participation and HCs were scanned at 3T (22 PD and 23 HCs) and 7T (17 PD and 21 HCs) MRI. Midbrain nuclei were segmented using a probabilistic subcortical atlas. QSM and R2* values were measured in midbrain subregions. For each measure, groups were contrasted, with Age and Sex as covariates, and receiver operating characteristic (ROC) curve analyses were performed with repeated k-fold cross-validation to test the potential of our measures to classify PD patients and HCs. Statistical differences of area under the curves (AUCs) were compared using the Hanley-MacNeil method (QSM versus R2*; 3T versus 7T MRI).PD patients had higher QSM values in the SNc at both 3T (padj = 0.001) and 7T (padj = 0.01), but not in SNr, total SN, or VTA, at either field strength. No significant group differences were revealed using R2* in any midbrain region at 3T, though increased R2* values in SNc at 7T MRI were marginally significant in PDs compared to HCs (padj = 0.052). ROC curve analyses showed that SNc iron measured with QSM, distinguished early PD patients from HCs at the single-subject level with good diagnostic accuracy, using 3T (mean AUC = 0.83, 95 % CI = 0.82–0.84) and 7T (mean AUC = 0.80, 95 % CI = 0.79–0.81) MRI. Mean AUCs reported here are from averages of tests in the hold-out fold of cross-validated samples. The Hanley-MacNeil method demonstrated that QSM outperforms R2* in discriminating PD patients from HCs at 3T, but not 7T. There were no significant differences between 3T and 7T in diagnostic accuracy of QSM values in SNc.This study highlights the importance of segmenting midbrain subregions, performed here using a standardized atlas, and demonstrates high accuracy of SNc iron measured with QSM at 3T MRI in identifying early PD patients. QSM measures of SNc show potential for inclusion in neuroimaging diagnostic biomarkers of early PD. An MRI diagnostic biomarker of PD would represent a significant clinical advance.

Different associated factors of subjective cognitive complaints in patients with early and advanced Parkinson's disease.

Subjective cognitive complaints (SCCs), defined as cognitive decline reported by subjects or their informants, are common in the early stage of Parkinson's disease (PD). Previous studies have shown a significant association between SCCs and non-motor features as well as objective cognitive decline in PD patients. However, the discrepancy in SCC prevalence and SCC-related factors between patients with early PD and those with advanced PD remains poorly understood. We recruited a total of 114 and 69 early PD patients and advanced PD patients, respectively. Univariate and multivariate logistic regression analyses were performed for early PD and advanced PD patients. The prevalence of SCCs in the early PD and advanced PD groups was 60.5 and 68.1%, respectively. In the early PD group, the presence of SCCs in early PD participants was significantly associated with a higher nonmotor symptoms questionnaire (NMSQ) score (OR = 1.05, 95% CI = 1.00-1.10, p = 0.040). SCCs in the advanced PD group were related to lower attention scores (OR = 0.24, 95% CI = 0.05-0.90, p = 0.043) and lower visuospatial/executive abilities scores (OR = 0.18, 95% CI = 0.04-0.86, p = 0.032). The prevalence and SCC-related factors are distinct in early PD and advanced PD. These findings suggest that SCCs in PD patients with different disease statuses appear to have different related factors that may depend on different disease severities.

Intrinsic brain functional connectivity predicts treatment-related motor complications in early Parkinson’s disease patients

BackgroundTreatment-related motor complications may develop progressively over the course of Parkinson’s disease (PD).ObjectiveWe investigated intrinsic brain networks functional connectivity (FC) at baseline in a cohort of early PD patients which successively developed treatment-related motor complications over 4 years.MethodsBaseline MRI images of 88 drug-naïve PD patients and 20 healthy controls were analyzed. After the baseline assessments, all PD patients were prescribed with dopaminergic treatment and yearly clinically re-assessed. At the 4-year follow-up, 36 patients have developed treatment-related motor complications (PD-Compl) whereas 52 had not (PD-no-Compl). Single-subject and group-level independent component analyses were used to investigate FC changes within the major large-scale resting-state networks at baseline. A multivariate Cox regression model was used to explore baseline predictors of treatment-related motor complications at 4-year follow-up.ResultsAt baseline, an increased FC in the right middle frontal gyrus within the frontoparietal network as well as a decreased connectivity in the left cuneus within the default-mode network were detected in PD-Compl compared with PD-no-Compl. PD-Compl patients showed a preserved sensorimotor FC compared to controls. FC differences were found to be independent predictors of treatment-related motor complications over time.ConclusionOur findings demonstrated that specific FC differences may characterize drug-naïve PD patients more prone to develop treatment-related complications. These findings may reflect the presence of an intrinsic vulnerability across frontal and prefrontal circuits, which may be potentially targeted as a future biomarker in clinical trials.

Imaging Protein Aggregates in Parkinson's Disease Serum Using Aptamer-Assisted Single-Molecule Pull-Down.

The formation of soluble α-synuclein (α-syn) and amyloid-β (Aβ) aggregates is associated with the development of Parkinson's disease (PD). Current methods mainly focus on the measurement of the aggregate concentration and are unable to determine their heterogeneous size and shape, which potentially also change during the development of PD due to increased protein aggregation. In this work, we introduce aptamer-assisted single-molecule pull-down (APSiMPull) combined with super-resolution fluorescence imaging of α-syn and Aβ aggregates in human serum from early PD patients and age-matched controls. Our diffraction-limited imaging results indicate that the proportion of α-syn aggregates (α-syn/(α-syn+Aβ)) can be used to distinguish PD and control groups with an area under the curve (AUC) of 0.85. Further, super resolution fluorescence imaging reveals that PD serums have a higher portion of larger and rounder α-syn aggregates than controls. Little difference was observed for Aβ aggregates. Combining these two metrics, we constructed a new biomarker and achieved an AUC of 0.90. The combination of the aggregate number and morphology provides a new approach to early PD diagnosis.

Neuroinflammation is linked to dementia risk in Parkinson's disease.

The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies.

Dopamine Transporter Availability in Early Parkinson's Disease is Dependent on Sunlight Exposure.

Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the seasons. We, therefore, investigated seasonal and sunlight-dependent effects on DAT availability in early Parkinson's disease (PD) patients and healthy controls. DAT single-photon emission computed tomography scans (n = 730) were gathered from the Parkinson's Progression Marker Initiative (PPMI) database. We used global horizontal irradiance (GHI) as proxy for sun exposure/month and assessed associations between striatal DAT availability and season (autumn/winter versus spring/summer), GHI and latitude of the PPMI site. In PD patients, DAT availability in the left caudate nucleus was higher in spring/summer (B [standard error (SE)] = 0.05 [0.02], P = 0.03) and positively associated with higher sun exposure (B [SE] = 0.59 [0.22] × 10-3 , P = 0.007). Latitude (in degrees north) of the PPMI site was negatively associated with DAT availability in both PD and healthy controls. Striatal DAT availability may be influenced by daylight exposure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuromuscular assessment of force development, postural, and gait performance under cognitive-motor dual-tasking in healthy older adults and early Parkinson's disease patients: Study protocol for a cross-sectional Mobile Brain/Body Imaging (MoBI) study

Background: Neuromuscular dysfunction is common in older adults and more pronounced in neurodegenerative diseases. In Parkinson's disease (PD), a complex set of factors often prevents the effective performance of activities of daily living that require intact and simultaneous performance of the motor and cognitive tasks. Methods: The cross-sectional study includes a multifactorial mixed-measure design. Between-subject factor grouping the sample will be Parkinson’s Disease (early PD vs. healthy). The within-subject factors will be the task complexity (single- vs. dual-task) in each motor activity, i.e., overground walking, semi-tandem stance, and isometric knee extension, and a walking condition (wide vs. narrow lane) will be implemented for the overground walking activity only. To study dual-task (DT) effects, in each motor activity participants will be given a secondary cognitive task, i.e., a visual discrimination task for the overground walking, an attention task for the semi-tandem, and mental arithmetic for the isometric extension. Analyses of DT effects and underlying neuronal correlates will focus on both gait and cognitive performance where applicable. Based on an a priori sample size calculation, a total N = 42 older adults (55-75 years) will be recruited. Disease-specific changes such as laterality in motor unit behavior and cortical control of movement will be studied with high-density surface electromyography and electroencephalography during static and dynamic motor activities, together with whole-body kinematics. Discussion: This study will be one of the first to holistically address early PD neurophysiological and neuromuscular patterns in an ecologically valid environment under cognitive-motor DT conditions of different complexities. The outcomes of the study aim to identify the biomarker for early PD either at the electrophysiological, muscular or kinematic level or in the communication between these systems. Clinical Trial Registration: ClinicalTrials.Gov, NCT05477654. This study was approved by the Medical Ethical Committee (106/2021).

Association between regular physical activity and biomarker changes in early Parkinson's disease patients

IntroductionPhysical activity benefits patients with Parkinson's disease (PD) and is assumed to possess disease-modifying potential. PD-related biomarkers, such as dopamine transporter (DAT) imaging and cerebrospinal fluid (CSF) α-synuclein (α-syn) and amyloid β (Aβ), correlate with disease severity and, to some extent, reflect disease progression and pathology. However, the association between regular physical activity and PD biomarker changes remains unknown. This study aimed to investigate the association between physical activity and longitudinal trajectories of PD biomarkers. MethodsThis retrospective study included 444 patients with a median follow-up time of 5 years from the Parkinson's Progression Markers Initiative cohort. Data collection included physical activity as scaled by the Physical Activity Scale for the Elderly questionnaire, dopamine transporter imaging, CSF assessment, and serum biomarkers. We analyzed the data using a linear mixed regression model. ResultsRegular physical activity was associated with a slower decline of DAT uptake in the caudate (β = 0.063, p = 0.011) and the putamen (β = 0.062, p = 0.023). No association was detected between regular physical activity and CSF, as well as serum biomarkers. ConclusionRegular physical activity is associated with favorable PD biomarker progression, indicating a potential disease-modifying effect.

An investigation of neuromelanin distribution in substantia nigra and locus coeruleus in patients with Parkinson’s disease using neuromelanin-sensitive MRI

Loss of neuromelanin in the midbrain is known in Parkinson’s disease(PD), which can now be directly detected by neuromelanin-sensitive MRI(NM-MRI). This case-control study was to investigate the distribution of neuromelanin in the substantia nigra(SN) and the locus coeruleus(LC) using NM-MRI technique and evaluate its potential as a diagnostic marker for PD. 10 early PD patients(H&Y stage I, II), 11 progressive PD patients(H&Y stage III-V), and 10 healthy controls matched in age and gender were recruited. All participants completed clinical and psychometric assessments as well as NM-MRI scans. Neuromelanin signal intensities in SN and LC were measured by contrast-to-noise ratios(CNRs) derived from NM-MRI scans. There were significant decreases of CNRs in SNpc(including anterior, central, and posterior) and LC in PD patients compared to controls. There were also significant differences of CNR between the left and right sides. CNR in LC had a negative correlation with the Non-Motor Symptoms Scale(NMSS) score in PD patients(|R|=0.49), whereas CNR in SNpc did not correlate with Unified Parkinson Disease Rating Scale(UPDRS) score(|R|<0.3). The receiver operating characteristic(ROC) curves revealed that the CNR in LC had a high diagnostic specificity of 90.1% in progressive patients. This study provides new evidence for the asymmetric distribution of neuromelanin in SN and the LC of patients with PD. The neuromelanin loss is bilateral and more predominately in LC than that in SN. This distinct neuromelanin distribution pattern may offer a potential diagnostic marker and a potential neuropharmacological intervention target for PD patients.