Parkinson's Disease Group Research Articles

Regulatory effect of bacterial melanin on the isoforms of new superoxide-producing associates from rat tissues in rotenone-induced Parkinson’s disease

According to recent research, selective neuronal vulnerability in Parkinson’s disease (PD) results from several phenotypic traits, including calcium-dependent, feed-forward control of mitochondrial respiration leading to elevated reactive oxygen species and cytosolic calcium concentration, an extensive axonal arbor, and a reactive neurotransmitter. Therefore, antioxidant therapy is a promising direction in the treatment of PD. In vitro studies have indicated the survival-promoting activity of bacterial melanin (BM) on midbrain dopaminergic neuron cultures. It has been established that BM has a number of protective and anti-inflammatory properties, so there is a high probability of a protective effect of BM in the early stages of PD. In this study, PD was induced through the unilateral intracerebral administration of rotenone followed by bacterial melanin. Tissues (brain, lungs, and small intestine) from the observed groups underwent isolation and purification to extract isoforms of new thermostable superoxide (О2−)-producing associates between NADPH-containing lipoprotein (NLP) and NADPH oxidase-Nox (NLP-Nox). The optical absorption spectral characteristics, specific amounts, stationary concentration of the produced О2−, and the content of NADPH in the observed associates were determined. The optical absorption spectra of the NLP-Nox isoforms in the visible and UV regions in the experimental groups did not differ from those of the control group. However, compared with the control group, the specific content of the total fractions of NLP-Nox isoforms associated with PD groups was higher, especially in the small intestine. These findings suggest that the described changes may represent a novel mechanism for rotenone-induced PD. Furthermore, bacterial melanin demonstrated antioxidant properties and regulated membrane formation in the brain, lung, and small intestine. This regulation occurred by inhibiting the release of new membrane-bound formations (NLP-Nox associates) from these membranes while simultaneously regulating the steady-state concentration of the formed О2−.

Comparison of 25-hydroxyvitamin D and bilirubin levels between patients with essential tremor and Parkinson’s disease

Introduction: Differential diagnoses between essential tremor and Parkinson’s disease is challenging in some individuals, with both disorders sharing similarities. Considering these links, we hypothesized that both conditions have a similar profile for some antioxidant molecules, including 25-hydroxyvitamin D and bilirubin. Methods: Weperformed a cross-sectional study comparing serum levels of 25-hydroxyvitamin D and bilirubin in 31 ET patients, 38 PD, and 65 controls matched for age. We used the Fahn-Tolosa-Marin scale for the severity of tremors in the ET group. We used Hohen-Yahr and MDS-UPDRS part III scales in the PD group. In addition, we evaluated sociodemographiccharacteristics, including age, sex, ethnicity, years of study, duration of disease, and use of primidone.Results: We found no differences in serum levels for 25-hydroxyvitamin D or bilirubin subtype levels between the ET and PD groups. We found low levels of indirect bilirubin in the PD group compared to the controls. We did not find differences between ET and controls in all biomarkers of the study. Conclusion: ET and PD patients have similar profiles for 25-hydroxyvitamin D and bilirubin serum levels. The discovery of differences in oxidative stressbiomarkers in both conditions, mainly low-cost substances available clinically, can assist in the differential diagnosis and, in the future, prognostication and better therapy management.

Multi-parametric radiomics of conventional T1 weighted and susceptibility-weighted imaging for differential diagnosis of idiopathic Parkinson’s disease and multiple system atrophy

ObjectivesThis study aims to investigate the potential of radiomics with multiple parameters from conventional T1 weighted imaging (T1WI) and susceptibility weighted imaging (SWI) in distinguishing between idiopathic Parkinson’s disease (PD) and multiple system atrophy (MSA).MethodsA total of 201 participants, including 57 patients with PD, 74 with MSA, and 70 healthy control (HCs) individuals, underwent T1WI and SWI scans. From the 12 subcortical nuclei (e.g. red nucleus, substantia nigra, subthalamic nucleus, putamen, globus pallidus, and caudate nucleus), 2640 radiomic features were extracted from both T1WI and SWI scans. Three classification models - logistic regression (LR), support vector machine (SVM), and light gradient boosting machine (LGBM) - were used to distinguish between MSA and PD, as well as among MSA, PD, and HC. These classifications were based on features extracted from T1WI, SWI, and a combination of T1WI and SWI. Five-fold cross-validation was used to evaluate the performance of the models with metrics such as sensitivity, specificity, accuracy, and area under the receiver operating curve (AUC). During each fold, the ANOVA and least absolute shrinkage and selection operator (LASSO) methods were used to identify the most relevant subset of features for the model training process.ResultsThe LGBM model trained by the features combination of T1WI and SWI exhibited the most outstanding differential performance in both the three-class classification task of MSA vs. PD vs. HC and the binary classification task of MSA vs. PD, with an accuracy of 0.814 and 0.854, and an AUC of 0.904 and 0.881, respectively. The texture-based differences (GLCM) of the SN and the shape-based differences of the GP were highly effective in discriminating between the three classes and two classes, respectively.ConclusionsRadiomic features combining T1WI and SWI can achieve a satisfactory differential diagnosis for PD, MSA, and HC groups, as well as for PD and MSA groups, thus providing a useful tool for clinical decision-making based on routine MRI sequences.

Rapid Metabolic Profiling of 1 μL Crude Cerebrospinal Fluid by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging Can Differentiate De Novo Parkinson's Disease.

Parkinson's disease (PD) is a highly prevalent neurodegenerative disorder affecting the motor system. However, the correct diagnosis of PD and atypical parkinsonism may be difficult with high clinical uncertainty. There is an urgent need to identify reliable biomarkers using high-throughput, molecular-specific methods to improve current diagnostics. Here, we present a matrix-assisted laser desorption/ionization mass spectrometry imaging method that requires minimal sample preparation and only 1 μL of crude cerebrospinal fluid (CSF). The method enables analysis of hundreds of samples in a single experiment while simultaneously detecting numerous metabolites with subppm mass accuracy. To test the method, we analyzed CSF samples from 12 de novo PD patients (that is, newly diagnosed and previously untreated) and 12 age-matched controls. Within the identified molecules, we found neurotransmitters and their metabolites such as γ-aminobutyric acid, 3-methoxytyramine, homovanillic acid, serotonin, histamine, amino acids, and metabolic intermediates. Limits of detection were estimated for multiple neurotransmitters with high linearity (R2 > 0.99) and sensitivity (as low as 16 pg/μL). Application of multivariate classification led to a highly significant (P < 0.001) model of PD prediction with a 100% classification rate, which was further thoroughly validated with a permutation test and univariate analysis. Molecules related to the neuromelanin pathway were found to be significantly increased in the PD group, indicated by their elevated relative intensities compared to the control group. Our method enables rapid detection of PD-related biomarkers in low sample volumes and could serve as a valuable tool in the development of robust PD diagnostics.

Development and internal validation of a prognostic model for loss of balance and falls in mid- to late-stage Parkinson's disease.

Mid- to late-stage Parkinson's disease (PD) is often linked with worsened and significant impairment of motor activities, but existing prognostic markers do not adequately capture the risk of loss of balance in PD patients. This study aims to develop a risk prognostic model for mid- to late-stage PD and identify prognostic factors that are indicative of impending loss of balance and falls. The study included 307 participants of which 75 were diagnosed with idiopathic PD and 232 were neurological or non-neurological controls. Among the PD group, 46 were early-stage (Hoehn and Yahr [H&Y] = 1,2) with no significant loss of balance while 29 were mid- to late-stage (H&Y = 3,4,5) which is characterized by loss of balance and falls. Multivariable logistic regression (MLR) was used to develop a prognostic model for mid- to late-stage PD. Model discrimination was assessed by ROC curves. The model was internally validated through bootstrapping and calibration plots. The relevant factors identified and included in the final MLR model were shortness of breath, age, swollen joints, heme oxygenase-1 (HO-1) protein, and total salivary protein. The model had an AUC of 0.82 (95% CI = 0.71-0.92) and was well calibrated (calibration slope = 0.77, intercept = 0.03). The likelihood of shortness of breath (OR = 7.91, 95% CI = 1.63-45.12) was significantly higher among mid- to late-stage PD than early-stage. Age and total salivary protein were also significantly higher among mid- to late-stage PD. The MLR prognostic model for mid- to late-stage PD may assist physicians in identifying patients at high risk for loss of balance and falls.

Investigation of non-invasive focused ultrasound efficacy on depressive-like behavior in hemiparkinsonian rats.

Depression is a common non-motor symptom in Parkinson's disease (PD) that includes anhedonia and impacts quality of life but is not effectively treated with conventional antidepressants clinically. Vagus nerve stimulation improves treatment-resistant depression in the general population, but research about its antidepressant efficacy in PD is limited. Here, we administered peripheral non-invasive focused ultrasound to hemiparkinsonian ('PD') and non-parkinsonian (sham) rats to mimic vagus nerve stimulation and assessed its antidepressant-like efficacy. Following 6-hydroxydopamine (6-OHDA) lesion, akinesia-like immobility was assessed in the limb-use asymmetry test, and despair- and anhedonic-like behaviors were evaluated in the forced swim test and sucrose preference test, respectively. After, tyrosine hydroxylase immuno-staining was employed to visualize and quantify dopaminergic degeneration in the substantia nigra pars compacta, ventral tegmental area, and striatum. We found that PD rats exhibited akinesia-like immobility and > 90% reduction in tyrosine hydroxylase immuno-staining ipsilateral to the lesioned side. PD rats also demonstrated anhedonic-like behavior in the sucrose preference test compared to sham rats. No 6-OHDA lesion effect on immobility in the forced swim test limited conclusions about the efficacy of ultrasound on despair-like behavior. However, ultrasound improved anhedonic-like behavior in PD rats and this efficacy was sustained through the end of the 1-week recovery period. The greatest number of animals demonstrating increased sucrose preference was in the PD group receiving ultrasound. Our findings here are the first to posit that peripheral non-invasive focused ultrasound to the celiac plexus may improve anhedonia in PD with further investigation needed to reveal its potential for clinical applicability.

Differential expression of PSMC4, SKP1, and HSPA8 in Parkinson's disease: insights from a Mexican mestizo population.

Parkinson's disease (PD) is a complex neurodegenerative condition characterized by alpha-synuclein aggregation and dysfunctional protein degradation pathways. This study investigates the differential gene expression of pivotal components (UBE2K, PSMC4, SKP1, and HSPA8) within these pathways in a Mexican-Mestizo PD population compared to healthy controls. We enrolled 87 PD patients and 87 controls, assessing their gene expression levels via RT-qPCR. Our results reveal a significant downregulation of PSMC4, SKP1, and HSPA8 in the PD group (p = 0.033, p = 0.003, and p = 0.002, respectively). Logistic regression analyses establish a strong association between PD and reduced expression of PSMC4, SKP1, and HSPA8 (OR = 0.640, 95% CI = 0.415-0.987; OR = 0.000, 95% CI = 0.000-0.075; OR = 0.550, 95% CI = 0.368-0.823, respectively). Conversely, UBE2K exhibited no significant association or expression difference between the groups. Furthermore, we develop a gene expression model based on HSPA8, PSMC4, and SKP1, demonstrating robust discrimination between healthy controls and PD patients. Notably, the model's diagnostic efficacy is particularly pronounced in early-stage PD. In conclusion, our study provides compelling evidence linking decreased gene expression of PSMC4, SKP1, and HSPA8 to PD in the Mexican-Mestizo population. Additionally, our gene expression model exhibits promise as a diagnostic tool, particularly for early-stage PD diagnosis.

Prognostic value of Hematoxylin and eosin staining tumor-infiltrating lymphocytes (H&E-TILs) in patients with esophageal squamous cell carcinoma treated with chemoradiotherapy

BackgroundTumor-infiltrating lymphocytes (TILs) by routine hematoxylin and eosin staining (H&E-TILs) are a robust prognostic biomarker in various cancers. However, the role of H&E-TILs in esophageal squamous cell carcinoma (ESCC) treated with concurrent chemoradiotherapy (CCRT) has not been reported. The purpose of this study was to assess the prognostic value of H&E-TILs in ESCC treated with CCRT.MethodsThe clinical data of 160 patients with ESCC treated with CCRT in our center between Jan. 2014 and Dec. 2021 were collected and retrospectively reviewed, and propensity score matching (PSM) analyses were performed. The H&E-TILs sections before CCRT were reassessed by two experienced pathologists independently. The H&E-TILs sections were classified into a positive group (+, > 10%) and a negative group (-, ≤ 10%) using 10% as the cutoff. The effects of H&E-TILs on overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) were explored using the Kaplan‒Meier method, and the log-rank test was used to test the differences. Multivariable analysis was performed using the Cox proportion hazards model.ResultsThe short-term response to CCRT and the OS (P < 0.001), DMFS (P = 0.001), and LRFS (P < 0.001) rates were significantly different between the H&E-TILs (+) and H&E-TILs (-) groups. Subgroup analysis showed that H&E-TILs(+) with CR + PR group had a longer survival than H&E-TILs(-) with CR + PR, H&E-TILs(+) with SD + PD and H&E-TILs(-) with SD + PD group, respectively(P < 0.001). Furthermore, based on TCGA data, patients in the high TILs group had a better prognosis than those in the low TILs group. Multivariate analyses indicated that H&E-TILs and the short-term response to CCRT were the only two independent factors affecting OS, PFS, DMFS, and LRFS simultaneously, and H&E-TILs expression was associated with an even better prognosis for those patients with CR + PR.ConclusionsH&E-TILs may be an effective and beneficial prognostic biomarker for ESCC patients treated with CCRT. Patients with H&E-TILs (+) with PR + CR would achieve excellent survival. Further prospective studies are required to validate the conclusions.

Multi‐task analysis of oculographic biomarkers to evaluate motoric and cognitive patterns in Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive loss or damage to the nervous system which can cause impairment in movement, coordination, and cognition. Due to the complexity of clinical features at different stages of the disease, it may require months for an accurate diagnosis. Oculomotor researchers have demonstrated the utility of examining eye movements for differentiating various neurodegenerative disorders including AD, Parkinson’s disease (PD), and other PD mimics (PDM). In this study, we propose an automatic pipeline to identify saccade, fixation, and blinks and extract response‐to‐stimuli‐derived interpretable biomarkers that could inform clinicians in making accurate assessment.MethodEye tracking data in smooth pursuit, pro‐saccade, and anti‐saccade tasks were recorded from 146 participants ‐ 14 with AD or Mild Cognitive Impairment (MCI), 46 with PD, 16 with PDM, and 70 age‐matched normal controls (CTL). Biomarkers based on the identified eye movement and interaction with the stimuli were extracted with our algorithms. Then, pairwise Kruskal‐Wallis H tests were conducted to determine if there were statistically significant differences between groups. The Benjamini‐Hochberg correction was performed to control the false discovery rate.ResultThe results show that, in the smooth pursuit task, the AD/MCI group had a significantly higher (p &lt; 0.05) saccade count than CTL and PD groups. The AD/MCI group also exhibited significantly longer (p &lt; 0.05) average saccade duration than CTL and PDM groups. The mean and standard deviation for the number of saccadic adjustments to reach and stay on the target significantly differed (p &lt; 0.05) between AD/MCI and CTL and between PD and CTL in trials of the pro‐saccade task. The magnitude of overshoot or undershoot was significantly greater (p &lt; 0.05) for AD/MCI, PD, and PDM compared to CTL. Moreover, the number of saccades in the wrong direction was significantly higher (p &lt; 0.05) for AD/MCI and PD compared to CTL in the anti‐saccade task.ConclusionOculographic biomarkers can be leveraged within a machine learning framework and may be useful in distinguishing different types of neurodegenerative diseases in their early stages yielding more objective and precise protocols to monitor disease progression than current methods.

Correlation of brain iron deposition and freezing of gait in Parkinson's disease: a cross-sectional study.

Quantitative susceptibility mapping (QSM) is a novel imaging method for detecting iron content in the brain. The study aimed determine whether the iron deposition in the brains of people with Parkinson's disease (PD) is correlated with freezing of gait (FOG). We retrospectively collected the data of 24 patients with PD from the Movement Disorders Program and 36 healthy controls (HCs) from January 2021 to December 2021. Clinical assessments included mental intelligence scales, Parkinson rating scales, motor-related scales, and clinical gait assessments. All exercise scales and gait assessments were performed in the "ON" and "OFF" states. Magnetic resonance imaging (MRI) data were collected using 3-dimensional fast low-angle shot sequences. We chose the bilateral red nucleus, substantia nigra, thalamus, putamen, caudate nucleus, and globus pallidus as regions of interest for QSM analysis. The iron deposition in the substantia nigra of the PD group was significantly higher than that of the HC group (P<0.01). In the PD group, the iron deposition in the substantia nigra of patients with FOG was significantly higher than that in patients without FOG (P=0.04). The iron deposition in the substantia nigra was positively correlated with the New Freezing of Gait Questionnaire (P=0.03). The scores for depression and anxiety of the PD group were significantly higher than those of the HC group, while the Berg balance scale score was significantly lower (P<0.01). The iron deposition in the substantia nigra of patients with PD is increased compared with that of controls and is associated with FOG. QSM can be used to detect brain iron deposition in patients with PD, which would help to explore the mechanism of abnormal neurobiological activity in FOG.

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.

T1w/T2w MRI ratio brain signature across degenerative syndromes and their cognitive impairment continuum and mixed presentations

AbstractBackgroundWe aimed to investigate the ratio’s signature in diverse clinically‐defined neurodegenerative syndromes and their cognitive impairment continuum. Our hypothesis was that higher cognitive impairment would be associated with lower cortical T1w/T2w ratio in all clinical subtypes.MethodWe used standardized MRI data obtained from participants in the COMPASS‐ND study of the Canadian Consortium on Neurodegeneration in Aging. T1w images were resampled down to T2w resolution; after co‐registration, intensities were standardized between 1‐100 and the ratio computed. Brain segmentation was then performed using FreeSurfer 6.0 on T1w images with the Desikan‐Killiany‐Tourville and default subcortical atlases. Participants included 109 cognitively intact elderly (CIE), 131 subjective cognitive decline (SCD), 252 mild cognitive impairment (MCI), 113 vascular‐MCI (V‐MCI), 55 mixed vascular‐Alzheimer’s dementia (V‐AD), 76 Alzheimer’s disease (AD), 21 Lewy‐body dementia (LBD), 33 fronto‐temporal‐dementia (FTD), 77 Parkinson’s disease (PD), 35 PD‐MCI and nine PD with dementia (PDD). Since the between‐vendor distributions differed (Fig1), Z scores were computed separately for each scanner vendor (GE, Philips, or Siemens) with CIE as a reference group. ANCOVA with age as covariate and FDR correction were conducted between each group and CIE.ResultNo significant effect of age was observed. Compared to CIE, significantly higher T1w/T2w ratios were observed in SCD for most of the brain (57/86 regions), in MCI for six frontal areas only, while decline was observed in AD throughout the brain (Fig1). V‐MCI showed lower ratios in subcortical areas only while V‐AD had pronounced lower ratios in subcortical areas as well as in 11 cortical areas. PD had marked lower ratios throughout the brain with the exception of an intact corpus callosum (Fig2). Contrariwise, FTD only displayed a lower ratio in the corpus callosum whereas PD‐MCI and LBD did not show any significant difference with CIE.ConclusionWe observed clear distinct patterns of T1w/T2w ratios for SCD, MCI, AD and PD groups. Since this ratio does not seem specific to a neural biological substrate, the meaning of these differences remains to be determined. Nevertheless, these results suggest that simple MRI measures such as the T1w/T2w ratio can highlight underlying mechanisms in various neurodegenerative processes.

Multi‐task analysis of oculographic biomarkers to evaluate motoric and cognitive patterns in Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive loss or damage to the nervous system which can cause impairment in movement, coordination, and cognition. Due to the complexity of clinical features at different stages of the disease, it may require months for an accurate diagnosis. Oculomotor researchers have demonstrated the utility of examining eye movements for differentiating various neurodegenerative disorders including AD, Parkinson’s disease (PD), and other PD mimics (PDM). In this study, we propose an automatic pipeline to identify saccade, fixation, and blinks and extract response‐to‐stimuli‐derived interpretable biomarkers that could inform clinicians in making accurate assessment.MethodEye tracking data in smooth pursuit, pro‐saccade, and anti‐saccade tasks were recorded from 146 participants ‐ 14 with AD or Mild Cognitive Impairment (MCI), 46 with PD, 16 with PDM, and 70 age‐matched normal controls (CTL). Biomarkers based on the identified eye movement and interaction with the stimuli were extracted with our algorithms. Then, pairwise Kruskal‐Wallis H tests were conducted to determine if there were statistically significant differences between groups. The Benjamini‐Hochberg correction was performed to control the false discovery rate.ResultThe results show that, in the smooth pursuit task, the AD/MCI group had a significantly higher (p &lt; 0.05) saccade count than CTL and PD groups. The AD/MCI group also exhibited significantly longer (p &lt; 0.05) average saccade duration than CTL and PDM groups. The mean and standard deviation for the number of saccadic adjustments to reach and stay on the target significantly differed (p &lt; 0.05) between AD/MCI and CTL and between PD and CTL in trials of the pro‐saccade task. The magnitude of overshoot or undershoot was significantly greater (p &lt; 0.05) for AD/MCI, PD, and PDM compared to CTL. Moreover, the number of saccades in the wrong direction was significantly higher (p &lt; 0.05) for AD/MCI and PD compared to CTL in the anti‐saccade task.ConclusionOculographic biomarkers can be leveraged within a machine learning framework and may be useful in distinguishing different types of neurodegenerative diseases in their early stages yielding more objective and precise protocols to monitor disease progression than current methods.

Cortical and substantia nigra 18F‐PI‐2620 tau PET signal in Lewy body disease

AbstractBackgroundTau PET imaging is a potential tool for measuring comorbid tau pathology in patients with Lewy body disease. Furthermore, tau PET ligands are known to bind to neuromelanin within substantia nigra (SN), with reduced binding in Parkinson’s disease relative to healthy individuals. We sought to characterize 18F‐PI‐2620, a next generation PET tracer, in patients from across the Lewy body disease spectrum.MethodA total of 126 participants from the Stanford Alzheimer’s Disease Center (ADRC) and the Stanford Aging and Memory Study (SAMS) were recruited for PET scanning with 18F‐PI‐2620. We compared 18F‐PI‐2620 uptake within medial temporal (entorhinal cortex, amygdala) and occipital (precuneus, lingual gyrus) regions as well as SN across patients with Parkinson’s disease (PD, n = 26), dementia with Lewy bodies (DLB, n = 6), and Alzheimer’s disease spectrum (AD, n = 21), in addition to cognitively normal older adults (healthy controls, HC, n = 73). Mean bilateral signal was extracted from cortical regions of interest in native space 18F‐PI‐2620 SUVRs (inferior cerebellar gray reference). Amyloid status was determined either by 18F‐florbetaben PET or CSF. To quantify SN, SUVRs were normalized to template space and an anatomical mask was used to extract mean signal. MDS‐UPDRS‐III motor exam scores, collected in an off‐medication state for all patients, were used as a measure of motor impairment.ResultEntorhinal and amygdala SUVR were significantly elevated in the AD group relative to all other groups, and in amyloid‐positive relative to amyloid‐negative HC (Fig 1). Tau burden in all regions was low across PD and DLB groups and did not differ based on amyloid status. SN SUVR was significantly lower in the PD group compared to the HC and AD group (Fig 2A). In patients with Lewy body disease (PD &amp; DLB), MDS‐UPDRS‐III scores were negatively associated with SN SUVR (Fig 2B).ConclusionThese findings suggest that cortical tau is low in Lewy body disease. Neuromelanin‐related 18F‐PI‐2620 signal within SN carries information about disease severity. Cortical tau and SN binding represent two unique signals in the same tau PET image that may be informative in the context of Lewy body disease.

Cortical and substantia nigra 18F‐PI‐2620 tau PET signal in Lewy body disease

AbstractBackgroundTau PET imaging is a potential tool for measuring comorbid tau pathology in patients with Lewy body disease. Furthermore, tau PET ligands are known to bind to neuromelanin within substantia nigra (SN), with reduced binding in Parkinson’s disease relative to healthy individuals. We sought to characterize 18F‐PI‐2620, a next generation PET tracer, in patients from across the Lewy body disease spectrum.MethodA total of 126 participants from the Stanford Alzheimer’s Disease Center (ADRC) and the Stanford Aging and Memory Study (SAMS) were recruited for PET scanning with 18F‐PI‐2620. We compared 18F‐PI‐2620 uptake within medial temporal (entorhinal cortex, amygdala) and occipital (precuneus, lingual gyrus) regions as well as SN across patients with Parkinson’s disease (PD, n = 26), dementia with Lewy bodies (DLB, n = 6), and Alzheimer’s disease spectrum (AD, n = 21), in addition to cognitively normal older adults (healthy controls, HC, n = 73). Mean bilateral signal was extracted from cortical regions of interest in native space 18F‐PI‐2620 SUVRs (inferior cerebellar gray reference). Amyloid status was determined either by 18F‐florbetaben PET or CSF. To quantify SN, SUVRs were normalized to template space and an anatomical mask was used to extract mean signal. MDS‐UPDRS‐III motor exam scores, collected in an off‐medication state for all patients, were used as a measure of motor impairment.ResultEntorhinal and amygdala SUVR were significantly elevated in the AD group relative to all other groups, and in amyloid‐positive relative to amyloid‐negative HC (Fig 1). Tau burden in all regions was low across PD and DLB groups and did not differ based on amyloid status. SN SUVR was significantly lower in the PD group compared to the HC and AD group (Fig 2A). In patients with Lewy body disease (PD &amp; DLB), MDS‐UPDRS‐III scores were negatively associated with SN SUVR (Fig 2B).ConclusionsThese findings suggest that cortical tau is low in Lewy body disease. Neuromelanin‐related 18F‐PI‐2620 signal within SN carries information about disease severity. Cortical tau and SN binding represent two unique signals in the same tau PET image that may be informative in the context of Lewy body disease.

ITRAQ‐based proteomic analysis reveals myeloperoxidase (MPO) as a diagnostic and prognostic biomarker of cognitive decline in Parkinson’s disease

AbstractBackgroundParkinson’s disease (PD) is the second most common progressive neurodegenerative disorder and is characterized by loss of dopaminergic neurons, leading to debilitating motor, cognitive, and behavioral symptoms. At present, there are no biological markers for antemortem PD diagnosis.MethodsTo identify potential blood biomarkers of PD, Isobaric Tags for Relative and Absolute Quantitation (iTRAQ)‐based mass spectrometry (MS) was performed to characterize alterations of serum proteins amongst PD patients of varying disease severity according to their Hoehn and Yahr (HY) stages. Sera of mild PD (HY 1.5‐2.0, n = 10), severe PD (HY 3.0‐4.0, n = 10) patients and healthy controls (n = 10) were enriched and subjected to 2D LC‐MS/MS for proteomic analysis. Candidate protein biomarkers were identified based on the relative abundance of the identified tryptic peptides, and were validated using ELISA in a validation set consisting of 103 early PD and 48 healthy controls (HC). Association with clinical outcomes were analyzed at cross‐sectional and longitudinal timepoints.ResultsA total of 96 proteins in the mild PD group and 78 proteins in the severe PD group were found to differ significantly between PD patients and healthy controls. Thirteen proteins were common between the mild PD and severe PD groups and were chosen for further analysis. These dysregulated proteins represent a diversity of biological processes, including innate immune response, complement activation, cytoskeleton reorganization and response to oxidative stress. Of which, myeloperoxidase showed higher serum levels in mild and severe PD. In the validation PD cohort, higher MPO was significantly associated with worse executive function over 4 years.ConclusionUsing an unbiased proteomic approach, we identified serum MPO (a marker of oxidative stress) as a promising biomarker for PD. Our results suggest that MPO could also potentially be an early marker for cognitive decline in PD. Further studies with larger cohorts are needed to validate these findings.

Systemic Inflammation Score Using Pretherapeutic Inflammatory Markers to Predict Prognosis for Hepatocellular Carcinoma Patients After Hepatic Arterial Infusion Chemotherapy.

To assess the clinical value of the pretherapeutic systemic inflammation score (SIS) in predicting the prognosis of hepatocellular carcinoma (HCC) after hepatic arterial infusion chemotherapy (HAIC). From February 2016 to April 2021, 415 advanced HCC patients who underwent HAIC at Sun Yat-sen University Cancer Center were randomly divided into training (n = 277) and validation cohorts (n = 138) and analyzed. The aspartate aminotransferase-alanine aminotransferase ratio (AAR), lymphocyte × albumin (L × A), and neutrophil × monocyte (N × M) were used to construct the SIS score based on a multivariate Cox analysis in the training cohort. A nomogram consisting of the SIS score was created and evaluated by calibration plot, areas under the receiver operating characteristic (AUC) curve, and decision curve analysis (DCA). Univariate and multivariate Cox analyses revealed that the SIS score was an independent predictor of OS. A high SIS score was associated with large tumor size (P < 0.05), multiple lesions (P < 0.01), high AFP level (P < 0.01), extrahepatic metastasis (P < 0.05), and advanced BCLC stage (P < 0.01). Kaplan-Meier analysis showed that the patients with a high SIS had shorter OS than those with a low SIS in both the non-PD (p = 0.015) and PD group (p = 0.023). The calibration plots showed good concordance between the nomogram's prediction and the actual observations in both the training and validation cohorts. In the training cohort, the AUCs of the nomogram predicting the 2-year and 3-year survival rates were 0.749 and 0.739, respectively; in the validation cohort, they were 0.760 and 0.681, respectively. Based on the AUC and DCA, the nomogram showed better predictive ability than other predictors. The pretherapeutic SIS score is a potential prognostic predictor for HCC patients undergoing HAIC.

Neural Correlates of Mild Behavioral Impairment in older adults across the neurodegenerative spectrum

AbstractBackgroundMild behavioral impairment (MBI) is a syndrome characterized by later life onset, persistent neuropsychiatric symptoms (NPS) in non‐demented older adults. MBI can co‐occur with Mild Cognitive Impairment (MCI) and has a range of neurodegenerative etiologies including Alzheimer’s disease (AD), Cerebrovascular Disease (CVD), and Parkinson’s disease (PD). MBI is associated with poorer cognitive and psychosocial function and an increased risk of developing dementia. Thus, we aimed to explore the structural neural correlates of MBI, specifically in the regions known to be associated with cognitive impairment (i.e., corticolimbic and frontal‐executive circuits), across multiple neurodegenerative diagnoses from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).MethodWe assessed the association between MBI and brain structural alterations via T1‐weighted imaging in three groups with Montreal Cognitive Assessment scores ³19: individuals with MCI (due to AD; n = 37), CVD (n = 129), and PD (n = 127). NPS scores were derived from the Neuropsychiatric Inventory (NPI‐Q) domains, and categorized as NPS+ (i.e., NPI score&gt;0); and NPS‐ (NPI score = 0). We selected regions of interest from the corticolimbic and frontal‐executive circuits to measure brain structure using cortical thickness and subcortical volume. Partial correlation, corrected for age, sex, and education was used to assess the association between MBI and brain structural alterations.ResultOverall, apathy, depression, and anxiety, which map to the decreased motivation and emotional dysregulation MBI domains, had a high prevalence across all the groups. In the brain‐MBI association analysis, apathy was associated with decreased thickness of the l‐rostral middle frontal, r‐superior temporal, and frontal pole in the PD and CVD (but not MCI) groups. Anxiety was associated with decreased volume of the right hippocampus and amygdala in the MCI group, but not CVD or PD (FDR p&lt; 0.05). No structural correlates were found for depression.ConclusionOur findings provide evidence of a specific association between apathy and reduced efficiency of the frontal‐executive system in individuals with PD and CVD. In addition, the well‐established AD corticolimbic atrophy patterns (e.g., hippocampus and amygdala) seen in MCI are prominent in the presence of anxiety. Overall, the relatively distinct brain‐MBI associations across neurodegenerative disorders suggest that pathological substrates may alter MBI neural correlates.

Association Study Between Kynurenine 3-Monooxygenase (KMO) Gene and Parkinson's Disease Patients.

The influence of various risk factors such as aging, intricate cellular molecular processes, and lifestyle factors like smoking, alcohol consumption, caffeine intake, and occupational factors has received increased focus in relation to the risk and development of Parkinson's disease (PD). Limited research has been conducted on the assessment of lifestyle impact on kynurenine 3-monooxygenase (KMO) gene in PD. A total of 164 subjects, including 82 PD cases and 82 healthy individuals, were recruited based on specific inclusion and exclusion criteria. The severity of PD and clinical assessment were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling. Sanger sequencing was performed to analyse the KMO gene in the recruited subjects, and case-control studies were conducted. The UPDRS assessment revealed significant impairments in smell, tremors, walking, and posture instability in the late-onset PD cohorts. The HY scaling indicated a higher proportion of late-onset cohorts in stage 2. Moreover, both alcoholic and non-alcoholic groups showed significantly increased levels of 3-HK in late-onset PD. Gene analysis identified missense variants at position g.241593373T > A (rs752312199) and intronic variants at positions g.241592623A > G (rs640718), g.241592800C > A (rs990388262), g.241592802A > C (rs1350160268), g.241592808T > C (rs1478255936), and g.241592812G > T (rs948928931). The alterations in the KMO gene were found to influence the levels of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). Genomic analysis revealed a high prevalence of missense mutations in the late-onset PD groups, leading to a decline in 3-HK levels in patients. This leads to the reduction of the progression of disease in late-onset groups which shows that this mutation may lead to the protective effect on the PD subjects. This study suggests the use of KYNA and 3-HK as potential biomarkers in analysing the progression of disease. This study is limited by its small sample size. To overcome this limitation, a larger study involving in greater number of participants is needed to thoroughly investigate the KMO gene and KP metabolites, to enhance our understanding of Parkinson's disease progression, and to enhance diagnostic capabilities.

Application of diffusional kurtosis imaging for insights into structurally aberrant topology in Parkinson's disease.

Parkinson's disease (PD) has been regarded as a disconnection syndrome with functional and structural disturbances. However, as the anatomic determinants, the structural disconnections in PD have yet to be fully elucidated. To non-invasively construct structural networks based on microstructural complexity and to further investigate their potential topological abnormalities in PD given the technical superiority of diffusion kurtosis imaging (DKI) to the quantification of microstructure. The microstructural data of gray matter in both the PD group and the healthy control (HC) group were acquired using DKI. The structural networks were constructed at the group level by a covariation approach, followed by the calculation of topological properties based on graph theory and statistical comparisons between groups. A total of 51 patients with PD and 50 HCs were enrolled. Individuals were matched between groups with respect to demographic characteristics (P >0.05). The constructed structural networks in both the PD and HC groups featured small-world properties. In comparison with the HC group, the PD group exhibited significantly altered global properties, with higher normalized characteristic path lengths, clustering coefficients, local efficiency values, and characteristic path lengths and lower global efficiency values (P <0.05). In terms of nodal centralities, extensive nodal disruptions were observed in patients with PD (P <0.05); these disruptions were mainly distributed in the sensorimotor network, default mode network, frontal-parietal network, visual network, and subcortical network. These findings contribute to the technical application of DKI and the elucidation of disconnection syndrome in PD.