Early Parkinson's Disease Patients Research Articles

0894 Impulsivity across early stages of synucleinopathy: from high-risk relatives, REM sleep behavior disorder to Parkinson’s disease

Abstract Introduction Increased impulsivity is a common neuropsychiatric feature in patients with Parkinson’s disease (PD), especially attributed to the use of dopaminergic medications. Interestingly, emerging evidence suggested that impulsivity had changed in drug-naïve PD patients. However, it remains unclear whether impulsivity has been altered in prodromal stage of PD, namely isolated rapid eye movement sleep behavior disorder (iRBD) and their high-risk relatives. Methods This was a cross-sectional study with four groups of subjects, including early drug-naive PD patients, patients with iRBD and their first-degree relatives (iRBD-FDRs, a high-risk group with potential prodromal RBD features), and controls. A panel of neuropsychological computerized tasks, including go/no-go task, four-choice serial reaction time task (4CSRTT), beads task, balloon analogue risk task (BART) and delay/effort discounting task, would measure various dimensions of motor and decisional impulsivity. Results A total of 331 subjects were recruited, including 27 early drug-naïve PD patients (mean age ± SD: 70.1 ± 5.8 years, 77.8% man), 152 iRBD patients (67.2 ± 6.6 years, 77.6% man), 68 iRBD-FDRs (63.2 ± 6.4 years, 51.5% man), and 84 controls (67.4 ± 8.1years, 61.9% man). Early drug-naïve PD and iRBD patients had fewer numbers of extracted beads in beads task 1 (P< 0.001) and task 2 (P< 0.001) in making decisions and fewer numbers of pumps of unexploded blue balloons in BART (P< 0.001) than controls and iRBD-FDRs, suggesting a higher level of reflection impulsivity and a lower level of risk taking, respectively. In addition, early drug-naïve PD and iRBD patients had more no-go errors in go/no-go task (P=0.023), suggesting a marginally lower level of response inhibition in PD and iRBD groups. Early drug-naïve PD and iRBD patients had more premature responses in 4CSRTT than iRBD-FDRs (P=0.008). The delay and effort discounting indexes were comparable among four groups. Conclusion While risk taking and response inhibition decreased, reflection impulsivity actually increased in iRBD and drug-naïve PD patients. These novel findings indicated that a complex construct of altered impulsivity has already occurred at the earlier stage (at iRBD) of α-synucleinopathy, which will have implications for pathophysiology and clinical management. Support (if any) This study has been supported by the General Research Fund (14116119).

Association of Dizziness-Related Handicap or Disability with Clinical Features in Patients with Early Parkinson's Disease.

Complaining of dizziness is common in patients with Parkinson's disease (PD) even at the early phase of the disease. Therefore, regarding motor or non-motor symptoms, clinical implication of subjective dizziness in early Parkinsonian patients is needed to be explored. Eighty patients diagnosed with early PD (defined by disease duration of five years or less) were retrospectively enrolled for the study. Dizziness handicap inventory (DHI), the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Functional Level Scale (FLS), and clinical features of parkinsonian motor and non-motor symptoms using representative measurements. Through simple and multiple linear regression analyses, we found that both DHI and FLS were significantly and positively correlated with postural instability/gait disorder (PIGD) score but negatively with the Montreal cognitive assessment (MoCA) score. We found that subjective dizziness in patients with early PD was related to not only axial symptoms of PIGD, but also global cognitive function of MoCA. Further research is required to confirm our results.

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).

Prevalence and Factors Associated with Drooling in Parkinson's Disease: Results from a Longitudinal Prospective Cohort and Comparison with a Control Group.

Drooling in Parkinson's disease (PD) is frequent but often goes underrecognized. Our aim was to examine the prevalence of drooling in a PD cohort and compare it with a control group. Specifically, we identified factors associated with drooling and conducted subanalyses in a subgroup of very early PD patients. Patients and Methods. PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30-day follow-up (V2) from 35 centers in Spain from the COPPADIS cohort were included in this longitudinal prospective study. Subjects were classified as with or without drooling according to item 19 of the NMSS (Nonmotor Symptoms Scale) at V0, V1 (1-year ± 15 days), and V2 for patients and at V0 and V2 for controls. The frequency of drooling in PD patients was 40.1% (277/691) at V0 (2.4% (5/201) in controls; p < 0.0001), 43.7% (264/604) at V1, and 48.2% (242/502) at V2 (3.2% (4/124) in controls; p < 0.0001), with a period prevalence of 63.6% (306/481). Being older (OR = 1.032; p = 0.012), being male (OR = 2.333; p < 0.0001), having greater nonmotor symptom (NMS) burden at the baseline (NMSS total score at V0; OR = 1.020; p < 0.0001), and having a greater increase in the NMS burden from V0 to V2 (change in the NMSS total score from V0 to V2; OR = 1.012; p < 0.0001) were identified as independent predictors of drooling after the 2-year follow-up. Similar results were observed in the group of patients with ≤2 years since symptom onset, with a cumulative prevalence of 64.6% and a higher score on the UPDRS-III at V0 (OR = 1.121; p = 0.007) as a predictor of drooling at V2. Drooling is frequent in PD patients even at the initial onset of the disease and is associated with a greater motor severity and NMS burden.

Serum levels of p-tau181 in patients with Parkinson’s disease

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease. Evidence has shown that phosphorylated tau-181 (p-tau181) is involved in the pathological process of PD. The goal of this study was to investigate the changes of serum phosphorylated Microtubule-associated protein tau at threonine-181 in patients with Parkinson's disease and it's correlation with disease severity, cognitive impairment and prognosis. Methods: A total of 40 patients with primary Parkinson's disease who were hospitalized or outpatient in the First Affiliated Hospital of Chongqing Medical University from July 2021 to February 2022 were selected as the study subjects. Patients with secondary Parkinson's disease, Parkinson's syndrome, stroke, Alzheimer's disease, craniocerebral surgery or trauma, severe systemic or infectious diseases, local or systemic infectious diseases, motor neurone disease or other central nervous system diseases were excluded. In addition, 35 healthy subjects with similar age and gender matching were selected as the healthy control group. Age, gender, course of disease, Hoehn-Yahr (H-Y) scale, Unified Parkinson's Disease Scale (UPDRS), and MoCA score were recorded in the Parkinson's disease group. According to the H-Y scale, PD group was divided into PD patients in the advanced stage (H-Y≤2.5, n=16) and PD patients in the advanced stage (H-Y&gt;2.5, n=24). Six months after blood sample collection, we assessed the H-Y rating and UPDRS score in the Parkinson's group again by telephone follow-up. Those with decreased or unchanged H-Y rating or total UPDRS score were divided into good prognosis group (n=25), and those with increased H-Y rating or total UPDRS score were divided into poor prognosis group (n=14). The serum p-tau181 concentration of all subjects was detected and compared by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA), and the correlation between serum p-tau181 level and UPDRS score, MoCA score and prognosis of Parkinson's disease patients was analyzed. Results: Compared with HC, serum p-tau181 concentration in PD patients were higher, but not statistically significant (1.01[0.28-2.63]vs 0.53[0.04-3.72]ug/mL, P=0.55, P&gt;0.05). There was no significant difference in p-tau181 concentration between PD patients in early stage and PD patients in advanced stage (P=0.80 P&gt;0.05), and no significant difference in p-tau181 level between PD patients with cognitive impairment, PD patients with normal cognition and HC patients (P=0.63, p&gt;0.05). P-tau181 was not significantly correlated with disease duration (r=-0.14, P=0.37, P&gt;0.05), UPDRS score (r=0.02, P=0.89, P&gt;0.05), and MoCA score (r= 0.16, P=0.32, P &gt; 0.05). There was no significant difference in serum P-tau181 expression between good prognosis group and poor prognosis group (P=0.74, P &gt; 0.05). Conclusions: Serum expression of p-tau181 increased in PD patients, but no statistical difference was observed, and no clear correlation was found between p-tau181 and disease severity and cognitive impairment. Serum p-tau181 level in PD patients has no significant prognostic significance.

Identifying clinical features and blood biomarkers associated with mild cognitive impairment in Parkinson's Disease using machine learning.

A broad list of variables associated with mild cognitive impairment (MCI) in Parkinson's Disease (PD) has been investigated separately. However, there is no study including all of them to assess variable importance yet. Shapley variable importance cloud (ShapleyVIC) can robustly assesses variable importance while accounting for correlation between variables. 1) To prioritise the important variables associated with PD-MCI; 2) To explore new blood biomarkers related to PD-MCI. ShapleyVIC-assisted variable selection was used to identify a subset of variables from 41 variables potentially associated with PD-MCI in a cross-sectional study. Backward selection was used to further identify the variables that associated with PD-MCI. Relative risk was used to quantify the association of final predictors and PD-MCI in the final multivariable log-binomial regression model. Among 41 variables analysed, 22 variables were identified as significantly important variables associated with PD-MCI and 8 variables were subsequently selected in the final model, indicating shorter education year, history of hypertension, higher MDS-UPDRS motor score, higher levels of TG, APOA1, and SNCA rs6826785 non-carrier were associated with increased risk of PD-MCI (p<0.05). Our study highlighted the strong association between TG, APOA1, SNCA rs6826785 and PD-MCI by machine learning approach. Screening and management of high TG and ApoA1 levels might help prevent the cognitive impairment in early PD patients. SNCA rs6826785 could be a novel therapeutic target for PD-MCI. ShapleyVIC-assisted variable selection is a novel and robust alternative to traditional approaches for future clinical study to prioritize the variables of interests.

B lymphocyte responses in Parkinson's disease and their possible significance in disease progression.

Inflammation contributes to Parkinson's disease pathogenesis. We hypothesized that B lymphocytes are involved in Parkinson's disease progression. We measured antibodies to alpha-synuclein and tau in serum from patients with rapid eye movement sleep behaviour disorder (n = 79), early Parkinson's disease (n = 50) and matched controls (n = 50). Rapid eye movement sleep behaviour disorder cases were stratified by risk of progression to Parkinson's disease (low risk = 30, high risk = 49). We also measured B-cell activating factor of the tumour necrosis factor receptor family, C-reactive protein and total immunoglobulin G. We found elevated levels of antibodies to alpha-synuclein fibrils in rapid eye movement sleep behaviour disorder patients at high risk of Parkinson's disease conversion (ANOVA, P < 0.001) and lower S129D peptide-specific antibodies in those at low risk (ANOVA, P < 0.001). An early humoral response to alpha-synuclein is therefore detectable prior to the development of Parkinson's disease. Peripheral B lymphocyte phenotyping using flow cytometry in early Parkinson's disease patients and matched controls (n = 41 per group) revealed reduced B cells in Parkinson's disease, particularly in those at higher risk of developing an early dementia [t(3) = 2.87, P = 0.01]. Patients with a greater proportion of regulatory B cells had better motor scores [F(4,24) = 3.612, P = 0.019], suggesting they have a protective role in Parkinson's disease. In contrast, B cells isolated from Parkinson's disease patients at higher risk of dementia had greater cytokine (interleukin 6 and interleukin 10) responses following in vitro stimulation. We assessed peripheral blood lymphocytes in alpha-synuclein transgenic mouse models of Parkinson's disease: they also had reduced B cells, suggesting this is related to alpha-synuclein pathology. In a toxin-based mouse model of Parkinson's disease, B-cell deficiency or depletion resulted in worse pathological and behavioural outcomes, supporting the conclusion that B cells play an early protective role in dopaminergic cell loss. In conclusion, we found changes in the B-cell compartment associated with risk of disease progression in rapid eye movement sleep behaviour disorder (higher alpha-synuclein antibodies) and early Parkinson's disease (lower levels of B lymphocytes that were more reactive to stimulation). Regulatory B cells play a protective role in a mouse model, potentially by attenuating inflammation and dopaminergic cell loss. B cells are therefore likely to be involved in the pathogenesis of Parkinson's disease, albeit in a complex way, and thus warrant consideration as a therapeutic target.

Artificial Intelligence-Based Voice Assessment of Patients with Parkinson's Disease Off and On Treatment: Machine vs. Deep-Learning Comparison.

Parkinson's Disease (PD) is one of the most common non-curable neurodegenerative diseases. Diagnosis is achieved clinically on the basis of different symptoms with considerable delays from the onset of neurodegenerative processes in the central nervous system. In this study, we investigated early and full-blown PD patients based on the analysis of their voice characteristics with the aid of the most commonly employed machine learning (ML) techniques. A custom dataset was made with hi-fi quality recordings of vocal tasks gathered from Italian healthy control subjects and PD patients, divided into early diagnosed, off-medication patients on the one hand, and mid-advanced patients treated with L-Dopa on the other. Following the current state-of-the-art, several ML pipelines were compared usingdifferent feature selection and classification algorithms, and deep learning was also explored with a custom CNN architecture. Results show how feature-based ML and deep learning achieve comparable results in terms of classification, with KNN, SVM and naïve Bayes classifiers performing similarly, with a slight edge for KNN. Much more evident is the predominance of CFS as the best feature selector. The selected features act as relevant vocal biomarkers capable of differentiating healthy subjects, early untreated PD patients and mid-advanced L-Dopa treated patients.

Impact of GBA variants on longitudinal freezing of gait progression in early Parkinson's disease.

Freezing of gait (FOG) is a common disabling gait disturbance among patients with Parkinson's disease (PD), but the influence of genetic variants on the incidence of FOG has been poorly studied to date. We aimed to evaluate the association of GBA variants with the risk of FOG development in a large early PD cohort. This study included 371 early PD patients from the Parkinson's Progression Markers Initiative (PPMI) who were divided into a GBA variant carrier group (GBA-PD group, n = 44) and an idiopathic PD group without GBA variants (iPD group, n = 327). They were followed up for up to 5years to examine the progression of FOG. The cumulative incidence of FOG and risk factors for FOG were assessed using Kaplan‒Meier and Cox regression analyses. At baseline, the GBA-PD group had lower CSF β-amyloid 1-42 (Aβ42) levels and more severe motor and nonmotor symptoms than the iPD group. During the 5-year follow-up, the GBA-PD group had a higher incidence of FOG than the iPD group, and the FOG progression rate was related to GBA variant severity. In the multivariable Cox model without CSF Aβ42, GBA variants were significant predictors of future FOG, and the association remained significant after adding CSF Aβ42 to the model. In the subgroup analyses, the effect of GBA variants was not observed in the "low-level" group. However, in the "high-level" group, GBA variants independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ42. GBA variants are novel genetic risk factors for future FOG development in early PD patients. This association seemed to be mediated by both Aβ-dependent pathways and Aβ-independent pathways.

Long-term levodopa ameliorates sequence effect in simple, but not complex walking in early Parkinson's disease patients

BackgroundThe sequence effect (SE) is characterized by the progressive decrement of movements and is often observed in Parkinson's disease (PD) patients. While acute effect of levodopa does not ameliorate the SE, the effect of long-term levodopa treatment for the SE remains unknown. ObjectiveWe aimed to elucidate the SEs during various gait conditions and their response to long-term levodopa treatment in drug-naïve PD patients. MethodsNineteen drug-naïve PD patients and 21 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors in the following conditions:1) straight walking, 2) circular walking: walking a circle of 1 m diameter in a clock-wise direction for 3 laps, 3) straight or circular walking under cognitive-motor dual-task (serial 7s subtractions). PD patients were evaluated at baseline, within 1 h after intravenous administration of levodopa, and after one, three, and six months treatment with levodopa. The SE was measured by a linear regression slope by plotting consecutive stride lengths over steps. Patients were also separately analyzed depending on laterality of symptoms. ResultsLong-term levodopa treatment ameliorated the SE only during single-task straight walking. The SE during circular walking was exacerbated after long-term levodopa treatment for right-side dominant patients. During dual-task straight walking, the SE at baseline was greater in right-side dominant PD patients. ConclusionsThe SE only during single-task straight walking can be ameliorated by long-term levodopa treatment. However, the SE may be exaggerated by cognitive motor interference or by asymmetrical stride length with/without long-term levodopa treatment, depending on the laterality of symptoms.

Capturing the Abnormal Brain Network Activity in Early Parkinsons Disease with Mild Cognitive Impairment based on Dynamic Functional Connectivity.

The early Parkinson's disease (PD) with mild cognitive impairment (ePD-MCI) is a typical non-motor symptom reflected by the brain dysfunction of PD, which can be well depicted by the dynamic characteristics of brain functional connectivity networks. The aim of this study is to determine the unclear dynamic changes in functional connectivity networks induced by MCI in early PD patients. In this paper, the electroencephalogram (EEG) of each subject was reconstructed into the dynamic functional connectivity networks with five frequency bands based on adaptive sliding window method. By evaluating the fluctuations of dynamic functional connectivity and the transition stability of functional network state in ePD-MCI patients compared with early PD without mild cognitive impairment patients, it was found that in the alpha band, the functional network stability of central region, right frontal, parietal, occipital, and left temporal lobes was abnormally increased, and the dynamic connectivity fluctuations in these regions were significantly decreased in ePD-MCI group. In the gamma band, ePD-MCI patients showed decreased functional network stability in the central, left frontal, and right temporal lobes, and active dynamic connectivity fluctuations in the left frontal, temporal, and parietal lobes. The aberrant duration of network state in ePD-MCI patients was significantly negatively correlated with cognitive function in the alpha band, which might pave the way to identify and predict cognitive impairment in early PD patients.

Frequency-dependent Microstate Characteristics for Mild Cognitive Impairment in Parkinson's Disease.

Cognitive impairment is typically reflected in the time and frequency variations of electroencephalography (EeG). Integrating time-domain and frequency-domain analysis methods is essential to better understand and assess cognitive ability. Timely identification of cognitive levels in early Parkinson's disease (ePD) patients can help mitigate the risk of future dementia. For the investigation of the brain activity and states related to cognitive levels, this study recruited forty ePD patients for EEG microstate analysis, including 13 with mild cognitive impairment (MCI) and 27 without MCI (control group). To determine the specific frequency band on which the microstate analysis relies, a deep learning framework was employed to discern the frequency dependence of the cognitive level in ePD patients. The input to the convolutional neural network consisted of the power spectral density of multi-channel multi-point EEG signals. The visualization technique of gradient-weighted class activation mapping was utilized to extract the optimal frequency band for identifying MCI samples. Within this frequency band, microstate analysis was conducted and correlated with the Montreal Cognitive Assessment (MoCA) Scale. The deep neural network revealed significant differences in the 1-11.5Hz spectrum of the ePD-MCI group compared to the control group. In this characteristic frequency band, ePD-MCI patients exhibited a pattern of global microstate disorder. The coverage rate and occurrence frequency of microstate A and D increased significantly and were both negatively correlated with the MoCA scale. Meanwhile, the coverage, frequency and duration of microstate C decreased significantly and were positively correlated with the MoCA scale. Our work unveils abnormal microstate characteristics in ePD-MCI based on time-frequency fusion, enhancing our understanding of cognitively related brain dynamics and providing electrophysiological markers for ePD-MCI recognition.

Postural stability in early Parkinson’s disease: effect of cognitive dual-tasking

Purpose: The primary aim of this study is to evaluate postural stability by using a static posturography in patients with early Parkinson’s disease (PD). Secondly, this paper addresses the need for illustrating the effect of dual-tasking on postural stability in early PD patients. &#x0D; Materials and Methods: Twenty-nine early PD patients with maximum 5 years of disease duration were included in this study. The selected group had no clinical PI while their age- and sex-matched healthy controls were carried out. Neurological examination and mini-mental state examination (MMSE) were performed in all subjects. Unified Parkinson Disease Rating Scale (UPDRS) and modified Hoehn and Yahr (H&amp;Y) scores were recorded in PD patients. Postural stability was assessed in all subjects on a static posturography platform under three different conditions: eyes open, eyes closed and a cognitive task of producing words with given letters. &#x0D; Results: The mean age of the PD was 59.2±10.5 whereas the control groups mean age was 56.3±7.6 (p&gt;0.05). The female-male ratio was 9/20 in the PD and 12/17 in the control group. There was no important difference between the two groups in terms of demographic characteristics. In the PD group, the mean UPDRS was 12.8±4.9. The patients were mostly receiving polytherapy. &#x0D; Eye closure and cognitive task caused an increase in most sway parameters in both groups. &#x0D; Conclusion: Early PD patients on medication, postural stability is preserved and cognitive dual-tasking does not affect postural stability in these patients in the early stage.

Caudate-anchored cognitive connectivity pursuant to orthostatic hypotension in early Parkinson's disease

18F-Florbetaben is a tracer used to evaluate the metabolic activity of and amyloid accumulation in the brain when measured in early- and late-phase, respectively. The metabolism of neural substrates could be viewed as a network and might be an important factor in cognition. Orthostatic hypotension (OH) might play an indirect moderating role in cognition, and its latent influence could modify the inherent cognitive network. This study aimed to identify changes of cognitive connectivity according to orthostatic stress in patients with early Parkinson’s disease (PD). This study included 104 early PD patients who were evaluated with a head-up tilt-test and18F-Florbetaben positron emission tomography (PET). Cognition was assessed with a comprehensive neuropsychological battery that gauged attention/working memory, language, visuospatial, memory, and executive functions. PET images were analyzed visually for amyloid deposits, and early-phase images were normalized to obtain standardized uptake ratios (SUVRs) of pre-specified subregions relevant to specific cognitive domains. The caudate nucleus was referenced and paired to these pre-specified regions. The correlations between SUVRs of these regions were assessed and stratified according to presence of orthostatic hypotension. Among the patients studied, 22 (21.2%) participants had orthostatic hypotension. Nineteen patients (18.3%) were positive for amyloid-β accumulation upon visual analysis. Moderate correlations between the caudate and pre-specified subregions were observed (Spearman’s rho, range [0.331–0.545]). Cognition did not differ, but the patterns of correlation were altered when the disease was stratified by presence of orthostatic stress. In conclusion, cognition in early PD responds to hemodynamic stress by adapting its neural connections between regions relevant to cognitive functions.

Clues to Reshaping Anti-α-Synuclein Immunotherapy in Early Parkinson's Disease Patients.

Clues to Reshaping Anti-α-Synuclein Immunotherapy in Early Parkinson's Disease Patients.

Polygenic risk score association with cognitive decline in Parkinson’s Disease

AbstractBackgroundCognitive impairment is a common and debilitating symptom in Parkinson’s disease (PD) with high variability in individual trajectory of decline. We sought to explore heterogeneity in the trajectory of individual cognitive change in a cohort of early stage PD patients and test association to cumulative genetic risk identified in large scale Genome Wide Association Studies (GWAS).MethodUsing longitudinal measures of the Montreal Cognitive Assessment (MoCA) we employed latent class mixed modelling (LCMM) to identify and investigate unknown populations in the Parkinson’s Progression Markers Inititative (PPMI) de‐novo PD cohort. Tranformed MoCA scores were modelled as a quadratic function of years from baseline, controlling for age, gender and motor symptom severity. Optimal group number was identified and determined using standardly advised model fit metrics. Polygenic risk scores (PRS) for five GWAS were calculated using PRSice‐2 applied to genotyping array data. Association of PRS with cognitive groups was tested using linear models and ANOVA tests.ResultLCMM showed optimal fit statistics for three classes (lowest BIC, high entropy) and these groups were retained for further analysis The largest identified class (n = 240) on average, presented at baseline with higher MoCA scores and remained stable over time. The second class (n = 132) presented with lower MoCA scores and showed a slow declining trajectory whilst the smallest class (n = 13) presented with lower MoCA scores but declined at a rapid rate. Educational attainment and Alzheimer’s disease (AD) GWAS derived PRS were significantly associated with cognitive class and explained the highest amount of phenotypic variance. For PD case‐control status, only the PD PRS was significantly associated with Parkinson’s status and explained a similar level of phenotypic variation.ConclusionLatent class analysis may provide utility in subsetting longitudinal cognitive outcome groups for use in groupwise comparisons. Using this method we show evidence for association of educational attainment and AD cumulative genetic risk and worse cognitive outcomes in early PD.

Application and progress of transcranial substantial ultrasound in Parkinson's disease.

Parkinson's disease (PD) is a common nervous system disease, mainly manifested as motor retardation, resting tremor, etc. (1). The clinical features of early PD patients are not characteristic, and diagnosis is very difficult. When obvious PD manifestations are found, the number of dopaminergic neurons in substantia nigra of patients has been reduced by more than half, and the treatment is difficult (2). Early diagnosis or auxiliary diagnosis of PD in clinical work is crucial for the treatment of PD and the prognosis of patients. In recent years, cerebral ultrasound has been widely used in the diagnosis and treatment of some diseases, such as Parkinson's disease, Alzheimer's disease, tuberculous meningitis, brain injury, etc., especially for the study of PD. The European Union of neuroscience and the latest diagnostic guidelines for PD in China have confirmed the role of the transcranial sonography (TCS). This article reviews the recent advances in the study of PD by transcranial sonography.

Integrated Clinical Features with Plasma and Multi-modal Neuroimaging Biomarkers to Diagnose Mild Cognitive Impairment in Early Drug-Naive Parkinson's Disease.

The pathogenesis of cognitive impairment in Parkinson's disease (PD) patients remains unclear, and there is no ideal diagnostic tool available at present. We assessed integrated clinical features with plasma and multi-modal neuroimaging biomarkers to identify mild cognitive impairment (MCI) in early drug-naive PD patients. 49 early drug-naive PD patients, including 26 with MCI (PD-MCI) and 23 with normal cognition (PD-NC), and 20 controls were recruited. Plasma markers [α-synuclein, beta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), and phosphorylated Tau 181 (p-Tau181) levels], functional connectivity (FC) of the default mode network, and cortical thickness (CTh) were evaluated to identify PD-MCI. The PD-MCI group had significantly higher plasma p-Tau181 levels and p-Tau181/Aβ42 ratio and lower Aβ42/Aβ40 ratio compared to the PD-NC group. Compared to PD-NC, the PD-MCI group showed increased FC between left posterior cingulate cortex (pCC) and the left parahippocampal gyrus (PHG), and between the right hippocampal formation and the left anterior cingulate and paracingulate gyri, and the right middle temporal gyrus. Additionally, the PD-MCI group had thinner cortex thickness in the right lateral occipital and frontal pole compared to the PD-NC group. The final model combining clinical characteristics and several variables (age, sex, plasma p-Tau181 level, Aβ42/Aβ40 ratio, the right lateral occipital CTh, and the FC value between the left pCC and left PHG) had the highest diagnostic accuracy for PD-MCI (AUC = 0.987, 95% CI 0.903-1.000; p = 0.001 compared to age and sex alone). The combination of clinical features, plasma biomarkers, and multi-modal neuroimaging biomarkers can identify early cognitive decline in PD patients.

Correlation between serum IGF-1 and EGF levels and neuropsychiatric and cognitive in Parkinson’s disease patients

BackgroundInsulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) exert neuroprotective effects in Parkinson’s disease (PD). To date, studies on the relationships between serum IGF-1 and EGF levels and nonmotor symptoms in PD patients have been rare.MethodsA Siemens automatic chemical analyzer was used to determine serum IGF-1 levels, and enzyme-linked immunosorbent assay was used to detect serum EGF levels in 100 healthy controls and 100 PD patients, including those in the early (n = 49) and middle-late (n = 51) stage of the disease. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales.ResultsSerum IGF-1 and EGF levels were higher in PD patients than in healthy controls, and serum IGF-1 and EGF levels were higher in early stage PD patients than in middle-late stage PD patients. Serum IGF-1 levels were significantly negatively correlated with anxiety, depression, and cognitive dysfunction; serum EGF levels were significantly negatively correlated with cognitive dysfunction. Combining IGF-1 and EGF in the diagnosis of PD was more valuable than using a single factor in the diagnosis.ConclusionsThis study shows that serum IGF-1 levels were correlated with the nonmotor symptoms of anxiety, depression, and cognitive dysfunction and that EGF levels were correlated with cognitive dysfunction. The combination of IGF-1 and EGF increased the value for a PD diagnosis. This is the first report of the simultaneous detection of IGF-1 and EGF levels to explore the correlation with nonmotor symptoms of PD.

Comparison of Olfactory Tract Diffusion Measures Between Early Stage Parkinson's Disease Patients and Healthy Controls Using Ultra-High Field MRI.

MRI is a valuable method to assist in the diagnostic work-up of Parkinson's disease (PD). The olfactory tract (OT) has been proposed as a potential MRI biomarker for distinguishing PD patients from healthy controls. This study aims to further investigate whether diffusion measures of the OT differ between early stage PD patients and healthy controls. Twenty hyposmic/anosmic PD patients, 65 normosmic PD patients, and 36 normosmic healthy controls were evaluated and a 7T diffusion weighted image scan was acquired. Manual seed regions of interest were drawn in the OT region. Tractography of the OT was performed using a deterministic streamlines algorithm. Diffusion measures (fractional anisotropy and mean- radial- and axial diffusivity) of the generated streamlines were compared between groups. Diffusion measures did not differ between PD patients compared to healthy controls and between hyposmic/anosmic PD patients, normosmic PD patients, and normosmic healthy controls. A positive correlation was found between age and mean- and axial diffusivity within the hyposmic/anosmic PD subgroup, but not in the normosmic groups. A positive correlation was found between MDS-UPDRSIII scores and fractional anisotropy. This study showed that fiber tracking of the OT was feasible in both early stage PD and healthy controls using 7T diffusion weighted imaging data. However, 7T MRI diffusion measures of the OT are not useful as an early clinical biomarker for PD. Future work is needed to clarify the role of other OT measurements as a biomarker for PD and its different subgroups.