Cognitive Impairment In Parkinson's Disease Patients Research Articles

Associations between Thyroid Hormones and Cognitive Impairment in Patients with Parkinson's Disease.

This study aims to explore the correlation of serum thyroid hormone levels to cognitive impairments in Parkinson's disease (PD) patients. In this retrospective study, 106 Chinese patients without cognitive impairments and 94 patients with cognitive impairments, including 55 with mild cognitive impairment (PD-MCI) and 39 with PD dementia (PDD), were analyzed. Clinical data regarding the PD assessments, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 scores, and Hoehn and Yahr (H-Y) staging, were analyzed. Cognitive functions were evaluated using the Montreal Cognitive Assessment score. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were measured using ELISA. Significantly altered H-Y staging, disease duration, and UPDRS Part 3 scores were observed in PD patients with cognitive impairment compared with those without. Serum levels of FT3 were significantly decreased, while FT4 and TSH levels were significantly elevated in PD patients with cognitive impairment compared with those without. Combined detection of TSH, FT3, and FT4 showed value in distinguishing PD patients with and without cognitive impairment. Furthermore, a comparison of serum levels between PD-MCI and PDD patients revealed significant association between thyroid hormone levels and the degree of cognitive impairment in PD patients. Our findings suggest a relationship between changes in serum thyroid hormone levels and cognitive impairments in PD patients. Thyroid hormone levels, particularly FT3, may serve as potential markers for cognitive dysfunction in PD.

Alzheimer's Disease Related Biomarkers Were Associated with Amnestic Cognitive Impairment in Parkinson's Disease: A Cross-Sectional Cohort Study.

Cognitive impairment is common in patients with Parkinson's disease (PD) and occurs through multiple mechanisms, including Alzheimer's disease (AD) pathology and the involvement of α-synucleinopathies. We aimed to investigate the pathological biomarkers of both PD and AD in plasma and neuronal extracellular vesicles (EVs) and their association with different types of cognitive impairment in PD patients. A total of 122 patients with PD and 30 healthy controls were included in this cross-sectional cohort study between March 2021 and July 2023. Non-dementia PD patients were divided into amnestic and non-amnestic groups according to the memory domain of a neuropsychological assessment. Plasma and neuronal EV biomarkers, including α-synuclein (α-syn), beta-amyloid (Aβ), total tau (T-tau), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP), were measured using a single-molecule array and a chemiluminescence immunoassay, respectively. Neuronal EV but not plasma α-syn levels, were significantly increased in PD as compared to healthy controls, and they were positively associated with UPDRS part III scores and the severity of cognitive impairment. A lower plasma Aβ42 level and higher neuronal EV T-tau level were found in the amnestic PD group compared to the non-amnestic PD group. The results of the current study demonstrate that neuronal EV α-syn levels can be a sensitive biomarker for assisting in the diagnosis and disease severity prediction of PD. Both AD and PD pathologies are important factors in cognitive impairment associated with PD, and AD pathologies are more involved in amnestic memory deficit in PD.

Sex-dependent associations of serum BDNF, glycolipid metabolism and cognitive impairments in Parkinson's disease with depression: a comprehensive analysis.

Brain-derived neurotrophic factor (BDNF) and glycolipid metabolism have been implicated in cognitive impairments and depression among Parkinson's disease (PD). However, the role of sex differences in this relationship remains elusive. This study aimed to investigate the potential sex differences in the link between serum BDNF levels, glycolipid metabolism and cognitive performance among depressive PD patients. PD patients comprising 108 individuals with depression and 108 without depression were recruited for this study. Cognitive function was assessed using the Montreal Cognitive Assessment Beijing version (MOCA-BJ). The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HAMD-17), while motor symptoms were evaluated using the Revised Hoehn and Yahr rating scale (H-Y) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Laboratory testing and enzyme-linked immunosorbent assay (ELISA) are used to measure serum levels of glycolipid metabolism and BDNF. Females showed superior performance in delayed recall (all p < 0.05), male PD patients exhibited higher scores in naming tasks compared to females in non-depression group. There was no sex differences in serum BDNF levels between depression and non-depression groups. Liner regression analysis indicated BDNF as an independent risk factor for language deficits in male PD patients with depression (p < 0.05), while cholesterol (CHOL) emerged as a cognitive influencing factor, particularly in delayed recall among male PD patients with depression (p < 0.05). Our study reveals extensive cognitive impairments in PD patients with depression. Moreover, BDNF and CHOL may contribute to the pathological mechanisms underlying cognitive deficits, particularly in male patients with depression.

Comparing Montreal Cognitive Assessment Performance in Parkinson's Disease Patients: Age- and Education-Adjusted Cutoffs vs. Machine Learning.

The Montreal Cognitive Assessment (MoCA) is recommended for general cognitive evaluation in Parkinson's disease (PD) patients. However, age- and education-adjusted cutoffs specifically for PD have not been developed or systematically validated across PD cohorts with diverse education levels. In this retrospective analysis, we utilized data from 1,293 Korean patients with PD whose cognitive diagnoses were determined through comprehensive neuropsychological assessments. Age- and education-adjusted cutoffs were formulated based on 1,202 patients with PD. To identify the optimal machine learning model, clinical parameters and MoCA domain scores from 416 patients with PD were used. Comparative analyses between machine learning. and different cutoff criteria were conducted on an additional 91 consecutive patients with PD. The cutoffs for cognitive impairment decrease with increasing age within the same education level. Similarly, lower education levels within the same age group correspond to lower cutoffs. For individuals aged 60-80 years, cutoffs were set as follows: 25 or 24 years for those with more than 12 years of education, 23 or 22 years for 10-12 years, and 21 or 20 years for 7-9 years. Comparisons between age- and education-adjusted cutoffs and the machine learning method showed comparable accuracies. The cutoff method resulted in a higher sensitivity (0.8627), whereas machine learning yielded higher specificity (0.8250). Both the age- and education-adjusted cutoff. and machine learning. demonstrated high effectiveness in detecting cognitive impairment in PD patients. This study highlights the necessity of tailored cutoffs and suggests the potential of machine learning to improve cognitive assessment in PD patients.

Changes of brain structure and structural covariance networks in Parkinson's disease associated cognitive impairment.

Cognitive impairment (CI) is common in Parkinson's disease (PD). Multiple brain regions and their interactions are involved in PD associated CI. Magnetic resonance imaging (MRI) technology is a non-invasive method in investigating brain structure and inter-regional connections. In this study, by comparing cortical thickness, subcortical volume, and brain network topology properties in PD patients with and without CI, we aimed to understand the changes of brain structure and structural covariance network properties in PD associated CI. A total of 18 PD patients with CI and 33 PD patients without CI were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, Mini Mental State Examination Scale, Non-motor Symptom Rating Scale, Hamilton Anxiety Scale, and Hamilton Depression Scale were assessed. All participants underwent structural 3T MRI. Cortical thickness, subcortical volume, global and nodal network topology properties were measured. Compared with PD patients without CI, the volumes of white matter, thalamus and hippocampus were lower in PD patients with CI. And decreased whole-brain local efficiency is associated with CI in PD patients. While the cortical thickness and nodal network topology properties were comparable between PD patients with and without CI. Our findings support the alterations of brain structure and disruption of structural covariance network are involved in PD associated CI, providing a new insight into the association between graph properties and PD associated CI.

Sensitivity of Clock Drawing Test Alone to Screen for Cognitive Impairment in Patients with Parkinson's Disease.

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), significantly impacting patient quality of life. The Clock Drawing Test (CDT) evaluates cognitive abilities, including planning, organization, and executive functions such as attention, memory, and visuospatial skills. This study aimed to determine the sensitivity of the CDT in diagnosing cognitive impairment in PD. We reviewed the records of 44 PD patients (16 female, 28 male) diagnosed with dementia (30 patients) or mild cognitive impairment (14 patients) between 2018 and 2022. These patients were compared to 106 visitors to the neurological outpatient clinic, serving as a control group. A separate researcher assessed the patients' CDT scores, maintaining confidentiality of all other patient data except age and education level. Among the 44 PD patients, two with mild cognitive impairment were rated as normal, while all PD dementia cases were identified solely through the CDT. In the healthy control group, 72 out of 106 individuals reported no cognitive complaints, whereas 34 individuals (32.1%) reported cognitive complaints as assessed by a blind investigator. The CDT demonstrated a positive predictive value of 55.3% and a negative predictive value of 97.3%. Sensitivity was calculated at 95.5%, and specificity was 67.9%. The findings suggest that the CDT is sensitive in detecting cognitive impairment in PD patients with cognitive deficits. While the CDT serves as an effective rapid screening tool, high scores indicate the absence of cognitive impairment, but low scores alone are insufficient for a definitive diagnosis of dementia. Comprehensive neurological evaluation and detailed cognitive assessment remain essential for confirming dementia diagnoses.

Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease

BackgroundCognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. ObjectiveTo investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. MethodsEighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. ResultsCompared with the control group, the macular GCIPL (t = −2.308, P = 0.023) was thinner and serum HMGB1 (z = −2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. ConclusionThe macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.

Third ventricular width by transcranial sonography is associated with cognitive impairment in Parkinson's disease.

One-fourth of Parkinson's disease (PD) patients suffer from cognitive impairment. However, few neuroimaging markers have been identified regarding cognitive impairment in PD. This study aimed to explore the association between third ventricular width by transcranial sonography (TCS) and cognitive decline in PD. Participants with PD were recruited from one medical center in China. Third ventricular width was assessed by TCS, and cognitive function was analyzed by the Mini-Mental State Examination (MMSE). Receiver operating characteristic (ROC) analysis and Cox model analysis were utilized to determine the diagnostic and predictive accuracy of third ventricular width by TCS for cognitive decline in PD patients. A total of 174 PD patients were recruited. Third ventricular width was negatively correlated with MMSE scores. ROC analysis suggested that the optimal cutoff point for third ventricular width in screening for cognitive impairment in PD was 4.75 mm (sensitivity 62.7%; specificity 75.6%). After 21.5 (18.0, 26.0) months of follow-up in PD patients without cognitive impairment, it was found that those with a third ventricular width greater than 4.75 mm exhibited a 7.975 times higher risk of developing cognitive impairment [hazard ratio = 7.975, 95% CI 1.609, 39.532, p = 0.011] compared with patients with a third ventricular width less than 4.75 mm. Third ventricular width based on TCS emerged as an independent predictor of developing cognitive impairment in PD patients.

Correlation analysis between 18F-fluorodeoxyglucose positron emission tomography and cognitive function in first diagnosed Parkinson's disease patients.

Evaluation of the correlation between 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and cognitive function in first-diagnosed and untreated Parkinson's disease (PD) patients. This cross-sectional study included 84 first diagnosed and untreated PD patients. The individuals were diagnosed by movement disorder experts based on the 2015 MDS Parkinson's disease diagnostic criteria. The patients also underwent 18F-FDG PET scans and clinical feature assessments including the Montreal Cognitive Assessment (MoCA) scale. Glucose metabolism rates were measured in 26 brain regions using region of interest (ROI) and pixel-wise analyses with displayed Z scores. The cognitive function was assessed by professionals using the MoCA scale, which covers five cognitive domains. Spearman's linear correlation and linear regression models were used to compare the correlations between 18F-FDG metabolism in each brain region and cognitive domain, using SPSS 25.0 software. The results indicated a positive correlation between executive function and glucose metabolism in the lateral prefrontal cortex of the left hemisphere (p = 0.041). Additionally, a positive correlation between memory function and glucose metabolism in the right precuneus (p = 0.014), right lateral occipital cortex (p = 0.017), left lateral occipital cortex (p = 0.031), left primary visual cortex (p = 0.008), and right medial temporal cortex (p = 0.046). Further regression analysis showed that for every one-point decrease in the memory score, the glucose metabolism in the right precuneus would decrease by 0.3 (B = 0.30, p = 0.005), the glucose metabolism in the left primary visual cortex would decrease by 0.25 (B = 0.25, p = 0.040), the glucose metabolism in the right lateral occipital cortex would decrease by 0.38 (B = 0.38, p = 0.012), and the glucose metabolism in the left lateral occipital cortex would decrease by 0.32 (B = 0.32, p = 0.045). This study indicated that cognitive impairment in PD patients mainly manifests as changes in executive function, visual-spatial function and memory functions, while glucose metabolism mainly decreases in the frontal and posterior cortex. Further analysis shows that executive function is related to glucose metabolism in the left lateral prefrontal cortex. On the other hand, memory ability involves changes in glucose metabolism in a more extensive brain region. This suggests that cognitive function assessment can indirectly reflect the level of glucose metabolism in the relevant brain regions.

NIMHANS Neuropsychological Battery for Elderly in Parkinson's Disease Patients: Validation and Diagnosis using MDS PD-MCI Task Force Criteria in Indian Population.

Cognitive impairment is a common non-motor feature of Parkinson's Disease (PD). Diagnosis of mild cognitive impairment is challenging and routinely missed in clinical practice. Our study aimed to study the efficacy of NIMHANS Neuropsychological Battery for Elderly (NNB-E) in diagnosing subtle cognitive deficits in PD patients. The aim of this study is to validate NNB-E and evaluate cognitive impairment in PD patients in comparison with healthy controls. We recruited 31 PD patients and 31 healthy controls in the current study. We validated NNB-E using receiver operating characteristic (ROC) curve analysis, Crohnbach's alpha, principal component analysis, and Pearson product-moment correlation, and studied the cognitive impairments using NNB-E in the non-demented PD patients and controls who scored ≥24 on HMSE. Cognitive performance of PD patients was poor compared to controls. NNB-E showed good internal consistency and construct validity with Crohnbach's alpha of 0.861 and area under the curve (AUC) of 0.878. The battery was able to detect mild cognitive impairment in 74.1% of patients and 6.4% of controls. The ROC curve showed that the overall sensitivity of the battery was 73.2% and specificity was 92.6% at an optimal cutoff score. Different cutoff values set for defining PD-MCI as per MDS task force criteria resulted in varying frequencies of MCI ranging from 25.8% to 71%. Our study established the validity of NNB-E in PD patients, and this tool was suitable for diagnosing PD-MCI and discriminating PD patients from normal controls in the Indian population. This study also showed PD-MCI at various cutoff scores with greater impairment in executive and attention domains.

Investigation of Paraoxonase-1 Genotype and Enzyme-Kinetic Parameters in the Context of Cognitive Impairment in Parkinson's Disease.

Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), which often progresses to PD dementia. PD patients with and without dementia may differ in certain biochemical parameters, which could thus be used as biomarkers for PD dementia. The enzyme paraoxonase 1 (PON1) has previously been investigated as a potential biomarker in the context of other types of dementia. In a cohort of PD patients, we compared a group of 89 patients with cognitive impairment with a group of 118 patients with normal cognition. We determined the kinetic parameters Km and Vmax for PON1 for the reaction with dihydrocoumarin and the genotype of four single nucleotide polymorphisms in PON1. We found that no genotype or kinetic parameter correlated significantly with cognitive impairment in PD patients. However, we observed associations between PON1 rs662 and PON1 Km (p < 10-10), between PON1 rs662 and PON1 Vmax (p = 9.33 × 10-7), and between PON1 rs705379 and PON1 Vmax (p = 2.21 × 10-10). The present study is novel in three main aspects. (1) It is the first study to investigate associations between the PON1 genotype and enzyme kinetics in a large number of subjects. (2) It is the first study to report kinetic parameters of PON1 in a large number of subjects and to use time-concentration progress curves instead of initial velocities to determine Km and Vmax in a clinical context. (3) It is also the first study to calculate enzyme-kinetic parameters in a clinical context with a new algorithm for data point removal from progress curves, dubbed iFIT. Although our results suggest that in the context of PD, there is no clinically useful correlation between cognitive status on the one hand and PON1 genetic and enzyme-kinetic parameters on the other hand, this should not discourage future investigation into PON1's potential associations with other types of dementia.

Longitudinal striatal dopamine transporter binding and cerebrospinal fluid alpha-synuclein, amyloid beta, total tau, and phosphorylated tau in Parkinson's disease.

Previous studies investigated CSF levels of α-synuclein (α-syn), amyloid-β (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) with clinical progression of Parkinson's disease (PD). However, there is limited data on the association between CSF biomarkers and dopamine uptake status in PD. In the current study, we aim to investigate the longitudinal association between striatal dopaminergic neuronal loss assessed by dopamine active transporter single photon emission computerized tomography (DaTSCAN) imaging with CSF α-syn, t-tau, p-tau, and Aβ1-42. A total of 413 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. Striatal binding ratios (SBRs) of DaTSCAN images in caudate and putamen nuclei were calculated. We investigated the cross-sectional and longitudinal association between CSF biomarkers and dopamine uptake using partial correlation models adjusted for the effect of age, sex, and years of education over 24months of follow-up. The level of CSF α-syn, Aβ1-42, t-tau, and p-tau was significantly higher in HCs compared to PD groups at any time point. We found that higher CSF α-syn was associated with a higher SBR score in the left caudate at baseline (P = 0.038) and after 12months (P = 0.012) in PD patients. Moreover, SBR scores in the left caudate and CSF Aβ1-42 were positively correlated at baseline (P = 0.021), 12months (P = 0.006), and 24months (P = 0.014) in patients with PD. Our findings demonstrated that change in CSF Aβ1-42 was positively correlated with change in SBR score in the left caudate after 24months in the PD group (P = 0.043). We found that cross-sectional levels of α-syn and Aβ1-42 could reflect the degree of dopaminergic neuron loss in the left caudate nucleus. Interestingly, longitudinal changes in CSF Aβ1-42 could predict the severity of left caudal dopaminergic neuron loss throughout the disease. This suggested that Aβ pathology might precede dopaminergic loss in striatal nuclei in this case left caudate and subsequently cognitive impairment in PD patients, although future studies are needed to confirm our results and expand the understanding of the pathophysiology of cognitive dysfunction in PD.

N200 and P300 component changes in Parkinson's disease: a meta-analysis.

Cognitive impairment can seriously affect the quality of life of Parkinson's disease (PD) patients. Although numerous studies showed that N200, P300 latency and amplitude are correlated with cognitive functions, there is a sufficient amount of controversial results. Therefore, it is necessary to conduct a meta-analysis of N200, P300 latency and amplitude data of event-related potential (ERP) in PD. We systematically searched on PubMed and Web of Science for PD-related ERP studies published before December 2021. Standard mean difference (SMD) and 95% confidence interval (CI) estimates of N200 and P300 components were compared among PD patients, PD dementia (PDD) patients, PD non-dementia (PDND) patient, and healthy control (HC). Our meta-analysis showed prolonged N200 latency at the Fz, Cz electrode sites, prolonged P300 latency at the Fz sites in PD patients, compared to HC; prolonged N200 latency at the Cz, Pz electrode sites in PDND patients, compared to HC; prolonged P300 latency at the Cz site in PDD patients, compared to PDND patients; and reduced P300 amplitude at the Fz electrode site in PDND patients, compared to HC. N200 and P300 component may be potential electrophysiological biomarkers of early cognitive impairment in PD patients. Future studies are needed to confirm this conclusion. Estimates of N200 and P300 component can be a valuable support for clinicians in diagnosis of early cognitive impairment in PD patients due to the simplicity and non-invasiveness of the procedure.

Combining quantitative susceptibility mapping to radiomics in diagnosing Parkinson's disease and assessing cognitive impairment.

To explore whether magnetic susceptibility value (MSV) and radiomics features of the nigrostriatal system could be used as imaging markers for diagnosing Parkinson's disease (PD) and its related cognitive impairment (CI). A total of 104 PD patients and 45 age-sex-matched healthy controls (HCs) underwent quantitative susceptibility mapping (QSM). The former completed Hoehn-Yahr Stage and Montreal Cognitive Assessment (MoCA). The patients were divided into several subgroups according to disease stages, courses, and MoCA scores. The ROI was subdivided into the substantia nigra (SN), head of caudate nucleus (HCN), and putamen. The MSVs and radiomics features were obtained from QSM. The multivariable logistic regression (MLR) and support vector machine (SVM) models were constructed to diagnose PD. The correlations between MSVs, radiomics features, and MoCA scores were evaluated. The MSVs in bilateral SN pars compacta (SNc) of PD patients were higher than those of the HCs (p < 0.001). There were differences in some radiomics features between the two groups (p < 0.05). The MSVs of the right SNc and the radiomics features of the right SN had the highest area under the curve (AUC), respectively. The comprehensive MLR model (0.90) and SVM model (0.95) revealed better classification performance than MSVs (p < 0.05) in diagnosing PD. The MSVs from the HCN were negatively correlated with MoCA scores in PD subgroups. There were correlations between radiomics features and MoCA scores in PD patients. Radiomics features and MSVs of the nigrostriatal system from QSM could have crucial role in diagnosing PD and assessing CI. • The MLR and the SVM models have excellent diagnostic performance in the diagnosis of PD. • A PD diagnostic nomogram, created based on MSV and the radiomics scores of SVM model, is very convenient for clinical use. • The radiomics features of the nigrostriatal system based on QSM help to evaluate the cognitive impairment in PD patients.

REM sleep behavior disorder and cerebrospinal fluid alpha-synuclein, amyloid beta, total tau and phosphorylated tau in Parkinson's disease: a cross-sectional and longitudinal study.

Proteinopathies as a consequence of cellular pathological pathways associated with Parkinson's disease (PD), leading to alteration of protein aggregation in cerebrospinal fluid (CSF). Rapid eye movement (REM) sleep behavior disorder (RBD is generally accepted as a prognostic factor predicting neurodegeneration, worse cognitive impairment, and the development of dementia PD. Here we aimed to investigate the difference and longitudinal alteration of the CSF level of α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with RBD and without RBD. We entered 413 early stage PD patients and 187 healthy controls (HCs) from PPMI. We compared the level of CSF biomarkers at baseline, 6months, 1year, and 2years visits. In addition, we used linear mixed models to assess longitudinal changes of CSF proteins over 6months, 1year, and 2years within groups. The level of CSF α-syn, Aβ1-42, t-tau, and p-tau was significantly higher in HCs compared to PD groups at any timepoint. In addition, there was a significantly lower CSF Aβ1-42 in PD-RBD subjects at 2years timepoint (p = 0.020). There was no difference in CSF Aβ1-42 at other timepoints. Furthermore, comparisons between PD subjects with RBD and without RBD did not show any significant difference in CSF α-syn, t-tau, and p-tau at timepoints. The longitudinal analysis demonstrated that there was only a significant change in CSF level of Aβ1-42 after 1year in PD patients with RBD (p = 0.031). In our study, baseline values and longitudinal changes in CSF α-syn, t-tau, and p-tau were not remarkable enough to distinguish PD patients with and without RBD. Both of these groups demonstrated a stable trend in the longitudinal changes of these biomarkers. However, CSF Aβ1-42 seems to decrease in short follow-up and represents a significant difference after a while in PD patients with and without RBD. These findings suggested that CSF Aβ1-42 could be a more sensitive biomarker for early neurodegeneration and cognitive impairment in PD patients. The stable trend in other CSF biomarkers such as α-syn, t-tau, and p-tau can be justified by the fact that severe neurodegeneration may not be predictable in the early stages of PD patients.

Longitudinal White Matter Damage Evolution in Parkinson's Disease.

White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial. To investigate the longitudinal evolution of micro- and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD. A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal-appearing white matter (NAWM). Using tract-based spatial statistics, diffusion tensor (DT) MRI metrics of whole-brain WM and NAWM were obtained. Linear mixed-effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models. At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment. Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society.

Cognitive Influences in Parkinson's Disease Patients and Their Caregivers: Perspectives From an Australian Cohort.

Objectives: Cognitive impairment impacts negatively on Parkinson's disease (PD) patient and caregiver quality of life (QoL). We examined cognitive impairment in PD patients and their caregivers to determine if caregiver cognition affected their PD relative.Methods: Validated cognition and clinical outcome measures were assessed in 103 PD patients and 81 caregivers.Results: PD patients showed more cognitive impairment than their carers, with 48.6% having possible Mild Cognitive Impairment (MCI) and 16.5% having PD dementia. Increasing age, male gender, lower education level, various non-motor symptoms and certain therapies, associated with poorer cognition in PD. Eighteen and a half percent of caregivers were found to have MCI, in association with a lower physical and mental QoL. This reflected in lower QoL and mood for the respective PD patients.Conclusion: Impaired cognition and QoL in caregivers was associated with decreased QoL and mood for respective PD patients, suggesting MCI in caregivers is an important consideration for the management of PD.

Hippocampal volume is related to olfactory impairment in Parkinson's disease.

Recent evidence has suggested that hyposmia in patients with Parkinson's disease (PD) may be due to impaired central processing. Furthermore, the hippocampus has been regarded as a critical structure linking olfactory impairment and cognitive impairment in PD patients. This study aimed to identify significant structural alterations of the hippocampus in PD patients with hyposmia, and to determine whether these structural changes are significantly associated with olfactory impairment severity. Eighteen idiopathic PD patients with hyposmia and 18 age- and sex-matched PD patients without hyposmia were enrolled. Hippocampal volume and its subfields were measured using FreeSurfer software and compared between hyposmic and normosmic PD patients. We also compared hippocampal substructures' volumes and correlated the hippocampal volumes with hyposmia severity. PD patients with hyposmia had significantly smaller hippocampal volumes. Among the three components of the hippocampus, the hippocampal body showed a markedly lower volume, which correlated significantly with the cross-cultural smell identification test score that represents olfactory function status. Hippocampal subfield analysis showed that substructures (subiculum, molecular layer) that constitute the hippocampal body showed the most significant volume difference. We suggest that atrophy of the bilateral hippocampus implies underlying problems in the central olfaction process in PD patients. In particular, the hippocampus might not only play a critical role in olfaction but could also be important for elucidating possible mechanisms of broad nonmotor symptoms in PD patients.

A novel dopamine D3R agonist SK609 with norepinephrine transporter inhibition promotes improvement in cognitive task performance in rodent and non-human primate models of Parkinson's disease

Mild cognitive impairment is present in a number of neurodegenerative disorders including Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) often manifests as deficits in executive functioning, attention, and spatial and working memory. Clinical studies have suggested that the development of mild cognitive impairment may be an early symptom of PD and may even precede the onset of motor impairment by several years. Dysfunction in several neurotransmitter systems, including dopamine (DA), norepinephrine (NE), may be involved in PD-MCI, making it difficult to treat pharmacologically. In addition, many agents used to treat motor impairment in PD may exacerbate cognitive impairment. Thus, there is a significant unmet need to develop therapeutics that can treat both motor and cognitive impairments in PD. We have recently developed SK609, a selective, G-protein biased signaling agonist of dopamine D3 receptors. SK609 was successfully used to treat motor impairment and reduce levodopa-induced dyskinesia in a rodent model of PD. Further characterization of SK609 suggested that it is a selective norepinephrine transporter (NET) inhibitor with the ability to increase both DA and NE levels in the prefrontal cortex. Pharmacokinetic analysis of SK609 under systemic administration demonstrated 98% oral bioavailability and high brain distribution in striatum, hippocampus and prefrontal cortex. To evaluate the effects of SK609 on cognitive deficits of potential relevance to PD-MCI, we used unilateral 6-hydroxydopamine (6-OHDA) lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus macaques, with deficits in performance in a sustained attention and an object retrieval task, respectively. SK609 dose dependently improved the performance of 6-OHDA-lesioned rats, with peak performance achieved using a 4 mg/kg dose. This improvement was predominantly due to a significant reduction in the number of misses and false alarm errors, contributing to an increase in sustained attention. In MPTP-lesioned monkeys, this same dose also improved performance in an object retrieval task, significantly reducing cognitive errors (barrier reaches) and motor errors (fine motor dexterity problems). These data demonstrate that SK609 with its unique pharmacological effects on modulating both DA and NE can ameliorate cognitive impairment in PD models and may provide a therapeutic option to treat both motor and cognitive impairment in PD patients.

Disentangling the Role of Working Memory in Parkinson’s Disease

Working memory (WM) represents a core cognitive function with a major striatal contribution, and thus WM deficits, commonly observed in Parkinson’s disease (PD), could also relate to many other problems in PD patients. Our online study aimed to determine the subdomains of WM that are particularly affected in PD and to clarify the links between WM and everyday cognitive deficits, other executive functions, psychiatric and PD symptoms, as well as early cognitive impairment. Fifty-two mild-to-moderate PD patients and 54 healthy controls performed seven WM tasks tapping selective updating, continuous monitoring, or maintenance of currently active information. Self-ratings of everyday cognition, depression, and apathy symptoms, as well as screenings of global cognitive impairment, were also collected. The data were analyzed using structural equation modeling. Of the three WM domains, only selective updating was directly predictive of PD group membership. More widespread WM deficits were observed only in relation to global cognitive impairment in PD patients. Self-rated everyday cognition or psychiatric symptoms were not linked to WM performance but correlated with each other. Our findings suggest that WM has a rather limited role in the clinical manifestation of PD. Nevertheless, due to its elementary link to striatal function, the updating component of WM could be a candidate for a cognitive marker of PD also in patients who are otherwise cognitively well-preserved.