Cognitive Impairment In Parkinson's Disease Research Articles

Changes in brain functional connectivity between on and off states and their relationship with cognitive impairment in Parkinson’s disease

Parkinson’s disease (PD) is characterized by motor and non-motor symptoms. Cognitive decline is crucial in disease progression and affect quality of life; however, their underlying mechanisms in PD remain unclear. We explored the relationship between cognitive impairment and functional connectivity (FC) using resting-state functional magnetic resonance imaging in 26 patients with sporadic PD, focusing on the changes in FC between on and off states. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) score. The correlation between MMSE scores and changes in FC values during on and off states was assessed using Pearson’s correlation coefficient. The correlation between changes in FC during the on and off periods and cognitive function differed for each cognitive function item. MMSE memory scores were positively correlated with FC between the brainstem and the left cerebral hemisphere. MMSE attention scores were positively correlated with FC between the bilateral thalamus and frontal lobes and negatively correlated with FC between the left cerebral hemispheres. These findings may facilitate our understanding of the neural correlates underlying cognitive impairment in PD and help develop treatment strategies to preserve cognitive function.

Deficits in or Preservation of Basic Number Processing in Parkinson's Disease? A Registered Report.

Neurodegenerative diseases such as Parkinson's disease (PD) have a huge impact on patients, caregivers, and the health care system. Until now, diagnosis of mild cognitive impairments in PD has been established based on domain-general functions such as executive functions, attention, or working memory. However, specific numerical deficits observed in clinical practice have not yet been systematically investigated. PD-immanent deterioration of domain-general functions and domain-specific numerical areas suggests mechanisms of both primary and secondary dyscalculia. The current study systematically investigated basic number processing performance in PD patients for the first time, targeting domain-specific cognitive representations of numerosity and the influence of domain-general factors. The overall sample consisted of patients with a diagnosis of PD, according to consensus guidelines, and healthy controls. PD patients were stratified into patients with normal cognition (PD-NC) or mild cognitive impairment (level I-PD-MCI based on cognitive screening). Basic number processing was assessed using transcoding, number line estimation, and (non-) symbolic number magnitude comparison tasks. Discriminant analysis was employed to assess whether basic number processing tasks can differentiate between a healthy control group and both PD groups. All participants were subjected to a comprehensive numerical and a neuropsychological test battery, as well as sociodemographic and clinical measures. Results indicate a profile of preserved (verbal representation) and impaired (magnitude representation, place × value activation) function in PD-MCI, hinting at basal ganglia dysfunction affecting numerical cognition in PD. Numerical deficits could not be explained by domain-general cognitive impairments, so that future research needs to incorporate domain-specific tasks of sufficient difficulty.

Increased dementia risk in patients with Parkinson's disease attributed to metabolic syndrome.

Metabolic syndrome (MetS) manifests resembling pathophysiological mechanisms with Parkinson's disease (PD). Current research on the overall population has emphasized MetS as a freestanding risk factor for cognition. This research aims to explore the impact of MetS on cognition in Parkinson's patients. We involved subjects identified as having early-stage PD patients. The MetS was diagnosed dependent on parameters overviewed in the National Cholesterol Education Program's Adult Treatment Panel III. The clinical severity and stages in patients with PD were dependent on the disease rating scales. The cognition was evaluated by the Turkısh version of the Montreal Cognitive Assessment Scale (MoCA-TR). The cases were categorized according to cognitive failure: mild cognitive impairment in PD (PD-MCI), and PD dementia (PDD). Metabolic syndrome was present in 39.6% of the participants. 22.0% of patients were in the normal cognition, 29.1% in the PD-MCI group, and 48.9% in the PD-D group. The cognitive scores in patients with MetS is considerably lower than MetS negative group. A statistically notable inverse association was detected between fasting blood glucose levels and the visual-spatial/executive functions, naming, language, and orientation scores. The multivariate logistic regression analysis showed individuals with MetS were found to have an 11.308 times higher risk of PD-D (odds ratio [OR]: 11,3, 95% confidence interval [CI]: 1.61-79.2 ). We discerned the occurrence of MetS in PD raises the possibility of advancing dementia. This suggests that considering MetS in this patient group could contribute to the effective management of dementia.

Peripheral biomarkers of Parkinson’s disease and its correlation with clinical symptoms: a case-control study

BackgroundInflammation significantly impacts Parkinson’s disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive.ObjectiveTo identify the peripheral biomarkers of PD and its correlation with the motor and non-motor symptoms of PD.Methods79 PD patients and 65 controls were included in this study. Clinical information and the serum levels of IL-8, IL-27, IL-33, β-NGF, AgRP, and TRAILR2 in the participants were collected. Appropriate scales were used to assess the symptoms of PD. For the factors with significant differences in the two groups, multivariable logistic regression was used to determine its relationship with PD. Moreover, spearman correlation was conducted to explore the correlation between the factors and PD related symptoms. The IL-27 level was compared between the cognitively healthy PD group and the mild cognitive impairment in PD (PD-MCI). The serum level of TRAILR2 was positively correlated with age and was not associated with other clinical characteristics related to PD.ResultsCompared to controls, the serum levels of IL-27(P = 0.013) were increased whereas the levels of TRAILR2(P = 0.008) were decreased in PD patients. IL-8, IL-33, β-NGF, and AgRP showed no significant differences between the two groups. After controlling for the other variables, IL-27 was considered as an independent risk factor for PD in the multivariable logistic regression model. The receiver operating characteristic (ROC) curve for diagnosing PD with IL-27 yielded an area under the curve (AUC) of 0.621. Additionally, IL-27 level in PD patients was positively correlated with age, the disease duration, LEDD and negatively correlated with the MoCA scores. However, no significant difference was found in IL-27 levels between cognitively healthy PD and PD-MCI groups.ConclusionElevated serum IL-27 was a risk factor for PD and positively correlated with the cognitive decline in PD.

Changes in serum uric acid, glutathione, and amyloid-β1-42 levels in Parkinson’s disease patients and their association with disease progression and cognitive decline

Objective This study aims to evaluate the diagnostic significance of serum uric acid (UA), glutathione (GSH), and amyloid-β1-42 (Aβ1-42) levels in relation to disease progression and cognitive impairment in patients with Parkinson’s disease (PD). Methods A total of 209 PD patients with disease duration ranging from 4.0 to 6.8 years were enrolled. Based on the Hoehn-Yahr staging system, patients were classified into Early (n = 67), Medium-term (n = 70), and Advanced (n = 72) stages. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), dividing the cohort into CD (cognitive dysfunction, n = 94) and NO-CD (no cognitive dysfunction, n = 115) groups. Serum UA, GSH, and Aβ1-42 levels were analyzed for correlations with clinical data. Independent risk factors and diagnostic value were determined through multivariable logistic regression models and receiver operating characteristic curve analysis. Results Serum UA and GSH levels progressively declined with advancing disease stage, while Aβ1-42 increased. Compared to the NO-CD group, the CD group showed lower serum UA and GSH levels, and higher Aβ1-42 levels. Serum UA and GSH were inversely correlated with disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale scores, while Aβ1-42 showed positive correlations. UA (p = 0.006), GSH (p < 0.001), and Aβ1-42 (p = 0.040) were independent predictors of disease stage. Similarly, UA (p = 0.003), GSH (p < 0.001), and Aβ1-42 (p < 0.001) were independent predictors of cognitive dysfunction. The combined assessment of these markers demonstrated a higher area under the curve (AUC) than individual markers for disease and cognitive decline identification. Conclusions Serum UA, GSH, and Aβ1-42 are independent predictors of disease progression and cognitive decline in PD patients. Their combined use offers enhanced diagnostic accuracy for disease staging and cognitive impairment in PD.

Mitochondrial Dysfunction in Parkinson's Disease: A Contribution to Cognitive Impairment?

Among the non-motor symptoms associated with Parkinson's disease (PD), cognitive impairment is one of the most common and disabling. It can occur either early or late during the disease, and it is heterogeneous in terms of its clinical manifestations, such as Subjective Cognitive Dysfunction (SCD), Mild Cognitive Impairment (MCI), and Parkinson's Disease Dementia (PDD). The aim of the present review is to delve deeper into the molecular mechanisms underlying cognitive decline in PD. This is extremely important to delineate the guidelines for the differential diagnosis and prognosis of the dysfunction, to identify the molecular and neuronal mechanisms involved, and to plan therapeutic strategies that can halt cognitive impairment progression. Specifically, the present review will discuss the pathogenetic mechanisms involved in the progression of cognitive impairment in PD, with attention to mitochondria and their contribution to synaptic dysfunction and neuronal deterioration in the brain regions responsible for non-motor manifestations of the disease.

Effects of biopsychosocial approach on cognition among Parkinson's population.

Cognitive decline is a debilitating symptom in Parkinson's disease (PD). Cognitive impairment in PD has a significant impact on many aspects of an individual's life, social interactions, and overall quality of life (QOL). It is also associated with a faster disease progression and an increased risk of developing dementia. A biopsychosocial approach is likely to address not only the underlying biological mechanisms of cognitive impairment in PD but also the psychological and social factors that can contribute to cognitive decline and influence treatment outcomes. This experimental study was conducted on 60 older adults with PD at Saveetha medical college and hospital. Participants who met the inclusion criteria were randomly allocated into two groups of Biopsychosocial (n=30) and conventional (n=30). Participants in the intervention group received the multiple interventions based on the biopsychosocial approach with a duration of 60min per session. Pre and post-test evaluation conducted using Scales for Outcomes in PD-cognition (SCOPA-cog) and Parkinson disease QOL Questionnaire (PDQ-8). The results of the study showed that there is a statistically significant difference in the median scores within the Groups for the outcome measures SCOPA-cog and PDQ-8 (p<0.001). For SCOPA-cog, the BPS group median score increased from 30 to 36, while the Conventional group median score increased from 31 to 33. For PDQ-8, the BPS group median reduced from 27 to 14, compared to the Conventional group's reduced from 30 to 24. On comparison between the post-test values, the biopsychosocial approach group showed more improvement in cognition and QOL with (p<0.001). The findings of this study concluded that the biopsychosocial approach is effective in improving cognition and QOL among the Parkinson population.

Relationships between Serum Lipid, Uric Acid Levels and Mild Cognitive Impairment in Parkinson's Disease and Multiple System Atrophy.

Mild cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD) and multiple system atrophy (MSA). Few studies have previously been conducted on the correlation between serum uric acid (SUA) and lipid levels and mild cognitive impairment in PD and MSA. Participants included 149 patients with PD and 99 patients with MSA. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Evaluations were conducted on SUA and lipid levels, which included triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC). Patients with PD and MSA diagnosed with mild cognitive impairment demonstrated multiple cognitive domain impairment when compared with patients with normal cognition. Attentional impairment was more pronounced in patients with MSA when compared with PD (p = 0.001). In PD, the risk of mild cognitive impairment was lower in the highest quartiles and secondary quartile of SUA than in the lowest quartiles (odds ratio [OR] = 0.281, 95% confidence intervals [CI]: 0.097-0.810, p = 0.019; and OR = 0.317, 95% CI: 0.110-0.911, p = 0.033). In MSA, the risk of mild cognitive impairment was lower in the third and highest quartile of SUA than in the lowest quartile (OR = 0.233, 95% CI: 0.063-0.868, p = 0.030; and OR = 0.218, 95% CI: 0.058-0.816, p = 0.024). In patients with PD, the MoCA scores were negatively correlated with TC levels (r = -0.226, p = 0.006) and positively correlated with SUA levels (r = 0.206, p = 0.012). In MSA, the MoCA scores were positively correlated with SUA levels (r = 0.353, p = 0.001). Lower SUA levels and higher TC levels are a possible risk factor for the risk and severity of mild cognitive impairment in PD. Lower SUA levels are a possible risk factor for the risk and severity of mild cognitive impairment in MSA.

Involvement of the basal forebrain and hippocampus in memory deficits in Parkinson's disease

IntroductionMagnetic resonance imaging (MRI)-determined atrophy of the nucleus basalis of Meynert (Ch4) predicts cognitive decline in Parkinson's disease (PD). However, interactions with other brain regions causing the decline remain unclear. This study aimed to describe how MRI-determined Ch4 atrophy leads to cognitive decline in patients with PD. MethodsWe evaluated 137 patients with PD and 39 healthy controls using neuropsychological examinations, MRI, and 123I-ioflupane single-photon emission computed tomography. First, we explored brain areas with regional gray matter loss correlated with Ch4 volume reduction using voxel-based morphometry (VBM). We then assessed the correlation between Ch4 volume reduction and cognitive impairments in PD using partial correlation coefficients (rpar). Finally, we examined whether the regional gray matter loss mediated the association between Ch4 volume reduction and cognitive impairments using mediation analysis. ResultsOur PD cohort was “advanced-stage enriched.” VBM analyses revealed that Ch4 volume loss was correlated with volume reduction in the medial temporal lobe in PD (P < 0.05, family-wise error corrected, >29 voxels). Ch4 volume reduction was significantly correlated with verbal memory deficits in PD when adjusted for age, sex, total brain volume, and 123I-ioflupane uptake in the caudate (rpar = 0.28, P < 0.001). The mediation analysis revealed that the hippocampus mediated the effects of Ch4 volumes on verbal memory (average causal mediation effect = 0.013, 95 % CI = 0.006–0.020, P < 0.001). ConclusionParticularly in advanced-stage PD, Ch4 atrophy was associated with medial temporal lobe atrophy, which played an intermediary role in the relationship between Ch4 atrophy and verbal memory impairments.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.

Duzhong Fang ameliorates cognitive impairment of Parkinsonian mice by suppressing neuronal apoptotic pathway.

Parkinson's disease (PD) is a complex multisystem neurodegenerative disease, and cognitive impairment is a common symptom in the trajectory of PD. Duzhong Fang (DZF) consists of Eucommia ulmoides, Dendrobium, Rehmanniae Radix, and Dried Ginger. Our previous study showed that DZF improves motor deficits in mice. However, whether DZF can ameliorate cognitive impairment in PD has not been reported. In this study, we established mice models of PD induced by rotenone and examined the effect of DZF on cognitive impairment in Parkinson's disease (PD-CI). The results confirmed that DZF treatment not only significantly improved the motor deficits in PD mice and decreased the loss of dopaminergic neurons, but also had significant effects in improving cognitive impairment. We further integrate serum metabolome and network pharmacology to explore the mechanisms by which DZF improves PD-CI. The results revealed that DZF can treat PD-CI by regulating sphingolipid metabolism to inhibit neuronal apoptotic pathway. In conclusion, preliminary studies confirmed that DZF contributes to the improvement of cognitive ability in PD, and our results provide a potential drug for the clinical treatment of PD and a theoretical foundation for DZF in clinical application.

Can volumetric magnetic resonance imaging evaluations be helpful in the follow-up of cognitive functions in cognitively normal Parkinson's disease patients?

In this study, besides the evaluation of gray and white matter changes in cognitively normal Parkinson's disease (PD-CN) patients with volumetric magnetic resonance imaging (MRI) parameters, it was tried to show that some neuropsychological tests may be impaired in PD-CN patients. Twenty-six PD-CN patients and 26 healthy elderly (HC) participants were included in the current study. Global cognitive status was assessed using the mini-mental state examination (MMSE), and the Montreal cognitive assessment scale (MoCA). Attention and executive functions were evaluated using the Wechsler memory scale-revised (WMS-R) digit span test and trail making test (TMT) part A and part B, the Stroop test, semantic and phonemic fluency tests, and clock drawing test. Magnetic resonance imaging (MRI) was acquired according to the Alzheimer's disease neuroimaging initiative (ADNI) protocol. There were no significant differences among groups regarding age, sex, handedness, and years of education. In the comparison of the PD-CN group and the HC group, there was a statistical decrease in the total animal scores, lexical fluency, TMT part A and TMT part B scores in the PD-CN group. Subcortical gray matter volumes (GMV) were significantly lower in PD-CN patients. The PD-CN group had a significantly reduced total volume of right putamen and left angular gyrus compared to that in the HC group. We observed that putamen and angular gyrus volumes were lower in PD-CN patients. On the other hand, TMT part B may be a useful pretest in detecting the conversion of mild cognitive impairment in PD. Significant MRI volumetric measurements and neuropsychological test batteries can be helpful in the clinical follow-up in PD-CN patients.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.

GDNF improves the cognitive ability of PD mice by promoting glycosylation and membrane distribution of DAT

The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. In this study, we investigated the effects of GDNF on both cellular and mouse models of PD, including the glycosylation and membrane transport of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. This study revealed that in animal trials, MPTP-induced Parkinson's Disease (PD) mice exhibited a marked decline in cognitive function. Utilizing ELISA and neurotransmitter fiber imaging techniques, we observed a decrease in dopamine levels and a significant reduction in the intensity of dopamine signal release in the Prefrontal Cortex (PFC) of PD mice induced by MPTP. Intriguingly, these alterations were reversed by Glial Cell Line-Derived Neurotrophic Factor (GDNF). In cellular experiments, following MPP + intervention, there was a decrease in Gly-DAT modification in both the cell membrane and cytoplasm, coupled with an increase in Nongly-DAT expression and aggregation of DAT within the cytoplasm. Conversely, GDNF augmented DAT glycosylation and facilitated its membrane transport in damaged dopaminergic neurons, concurrently reversing the effects of GRASP65 depletion and Golgi fragmentation, thereby reducing the accumulation of DAT in the Golgi apparatus. Furthermore, overexpression of GRASP65 enhanced DAT transport in PD cells and mice, while suppression of GRASP65 attenuated the efficacy of GDNF on DAT. Additionally, GDNF potentiated the reutilization of neurotransmitters by the PFC presynaptic membrane, boosting the effective release of dopamine following a single electrical stimulation, ultimately ameliorating the cognitive impairments in PD mice.Therefore, we propose that GDNF enhances the glycosylation and membrane trafficking of DAT by facilitating the re-aggregation of the Golgi apparatus, thereby amplifying the utilization of DA signals. This ultimately leads to the improvement of cognitive abilities in PD mouse models. Our study illuminates, from a novel angle, the beneficial role of GDNF in augmenting DA utilization and cognitive function in PD, providing fresh insights into its therapeutic potential.

Towards multimodal cognition-based treatment for cognitive impairment in Parkinson's disease: drugs, exercise, non-invasive brain stimulation and technologies.

Cognitive impairment is one of the most challenging non-motor symptoms of Parkinson's disease (PD) and may occur during all PD stages. There are no established pharmacological treatments for PD-related cognitive impairment, which may be improved by cognition-based interventions (i.e., cognitive stimulation, cognitive training, cognitive rehabilitation). Multimodal cognition-based interventions by adjunctive drugs, exercise, non-invasive brain stimulation and technologies may be effective in PD. Exercise combined with cognitive training may enhance global, memory, visuospatial and executive functioning, transcranial direct current stimulation delivered alongside cognitive training may improve attention and executive functioning, and exergames, semi-immersive virtual reality (VR) and telerehabilitation plus non-immersive VR combined with cognitive training may ameliorate global and executive functioning in PD patients. The evidence reviewed here, despite preliminary, is very encouraging and suggests strong rationale for combining pharmacological and non-pharmacological interventions with cognition-based treatments in PD. To overcome limitations of current studies, we propose some recommendations for future trials on drugs, exercise, non-invasive brain stimulation and technologies combined with cognition-based treatments for cognitive impairment in PD.

Spatiotemporal Progression Patterns of Dopamine Availability and Deep Gray Matter Volume in Parkinson Disease-Related Cognitive Impairment.

Cognitive impairment is a frequent nonmotor symptom in patients with Parkinson disease (PD), and early cognitive decline is often attributed to dopaminergic system dysfunction. We aimed to explore spatiotemporal progression patterns of striatal dopamine availability and regional brain volume based on cognitive status among patients with PD. This retrospective, cross-sectional study included patients with newly diagnosed PD who were not taking medication for this condition who visited a university-affiliated hospital in Seoul between January 2018 and December 2020. Patients were classified as having normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or PD dementia (PDD) based on Seoul Neuropsychological Screening Battery-II, which includes 31 subsets covering activities of daily living and 5 cognitive domains. They all had brain imaging with MRI and PET with 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane at baseline. Subsequently, standardized uptake value ratios (SUVRs) for regional dopamine availability and regional gray matter volumes were obtained using automated segmentation. These metrics were compared across cognitive status groups, and spatiotemporal progression patterns were analyzed using the Subtype and Stage Inference machine learning technique. Among 168 patients (mean age, 73.3 ± 6.1 years; 81 [48.2%] women), 65 had PD-NC, 65 had PD-MCI, and 38 had PDD. Patients with PD-MCI exhibited lower SUVRs (3.61 ± 1.31, p < 0.001) in the caudate than patients with PD-NC (4.43 ± 1.21) but higher SUVRs than patients with PDD (2.39 ± 1.06). Patients with PD-NC had higher thalamic SUVRs (1.55 ± 0.16, p < 0.001) than patients with both PD-MCI (1.45 ± 0.16) and PDD (1.38 ± 0.19). Regional deep gray matter volumes of the caudate (p = 0.015), putamen (p = 0.012), globus pallidus (p < 0.001), thalamus (p < 0.001), hippocampus (p < 0.001), and amygdala (p < 0.001) were more reduced in patients with PD-MCI or PDD than in patients with PD-NC, and the SUVR of the caudate correlated with caudate volume (r = 0.187, p = 0.015). Hippocampal atrophy was the initial change influencing cognitive impairment. The reduced dopamine availability of the thalamus preceded reductions in volume across most deep gray matter regions. Our finding underscores the association between decreased dopamine availability and volume of the caudate and thalamus with cognitive dysfunction in PD. The dopamine availability of the caudate and thalamus was reduced before the volume of the caudate and thalamus was decreased, highlighting the spatiotemporal association between dopaminergic and structural pathology in cognitive impairment in PD.

Cognitive Speed in Neurodegenerative Disease: Comparing Mean Rate and Inconsistency Within and Across the Alzheimer's and Lewy Body Spectra in the COMPASS-ND Study.

Alzheimer's disease (AD) and Lewy body disease (LBD) are characterized by early and gradual worsening perturbations in speeded cognitive responses. Using simple and choice reaction time tasks, we compared two indicators of cognitive speed within and across the AD and LBD spectra: mean rate (average reaction time across trials) and inconsistency (within person variability). The AD spectrum cohorts included subjective cognitive impairment (SCI, n = 28), mild cognitive impairment (MCI, n = 121), and AD (n = 45) participants. The LBD spectrum included Parkinson's disease (PD, n = 32), mild cognitive impairment in PD (PD-MCI, n = 21), and LBD (n = 18) participants. A cognitively unimpaired (CU, n = 39) cohort served as common benchmark. We conducted multivariate analyses of variance and discrimination analyses. Within the AD spectrum, the AD cohort was slower and more inconsistent than the CU, SCI, and MCI cohorts. The MCI cohort was slower than the CU cohort. Within the LBD spectrum, the LBD cohort was slower and more inconsistent than the CU, PD, and PD-MCI cohorts. The PD-MCI cohort was slower than the CU and PD cohorts. In cross-spectra (corresponding cohort) comparisons, the LBD cohort was slower and more inconsistent than the AD cohort. The PD-MCI cohort was slower than the MCI cohort. Discrimination analyses clarified the group difference patterns. For both speed tasks, mean rate and inconsistency demonstrated similar sensitivity to spectra-related comparisons. Both dementia cohorts were slower and more inconsistent than each of their respective non-dementia cohorts.

GWAS Identifies DPP6 as Risk Gene of Cognitive Decline in Parkinson's Disease.

Cognitive decline is among the most common non-motor symptoms in Parkinson's disease (PD), while its physiological mechanisms remain poorly understood. Genetic factors constituted a fundamental determinant in the heterogeneity of cognitive decline among PD patients. However, the underlying genetic background was still less studied. To explore the genetic determinants contributing to cognitive decline in PD, we performed genome-wide survival analysis using a Cox proportional hazards model in a longitudinal cohort of 450 Chinese patients with PD, and further explored the functional effect of the target variant. Additionally, we built a clinical-genetic model by incorporating clinical characteristics and polygenic risk score (PRS) to predict cognitive decline in PD. The cohort was followed up for an average of 5.25 (SE = 2.46) years, with 95 incidents of cognitive impairment. We identified significant association between locus rs75819919 (DPP6) and accelerated cognitive decline (p = 8.63E-09, beta = 1.74, SE = 0.30). Dual-luciferase reporter assay suggested this locus might be involved in the regulation of DPP6 expression. Using data set from the UK Biobank, we identified rs75819919 was associated with cognitive performance in the general population. Incorporation of PRS increased the model's predictability, achieving an average AUC of 75.6% through fivefold cross-validation in 1000 iterations. These findings improve the current understanding of the genetic etiology of cognitive impairment in PD, and provide a novel target DPP6 to explore therapeutic options. Our results also demonstrate the potential to develop clinical-genetic model to identify patients susceptible to cognitive impairment and thus provide personalized clinical guidance.

NIR-II light therapy improves cognitive performance in MPTP induced Parkinson's disease rat models: A preliminary experimental study

Cognitive impairment is an important component of non motor symptoms in Parkinson's disease (PD), and if not addressed in a timely manner, it can easily progress to dementia. However, no effective method currently exists to completely prevent or reverse cognitive impairment associated with PD. We therefore aimed to investigate the therapeutic effect of near-infrared region II light (NIR-II) region illumination on cognitive impairment in PD through behavioral experiments (water maze and rotary rod) and multiple fluorescence immunohistochemistry techniques. The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced group was compared with the MPTP- untreated rat group, showing a significant reduction in escape latency and significant increase in the fall latency in the MPTP-treated group. The horizontal analysis results indicated that NIR-II phototherapy improved the learning and cognitive abilities as well as coordination and balance abilities of rats. Post-treatment, the MPTP rats showed significantly shortened, escape latency, prolonged target quadrant residence time, and prolonged fall latency compared with pre-treatment. The longitudinal analysis results reaffirmed that NIR-II phototherapy improved the learning and cognitive abilities as well as coordination and balance abilities of rats. The multiple fluorescence immunohistochemistry analysis trend plot showed that the activated microglia and astrocytes in the hippocampus were highest in MPTP-induced PD untreated group, moderate in MPTP-induced PD treatment group, and lowest in the control group. Our data indicates that NIR-II illumination improves learning and cognitive impairment as well as coordination and balance abilities in PD rats by downregulating the activation of microglia and astrocytes in the hippocampus.

Analysis of cognitive dysfunction in Parkinson's disease using voxel based morphometry and radiomics.

Cognitive impairment in Parkinson's disease (PD) is associated with changes in the brain anatomical structures. The objective of this study, is to identify the atrophy patterns based on the severity of cognitive decline and evaluate the disease progression. In this study, gray matter alterations are analysed in 135 PD subjects under 3 cognitive domains (91 Cognitively normal PD (NC-PD), 25 PD with Mild Cognitive Impairment (PD-MCI) and 19 PD with Dementia (PD-D)) by comparing them with 58 Healthy Control (HC) subjects. Voxel Based Morphometry (VBM) is used to segment the gray matter regions in magnetic resonance images and analyse the atrophy patterns statistically. Significant patterns of gray matter variations observed in the middle temporal and medial frontal region differentiate between HC and PD subject groups based on the severity of cognitive decline. Abnormalities in gray matter is substantiated through radiomic features extracted from the significant gray matter clusters. Significant radiomic features of the clusters are able to differentiate between the HC and PD-D subjects with an accuracy of 81.82%. Higher atrophy levels identified in PD-D subjects compared to NC-PD and PD-MCI group enables early diagnosis and treatment procedures. The combined and comprehensive analysis of gray matter alterations through VBM and radiomic features gives better assessment of cognitive impairment in PD.