Cognitive Deficits In Parkinson's Disease Research Articles

Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N=42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. The posterior-cortical subtype (N=19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N=11) group, p-false discovery rate (FDR)=.01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N=20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR=.01). Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Hope vs. Hype I: Spreading alpha-synuclein explains cognitive deficits in Parkinson disease

The Parkinson Study Group (PSG) gathered North American experts in Parkinson disease during the 9th Annual Symposium on “Shaping the Management of Parkinson Disease: Debating Current Controversies”. Debaters were tasked with agree or disagree positions to a particular prompt. This is the first in three-part series of “Hype vs. Hope” debates involving current trends and advances in Parkinson disease. With the prompt of “Spreading alpha-synuclein explains cognitive deficits in Parkinson disease,” Dr. Kelly Mills, MD, MHS was tasked with the “agree” stance and Dr. Abhimanyu Mahajan, MD, MHS was tasked with the “disagree” stance. The following point-of-view article is an adaptation of this debate

Theory of mind in mild cognitive impairment and Parkinson’s disease: The role of memory impairment

BackgroundSocial cognition is impaired in Parkinson’s disease (PD). Whether social cognitive impairment (iSC) is a by-product of the underlying cognitive deficits in PD or a process independent of cognitive status is unknown. To this end, the present study was designed to investigate the weight of specific cognitive deficits in social cognition, considering different mild cognitive impairment subtypes of PD (PD-MCI).MethodsFifty-eight PD patients underwent a neuropsychological battery assessing executive functions, memory, language, and visuospatial domains, together with social cognitive tests focused on theory of mind (ToM). Patients were divided into subgroups according to their clinical cognitive status: amnestic PD-MCI (PD-aMCI, n = 18), non-amnestic PD-MCI (PD-naMCI, n = 16), and cognitively unimpaired (PD-CU, n = 24). Composite scores for cognitive and social domains were computed to perform mediation analyses.ResultsMemory and language impairments mediated the effect of executive functioning in social cognitive deficits in PD patients. Dividing by MCI subgroups, iSC occurred more frequently in PD-aMCI (77.8%) than in PD-naMCI (18.8%) and PD-CU (8.3%). Moreover, PD-aMCI performed worse than PD-CU in all social cognitive measures, whereas PD-naMCI performed worse than PD-CU in only one subtype of the affective and cognitive ToM tests.ConclusionsOur findings suggest that ToM impairment in PD can be explained by memory dysfunction that mediates executive control. ToM downsides in the amnesic forms of PD-MCI may suggest that subtle changes in social cognition could partly explain future transitions into dementia. Hence, the evaluation of social cognition in PD is critical to characterize a possible behavioral marker of cognitive decline.

Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD.

Task-Related Reorganization of Cognitive Network in Parkinson's Disease Using Electrophysiology.

Cognitive deficits in Parkinson's disease (PD) patients are well described, however, their underlying neural mechanisms as assessed by electrophysiology are not clear. To reveal specific neural network alterations during the performance of cognitive tasks in PD patients using electroencephalography (EEG). Ninety participants, 60 PD patients and 30 controls underwent EEG recording while performing a GO/NOGO task. Source localization of 16 regions of interest known to play a pivotal role in GO/NOGO task was performed to assess power density and connectivity within this cognitive network. The connectivity matrices were evaluated using a graph-theory approach that included measures of cluster-coefficient, degree, and global-efficiency. A mixed-model analysis, corrected for age and levodopa equivalent daily dose was performed to examine neural changes between PD patients and controls. PD patients performed worse in the GO/NOGO task (P < 0.001). The power density was higher in δ and θ bands, but lower in α and β bands in PD patients compared to controls (interaction group × band: P < 0.001), indicating a general slowness within the network. Patients had more connections within the network (P < 0.034) than controls and these were used for graph-theory analysis. Differences between groups in graph-theory measures were found only in cluster-coefficient, which was higher in PD compared to controls (interaction group × band: P < 0.001). Cognitive deficits in PD are underlined by alterations at the brain network level, including higher δ and θ activity, lower α and β activity, increased connectivity, and segregated network organization. These findings may have important implications on future adaptive deep brain stimulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognitive Deficits in Parkinson's Disease Are Associated with Neuronal Dysfunction and Not White Matter Lesions.

Cognitive deficits considerably contribute to the patient's burden in Parkinson's disease (PD). While cognitive decline is linked to neuronal dysfunction, the additional role of white matter lesions (WML) is discussed controversially. To investigate the influence of WML, in comparison to neuronal dysfunction, on cognitive deficits in PD. We prospectively recruited patients with PD who underwent neuropsychological assessment using the Mattis Dementia Rating Scale 2 (DRS-2) or Parkinson Neuropsychometric Dementia Assessment (PANDA) and both MRI and PET with [18F]fluorodeoxyglucose (FDG). WML-load and PD cognition-related covariance pattern (PDCP) as a measure of neuronal dysfunction were read out. Relationship between cognitive performance and rank-transformed WML was analyzed with linear regression, controlling for the patients' age. PDCP subject scores were investigated likewise and in a second step adjusting for age and WML load. Inclusion criteria were met by 76 patients with a mean (± SD) age of 63.5 ± 9.0 years and disease duration of 10.7 ± 5.4 years. Neuropsychological testing revealed front executive and parietal deficits and a median DRS-2 score of 137 (range 119-144)/144 and PANDA score of 22 (range 3-30)/30. No association between WML and cognition was observed, whereas PDCP subject scores showed a trend-level negative correlation with the DRS-2 (P = 0.060) as well as a negative correlation with PANDA (P = 0.049) which persisted also after additional correction for WML (P = 0.039). The present study indicates that microangiopathic WML do not have a relevant impact on neurocognitive performance in PD whereas neuronal dysfunction does.

The Role of Monoaminergic Tones and Brain Metabolism in Cognition in De Novo Parkinson's Disease.

Cognitive impairment is frequent in Parkinson's disease (PD) and several neurotransmitter changes have been reported since the time of diagnosis, although seldom investigated altogether in the same patient cohort. Our aim was to evaluate the association between neurotransmitter impairment, brain metabolism, and cognition in a cohort of de novo, drug-naïve PD patients. We retrospectively selected 95 consecutive drug-naïve PD patients (mean age 71.89±7.53) undergoing at the time of diagnosis a brain [18F]FDG-PET as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT as a marker and dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological battery. Positive correlations were observed between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic tone and working memory (r = 0.304, p = 0.003), (iii) qEEG slowing in the posterior leads and both memory (r = 0.299, p = 0.004) and visuo-spatial functions (r = 0.357, p < 0.001). In subjects with PD, the impact of regional metabolism and diffuse projection systems degeneration differs across cognitive domains. These findings suggest possible tailored approaches to the treatment of cognitive deficits in PD.

Effects of cognitive rehabilitation in Parkinson disease: a meta-analysis.

Cognitive symptoms are common in Parkinson's disease (PD) and affect patients' quality of life. Pharmacological interventionsoften do not improve such deficits that might benefit of cognitive rehabilitation. However, previous meta-analysis on this topic reported inconsistent results. Clarifying the efficacy of cognitive rehabilitation would be pivotal to optimize treatment and reduce care's costs. This meta-analysis aims at determining whether current literature lays in favor of the effectiveness of cognitive rehabilitation in PD and at understanding whether its effect might change depending on the trained cognitive domain. We searched online databases for studies concerning cognitive rehabilitation in PD. Fourteen studies encompassing 767 participants were included. Analyses were conducted for each cognitive domain separately, examining several neuropsychologicalmeasures for each function. We found that rehabilitation improves global cognition, executive functions, and long- and short-term memory. The current body of research indicates that cognitive rehabilitation improves specific cognitive deficits in PD and that it should be tailored on patients' specific impairments. These interventions should be employed considering that not all the cognitive domains might benefit of a cognitive training. Finally, the high heterogeneity among studies suggests the need for more controlled clinical trials.

Shannon entropy: A novel parameter for quantifying pentagon copying performance in non-demented Parkinson's disease patients

IntroductionImpaired copy of intersecting pentagons from the Mini-Mental State Examination (MMSE), has been used to assess dementia in Parkinson's disease (PD). We used a digitizing tablet during the pentagon copying test (PCT) as a potential tool for evaluating early cognitive deficits in PD without major cognitive impairment. We also aimed to uncover the neural correlates of the identified parameters using whole-brain magnetic resonance imaging (MRI). MethodsWe enrolled 27 patients with PD without major cognitive impairment and 25 age-matched healthy controls (HC). We focused on drawing parameters using a digitizing tablet. Parameters with between-group differences were correlated with cognitive outcomes and were used as covariates in the whole-brain voxel-wise analysis using voxel-based morphometry; familywise error (FWE) threshold p < 0.001. ResultsPD patients differed from HC in attention domain z-scores (p < 0.0001). In terms of tablet parameters, the groups differed in Shannon entropy (horizontal in-air, p = 0.003), which quantifies the movements between two strokes. In PD, a correlation was found between the median of Shannon entropy (horizontal in-air) and attention z-scores (R = −0.55, p = 0.006). The VBM revealed an association between our drawing parameter of interest and gray matter (GM) volume variability in the right superior parietal lobe (SPL). ConclusionUsing a digitizing tablet during the PCT, we identified a novel entropy-based parameter that differed between the nondemented PD and HC groups. This in-air parameter correlated with the level of attention and was linked to GM volume variability of the region engaged in spatial attention.

Neural correlates of self-awareness of cognitive deficits in non-demented patients with Parkinson's disease.

The aim was to investigate the neural correlates of impaired self-awareness of cognitive deficits (IACd) in non-demented patients with Parkinson's disease (PD). This cross-sectional study enrolled 153 drug-naïve and non-demented PD patients who underwent brain magnetic resonance imaging, dopamine transporter (DAT) positron emission tomography, detailed neuropsychological testing, and the Cognitive Complaints Interview at baseline. Based on the presence of mild cognitive impairment and subjective cognitive complaints, patients were grouped into those with IACd (PD-IACd+, n=33) and those with normal recognition of cognitive function (n=82) or underestimation of cognitive function (n=38). Cortical thickness, white matter (WM) integrity, DAT availability and cognitive function were compared between the groups. The prevalence of IACd was 21.6% in drug-naïve patients with PD. The PD-IACd+ group had a lower z-score in the Stroop color reading test than the other groups. Patients in the PD-IACd+ group had WM disintegrity, especially in the genu of the corpus callosum and anterior limb of the internal capsule, compared to those without IACd, whilst cortical thickness or striatal DAT availability was comparable regardless of the presence of IACd. Amongst patients with mild cognitive impairment, those with IACd had more severe WM disintegrity than those without IACd. Structural connectivity between and from the frontal lobes is closely associated with self-awareness of cognitive deficits in PD. Evaluating frontal structural connectivity from the early stages of PD will be important in assessing the actual cognitive and daily life performance of patients with PD.

Altered Cerebellar Resting-State Functional Connectivity in Early-Stage Parkinson's Disease Patients With Cognitive Impairment.

Background: Cognitive impairment is one of the most prominent non-motor symptoms in Parkinson's disease (PD), due in part to known cerebellar dysfunctions. Furthermore, previous studies have reported altered cerebellar functional connectivity (FC) in PD patients. Yet whether these changes are also due to the cognitive deficits in PD remain unclear.Methods: A total of 122 non-dementia participants, including 64 patients with early PD and 58 age- and gender-matched elderly controls were stratified into four groups based on their cognitive status (normal cognition vs. cognitive impairment). Cerebellar volumetry and FC were investigated by analyzing, respectively, structural and resting-state functional MRI data among groups using quality control and quantitative measures. Correlation analysis between MRI metrics and clinical features (motor and cognitive scores) were performed.Results: Compared to healthy control subjects with no cognitive deficits, altered cerebellar FC were observed in early PD participants with both motor and cognitive deficits, but not in PD patients with normal cognition, nor elderly subjects showing signs of a cognitive impairment. Moreover, connectivity between the “motor” cerebellum and SMA was positively correlated with motor scores, while intracerebellar connectivity was positively correlated with cognitive scores in PD patients with cognitive impairment. No cerebellar volumetric difference was observed between groups.Conclusions: These findings show that altered cerebellar FC during resting state in early PD patients may be driven not solely by the motor deficits, but by cognitive deficits as well, hence highlighting the interplay between motor and cognitive functioning, and possibly reflecting compensatory mechanisms, in the early PD.

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

IntroductionWe aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia. MethodsThe study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. ResultsCompared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02). ConclusionsEarly cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson's disease.

After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist Nourianz® (istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A2A receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.

Voltage-Gated Sodium Channels Are Involved in Cognitive Impairments in Parkinson's Disease- like Rats

Cognitive impairment is one of the common non-motor symptoms in Parkinson's disease (PD). The hippocampus is a critical structure for learning and memory processes. The abnormal synaptic plasticity in the hippocampus is suggested to be associated with cognitive dysfunction in PD. Voltage gated sodium channels (VGSCs) are key molecules involved in synaptic transmission in the nervous system. Here, the expression patterns of VGSC subtypes Nav1.1, Nav1.3, Nav1.6 in the hippocampus of 6-hydroxydopamine (6-OHDA) lesioned rats were investigated at different time points after 6-OHDA injection. The results showed that the expression of Nav1.1 was remarkably increased in reactive astrocytes at 28days, whereas was sharply reduced at 49days after 6-OHDA injection. However, the expression of Nav1.6 was not different from the control hippocampus at 28days, but was abundantly increased in neurons of the contralateral and ipsilateral hippocampus at 49days after 6-OHDA injection. Moreover, Nav1.3, a subtype predominantly expressed at embryonic stage, was scatteredly re-expressed in neurons of the CA area in the contralateral and ipsilateral hippocampus at 49days after 6-OHDA injection. Furthermore, spatial learning and memory in 6-OHDA lesioned rats were effectively improved by acute treatment with a VGSCs blocker, phenytoin. These findings suggested that VGSCs may play an important role in the genesis of cognitive deficits in PD.

Affective theory of mind in Parkinson's disease: the effect of cognitive performance.

PurposeAmong other non-motor symptoms, theory of mind (ToM), the ability to recognize, understand and infer others’ mental states, beliefs, intents and wishes, has been shown to deteriorate during the course of Parkinson’s disease (PD). It has been speculated that ToM impairments could be related to cognitive deficits in PD. However, the current state of literature suggests that there is heterogeneity regarding the involvement of cognitive functioning in the relationship of PD and ToM. The study aimed to measure affective ToM abilities and cognitive performance in a sample of PD patients, to explore the link between affective ToM abilities and cognitive status, and to examine the impact of PD on affective ToM through the mediator effect of cognitive performance.Patients and methodsSixty-five patients diagnosed with idiopathic PD and 51 healthy controls matched for age, gender and educational level completed a visual affective ToM task (Reading the Mind in the Eyes – RMET), cognitive performance was evaluated with Montreal Cognitive Assessment, and psychiatric symptoms were measured with BPRS-E (Brief Psychiatric Rating Scale).ResultsAffective ToM abilities were preserved in early PD patients, declining as the disease progressed. Deficits in cognitive functioning predicted deficiencies in affective ToM. Although attention (AT), executive functions (EF) and visuospatial abilities (VSA) together mediated the relationship between PD and affective ToM, only VSA impairment had a specific negative impact on affective ToM. Moreover, 41% of the total effect of attention and executive functions on affective ToM was mediated by visuospatial skills.ConclusionCognitive performance may have an impact on the relationship between PD and affective ToM through the involvement of VSA. The influence of AT and EF in this relationship appears to be also exerted by PD patients’ VSA.

Trx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson's disease model in mice

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characteristic motor symptoms and cognitive impairment. Thioredoxin-1 (Trx-1) is a redox protein and protects neurons from various injuries. Our previous study has shown that Trx-1 overexpression attenuates movement disorder in PD. However, whether Trx-1 ameliorates cognitive deficits in PD is still unknown. In the present study, we investigated the effects of Trx-1 on learning and memory in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in mice. We demonstrated that deficits in learning and memory were induced by MPTP in mice through the elevated plus-maze test. We found that the retention transfer latency time was shorten, escape latency was decreased and the number of platform crossings was increased in the Morris water maze (MWM) in Trx-1 transgenic (TG) mice when compared with wild type mice. The expressions of tyrosine hydroxylase (TH) and dopamine D1 receptor (D1R) were decreased by MPTP, which were restored in Trx-1 TG mice. The expression of N-methyl-D-aspartate receptor 2B subunit (NR2B), the levels of phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cAMP-response element binding protein (CREB) in the hippocampus were decreased by MPTP, which were reversed in Trx-1 TG mice. These results suggest that Trx-1 ameliorates learning and memory deficits in MPTP-induced PD model in mice via modulating the D1R and the NMDAR-ERK1/2-CREB pathway. Trx-1 may be a therapy target for learning and memory deficits in PD.

Resting State fMRI: A Valuable Tool for Studying Cognitive Dysfunction in PD.

Cognitive impairment is a common disabling symptom in PD. Unlike motor symptoms, the mechanism underlying cognitive dysfunction in Parkinson's disease (PD) remains unclear and may involve multiple pathophysiological processes. Resting state functional magnetic resonance imaging (rs-fMRI) is a fast-developing research field, and its application in cognitive impairments in PD is rapidly growing. In this review, we summarize rs-fMRI studies on cognitive function in PD and discuss the strong potential of rs-fMRI in this area. rs-fMRI can help reveal the pathophysiology of cognitive symptoms in PD, facilitate early identification of PD patients with cognitive impairment, distinguish PD dementia from dementia with Lewy bodies, and monitor and guide treatment for cognitive impairment in PD. In particular, ongoing and future longitudinal studies would enhance the ability of rs-fMRI in predicting PD dementia. In combination with other modalities such as positron emission tomography, rs-fMRI could give us more information on the underlying mechanism of cognitive deficits in PD.

The genetic predictors of cognitive impairment in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder that can be both sporadic and familial. A number of studies are devoted to the study of non-motor symptoms in PD today. Cognitive deficits, and especially dementia, are one of the most severe and disabling non-motor symptoms of PD. More than a quarter of patients in the early stages of PD have a moderate cognitive impairment, more than half of patients with PD develop dementia within 10 years from the date of diagnosis. Using genome-wide association studies (GWAS), a number of genes associated with cognitive impairment have been identified based on a comparison of genetic and clinical phenotypes. These genes can be divided into three groups: genes that lead to the development of PD and are inherited according to the laws of Mendel (SNCA), genes that are risk factors for PD development (GBA, MAPT) and genes associated with the development of cognitive impairment, but not with PD (COMT, APOE, BDNF). This review examines the effect of genetic variants in the above-mentioned genes on cognitive functions in patients with PD. The elucidation of the genetic basis of cognitive deficits in PD could help in choice of treatment tactics and in development of new therapeutic strategies.

Altered N100-potential associates with working memory impairment in Parkinson's disease.

The diagnosis of cognitive impairment and dementia often occurring with Parkinson's disease (PD) is still based on the clinical picture and neuropsychological examination. Ancillary methods to detect cognitive decline in these patients are, therefore, needed. Alterations in the latencies and amplitudes of evoked response potential (ERP) components N100 and P200 have been described in PD. Due to limited number of studies their relation to cognitive deficits in PD remains obscure. The present study was designed to examine if alterations in the N100- and P200-potentials associate with neuropsychological impairment in PD. EEG-ERP was conducted to 18 PD patients and 24 healthy controls. The patients underwent a thorough neuropsychological evaluation. The controls were screened for cognitive impairment with Consortium to Establish Alzheimer's disease (CERAD)-testing and a normal result were required to be included in the study. The N100-latency was prolonged in the patients compared to the controls (p=0.05). In the patients, the N100 latency correlated significantly with a visual working memory task (p=0.01). Also N100 latency was prolonged and N100 amplitude habituation diminished in the patients achieving poorly in this task. We conclude that prolonged N100-latency and diminished amplitude habituation associate with visual working memory impairment in PD.