Cognitive Performance In Parkinson's Disease Research Articles

Assessment tools for cognitive performance in Parkinson's disease and its genetic contributors.

We have shown that genetic factors associating with motor progression of Parkinson's disease (PD), but their roles in cognitive function is poorly understood. One reason is that while cognitive performance in PD can be evaluated by various cognitive scales, there is no definitive guide indicating which tool performs better. Data were obtained from the Parkinson's Progression Markers Initiative, where cognitive performance was assessed using five cognitive screening tools, including Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment, Benton Judgment of Line Orientation, Modified Semantic Fluency Test, and Letter Number Sequencing Test, at baseline and subsequent annual follow-up visit for 5 years. Genetic data including ApoE and other PD risk genetic information were also obtained. We used SPSS-receiver operating characteristic and ANOVA repeated measures to evaluate which cognitive assessment is the best reflecting cognitive performance in PD at early stage and over time. Logistic regression analyses were used to determine the genetic associations with the rapidity of cognitive decline in PD. SDMT performed better in detecting mild cognitive impairment at baseline (AUC = 0.763), and SDMT was the only tool showing a steady cognitive decline during longitudinal observation. Multigenetic factors significantly associated with cognitive impairment at early stage of the disease (AUC = 0.950) with IP6K2 rs12497850 more evident, and a significantly faster decline (AUC = 0.831) within 5 years after motor onset, particularly in those carrying FGF20 rs591323. SDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD.

A - 97 Anticholinergic Burden Scales Are Not Created Equal: Differential Relationships to Cognition in Parkinson's Disease.

Cognitive changes are common in Parkinson's disease (PD). While previous research suggests greater anticholinergic medication use relates to worse broad cognition in PD, its domain-specific relationships remain unknown. This study compared three anticholinergic scales to examine their relationship to worse memory and executive function in individuals with PD. Participants included 493 non-demented individuals with PD (mean age = 65.74, SD = 9.04; mean education = 15.0, SD = 2.79; 72% male; 94% White (non-Hispanic)) from a movement disorders specialty clinic. Medications were identified via chart review. Each medication was scored (0-3) and summed using three scales: Anticholinergic Risk Scale (ARS), Anticholinergic Drug Scale (ADS), Anticholinergic Cognitive Burden Scale (ACBS). Cognitive composites averaged normative z-scores: Executive Function (EF; Trails B, Stroop Color-Word, Letter Fluency) and Memory (HVLT-R and WMS-III Logical Memory delayed recalls). Analyses included Bonferroni-adjusted, bootstrapped Spearman correlations. The three scales were significantly related, but with only fair agreement (Kendall's W(2) = 0.37, p < 0.001). Worse memory related to higher cholinergic burden on only the ACBS (r = -0.10, p = 0.02). Exploratory analyses indicated sex differences in the relationship between cognition and anticholinergic burden. For men, worse memory related to higher scores on both the ACBS (r = -0.11, p = 0.04) and ARS (r = -0.11, p = 0.045). For women, higher ACBS scores related to worse EF (r = -0.18, p = 0.03), whereas higher ADS scores related to worse memory and EF (r = -0.18, p = 0.04; r = -0.26, p = 0.002). Anticholinergic burden scales differentially related to cognitive performance in PD, with only ACBS showing a significant relationship to memory. Exploratory analyses suggest that scales may have differential relationships to memory and EF in men and women.

Validating virtual administration of neuropsychological testing in Parkinson disease: a pilot study

COVID-19 has highlighted the need for remote cognitive testing, but the reliability and validity of virtual cognitive testing in Parkinson disease (PD) is unknown. Therefore, we assessed PD participants enrolled in an observational, cognition-focused study with an extensive cognitive battery completed both in-person and via video conference close in time. Data for 35 PD participants with normal cognition to mild dementia were analyzed. Only one test (semantic verbal fluency) demonstrated a difference in score by administration type, with a significantly better score virtually. Only three tests demonstrated good reliability for in-person versus virtual testing, but reliability values for visit 1 versus visit 2 were similarly low overall. Trail Making Test B was successfully administered virtually to only 18 participants due to technical issues. Virtual and in-person cognitive testing generate similar scores at the group level, but with poor to moderate reliability for most tests. Mode of test administration, learning effects, and technical difficulties explained little of the low test–retest reliability, indicating possible significant short-term variability in cognitive performance in PD in general, which has implications for clinical care and research. In-person cognitive testing with a neuropsychologist remains the gold standard, and it remains to be determined if virtual cognitive testing is feasible in PD.

Cognitive Performance is Associated with Altered Cerebral Hemodynamics Assessed by Transcranial Ultrasound in Parkinson's Disease.

PurposeCognitive impairment (CI) is a common but debilitating non-motor symptom in Parkinson’s disease (PD). Although cerebrovascular functions are related to cognitive performance in healthy individuals, such a relation in PD remains elusive. This study aims to assess the association between cerebrovascular function and cognitive performance in PD individuals.Patients and MethodsTwo-hundred-and-one PD individuals were retrospectively included. They were subsequently divided into two groups: PD with normal cognition (PD-NC) and PD with CI (PD-CI). Cerebral hemodynamic characteristics of the middle cerebral arteries were assessed by transcranial ultrasound. The association between scores in each cognitive domain and cerebral hemodynamic parameters was further analyzed using regression analyses. Additionally, a binary logistic regression model with backward stepwise procedure was applied to build the model for discriminating CI in PD individuals. An independent dataset of additional 46 PD individuals was used further.ResultsThe PD-CI group showed a relatively lower end-diastolic blood flow velocity (EDV, p < 0.05) and a higher resistive index (RI, p < 0.05) compared to the PD-NC group. RI showed significant associations with the memory item score of Montreal Cognitive Assessment (p < 0.05). A model combining clinical and hemodynamic variables was established with optimal efficiency (area under the curve, AUC = 0.651). Further replication of the model in an independent dataset yielded a great consistency (AUC = 0.704).ConclusionIn our study, cerebrovascular functions were significantly associated with the cognitive performance in PD individuals, especially with the memory task. The established model was effective in identifying CI in PD individuals, which might be a potentially useful tool to screen the cognitive decline in PD individuals at an early stage of the disease. Further studies with larger sample sizes in different populations are warranted.

Dopamine depletion and subcortical dysfunction disrupt cortical synchronization and metastability affecting cognitive function in Parkinson's disease.

Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these pathological changes on large‐scale dynamic integration and segregation of the cortex are not well understood. In this study, we investigated the effect of subcortical dysfunction on cortical dynamics and cognition in PD. Spatiotemporal dynamics of the phase interactions of resting‐state blood‐oxygen‐level‐dependent signals in 159 PD patients and 152 normal control (NC) individuals were estimated. The relationships between subcortical atrophy, subcortical–cortical fiber connectivity impairment, cortical synchronization/metastability, and cognitive performance were then assessed. We found that cortical synchronization and metastability in PD patients were significantly decreased. To examine whether this is an effect of dopamine depletion, we investigated 45 PD patients both ON and OFF dopamine replacement therapy, and found that cortical synchronization and metastability are significantly increased in the ON state. The extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediates the difference in cognitive performance between the PD and NC groups. Furthermore, both the thalamic volume and thalamocortical fiber connectivity had positive relationships with cortical synchronization and metastability in the dopaminergic OFF state, and mediate the difference in cortical synchronization between the PD and NC groups. In addition, thalamic volume also reflected cognitive performance, and cortical synchronization/metastability mediated the relationship between thalamic volume and cognitive performance in PD patients. Together, these results highlight that subcortical dysfunction and reduced dopamine levels are responsible for decreased cortical synchronization and metastability, further affecting cognitive performance in PD. This might lead to biomarkers being identified that can predict if a patient is at risk of developing dementia.

Visual dysfunction is associated with cognitive impairment in Parkinson's disease

IntroductionVisual dysfunction and cognitive impairment are common in Parkinson's disease (PD) but the precise contribution of lower-level visual impairment to visual-input based cognitive performance has not been extensively characterized in PD. MethodsWe included 49 PD patients and 22 healthy controls (HC). Lower-level visual function tests [high and low contrast visual acuity (HCVA and LCVA) and contrast sensitivity (CS)] and a neuropsychological battery (involving visual cognition) were performed. Pairwise correlations between lower-level visual functions and visual cognition were computed and stepwise linear regressions were fitted introducing age, Geriatric Depression Scale, and lower-level visual functions in the model to calculate their predicted effect on visual cognition. ResultsCompared to controls, patients presented a significant impairment in all cognitive domains (visual attention, visual processing speed and visual perception, visuospatial abilities, visuoconstructive abilities, and visual memory), and lower-level visual functions. HCVA and LCVA were significantly associated with visual cognition in PD. HCVA explained up to 49.3% and 34.2% of the variability in visual perception and visuospatial abilities, respectively, whereas LCVA was mainly associated with short- and long-term visual memory and visuospatial abilities. ConclusionLower-level visual dysfunction is highly associated with cognitive performance in PD, when cognitive tests are based on visual input. Our results support that lower-level visual functions should be considered when assessing cognitive status of PD patients and might be useful for predicting cognitive deterioration.

Thalamic volume mediates associations between cardiorespiratory fitness (VO2max) and cognition in Parkinson's disease

IntroductionCognitive deficits occur in Parkinson's disease (PD). Cardiorespiratory fitness (CRF) is associated with better cognitive performance in aging especially in executive function (EF) and memory. The association between CRF and cognitive performance is understudied in people with PD. Brain structures underlying associations also remains unknown. This cross-sectional study examined the associations between CRF and cognitive performance in PD. We also examined associations between CRF and brain structures impacted in PD. Mediation analysis were conducted to examine whether brain structures impacted in PD mediate putative associations between CRF and cognitive performance. MethodsIndividuals with PD (N = 33) underwent magnetic resonance imaging (MRI), CRF evaluation (estimated VO2max), and neuropsychological assessment. Composite cognitive scores of episodic memory, EF, attention, language, and visuospatial functioning were generated. Structural equation models were constructed to examine whether MRI volume estimates (thalamus and pallidum) mediated associations between CRF and cognitive performance (adjusting for age, education, PD disease duration, sex, MDS-UPDRS motor score, and total intracranial volume). ResultsHigher CRF was associated with better episodic memory (Standardized β = 0.391; p = 0.008), EF (Standardized β = 0.324; p = 0.025), and visuospatial performance (Standardized β = 0.570; p = 0.005). Higher CRF was associated with larger thalamic (Standardized β = 0.722; p = 0.004) and pallidum (Standardized β = 0.635; p = 0.004) volumes. Thalamic volume mediated the association between higher CRF and better EF (Indirect effect = 0.309) and episodic memory (Indirect effect = 0.209) performance (p < 0.05). The pallidum did not significantly mediate associations between CRF and cognitive outcomes. ConclusionThe thalamus plays an important role in the association between CRF and both EF and episodic memory in PD.

Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1–4 Hz SWA in a region-dependent manner (F2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1–2 Hz SWA (F2, 687 =18.0, p < 0.001). The association of MoCA with 1–2 Hz SWA (and 1–4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1–2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD.

Cerebello-basal ganglia connectivity fingerprints related to motor/cognitive performance in Parkinson's disease

IntroductionThe role of the cerebellum in Parkinson's disease (PD) has attracted increasing attention; however, the role of functional connectivity (FC) between the basal ganglia and particular cerebellar subregions remains to be elucidated. We aimed to clarify the FC and its contribution to motor and cognitive performances in patients with PD. MethodsWe included 99 patients with PD and 99 age- and sex-matched healthy controls in this study. We created a cerebellar functional parcellation by performing cerebellum-only independent component analysis. Using the functional parcellation map, we performed seed-based connectivity analysis using each region as a seed and extracted the mean correlation coefficients within the thalamus and basal ganglia, including the caudate, pallidum, putamen and subthalamic nucleus. We examined the group differences and correlations with the motor and general cognitive scores. In addition, we conducted a mediation analysis to clarify the relationship among FC, motor severity, and cognition. ResultsThe PD group showed decreased FC between a wide range of cerebellar subregions and the basal ganglia. Motor severity was correlated with FC between the subthalamic nucleus and posterior Crus I/II, and general cognitive performance scores correlated with FC between the caudate nucleus and medial-posterior part of the Crus I/II (p < 0.05, corrected for multiple comparisons). The cerebello-caudate network had a direct effect on cognitive performance (p = 9.0 × 10−3), although partially mediated by motor performance (p = 8.2 × 10−3). ConclusionFC between cerebellar Crus I/II and divergent basal ganglia related to motor and cognitive performance in PD.

Individual changes in visual performance in non-demented Parkinson's disease patients: a 1-year follow-up study.

Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, and the cognitive status fluctuates over time. However, individual changes in longitudinal cognitive performance in PD are not fully understood. We evaluated three visual indices (visuoperception, visuoconstruction, and visuospatial ability) and four cognitive domains (attention/working memory, executive function, memory, and language) at baseline (Time1) and at 1-year follow-up (Time2) in 36 patients with PD and 32 healthy controls (HCs). To explore the magnitude and frequency of cognitive changes, we analyzed data using the simple difference method and the standardized regression-based method. We also explored the correlations between changes in test scores and several clinical predictors, using logistic regression analysis. At 1 year, patients with PD showed higher rates of change in scores on several cognitive tests, especially the Incomplete Letters test of visuoperception, compared to HCs. After adjusting for demographic variables, the visuoperceptual change was 61.1% overall, with the largest effect size. The changes in scores of visuoperception correlated with those of memory (r = 0.672, p < 0.001), language (r = 0.389, p < 0.05), and visuospatial ability (r = 0.379, p < 0.05). The severity of olfactory disturbance, the MDS-UPDRS Part I score, and younger PD onset predicted the significant changes observed in the Incomplete Letters test scores. Visuoperception changed more in non-demented PD patients than in HCs at 1-year follow-up. The changes in visuoperception could relate to involvement of the ventral occipitotemporal pathway, the more widespread temporal lobe, and brain reserve in PD.

Mild cognitive impairment, psychiatric symptoms, and executive functioning in patients with Parkinson's disease.

Mild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association. Participants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD-MCI (N = 73) or PD-normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating effect of PD-MCI status. There were no differences in mean psychiatric symptoms between PD-MCI and PD-NC. Psychiatric symptoms were predominantly associated with worse EF. The magnitude of the association between anxiety and worse EF was larger in participants with PD-MCI compared with PD-NC. A multivariable regression analysis examining the independent contributions of each symptom demonstrated the most robust association between EF and anxiety. Symptoms of anxiety, depression, and apathy are associated with worse executive functioning in individuals with PD. PD-MCI may be important in moderating the association between cognitive performance, specifically anxiety, and EF. Factors that promote cognitive resilience may serve as key therapeutic modalities in managing neuropsychiatric symptoms in PD.

Effect of single‐session transcranial direct current stimulation on cognition in Parkinson's disease

AimsNonmotor symptoms (NMS) such as cognitive impairment and impulse‐control disorders in Parkinson's disease (PD) remain a therapeutic challenge. Transcranial direct current stimulation (tDCS) has emerged as a promising alternative, although its immediate effects on NMS have been less well defined. In this randomized, sham‐controlled, crossover study, we aimed to explore the single‐session tDCS effects on cognitive performance in PD.MethodsTen nondemented patients with PD completed two sessions in counterbalanced order, receiving 20 minutes of either 2 mA anodal or sham tDCS over the left dorsolateral prefrontal cortex (DLPFC). During stimulation, they performed the visual working memory and go/no‐go tasks. Performance of the tasks was compared between the two conditions.ResultsSingle‐session anodal tDCS over the left DLPFC did not significantly improve cognitive tasks in PD compared with sham (P > .05).ConclusionSingle‐session tDCS is ineffective in improving visual working memory and inhibitory control in PD. Further research may worth exploring alternative tDCS parameters, ideally with repeated sessions and concomitant training.

Statins and Cognition in Parkinson's Disease.

The relationship between statins and cognition in Parkinson's disease (PD) is poorly understood. Analyses were performed to determine associations between statin use and cross-sectional and longitudinal cognitive performance in PD. Neuropsychological tests, medication logs, and ratings of functional abilities were collected from 313 PD participants longitudinally. At baseline, statin users (SU; N = 129) were older, more likely male, and had shorter PD duration than non-statin users (NSU; N = 184). In Cross-sectional analysis, SU performed better on global cognition, Trails B, semantic fluency, and phonemic fluency tasks. Rate of long-term global cognitive (Dementia Rating Scale-2 and MoCA) decline was significantly less in SU.

Mentally stimulating activities associate with better cognitive performance in Parkinson disease.

Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N=41, 33 males; age 68.5±7.2; Hoehn and Yahr stage 2.6±0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [11C]dihydrotetrabenazine dopaminergic and [11C]piperidinyl propionate acetylcholinesterase PET imaging. The subset of mentally stimulating activity items of the Community Health Activities Model Program for Seniors questionnaire was used to develop a rating scale as primary outcome variable in this study. Findings showed that mean rating scale score of time spent in mentally stimulating activities over a 4-week timespan was 20.0±8.3h and mean MMSE score was 28.4±1.9. Regression analysis showed that duration of participation in mentally stimulating activities was a significant predictor of MMSE scores (standardized β=0.39, t=2.8, p=0.009; total model: F (6,34)=3.5, p=0.005) independent from significant effects for cortical cholinergic activity (β=0.35, t=2.4, p=0.024). Caudate nucleus dopaminergic activity, age, education, or duration of disease were not significant regressors. Post hoc analysis did not show significant effects of motor disease severity or level of physical activities. We conclude that engagement in mentally stimulating activities is associated with better cognitive abilities in PD, independent of education, severity of motor disease, nigrostriatal dopaminergic and cortical cholinergic degenerations.

Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia.

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-β accumulation to these problems is unclear. We hypothesized that amyloid-β PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-β plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-β amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.

Effect of olfactory impairment and white matter hyperintensities on cognition in Parkinson's disease

IntroductionAlthough white matter hyperintensities (WMH) and olfactory dysfunction are independently associated with the cognitive impairments in Parkinson's disease (PD), the effects of simultaneous presence of these abnormalities remain unknown. Thus, we investigated the different effects of deep WMH and periventricular WMH on olfactory and cognitive performance and evaluated the additive effects of the concurrent presence of WMH and olfactory dysfunction on cognitive performance in PD. MethodsWe enrolled 171 patients with non-demented PD whose WMH scores were assessed using a semi-quantitative visual rating system. The olfactory and cognitive performance was assessed using the Cross-Cultural Smell Identification (CCSI) test and the Seoul Neuropsychological Screening Battery. Additionally, the additive effects of concurrent WMH and olfactory dysfunction on cognitive performance were investigated using binary logistic regression. ResultsThe deep WMH score exhibited a significant negative correlation with the CCSI score (p = 0.026) but the total WMH and periventricular WMH did not. A multiple regression analysis revealed that the total WMH (β = −0.109, p = 0.011) and deep WMH (β = −0.153, p = 0.020) severities had significant negative correlations with semantic fluency. A logistic regression analysis revealed that the simultaneous presence of severe olfactory dysfunction and deep WMH was associated with a greater risk for the semantic fluency impairments (odds ratio = 15.909, p = 0.0005) compared to patients with mild deep WMH or high CCSI scores. ConclusionsThese data indicate that deep WMH was closely coupled with olfactory impairments and cognitive decline in PD. Moreover, the concurrent presence of severe deep WMH and olfactory impairments has a greater influence on semantic fluency.

Differential optimal dopamine levels for set-shifting and working memory in Parkinson's disease

Parkinson's disease (PD) is an important model for the role of dopamine in supporting human cognition. However, despite the uniformity of midbrain dopamine depletion only some patients experience cognitive impairment. The neurocognitive mechanisms of this heterogeneity remain unclear. A genetic polymorphism in the catechol O-methyltransferase (COMT) enzyme, predominantly thought to exert its cognitive effect through acting on prefrontal cortex (PFC) dopamine transmission, provides us with an experimental window onto dopamine’s role in cognitive performance in PD. In a large cohort of PD patients (n=372), we examined the association between COMT genotype and two tasks known to implicate prefrontal dopamine (spatial working memory and attentional set-shifting) and on a task less sensitive to prefrontal dopamine (paired associates learning). Consistent with the known neuroanatomical locus of its effects, differences between the COMT genotype groups were observed on dopamine-dependant tasks, but not the paired associates learning task. However, COMT genotype had differential effects on the two prefrontal dopamine tasks. Putative prefrontal dopamine levels influenced spatial working memory in an ‘Inverted-U’-shaped fashion, whereas a linear, dose-dependant pattern was observed for attentional set-shifting. Cumulatively, these results revise our understanding of when COMT genotype modulates cognitive functioning in PD patients by showing that the behavioural consequences of genetic variation vary according to task demands, presumably because set-shifting and working memory have different optimal dopamine levels.

Topography of cortical thinning associated with white matter hyperintensities in Parkinson's disease.

Although white matter hyperintensities (WMHs) are associated with cognitive impairments in Parkinson's disease (PD), the relationships between WMHs and cortical atrophy in regard to cognitive impairments are unknown. Here, we investigated the topography of cortical thinning related to deep (DWMHs) and periventricular WMHs (PWMHs) and their differential impacts on cognitive performance in PD. We enrolled 87 patients with non-demented PD and evaluated WMH scores using a semi-quantitative visual rating system. The patients were divided into low-, moderate-, and high-grade groups based on WMH severity for total WMHs (TWMHs), DWMHs, and PWMHs, and cortical thickness was measured using a surface-based method according to the WMHs severity. Additionally, the correlations between WMH-associated cortical thinning and neuropsychological performance were analyzed. The detailed neuropsychological test demonstrated that PD patients with high-grade WMHs showed poorer performance on frontal lobe-based cognitive tasks compared with those with low-grade DWMHs. The areas of cortical thinning were more extensive in patients with DWMHs, involving the entire frontal areas and restricted temporoparietal areas, whereas in patients with PWMHs, cortical thinning was localized in the small frontal areas. A multiple regression analysis of the relationships between WMH-associated cortical thickness and cognition revealed that DWMH-associated frontal thickness had an independent effect on frontal lobe-based cognition, while frontal thickness related to PWMHs did not have a significant correlation with cognitive tasks. These data suggest that in patients with PD, DWMHs are closely coupled with decreased cortical thickness in the frontal areas and may lead to declines in executive function.

Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson's Disease

Objective: The aim of this study was to test plasma insulin-like growth factor 1 (IGF-1) change in Parkinson's disease (PD) and essential tremor (ET), and assess the association of plasma IGF-1 level with motor and nonmotor symptoms in PD and ET. Methods: Plasma IGF-1 was measured in 100 PD patients, 40 ET patients, and 76 healthy controls. Motor and nonmotor symptoms were assessed by different scales. Spearman correlation test and linear logistic model were used to analyze the correlation of plasma IGF-1 with motor and nonmotor symptoms of PD and ET. Results: The plasma IGF-1 level was significantly increased in PD compared to healthy controls and ET patients. In addition, low plasma IGF-1 was correlated with low Mini-Mental State Examination (MMSE) scores in PD patients. However, no correlation was found between plasma IGF-1 and MMSE scores in ET patients. Conclusion: Plasma IGF-1 increased significantly in PD but remained unchanged in ET. A low plasma IGF-1 level was associated with poor cognitive performance in PD but not in ET patients.

APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.

Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature. To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD. We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene. Nine variables derived from 7 psychometric tests. The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests. Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.