Cognitive Deficits In Parkinson's Disease Research Articles

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.

LONGITUDINAL DIFFUSION TENSOR IMAGING AS A PREDICTOR OF COGNITIVE DOMAIN DECLINE IN EARLY-STAGE PARKINSON’S DISEASE: ICICLE-PD STUDY

The risk of patients with Parkinson's disease developing dementia is five times greater than the general population. As the pathophysiological processes underlying Parkinson's disease (PD) dementia are heterogeneous, monitoring the progression of white matter microstructural changes might help identify its role in mediating cognitive deficits in PD. This study investigated whether white matter microstructural abnormalities are predictors of cognitive domains changes in early Parkinson's disease (PD). A total of 123 patients with early PD were enrolled along with 49 controls. Participants were part of the ICICLE-PD (Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation) study and underwent clinical, cognitive and DTI investigations at baseline and 18 months later with cognitive and diffusion tensor imaging. General cognition was tested using the Mini-Mental State Examination. Attention, memory, language, executive and visuospatial functions were assessed based on a selection of subtests from different batteries. Imaging parameters were analysed using Tract Based Spatial Statistics. The relationships between fractional anisotropy (FA) and mean diffusivity (MD) with cognition were investigated using multiple linear regression. All analyses were controlled for age, sex, education, levodopa dose and visit intervals. At baseline, patients with PD had significantly higher widespread MD then controls. At follow-up, both groups showed a further significant FA decrease and MD increase. Baseline MD was a significant predictor of executive function (β (95%CI) -7.85 (-11.81; -3.88), p<0.001) and general cognitive change (β (95%CI) -9.58 (-16.56; -2.60), p 0.008) among patients with PD. MD represents an important correlate and predictor of cognitive change and in PD: DTI is potentially a useful tool in stratification of patients into clinical trials and to monitor the impact of treatment on cognition.

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10−4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

Effects of orthostatic hypotension on cognition in Parkinson disease.

To investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in Parkinson disease (PD) using a cross-sectional and within-group design. Individuals without dementia with idiopathic PD included 18 with OH (PDOH) and 19 without OH; 18 control participants were also included. Neuropsychological tests were conducted in supine and upright-tilted positions. Blood pressure was assessed in each posture. The PD groups performed similarly while supine, demonstrating executive dysfunction in sustained attention and response inhibition, and reduced semantic fluency and verbal memory (encoding and retention). Upright posture exacerbated and broadened these deficits in the PDOH group to include phonemic fluency, psychomotor speed, and auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, with the PDOH group exhibiting a wider range of deficits in executive function and memory as well as significant changes in visuospatial function. Cognitive deficits in PD have been widely reported with assessments performed in the supine position, as seen in both our PD groups. Here we demonstrated that those with PDOH had transient, posture-mediated changes in excess of those found in PD without OH. These observed changes suggest an acute, reversible effect. Understanding the effects of OH due to autonomic failure on cognition is desirable, particularly as neuroimaging and clinical assessments collect data only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with OH has quality of life implications, and OH presents itself as a possible target for intervention in cognitive disturbance.

Naturally Occurring Autoantibodies against Tau Protein Are Reduced in Parkinson's Disease Dementia.

Background and ObjectiveAltered levels of naturally occurring autoantibodies (nAbs) against disease-associated neuronal proteins have been reported for neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). Recent histopathologic studies suggest a contribution of both Lewy body- and AD-related pathology to Parkinson's disease dementia (PDD). Therefore, we explored nAbs against alpha-synuclein (αS), tau and β-amyloid (Aβ) in PDD compared to cognitively normal PD patients.Materials and MethodsWe established three different ELISAs to quantify the nAbs-tau, nAbs-αS, and nAbs-Aβ levels and avidity towards their specific antigen in serum samples of 18 non-demented (PDND) and 18 demented PD patients (PDD), which were taken from an ongoing multi-center cohort study (DEMPARK/LANDSCAPE).ResultsPDD patients had significantly decreased nAbs-tau serum levels compared to PDND patients (p = 0.007), whereas the serum titers of nAbs-αS and nAbs-Aβ were unchanged. For all three nAbs, no significant differences in avidity were found between PDD and PDND cohorts. However, within both patient groups, nAbs-tau showed lowest avidity to their antigen, followed by nAbs-αS, and nAbs-Aβ. Though, due to a high interassay coefficient of variability and the exclusion of many samples below the limit of detection, conclusions for nAbs-Aβ are only conditionally possible.ConclusionWe detected a significantly decreased nAbs-tau serum level in PDD patients, indicating a potential linkage between nAbs-tau serum titer and cognitive deficits in PD. Thus, further investigation in larger samples is justified to confirm our findings.

Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease

ObjectivesDopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD. MethodsPD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing. ResultsMean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036). ConclusionsImpaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.

Learning to be inflexible: Enhanced attentional biases in Parkinson's disease

Impaired attentional flexibility is considered to be one of the core cognitive deficits in Parkinson's disease (PD). However, the mechanisms that underlie this impairment are contested. Progress in resolving this dispute has also been hindered by the fact that cognitive deficits in PD are heterogeneous; therefore, it is unclear whether attentional impairments are only present in a subgroup of patients. Here, we demonstrate that what differentiates PD patients from age-matched controls is an inability to shift attention away from previously relevant information (perseveration) and an inability to shift attention towards previously irrelevant information (learned irrelevance). In contrast, there was no evidence that PD patients, compared to controls, were impaired in being able to appropriately attend to, or ignore, novel information. Furthermore, when patients were stratified according to their level of executive impairment, the executively impaired group showed a selective deficit in set formation compared to the unimpaired group, a behavioural pattern reminiscent of cortical dopamine depletion. Cumulatively, these results suggest that cognitive inflexibility in PD relates to a specific form of attentional dysfunction, in which learned attentional biases cannot be overcome.

Cerebrospinal fluid biomarkers for Parkinson's disease - a systematic review.

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha-synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau-proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

Interrelations between cognitive dysfunction and motor symptoms of Parkinson's disease: behavioral and neural studies.

Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD.

Comparison of Test Your Memory and Montreal Cognitive Assessment Measures in Parkinson's Disease.

Background. MoCA is widely used in Parkinson's disease (PD) to assess cognition. The Test Your Memory (TYM) test is a cognitive screening tool that is self-administered. Objectives. We sought to determine (a) the optimal value of TYM to discriminate between PD patients with and without cognitive deficits on MoCA testing, (b) equivalent MoCA and TYM scores, and (c) interrater reliability in TYM testing. Methods. We assessed the discriminant ability of TYM and the equivalence between TYM and MoCA scores and measured the interrater reliability between three raters. Results. Of the 135 subjects that completed both tests, 55% had cognitive impairment according to MoCA. A MoCA score of 25 was equivalent to a TYM score of 43-44. The area under the receiver operator characteristic (ROC) curve for TYM to differentiate between PD-normal and PD-cognitive impairment was 0.82 (95% CI 0.75 to 0.89). The optimal cutoff to distinguish PD-cognitive impairment from PD-normal was ≤45 (sensitivity 90.5%, specificity 59%) thereby correctly classifying 76.3% of patients with PD-cognitive impairment. Interrater agreement was high (0.97) and TYM was completed in under 7 minutes (interquartile range 5.33 to 8.52 minutes). Conclusions. The TYM test is a useful and less resource intensive screening test for cognitive deficits in PD.

Mild cognitive impairment and Parkinson's disease--something to remember.

Cognitive impairment is common in Parkinson's disease (PD), and many patients will eventually develop a dementia, which has a devastating impact on the patient and their family. As such, there has been much interest in identifying a prodromal state to inform prognosis and facilitate earlier management, similar to the concept of 'MCI' in the Alzheimer's field. However, grouping the early cognitive deficits of PD together as 'PD-MCI' may not be the best way forward as it implies a single aetiological basis with one clinical consequence. In this review, we argue that cognitive deficits in PD arise from a number of different pathological pathways, only some of which herald a dementing process. This has important implications both for treatment of individual patients, and for the design of future disease-modifying therapy trials.

Biomarkers of cognitive decline in Parkinson's disease.

Cognitive impairment is a frequent and devastating non-motor symptom of Parkinson's disease (PD). Impaired cognition has a major impact on either quality of life or mortality in patients with PD. Notably, the rate of cognitive decline and pattern of early cognitive deficits in PD are highly variable between individuals. Given that the underlying mechanisms of cognitive decline or dementia associated with PD remain unclear, there is currently no mechanism-based treatment available. Identification of biological markers, including neuroimaging, biofluids and common genetic variants, that account for the heterogeneity of PD related cognitive decline could provide important insights into the pathological processes that underlie cognitive impairment in PD. These combined biomarker approaches will enable early diagnosis and provide indicators of cognitive progression in PD patients. This review summarizes recent advances in the development of biomarkers for cognitive impairments in PD.

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.

L-DOPA reverses the impairment of Dentate Gyrus LTD in experimental parkinsonism via β-adrenergic receptors

Parkinson's disease (PD) patients exhibit motor and non-motor symptoms that severely affect quality of life. Cognitive alterations in PD subjects have been related to both structural and functional hippocampal changes. Here we investigated the effects of the 6-hydroxydopamine (6-OHDA) lesion in the Medial Forebrain Bundle (MFB) on the hippocampus focusing on the Dentate Gyrus (DG). In vivo microdialysis measurements revealed that the 6-OHDA injection disrupts both dopaminergic and noradrenergic transmission in rat DG. In vitro electrophysiological recordings showed that these neurochemical alterations were accompanied by impairment of long-term depression (LTD) at medial perforant path/DG synapses. Furthermore, this alteration was reversed by l-DOPA treatment. Notably, the therapeutic effect of l-DOPA on LTD was blocked by the antagonism of β-noradrenergic receptors, but not by dopamine D1 or D2 receptor antagonists. Thus, while the dopaminergic transmission does not seem to be implicated in this therapeutic effect of l-DOPA, the noradrenergic system plays a central role in the synaptic dysfunction of the DG in experimental PD. Our work provides new evidence on the role of catecholamines in DG synaptic plasticity and sheds light on the possible synaptic mechanisms underlying cognitive deficits in PD. Furthermore, our results indicate that l-DOPA exerts a therapeutic effect on the parkinsonian brain through different, coexistent, mechanisms.

Examining dorsal striatum in cognitive effort using Parkinson's disease and fMRI.

ObjectiveUnderstanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson's disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions.MethodsTwenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI.ResultsThe symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI.InterpretationThese findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment.

Cognitive and MRI correlates of orthostatic hypotension in Parkinson’s disease

Orthostatic hypotension (OH) is a frequent nonmotor feature of Parkinson's disease (PD), and its occurrence has been associated with cognitive impairment. The underlying mechanism could be mediated by development of cerebrovascular disease induced by chronic or episodic hypoperfusion, but the extent of brain vascular load in PD patients with OH has never been investigated. This study aimed to assess the relationship between OH and cognitive function in PD patients and to investigate the contribution of brain vascular lesions. Forty-eight PD patients underwent a tilt table test (TT) to assess supine and orthostatic blood pressure as well as an extensive neuropsychological evaluation to evaluate cognitive function. Brain magnetic resonance imaging was acquired in 44/48 patients and analyzed by a visual semiquantitative scale. Twenty-three patients presented OH at TT (13/23 were symptomatic), and 25 did not. There were no differences in motor severity or disease duration between patients with and without OH. In patients with OH we found significantly worse cognitive performance in specific tasks, such as sustained attention, visuospatial and verbal memory, compared with patients without OH. However, there were no differences in vascular burden between the two groups. Our study confirms that there is an association between OH and selective cognitive deficits in PD, but rebuts the hypothesis that this is underlined by the development of cerebrovascular disease.

The histone deacetylase inhibitor, sodium butyrate, alleviates cognitive deficits in pre-motor stage PD

Parkinson's disease (PD) patients often times experience impairment in their cognitive abilities early on in the progression of the disease. The reported deficits appear to mainly involve functions that are associated with frontal lobe and frontal-striatal pathways subserving attentional set-shifting, working memory and executive function.The current study explored executive function deficits in a rat model of PD in the pre-motor deficit stage. The rats were lesioned with 12 μg of 6-hydroxydonpamine (6-OHDA) in the striatum in a two step process (10 μg/μl followed by 2 μg/μl) 48 hours apart. Executive function was tested at 3 weeks post-surgery using a rat analogue of Wisconsin card sorting test called the Extra Dimensional/Intra Dimensional (ED/ID) set-shifting task. The results demonstrated that performance by the pre-motor rat model of PD was equivalent to that of the control groups in the simple and the compound discriminations as well as the intra-dimensional set-shifting. However the PD group exhibited attentional set-shifting deficits similar to those observed in PD patients.Additionally, sodium butyrate, a short chain fatty acid derivative and inhibitor of class I and II histone deacetylase (HDACi), was tested as a potential therapeutic agent to mitigate the pre-motor cognitive deficits in PD. The results indicated that the sodium butyrate treatment not only effectively alleviated the set-shifting deficits, but also improved the attentional set formation in the treated rats.

Patterns of cortical thickness and surface area in early Parkinson's disease

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder diagnosed on the basis of motor symptoms, but that also includes cognitive and visuo-spatial deficits. Though PD is known to initially affect subcortical regions, the cortex also exhibits neuronal loss in the course of the disease as post mortem studies have shown. So far, PD-related pattern of cortical damage remains unclear, because of disease-caused heterogeneity, and also in part because of methodological issues such as the limitations of Voxel Based Morphometry. Here corticometry was used, a technique that decouples local surface from thickness, to obtain a better picture of PD corticomorphometric patterns.We acquired MRI volumes for 33 healthy controls (HC) and 49 PD patients, extracted local cortical thickness and surface area and modeled both of them as a function of group and age for each participant. Cortical thickness averaged on the whole cortex did not differ between the two groups while mean surface area was significantly larger in the PD group. The bilateral parietal lobule, the right superior frontal gyrus, the left cingulate cortex and the left insular cortex exhibited larger local surface area in the PD group. The right precuneus exhibited cortical thinning associated with age in the PD group and not in the HC group. Furthermore, cortical thinning was observed in the PD group compared with the control group in the left medial supplementary motor area (SMA) and in the right dorsal pre-SMA. Finally, we found the left temporal pole thickness to correlate with disease duration, as well as the bilateral occipital cortex and Broca's area.These results suggest that PD etiology is associated with specific cortical alterations, which could account for cognitive deficits that arise as the disease evolves. Finally, our results observed in the occipital cortex as a function of disease duration may indicate the increase in PD-related visuo-spatial deficits, which can sometimes result in hallucinations later on in the disease. In the future, MRI-generated corticometry, combined with additional behavioral markers, may prove to be a useful diagnosis tool to characterize the evolution of motor and cognitive deficits in PD.

Mild cognitive deficits in Parkinson disease

In this issue of Neurology ®, Aarsland et al.1 demonstrate that among patients with Parkinson disease (PD) without dementia, mild cognitive impairment (MCI) is common. These data are consistent with recent investigations emphasizing the nonmotor aspects of PD. When James Parkinson2 first described PD as the “shaking palsy” in 1817, he focused on motor symptoms and described the “intellects” as “uninjured.” Approximately 10 years later, Wilhelm von Humboldt began writing detailed descriptions of his own PD symptoms that included micrographia and veiled references to fluctuating attention.3 When he died, his doctors described his intellect as “undisturbed.” It was not until the latter part of the 20th century that investigators began to address nonmotor symptoms of PD, including specific cognitive changes.4 Most clinicians in current practice acknowledge the possibility of cognitive changes in PD, but focus on motor manifestations until more severe decline, or dementia, cannot be ignored. Studies addressing mild cognitive changes have emphasized deficits in complex attention, executive functions (e.g., initiation, planning, speed of processing),5,6 visuoconstructive skills, and memory, prompting use of the term MCI to characterize a predementia stage. Recognizing these relatively mild …

Decreased glutamic acid decarboxylase mRNA expression in prefrontal cortex in Parkinson's disease

Parkinson's disease (PD) patients typically suffer from motor disorders but mild to severe cognitive deficits can also be present. Neuropathology of PD primarily involves loss of dopaminergic neurons in the substantia nigra, pars compacta, although more widespread pathology from the brainstem to the cerebral cortex occurs at different stages of the disease. Cognitive deficits in PD are thought to involve the cerebral cortex, and imaging studies have identified the dorsolateral prefrontal cortex (DLPFC) as a possible site for some of the symptoms. GABAergic neurons in the cerebral cortex play a key role in the modulation of pyramidal neurons and alterations in muscimol binding to GABA A receptors have been reported in Brodmann area 9 (BA9) of the prefrontal cortex in PD patients (Nishino et al., 1988). In order to further assess the likelihood that GABAergic activity is altered in the prefrontal cortex in PD, gene expression of the 67 kilodalton isoform of the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD67 encoded by the GAD1 gene), was examined in BA9 of post-mortem brains from 19 patients and 20 controls using isotopic in situ hybridization histochemistry. GAD67 mRNA labeling was examined and quantified on X-ray films and emulsion radioautographs. We show that GAD67 mRNA labeling is significantly lower in PD compared to control cases. Analysis of emulsion radioautographs indicates that GAD67 mRNA labeling is decreased in individual neurons and is not paralleled by a decrease in the number of GAD67 mRNA-labeled neurons. Analysis of expression data from a microarray study performed in 29 control and 33 PD samples from BA9 confirms that GAD67 expression is decreased in PD. Another finding from the microarray study is a negative relationship between GAD67 mRNA expression and age at death. Altogether, the results support the possibility that GABAergic neurotransmission is impaired in the DLPFC in PD, an effect that may be involved in some of the behavioral deficits associated with the disease.