Models of probabilistic category learning in Parkinson's disease: Strategy use and the effects of L-dopa

Probabilistic category learning (PCL) has become an increasingly popular paradigm to study the brain bases of learning and memory. It has been argued that PCL relies on procedural habit learning, which is impaired in Parkinson's disease (PD). However, as PD patients were typically tested under medication, it is possible that levodopa (L-dopa) caused impaired performance in PCL. We present formal models of rule-based strategy switching in PCL, to re-analyse the data from [Jahanshahi, M., Wilkinson, L, Gahir, H., Dharminda, A., & Lagnado, D.A., (2009). Medication impairs probabilistic classification learning in Parkinson's disease. Manuscript submitted for publication] comparing PD patients on and off medication (within subjects) to matched controls. Our analysis shows that PD patients followed a similar strategy switch process as controls when off medication, but not when on medication. On medication, PD patients mainly followed a random guessing strategy, with only few switching to the better Single Cue strategies. PD patients on medication and controls made more use of the optimal Multi-Cue strategy. In addition, while controls and PD patients off medication only switched to strategies which did not decrease performance, strategy switches of PD patients on medication were not always directed as such. Finally, results indicated that PD patients on medication responded according to a probability matching strategy indicative of associative learning, while the behaviour of PD patients off medication and controls was consistent with a rule-based hypothesis testing procedure. (C) 2009 Elsevier Inc. All rights reserved

Cognitive processes that indirectly affect olfactory dysfunction in Parkinson\u27s disease

Introduction Accurate early diagnosis of Parkinson\u27s disease is hampered by its long prodromal period and the variable manifestations of its motor symptoms. While olfactory dysfunction can occur before motor-symptom onset and serve as a non-disease-specific diagnostic aid, its underlying causes are incompletely understood. Methods Correlation analyses, univariate density estimates, ANOVA and regression evaluated relationships between scores on the Montreal Cognitive Assessment and Hopkins Verbal Learning Test and those on the University of Pennsylvania Smell Identification Test in 1280 Parkinson\u27s Progression Markers Initiative subjects placed into five diagnostic categories. Structural equation modeling identified cognitive measures having significant indirect effects on olfactory-function-test scores. Results Global cognition, verbal learning and memory, attention, delayed-recall, and visuospatial/executive function scores show weak-to-moderate, significant associations with olfactory-function-test scores. Associations are stronger in symptomatic than asymptomatic subjects having mutations in LRRK2, GBA or SNCA. Score distributions are nonuniform across diagnostic categories. Linear regression found that all cognitive measures except attention predicted olfactory-function-test scores. Three structural equation models assessing indirect effects of verbal learning/memory with either global cognition, visuospatial/executive function, or delayed-recall had a good statistical fit to the data. Only verbal learning/memory scores significantly help explain olfactory-function-test scores in all symptomatic diagnostic categories (−0.56 \u3c b \u3c −0.23, 0.001 \u3c P \u3c .005). Visuospatial/executive-function test scores help explain olfactory-function-test scores in both genetic Parkinson\u27s disease diagnostic categories (−0.25 \u3c b \u3c −0.17, 0.032 \u3c P \u3c .033). Conclusion Impaired verbal learning/memory and visuospatial/executive function contributes to lower performance on olfactory function tests in Parkinson\u27s disease. As both of these domains impact decision-making, decision-making in turn may impact olfactory assessment in Parkinson\u27s disease

Molecular imaging in Parkinson's disease

The present work explores brain functional changes in drug-naïve Parkinson's disease (PD) patients by means of molecular imaging techniques. Thirty-one consecutive drug-naïve PD patients from the Neurological Clinic of the University of Flor-ence underwent clinical assessment, neuropsychological assessment, MRI, [123I]FP-CIT SPECT, [18F]FDG PET. First, [18F]FDG-PET was employed to identify in drug-naïve PD patients brain metabolic alteration uniquely related to disease process and not modulated by anti-parkinsonian therapeutic intervention. Second, [18F]FDG-PET and [123I]FP-CIT SPECT were employed together to explore the early functional changes in brain function related to dopaminergic depletion in the putamen and in the caudate nucleus

2008 Progress Report on Brain Research

Highlights new research on various disorders, nervous system injuries, neuroethics, neuroimmunology, pain, sense and body function, stem cells and neurogenesis, and thought and memory. Includes essays on arts and cognition and on deep brain stimulation

Doctor of Philosophy

dissertationParkinson disease (PD) is a progressive neurodegenerative disorder with selective damage of dopaminergic neurons within the Basal Ganglia (BG), leading to the most clearly recognized sequelae of motor deficits observed in PD. The BG have also been shown to be important during implicit motor sequence learning (IMSL), and individuals with BG lesions have demonstrated impairment in IMSL compared to healthy age matched controls. Additionally, individuals with PD are typically prescribed dopamine replacement or agonist medications, which have been found to reduce the observed movement deficits. However, it has been observed that dopamine addition may potentially impair IMSL. The primary purpose of this paper was to describe impairments in IMSL in individuals with PD, describe a neurobiological model for the observed deficits in IMSL, and to determine the impact of dopamine addition on acquisition performance and retention learning of repeated segments during a standing implicit continuous tracking task in individuals with PD. We hypothesized that IMSL would be impaired in individuals with PD on their usual dosage of dopamine. Secondarily, the impact of age, PD, and dopamine on sequence-specific integration was assessed, and it was hypothesized that there would be a graded deficit related to age, PD, and dopamine on sequencespecific integration. Finally, the relationship of spatial and temporal parameters within sequence learning was assessed as an exploratory aim. The results of this study supported an IMSL deficit primarily related to age and secondarily related to PD, but not dopamine replacement. Additionally, individuals with PD, regardless of medication, demonstrated impaired spatial integration compared to healthy young and elder participants. The type of task performed in this study was a demanding postural task compared to the traditional IMSL paradigms using the upper extremity and task difficulty could account for the lack of observed difference during acquisition. Longer time to practice the paradigm may be required to observe improved performance. Finally, although IMSL has been observed to be impaired in individuals with PD, a better understanding of the IMSL deficit related to the impact of medication and age during a standing motor task is warranted

Prospective Memory Impairment in Parkinson Disease without Dementia: Cognitive Mechanisms and Intervention

Cognitive impairment among non-demented individuals with Parkinson disease (PD) produces significant disability, reduced quality of life, and restricted participation. This dissertation will cover PD-related impairment in prospective memory, or the ability to remember to execute delayed intentions at the appropriate moment in the future. Prospective memory impairment in PD is increasingly recognized as a functionally and clinically relevant problem and viable target for cognitive intervention. To lay the groundwork for the development of effective interventions for prospective memory in PD, this dissertation examines the cognitive mechanisms underlying prospective memory impairment in PD and the potential of training in a targeted strategy to improve prospective memory in PD. Specifically, it focuses on the efficacy of an associative encoding strategy called implementation intentions for addressing PD-related deficits in prospective memory in a laboratory setting and as reported in everyday life. Results indicate that implementation intentions training holds promise for improving prospective memory in PD. A synthesis and analysis of the dissertation studies reveals avenues for future research that will bolster the scientific and clinical impact of this line of work

Gait in Parkinson’s disease: a visuo-cognitive challenge

Vision and cognition have both been related to gait impairment in Parkinson’s disease (PD) through separate strands of research. The cumulative and interactive effect of both (which we term visuo-cognition) has not been previously investigated and little is known about the influence of cognition on vision with respect to gait. Understanding the role of vision, cognition and visuo-cognition in gait in PD is critical for data interpretation and to infer and test underlying mechanisms. The purpose of this comprehensive narrative review was to examine the interdependent and interactive role of cognition and vision in gait in PD and older adults. Evidence from a broad range of research disciplines was reviewed and summarised. A key finding was that attention appears to play a pivotal role in mediating gait, cognition and vision, and should be considered emphatically in future research in this field

Motor Sequence Learning and Consolidation in Unilateral De Novo Patients with Parkinson's Disease

Previous research investigating motor sequence learning (MSL) and consolidation in patients with Parkinson's disease (PD) has predominantly included heterogeneous participant samples with early and advanced disease stages; thus, little is known about the onset of potential behavioral impairments. We employed a multisession MSL paradigm to investigate whether behavioral deficits in learning and consolidation appear immediately after or prior to the detection of clinical symptoms in the tested (left) hand. Specifically, our patient sample was limited to recently diagnosed patients with pure unilateral PD. The left hand symptomatic (LH-S) patients provided an assessment of performance following the onset of clinical symptoms in the tested hand. Conversely, right hand affected (left hand asymptomatic, LH-A) patients served to investigate whether MSL impairments appear before symptoms in the tested hand. LH-S patients demonstrated impaired learning during the initial training session and both LH-S and LH-A patients demonstrated decreased performance compared to controls during the next-day retest. Critically, the impairments in later learning stages in the LH-A patients were evident even before the appearance of traditional clinical symptoms in the tested hand. Results may be explained by the progression of disease-related alterations in relevant corticostriatal networks.status: publishe

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies