Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.

Dopamine is associated with prioritization of reward-associated memories in Parkinson's disease.

Patients with Parkinson's disease have reduced reward sensitivity related to dopaminergic neuron loss, which is associated with impairments in reinforcement learning. Increasingly, however, dopamine-dependent reward signals are recognized to play an important role beyond reinforcement learning. In particular, it has been shown that reward signals mediated by dopamine help guide the prioritization of events for long-term memory consolidation. Meanwhile, studies of memory in patients with Parkinson's disease have focused on overall memory capacity rather than what is versus what isn't remembered, leaving open questions about the effect of dopamine replacement on the prioritization of memories by reward and the time-dependence of this effect. The current study sought to fill this gap by testing the effect of reward and dopamine on memory in patients with Parkinson's disease. We tested the effect of dopamine modulation and reward on two forms of long-term memory: episodic memory for neutral objects and memory for stimulus-value associations. We measured both forms of memory in a single task, adapting a standard task of reinforcement learning with incidental episodic encoding events of trial-unique objects. Objects were presented on each trial at the time of feedback, which was either rewarding or not. Memory for the trial-unique images and for the stimulus-value associations, and the influence of reward on both, was tested immediately after learning and 2 days later. We measured performance in Parkinson's disease patients tested either ON or OFF their dopaminergic medications and in healthy older control subjects. We found that dopamine was associated with a selective enhancement of memory for reward-associated images, but that it did not influence overall memory capacity. Contrary to predictions, this effect did not differ between the immediate and delayed memory tests. We also found that while dopamine had an effect on reward-modulated episodic memory, there was no effect of dopamine on memory for stimulus-value associations. Our results suggest that impaired prioritization of cognitive resource allocation may contribute to the early cognitive deficits of Parkinson's disease.

Dopamine selectively remediates 'model-based' reward learning: a computational approach.

Patients with loss of dopamine due to Parkinson's disease are impaired at learning from reward. However, it remains unknown precisely which aspect of learning is impaired. In particular, learning from reward, or reinforcement learning, can be driven by two distinct computational processes. One involves habitual stamping-in of stimulus-response associations, hypothesized to arise computationally from 'model-free' learning. The other, 'model-based' learning, involves learning a model of the world that is believed to support goal-directed behaviour. Much work has pointed to a role for dopamine in model-free learning. But recent work suggests model-based learning may also involve dopamine modulation, raising the possibility that model-based learning may contribute to the learning impairment in Parkinson's disease. To directly test this, we used a two-step reward-learning task which dissociates model-free versus model-based learning. We evaluated learning in patients with Parkinson's disease tested ON versus OFF their dopamine replacement medication and in healthy controls. Surprisingly, we found no effect of disease or medication on model-free learning. Instead, we found that patients tested OFF medication showed a marked impairment in model-based learning, and that this impairment was remediated by dopaminergic medication. Moreover, model-based learning was positively correlated with a separate measure of working memory performance, raising the possibility of common neural substrates. Our results suggest that some learning deficits in Parkinson's disease may be related to an inability to pursue reward based on complete representations of the environment.

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study.

BACKGROUND: Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS). METHODS: The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers. RESULTS: Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13). CONCLUSIONS: First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

Parkinson's disease with Lewy bodies associated with a heterozygous PARKIN dosage mutation.

BACKGROUND: PARKIN-related disease remains incompletely understood. First, the pathogenicity of heterozygous PARKIN mutations is unclear, although some evidence supports causality. Second, unlike sporadic Parkinson's disease (PD), Lewy bodies are present only in a minority of cases. Only one other heterozygote PARKIN carrier with autopsy findings has been described. Our case adds to the broadening pathological and clinical phenotype of PARKIN-related disease. METHODS: Clinical chart, genetic analysis, and pathological findings of a patient with familial PD are reviewed. RESULTS: A 44-year-old man developed slowly progressive tremor-predominant PD with excellent response to levodopa. Genetic analysis revealed a heterozygous PARKIN exon 3-4 deletion, also present in 2 family members with early-onset PD. Postmortem examination showed severe neuronal loss in the substantia nigra and nucleus coeruleus with the presence of diffuse Lewy bodies. CONCLUSIONS: The deletion is unlikely an incidental finding considering family history, age at onset, and the presence of clinical and pathological features not typical of sporadic PD.

Stem cell transplantation for adult-onset krabbe disease: report of a case.

Krabbe disease is an autosomal recessive demyelinating lysosomal storage disorder caused by a deficiency of galactocerebrosidase. The adult-onset variant is very rare. Hematopoietic stem cell transplantation (HSCT) is reported to be successful in treating infants with Krabbe disease prior to the onset of symptoms, but there are no reported cases of its use for adult-onset disease. We report the first follow-up data for a patient with adult-onset Krabbe disease who underwent HSCT at age 41, 16 years after the onset of symptoms. HSCT resulted in a sustained normalization of peripheral GALC enzyme activity, halted the progression of symptoms at 24 months post-allograft, and led to improvements in gait and balance. Serial imaging also confirmed that no significant progression of demyelination has occurred. Although long-term follow-up is needed to confirm the effects of HSCT, our 24-month results suggest that HSCT is a viable therapeutic option for symptomatic patients with adult-onset Krabbe disease.

Decisions under risk in Parkinson's disease: preserved evaluation of probability and magnitude.

INTRODUCTION: Unmedicated Parkinson's disease patients tend to be risk-averse while dopaminergic treatment causes a tendency to take risks. While dopamine agonists may result in clinically apparent impulse control disorders, treatment with levodopa also causes shift in behaviour associated with an enhanced response to rewards. Two important determinants in decision-making are how subjects perceive the magnitude and probability of outcomes. Our objective was to determine if patients with Parkinson's disease on or off levodopa showed differences in their perception of value when making decisions under risk. METHODS: The Vancouver Gambling task presents subjects with a choice between one prospect with larger outcome and a second with higher probability. Eighteen age-matched controls and eighteen patients with Parkinson's disease before and after levodopa were tested. In the Gain Phase subjects chose between one prospect with higher probability and another with larger reward to maximize their gains. In the Loss Phase, subjects played to minimize their losses. RESULTS: Patients with Parkinson's disease, on or off levodopa, were similar to controls when evaluating gains. However, in the Loss Phase before levodopa, they were more likely to avoid the prospect with lower probability but larger loss, as indicated by the steeper slope of their group psychometric function (t(24) = 2.21, p = 0.04). Modelling with prospect theory suggested that this was attributable to a 28% overestimation of the magnitude of loss, rather than an altered perception of its probability. CONCLUSION: While pre-medicated patients with Parkinson's disease show risk-aversion for large losses, patients on levodopa have normal perception of magnitude and probability for both loss and gain. The finding of accurate and normally biased decisions under risk in medicated patients with PD is important because it indicates that, if there is indeed anomalous risk-seeking behaviour in such a cohort, it may derive from abnormalities in components of decision making that are separate from evaluations of size and probability.

Sensitivity and bias in decision-making under risk: evaluating the perception of reward, its probability and value.

BACKGROUND: There are few clinical tools that assess decision-making under risk. Tests that characterize sensitivity and bias in decisions between prospects varying in magnitude and probability of gain may provide insights in conditions with anomalous reward-related behaviour. OBJECTIVE: We designed a simple test of how subjects integrate information about the magnitude and the probability of reward, which can determine discriminative thresholds and choice bias in decisions under risk. DESIGN/METHODS: Twenty subjects were required to choose between two explicitly described prospects, one with higher probability but lower magnitude of reward than the other, with the difference in expected value between the two prospects varying from 3 to 23%. RESULTS: Subjects showed a mean threshold sensitivity of 43% difference in expected value. Regarding choice bias, there was a 'risk premium' of 38%, indicating a tendency to choose higher probability over higher reward. An analysis using prospect theory showed that this risk premium is the predicted outcome of hypothesized non-linearities in the subjective perception of reward value and probability. CONCLUSIONS: This simple test provides a robust measure of discriminative value thresholds and biases in decisions under risk. Prospect theory can also make predictions about decisions when subjective perception of reward or probability is anomalous, as may occur in populations with dopaminergic or striatal dysfunction, such as Parkinson's disease and schizophrenia.