Sleep spindle density and temporal clustering are associated with sleep-dependent memory consolidation in Parkinson's disease.

STUDY OBJECTIVES: Sleep is required for successful memory consolidation. Sleep spindles, bursts of oscillatory activity occurring during non-rapid eye movement sleep, are known to be crucial for this process and, recently, it has been proposed that the temporal organization of spindles into clusters might additionally play a role in memory consolidation. In Parkinson's disease, spindle activity is reduced, and this reduction has been found to be predictive of cognitive decline. However, it remains unknown whether alterations in sleep spindles in Parkinson's disease are predictive of sleep-dependent cognitive processes such as memory consolidation, leaving open questions about the possible mechanisms linking sleep and a more general cognitive state in Parkinson's patients. METHODS: The current study sought to fill this gap by recording overnight polysomnography and measuring overnight declarative memory consolidation in a sample of 35 patients with Parkinson's. Memory consolidation was measured using a verbal paired-associates task administered before and after the night of recorded sleep. RESULTS: We found that lower sleep spindle density at frontal leads during non-rapid eye movement stage 3 was associated with worse overnight declarative memory consolidation. We also found that patients who showed less temporal clustering of spindles exhibited worse declarative memory consolidation. CONCLUSIONS: These results suggest alterations to sleep spindles, which are known to be a consequence of Parkinson's disease, might represent a mechanism by which poor sleep leads to worse cognitive function in Parkinson's patients. CITATION: Lahlou S, Kaminska M, Doyon J, Carrier J, Sharp M. Sleep spindle density and temporal clustering are associated with sleep-dependent memory consolidation in Parkinson's disease. J Clin Sleep Med. 2024;20(7):1153-1162.

Longitudinal brain structure changes in Parkinson's disease: A replication study.

CONTEXT: An existing major challenge in Parkinson's disease (PD) research is the identification of biomarkers of disease progression. While magnetic resonance imaging is a potential source of PD biomarkers, none of the magnetic resonance imaging measures of PD are robust enough to warrant their adoption in clinical research. This study is part of a project that aims to replicate 11 PD studies reviewed in a recent survey (JAMA neurology, 78(10) 2021) to investigate the robustness of PD neuroimaging findings to data and analytical variations. OBJECTIVE: This study attempts to replicate the results in Hanganu et al. (Brain, 137(4) 2014) using data from the Parkinson's Progression Markers Initiative (PPMI). METHODS: Using 25 PD subjects and 18 healthy controls, we analyzed the rate of change of cortical thickness and of the volume of subcortical structures, and we measured the relationship between structural changes and cognitive decline. We compared our findings to the results in the original study. RESULTS: (1) Similarly to the original study, PD patients with mild cognitive impairment (MCI) exhibited increased cortical thinning over time compared to patients without MCI in the right middle temporal gyrus, insula, and precuneus. (2) The rate of cortical thinning in the left inferior temporal and precentral gyri in PD patients correlated with the change in cognitive performance. (3) There were no group differences in the change of subcortical volumes. (4) We did not find a relationship between the change in subcortical volumes and the change in cognitive performance. CONCLUSION: Despite important differences in the dataset used in this replication study, and despite differences in sample size, we were able to partially replicate the original results. We produced a publicly available reproducible notebook allowing researchers to further investigate the reproducibility of the results in Hanganu et al. (2014) when more data is added to PPMI.

The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of [18F]MK6240 Tau PET in Target Regions.

6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [18F]MK6240 in target regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [18F]MK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.25 ± 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 ± 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-ß-negative and tau-negative, 58.50 ± 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-ß status, cross-sectionally and over time. [18F]MK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting ∼75% of the region) and in the Braak II region (affecting ∼35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification.

Dopaminergic medication increases motivation to exert cognitive control by reducing subjective effort costs in Parkinson's patients.

Engaging in demanding mental activities requires the allocation of cognitive control, which can be effortful and aversive. Individuals thus tend to avoid exerting cognitive effort if less demanding behavioral options are available. Recent accounts propose a key role for dopamine in motivating behavior by increasing the sensitivity to rewards associated with effort exertion. Whether dopamine additionally plays a specific role in modulating the sensitivity to the costs of cognitive effort, even in the absence of any incentives, is much less clear. To address this question, we assessed cognitive effort avoidance in patients (n = 38) with Parkinson's disease, a condition characterized by loss of midbrain dopaminergic neurons, both ON and OFF dopaminergic medication and compared them to healthy controls (n = 24). Effort avoidance was assessed using the Demand Selection Task (DST), in which participants could freely choose between performing a high-demand or a low-demand version of a task-switching paradigm. Critically, participants were not offered any incentives to choose the more effortful option, nor for good performance. While healthy controls and patients OFF their dopaminergic medications consistently preferred the low-demand option, effort avoidance in patients ON dopaminergic medications was reduced compared to patients OFF, a difference which seems to lessen over trials. These differences in preference could not be explained by altered task-switching performance. Although patients ON were less accurate at detecting the different effort levels, as measured during instructed forced-choice blocks, their detection ability was not associated with effort avoidance, unlike in the healthy controls and the patients OFF. Our findings provide evidence that dopamine replacement in Parkinson's patients increases the willingness to engage in cognitively demanding behavior, and that this cannot be explained by possible effects of dopamine replacement on performance nor on the ability to detect effort demands. These results suggest that dopamine plays a role in reducing the sensitivity to effort costs that is independent of its role in enhancing the sensitivity to the benefits of effort exertion.

Preserved motor memory in Parkinson's disease.

Patients with Parkinson's disease, who lose the dopaminergic projections to the striatum, are impaired in certain aspects of motor learning. Recent evidence suggests that, in addition to its role in motor performance, the striatum plays a key role in the memory of motor learning. Whether Parkinson's patients have impaired motor memory and whether motor memory is modulated by dopamine at the time of initial learning is unknown. To address these questions, we measured memory of a learned motor sequence in Parkinson's patients who were either On or Off their dopaminergic medications at the time of initial learning. We compared them to a group of older and younger controls. Contrary to our predictions, motor memory was not impaired in patients compared to older controls, and was not influenced by dopamine state at the time of initial learning. To probe post-learning consolidation processes, we also tested whether learning a new sequence shortly after learning the initial sequence would interfere with later memory. We found that, in contrast to younger adults, neither older adults nor patients were susceptible to this interference. These findings suggest that motor memory is preserved in Parkinson's patients and raise the possibility that motor memory in patients is supported by compensatory non-dopamine sensitive mechanisms. Furthermore, given the similar performance characteristics observed in the patients and older adults and the absence of an effect of dopamine, these results raise the possibility that aging and Parkinson's disease affect motor memory in similar ways.

The impact of pandemic-related worry on cognitive functioning and risk-taking.

Here, we sought to quantify the effects of experienced fear and worry, engendered by the COVID-19 pandemic, on both cognitive abilities-speed of information processing, task-set shifting, and proactive control-as well as economic risk-taking. Leveraging a repeated-measures cross-sectional design, we examined the performance of 1517 participants, collected during the early phase of the pandemic in the US (April-June 2020), finding that self-reported pandemic-related worry predicted deficits in information processing speed and maintenance of goal-related contextual information. In a classic economic risk-taking task, we observed that worried individuals' choices were more sensitive to the described outcome probabilities of risky actions. Overall, these results elucidate the cognitive consequences of a large-scale, unpredictable, and uncontrollable stressor, which may in turn play an important role in individuals' understanding of, and adherence to safety directives both in the current crisis and future public health emergencies.

Exploring reward-related attention selectivity deficits in Parkinson's disease.

An important aspect of managing a limited cognitive resource like attention is to use the reward value of stimuli to prioritize the allocation of attention to higher-value over lower-value stimuli. Recent evidence suggests this depends on dopaminergic signaling of reward. In Parkinson's disease, both reward sensitivity and attention are impaired, but whether these deficits are directly related to one another is unknown. We tested whether Parkinson's patients use reward information when automatically allocating their attention and whether this is modulated by dopamine replacement. We compared patients, tested both ON and OFF dopamine replacement medication, to older controls using a standard attention capture task. First, participants learned the different reward values of stimuli. Then, these reward-associated stimuli were used as distractors in a visual search task. We found that patients were generally distracted by the presence of the distractors but that the degree of distraction caused by the high-value and low-value distractors was similar. Furthermore, we found no evidence to support the possibility that dopamine replacement modulates the effect of reward on automatic attention allocation. Our results suggest a possible inability in Parkinson's patients to use the reward value of stimuli when automatically allocating their attention, and raise the possibility that reward-driven allocation of resources may affect the adaptive modulation of other cognitive processes.

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.

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository.

BACKGROUND: Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository. OBJECTIVE: To present the QPN and to perform preliminary analysis of the QPN data. METHODS: A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups. RESULTS: QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN. CONCLUSIONS: The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

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 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.

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.

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.

Immunomodulation in adult epilepsy: the role of IVIG.

Much of the research for intravenous immunoglobulins (IVIG) use in epilepsy has focused on childhood epilepsies and the results have been inconclusive. As evidence for inflammation in epilepsy and epileptogenesis is accumulating, IVIG might have a role to play in adult epilepsy. Our literature review focuses on the purported mechanisms of IVIG, the link between inflammation and the various causes of adult epilepsy and the different steps of epileptogenesis at which inflammation might play a role. We also review the current clinical evidence supporting IVIG as a treatment for epilepsy in the adult population. Though there is interesting theoretical potential for treatment of refractory epilepsy in adults with IVIG, insufficient evidence exists to support its standard use. The question remains if IVIG should still be considered as an end-of-the-line option for patients with epilepsy poorly responsive to all other treatments.

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.