Omics data integration suggests a potential idiopathic Parkinson's disease signature.

The vast majority of Parkinson's disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis. Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson's disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes.

Understanding visual hallucinations: A new synthesis.

Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been published since 2000, including Deafferentation, Reality Monitoring, Perception and Attention Deficit, Activation, Input, and Modulation, Hodological, Attentional Networks, Active Inference, and Thalamocortical Dysrhythmia Default Mode Network Decoupling. Each was derived from different understandings of brain organisation. To reduce this variability, representatives from each research group agreed an integrated Visual Hallucination Framework that is consistent with current theories of veridical and hallucinatory vision. The Framework delineates cognitive systems relevant to hallucinations. It allows a systematic, consistent, investigation of relationships between the phenomenology of visual hallucinations and changes in underpinning cognitive structures. The episodic nature of hallucinations highlights separate factors associated with the onset, persistence, and end of specific hallucinations suggesting a complex relationship between state and trait markers of hallucination risk. In addition to a harmonised interpretation of existing evidence, the Framework highlights new avenues of research, and potentially, new approaches to treating distressing hallucinations.

An individualized functional magnetic resonance imaging protocol to assess semantic congruency effects on episodic memory in an aging multilingual population.

The cognitive stimulation induced by multilingualism may slow down age-related memory impairment. However, a suitable neuroscientific framework to assess the influence of multilingualism on age-related memory processes is missing. We propose an experimental paradigm that assesses the effects of semantic congruency on episodic memory using functional magnetic resonance imaging (fMRI). To this end, we modified the picture-word interference (PWI) task to be suitable for the assessment of older multilingual subjects undergoing fMRI. In particular, stimulus materials were prepared in multiple languages (French, German, Luxembourgish, English) and closely matched in semantic properties, thus enabling participants to perform the experiment in a language of their choice. This paradigm was validated in a group (n = 62) of healthy, older participants (over 64 years) who were multilingual, all practicing three or more languages. Consistent with the engagement of semantic congruency processes, we found that the encoding and recognition of semantically related vs. unrelated picture-word pairs evoked robust differences in behavior and the neural activity of parietal-temporal networks. These effects were negligibly modulated by the language used to perform the task. Based on this validation in a multilingual population, we conclude that the proposed paradigm will allow future studies to evaluate whether multilingualism aptitude engages neural systems in a manner that protects long-term memory from aging-related decline.

[Causes of visual hallucinations in Parkinson's disease]. / Ursachen visueller Halluzinationen bei der Parkinson-Krankheit.

BACKGROUND: Visual hallucinations (VH) have mainly been considered as late symptoms of Parkinson's disease (PD); however, minor forms of VH also occur in early stages of the disease. Initially dopaminergic overstimulation was discussed as the cause and later on VH have been considered as an early red flag of dementia in PD. OBJECTIVE: The present study analyzed whether the pathophysiological concept of VH has been enlarged in recent years. MATERIAL AND METHODS: Clinical, pharmacological, neuropathological as well as functional magnetic resonance imaging studies dealing with VH were reviewed. A systematic classification in monomodal and multimodal models of VH is proposed. The applicability to various forms of VH and various triggering situations is critically examined. RESULTS: Reduction of the visual information input, erroneous visual processing, attention deficits, and dysfunctional connectivity between various cerebral networks have been shown. There is partial overlapping with the Lhermitte syndrome and the Charles Bonnet syndrome. No model is able to fully explain all VH variants. Not all VH have the same pathogenesis and the same poor prognosis. CONCLUSION: The chain of causes underlying VH is complex and can vary from patient to patient. So far the therapeutic applications are largely unexplored; however, there is preliminary evidence that beside adjustment of the medication, improvement of visual acuity, active involvement of the partner, and possibly, individually adaptable coping strategies could be successfully implemented.

Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

Contributing Factors and Evolution of Impulse Control Disorder in the Luxembourg Parkinson Cohort.

Background: To establish the frequency of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Within the Luxembourg Parkinson's Study, PD patients were evaluated for ICD presence (score ≥ 1 on MDS-UPDRS I item 1.6), use of dopamine agonists (DA) and other medications. Results: 470 patients were enrolled. Among 217 patients without DA use, 6.9% scored positive for ICD, vs. 15.4% among 253 patients with DA use (p = 0.005). The regression analysis showed that age at PD diagnosis had only a minor impact on ICD occurrence, while there was no influence by gender or co-medications. The longitudinal study over 2 years in 156 patients demonstrated increasing ICD frequency in DA users (p = 0.005). Conclusion: This large and non-interventional study confirms that PD patients with DA treatment show higher frequency of ICD than patients without DA use. It newly demonstrates that ICD can develop independently from age, gender, or co-medications.

Mitochondria interaction networks show altered topological patterns in Parkinson's disease.

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

The Clinical Non-Motor Connectome in Early Parkinson's Disease.

BACKGROUND: Non-motor symptoms (NMS) of various anatomical origins are seen in early stage idiopathic Parkinson's disease (IPD). OBJECTIVE: To analyse when and how NMS are linked together at this stage of the disease. METHODS: Prospective study recruiting 64 IPD patients with ≤3 years of disease duration and 71 age-matched healthy controls (HC). NMS were clustered in 7 non-motor domains (NMD): general cognition, executive function, visuospatial function, autonomic function, olfaction, mood, and sleep. Correlation coefficients ≥|0.3| were considered as significant. Bootstrapped correlation coefficients between the scores were generated in both groups. Fourteen IPD patients and 19 HC were available for a follow-up study two years later. RESULTS: The mean age of both groups was similar. 58% of IPD patients and 37% of HC were male (p = 0.01). At baseline IPD patients performed less well than HC on all NMD (p value between 0.0001 and 0.02). Out of 91 possible correlations between NMD, 21 were significant in IPD patients and 14 in HC at the level of ≥|0.3|. The mean correlation level was higher in IPD patients than in HC, as evidenced by the higher box plot of correlation coefficients. Visuospatial scores at baseline were predictive of the motor deterioration at the follow-up exam. CONCLUSION: At early IPD stage various NMS are linked together, although not connected by anatomical networks. Such a clinical NMD connectome suggests almost synchronous disease initiation at different sites as also supported by fMRI findings. Alternatively, there may be compensation-driven interconnectivity of NMD.

The Evolution-Driven Signature of Parkinson's Disease.

In this review, we approach Parkinson's disease (PD) in the context of an evolutionary mismatch of central nervous system functions. The neurons at risk have hyperbranched axons, extensive transmitter release sites, display spontaneous spiking, and elevated mitochondrial stress. They function in networks largely unchanged throughout vertebrate evolution, but now connecting to the expanded human cortex. Their breakdown is favoured by longevity. At the cellular level, mitochondrial dysfunction starts at the synapses, then involves axons and cell bodies. At the behavioural level, network dysfunctions provoke the core motor syndrome of parkinsonism including freezing and failed gait automatization, and non-motor deficits including inactive blindsight and autonomic dysregulation. The proposed evolutionary re-interpretation of PD-prone cellular phenotypes and of prototypical clinical symptoms allows a new conceptual framework for future research.

Corrigendum: Contributing Factors and Evolution of Impulse Control Disorder in the Luxembourg Parkinson Cohort.

[This corrects the article DOI: 10.3389/fneur.2020.578924.].

The Luxembourg Parkinson's Study: A Comprehensive Approach for Stratification and Early Diagnosis.

While genetic advances have successfully defined part of the complexity in Parkinson's disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson's study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches.

Reduced Rapid Eye Movement Density in Parkinson Disease: A Polysomnography-Based Case-Control Study.

STUDY OBJECTIVES: To explore rapid eye movement density (RD) in patients with idiopathic Parkinson disease (IPD) and to investigate its usefulness as surrogate marker of excessive daytime sleepiness, a frequent complaint in IPD patients. METHODS: Retrospective polysomnography study on 81 subjects without dementia: 29 patients with early stage IPD (disease duration ≤ 3 y), 21 patients with middle- stage IPD (disease duration > 3 and < 8 y) and 31 healthy controls (HC). Rapid eye movement (REM) sleep was defined as any REM episode with > 3 min of continuous REM sleep. RD was defined as number of ocular movements per minute of REM sleep. Patients with early stage IPD and HC fulfilled the PD-specific sleepiness questionnaires Parkinson's Disease Sleep Scale (PDSS) and the Nonmotor Symptoms Questionnaire for Parkinson's disease (NMSQuest). RESULTS: RD was lower in patients with IPD than in HC. The difference was most significant between patients with middle stage IPD and HC (P = 0.001), and most prominent for the third REM episode, again when comparing patients with middle stage IPD and HC (P = 0.03). RD was independent from sex, age, and other sleep parameters. In early stage IPD, RD correlated with the PDSS score (r = -0.63, P = 0.001) and the sleep-related questions of the NMSQuest score (r = 0.48, P = 0.017). CONCLUSIONS: REM density is reduced in patients with IPD and correlates with subjective scores on sleep impairment. As an indicator of persistent high sleep pressure, reduced RD in IPD is eligible as a biomarker of excessive daytime sleepiness in IPD. It possibly reflects direct involvement of the brainstem REM generation sites by the disease process. RD is a promising new tool for sleep research in IPD.