Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease.

OBJECTIVE: The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. METHODS: We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. RESULTS: Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. INTERPRETATION: OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.

[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.

GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes.

BACKGROUND: Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. OBJECTIVE: This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. METHODS: GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. RESULTS: Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. CONCLUSIONS: This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Integrative analysis of blood metabolomics and PET brain neuroimaging data for Parkinson's disease.

BACKGROUND: The diagnosis of Parkinson's disease (PD) often remains a clinical challenge. Molecular neuroimaging can facilitate the diagnostic process. The diagnostic potential of metabolomic signatures has recently been recognized. METHODS: We investigated whether the joint data analysis of blood metabolomics and PET imaging by machine learning provides enhanced diagnostic discrimination and gives further pathophysiological insights. Blood plasma samples were collected from 60 PD patients and 15 age- and gender-matched healthy controls. We determined metabolomic profiles by gas chromatography coupled to mass spectrometry (GC-MS). In the same cohort and at the same time we performed FDOPA PET in 44 patients and 14 controls and FDG PET in 51 patients and 16 controls. 18 PD patients were available for a follow-up exam after one year. Both data sets were analysed by two machine learning approaches, applying either linear support vector machines or random forests within a leave-one-out cross-validation scheme and computing receiver operating characteristic (ROC) curves. RESULTS: In the metabolomics data, the baseline comparison between cases and controls as well as the follow-up assessment of patients pointed to metabolite changes associated with oxidative stress and inflammation. For the FDOPA and FDG PET data, the diagnostic predictive performance (DPP) in the ROC analyses was highest when combining imaging features with metabolomics data (ROC AUC for best FDOPA + metabolomics model: 0.98; AUC for best FDG + metabolomics model: 0.91). DPP was lower when using only PET attributes or only metabolomics signatures. CONCLUSION: Integrating blood metabolomics data combined with PET data considerably enhances the diagnostic discrimination power. Metabolomic signatures also indicate interesting disease-inherent changes in cellular processes, including oxidative stress response and inflammation.

Failing as doorman and disc jockey at the same time: Amygdalar dysfunction in Parkinson's disease.

In Braak's model of ascending degeneration in Parkinson's disease (PD), involvement of the amygdala occurs simultaneously with substantia nigra degeneration. However, the clinical manifestations of amygdalar involvement in PD have not been fully delineated. Considered a multitask manager, the amygdala is a densely connected "hub," coordinating and integrating tasks ranging from prompt, multisensorial emotion recognition to adequate emotional responses and emotional tuning of memories. Although phylogenetically predisposed to handle fear, the amygdala handles both aversive and positive emotional inputs. In PD, neuropathological and in vivo studies suggest primarily amygdalar hypofunction. However, as dopamine acts as an inverted U-shaped amygdalar modulator, medication-induced hyperactivity of the amygdala can occur. We propose that amygdalar (network) dysfunction contributes to reduced recognition of negative emotional face expressions, impaired theory of mind, reactive hypomimia, and impaired decision making. Similarly, impulse control disorders in predisposed individuals, hallucinations, anxiety, and panic attacks may be related to amygdalar dysfunction. When available, we discuss amygdala-independent trigger mechanisms of these symptoms. Although dopaminergic agents have mostly an activation effect on amygdalar function, adaptive and compensatory network changes may occur as well, but these have not been sufficiently explored. In conclusion, our model of amygdalar involvement brings together several elements of Parkinson's disease phenomenology heretofore left unexplained and provides a framework for testable hypotheses in patients during life and in autopsy analyses.

Similar α-Synuclein staining in the colon mucosa in patients with Parkinson's disease and controls.

BACKGROUND: The gut is proposed as a starting point of idiopathic IPD, but the presence of α-synuclein in the IPD colon mucosa is debated. OBJECTIVES: The objective of this study was to evaluate if α-synuclein in the colon mucosa can serve as a biomarker of IPD. METHODS: Immunohistochemistry was used to locate and quantify in a blinded approach α-synuclein in the mucosa from biopsies of the right and left colon in 19 IPD patients and 8 controls. RESULTS: Total α-synuclein was present in all but 1 IPD patients and in all controls; phosphorylated α-synuclein was present in all subjects. There was no intensity difference depending on disease status. Staining of total α-synuclein was stronger in the right colon (p = .04). CONCLUSIONS: Conventional immunohistochemistry α-synuclein staining in colon mucosal biopsies cannot serve as a biomarker of idiopathic PD. These findings do not contradict the assumption of disease starting in the colon, and a colon segment-specific risk for disease initiation can still be hypothesized. © 2016 International Parkinson and Movement Disorder Society.

Are patients with Parkinson's disease blind to blindsight?

In Parkinson's disease, visual dysfunction is prominent. Visual hallucinations can be a major hallmark of late stage disease, but numerous visual deficits also occur in early stage Parkinson's disease. Specific retinopathy, deficits in the primary visual pathway and the secondary ventral and dorsal pathways, as well as dysfunction of the attention pathways have all been posited as causes of hallucinations in Parkinson's disease. We present data from patients with Parkinson's disease that contrast with a known neuro-ophthalmological syndrome, termed 'blindsight'. In this syndrome, there is an absence of conscious object identification, but preserved 'guess' of the location of a stimulus, preserved reflexive saccades and motion perception and preserved autonomical and expressive reactions to negative emotional facial expressions. We propose that patients with Parkinson's disease have the converse of blindsight, being 'blind to blindsight'. As such they preserve conscious vision, but show erroneous 'guess' localization of visual stimuli, poor saccades and motion perception, and poor emotional face perception with blunted autonomic reaction. Although a large data set on these deficits in Parkinson's disease has been accumulated, consolidation into one specific syndrome has not been proposed. Focusing on neuropathological and physiological data from two phylogenetically old and subconscious pathways, the retino-colliculo-thalamo-amygdala and the retino-geniculo-extrastriate pathways, we propose that aberrant function of these systems, including pathologically inhibited superior colliculus activity, deficient corollary discharges to the frontal eye fields, dysfunctional pulvinar, claustrum and amygdaloid subnuclei of the amygdala, the latter progressively burdened with Lewy bodies, underlie this syndrome. These network impairments are further corroborated by the concept of the 'silent amygdala'. Functionally being 'blind to blindsight' may facilitate the highly distinctive 'presence' or 'passage' hallucinations of Parkinson's disease and can help to explain handicaps in driving capacities and dysfunctional 'theory of mind'. We propose this synthesis to prompt refined neuropathological and neuroimaging studies on the pivotal nuclei in these pathways in order to better understand the networks underpinning this newly conceptualized syndrome in Parkinson's disease.

Lack of polysomnographic Non-REM sleep changes in early Parkinson's disease.

BACKGROUND: Polysomnography (PSG) data are rare in patients who have early stage idiopathic Parkinson's disease (IPD). METHODS: Thirty-three patients who had IPD with a disease duration ≤ 3 years and 37 age-matched controls were recruited. PSG analysis was performed on current medication. RESULTS: Patients with IPD had a reduced mean percentage of muscle atonia during rapid eye movement (REM) sleep (80% vs 93%; P < 0.05). Total sleep time, sleep efficiency, indices/hour of arousals, awakenings, apnea/hypopnea, and periodic leg movements were similar in both groups. Age, but not dopaminergic medication, had a negative impact on sleep architecture in patients with IPD. There was no correlation between sleep efficiency assessed by PSG and sleep quality assessed by questionnaire. CONCLUSIONS: The results confirmed a reduction in muscle atonia during REM sleep as a characteristic finding in early IPD. However, there were no further disease-inherent or medication-induced changes in sleep architecture. Although sleep disturbances are considered to be an integral part of IPD, PSG cannot yet identify them objectively at an early stage.

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.

Luxembourg Parkinson's study -comprehensive baseline analysis of Parkinson's disease and atypical parkinsonism.

Background: Deep phenotyping of Parkinson's disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson's study. Objective: To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls. Methods: Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders. Results: The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003). Conclusion: Luxembourg Parkinson's study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872.

The epidemiology of mild cognitive impairment (MCI) and Alzheimer's disease (AD) in community-living seniors: protocol of the MemoVie cohort study, Luxembourg.

BACKGROUND: Cognitive impairment and Alzheimer's disease (AD) are increasingly considered a major public health problem. The MemoVie cohort study aims to investigate the living conditions or risk factors under which the normal cognitive capacities of the senior population in Luxembourg (≥ 65 year-old) evolve (1) to mild cognitive impairment (MCI) - transitory non-clinical stage - and (2) to AD. Identifying MCI and AD predictors undeniably constitutes a challenge in public health in that it would allow interventions which could protect or delay the occurrence of cognitive disorders in elderly people. In addition, the MemoVie study sets out to generate hitherto unavailable data, and a comprehensive view of the elderly population in the country. METHODS/DESIGN: The study has been designed with a view to highlighting the prevalence in Luxembourg of MCI and AD in the first step of the survey, conducted among participants selected from a random sample of the general population. A prospective cohort is consequently set up in the second step, and appropriate follow-up of the non-demented participants allows improving the knowledge of the preclinical stage of MCI. Case-control designs are used for cross-sectional or retrospective comparisons between outcomes and biological or clinical factors. To ensure maximal reliability of the information collected, we decided to opt for structured face to face interviews. Besides health status, medical and family history, demographic and socio-cultural information are explored, as well as education, habitat network, social behavior, leisure and physical activities. As multilingualism is expected to challenge the cognitive alterations associated with pathological ageing, it is additionally investigated. Data relative to motor function, including balance, walk, limits of stability, history of falls and accidents are further detailed. Finally, biological examinations, including ApoE genetic polymorphism are carried out. In addition to standard blood parameters, the lipid status of the participants is subsequently determined from the fatty acid profiles in their red blood cells. The study obtained the legal and ethical authorizations. DISCUSSION: By means of the multidisciplinary MemoVie study, new insights into the onset of cognitive impairment during aging should be put forward, much to the benefit of intervention strategies as a whole.

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.

Parkinson's disease mouse models in translational research.

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson's disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research.

Reduced sympathetically driven heart rate variability during sleep in Parkinson's disease: a case-control polysomnography-based study.

OBJECTIVES: To study heart rate variability during nocturnal sleep in idiopathic Parkinson's disease. METHODS: Retrospective study, using part of the data set accumulated in an earlier study, in which polysomnography was performed in 35 idiopathic Parkinson's disease patients under their usual medication and in 35 non-idiopathic Parkinson's disease controls, matched for age, gender, and amount of apneas/hypopneas per hour. R-R intervals were calculated separately for non-rapid eye movements and rapid eye movements sleep stages. R-R variability was analyzed for time and frequency domains. Selected variables considered were high frequency band (0.15-0.40 Hz) influenced by parasympathetic input and low frequency band (0.04-0.15 Hz) influenced by sympathetic input. Both frequency bands were considered in normalized units (low frequency and high frequency normalized units). Low frequency/high frequency ratio was calculated as an estimate of sympathicovagal balance. RESULTS: All respiratory and sleep stage characteristics were similar in both groups. Low frequency normalized unit was reduced in idiopathic Parkinson's disease patients, both for non-rapid eye movements and rapid eye movements sleep (P = 0.005). Low frequency/high frequency was smaller in idiopathic Parkinson's disease for both sleep portions (P = 0.02). CONCLUSIONS: Idiopathic Parkinson's disease patients show reduced sympathetic influence on heart rate variability in both non-rapid eye movements and rapid eye movements sleep stages. We speculate that these findings are a consequence of the postganglionic noradrenergic cardiac denervation found in idiopathic Parkinson's disease patients.

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered "idiopathic" (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions-a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.

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.