[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.

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.

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.

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.

Diffusion tensor imaging in idiopathic REM sleep behavior disorder reveals microstructural changes in the brainstem, substantia nigra, olfactory region, and other brain regions.

STUDY OBJECTIVES: Idiopathic rapid eye movement sleep behavior disorder (iRBD)--a parasomnia characterized by dream enactments--is a risk marker for the development of Parkinson disease (PD) and other alpha-synucleinopathies. The pathophysiology of iRBD is likely due to dysfunction of brainstem nuclei that regulate REM sleep. Diffusion tensor imaging (DTI) is a method for studying microstructural brain tissue integrity in vivo. We investigated whether DTI detects microstructural abnormalities in the brain of patients with iRBD--compared with age-matched control subjects--as an in vivo potential indicator for changes related to "preclinical (premotor)" neuropathology in PD. DESIGN: N/A. PATIENTS: Patients with iRBD (n = 12) and age-matched healthy control subjects (n = 12) were studied. INTERVENTIONS: At a 1.5T MRI maschine, whole-head DTI scans of fractional anisotropy, axial diffusivity (a potential marker of neuronal loss), and radial diffusivity (a potential marker of glial pathology) were analyzed using track-based spatial statistics, and 2 types of group analysis tools (FreeSurfer and FSL). MEASUREMENTS AND RESULTS: We found significant microstructural changes in the white matter of the brainstem (P < 0.0001), the right substantia nigra, the olfactory region, the left temporal lobe, the fornix, the internal capsule, the corona radiata, and the right visual stream of the patients with iRBD. CONCLUSIONS: Changes were identified in regions known to be involved in REM-sleep regulation and/or to exhibit neurodegenerative pathology in iRBD and/or early PD. The study findings suggest that iRBD-related microstructural abnormalities can be detected in vivo with DTI, a widely available MRI technique.

Discriminative power of different nonmotor signs in early Parkinson's disease. A case-control study.

The objective of this study was to evaluate the discriminative power of different nonmotor signs for early diagnosis of Parkinson's disease (PD). Thirty patients with PD with

Myocardial MIBG scintigraphy: a useful clinical tool? : A retrospective study in 50 parkinsonian patients.

Meta-iodbenzylguanidine scintigraphy (MIBG scintigraphy) shows reduced uptake in idiopathic Parkinson's disease (IPD), idiopathic REM sleep behavior disorder (IRBD) and Lewy body dementia (LBD), but not in other parkinsonian or dementia syndromes. We retrospectively reevaluated 50 patients. Concordance rate between last clinical diagnosis and scintigraphy diagnosis was only given in two-thirds of the patients. Confounding factors were: decreasing heart/mediastinum ratio (HMR) with progressive age, higher HMR in women and possibly interference with antihypertensive medication. Standardization of the methods and precise clinical guidelines are warranted for better clinical use.

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.

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.

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

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