alpha-synuclein and Psychotic-Disorders

Patients with idiopathic Parkinson's disease develop symptoms of the hallucination-psychosis spectrum in more than 20%. Most common are visual hallucinations. The pathogenesis of hallucinations mainly depends on disease duration, the distribution and extent of alpha-synuclein pathology, and modulating effects of the dopaminergic therapy. When managing PD hallucinations both anti-delirogenic actions and medication management are important. However, decrease in dopaminergic medication may lead to critical worsening of akinesia. If appropriate neuroleptic medication - essentially quetiapin or clozapin - can be considered. Instead, anti-dopaminergic neuroleptics should not be used owing to their pro-akinetic side-effects. Here, we provide therapy recommendations to manage PD hallucinations based on an up-to-date targeted review of the literature and expert-based empirical evidence.. Mehr als 20% der Patienten mit idiopathischem Parkinson-Syndrom (IPS) entwickeln Psychosen. Am häufigsten sind visuelle Halluzinationen. Bei der Entwicklung der Psychosen scheinen die Pathogenese der Parkinson-Erkrankung sowie ihre Dauer ebenso eine Rolle zu spielen wie modulierende Effekte der dopaminergen Therapie. Beim Therapiemanagement steht neben allgemeinen Maßnahmen zunächst die Anpassung der dopaminergen Therapie im Vordergrund. Dies kann zu einer Gratwanderung werden zwischen Besserung der Halluzinationen und Verschlechterung der Motorik. Bei unzureichendem Erfolg kann eine antipsychotische Therapie notwendig werden – dabei ist die Auswahl auf sehr wenige Antipsychotika beschränkt, um nicht ernsthafte motorische Verschlechterungen zu riskieren. In der vorliegenden Arbeit wurden basierend auf dem aktuellen Stand der Literatur sowie empirischen Experten-basierten Erfahrungen aus dem klinischen Alltag relevante Aspekte zu Halluzinationen bei IPS-Patienten in der Praxis zusammengefasst und Empfehlungen zum Therapiemanagement erarbeitet.

Topics: alpha-Synuclein; Antipsychotic Agents; Hallucinations; Humans; Parkinson Disease; Psychotic Disorders

Parkinson's disease psychosis is a prevalent yet underreported and understudied nonmotor manifestation of Parkinson's disease and, arguably, the most debilitating. It is unknown if α-synuclein plays a role in psychosis, and if so, this endophenotype may be crucial for elucidating the neurodegenerative process.. We sought to dissect the underlying neurobiology of novelty-induced hyperactivity, reminiscent of psychosis-like behavior, in human α-synuclein BAC rats.. Herein, we demonstrate a prodromal psychosis-like phenotype, including late-onset sensorimotor gating disruption, striatal hyperdopaminergic signaling, and persistent novelty-induced hyperactivity (up to 18 months), albeit reduced baseline locomotor activity, that is augmented by d-amphetamine and reversed by classical and atypical antipsychotics. MicroRNA-mediated α-synuclein downregulation in the ventral midbrain rescues the hyperactive phenotype and restores striatal dopamine levels. This phenotype is accompanied by an abundance of age-, brain region- and gene dose-dependent aberrant α-synuclein, including hyperphosphorylation, C-terminal truncation, aggregation pathology, and mild nigral neurodegeneration (27%).. Our findings demonstrate a potential role of α-synuclein in Parkinson's disease psychosis and provide evidence of region-specific perturbations prior to neurodegeneration phenoconversion. The reported phenotype coincides with the latest clinical findings that suggest a premotor hyperdopaminergic state may occur, while at the same time, premotor psychotic symptoms are increasingly being recognized. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Parkinson Disease; Psychotic Disorders; Rats; Rats, Transgenic; Substantia Nigra

G209A SNCA mutation carriers represent an important group of genetic PD. We describe motor and nonmotor features of G209A SNCA mutation carriers.. Longitudinal clinical assessments over 2 years were collected in 22 symptomatic and 8 asymptomatic G209A SNCA mutation carriers. Motor and nonmotor rating scales were administered. Correlations were performed between clinical variables and disease duration or age. Penetrance was calculated using Kaplan-Meier survival curves.. Asymptomatic carriers did not manifest clear premotor symptoms, but symptomatic carriers often reported that olfactory dysfunction and rapid eye movement sleep behavior disorder preceded motor symptoms. Prominent motor decline and deterioration of autonomic and cognitive function occurred at follow-up; such nonmotor features correlated with disease duration, but not age. Disease penetrance was estimated at around 90%.. This study may help to inform clinical trials and provide the basis for studies of disease modifiers in genetic synucleinopathy cohorts. © 2016 International Parkinson and Movement Disorder Society.

Topics: Adult; Aged; alpha-Synuclein; Autonomic Nervous System Diseases; Dementia; Female; Heterozygote; Humans; Longitudinal Studies; Male; Middle Aged; Mutation; Olfaction Disorders; Parkinson Disease; Penetrance; Psychotic Disorders

To study the relationship between neurodegenerative diseases including argyrophilic grain disease (AGD) and late-onset schizophrenia and delusional disorders (LOSD; onset ≥40 years of age), we pathologically examined 23 patients with LOSD, 71 age-matched normal controls, and 22 psychiatric disease controls (11 depression, six personality disorder, two bipolar disorders, and three neurotic disorders cases). In all LOSD cases (compared to age-matched normal controls), the frequencies of Lewy body disease (LBD), AGD, and corticobasal degeneration (CBD) were 26.1 % (11.3 %), 21.7 % (8.5 %), and 4.3 % (0.0 %), respectively. There was no case of pure Alzheimer's disease (AD). The total frequency of LBD, AGD, and CBD was significantly higher in LOSD cases than in normal controls. Argyrophilic grains were significantly more severe in LOSD than in controls, but were almost completely restricted to the limbic system and adjacent temporal cortex. In LOSD patients whose onset occurred at ≥65 years of age (versus age-matched normal controls), the frequencies of LBD and AGD were 36.4 % (19.4 %) and 36.4 % (8.3 %), respectively, and AGD was significantly more frequent in LOSD patients than in normal controls. In LOSD patients whose onset occurred at <65 years of age, the frequencies of LBD, AGD, and CBD were 16.7, 8.3, and 8.3 %, comparable to those of age-matched normal controls (10.2, 5.1, and 0.0 %). In all psychiatric cases, delusion was significantly more frequent in AGD cases than in cases bearing minimal AD pathology alone. Given these findings, LOSD patients may have heterogeneous pathological backgrounds, and AGD may be associated with the occurrence of LOSD especially after 65 years of age.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; alpha-Synuclein; Brain; Case-Control Studies; DNA-Binding Proteins; Female; Humans; Intermediate Filaments; Male; Middle Aged; Neurodegenerative Diseases; Psychotic Disorders; Schizophrenia; Statistics, Nonparametric; tau Proteins

Converging evidence suggests that psychotic Alzheimer's disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of α-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Enzyme-Linked Immunosorbent Assay; Female; Frontal Lobe; Humans; Male; Neurofibrillary Tangles; Phosphorylation; Psychotic Disorders; Sex Characteristics; tau Proteins

Our aim was to examine disease-related and genetic correlates of the development of psychotic symptoms in a large population of patients with Parkinson's disease. We studied 500 patients with Parkinson's disease from the NeuroGenetics Research Consortium using logistic regression models. Predictors were demographic, clinical (motor/nonmotor features), and genetic, measured as continuous or dichotomous variables. Continuous measures were divided into population-based tertiles. Results are given as odds ratios (95% confidence intervals) for dichotomous variables and by ascending tertile for continuous variables. Psychotic symptoms were associated with increasing age: 4.86 (1.62-14.30) and 6.25 (2.09-18.74) (test for trend: P = 0.01); and duration of disease: 3.81 (1.23-11.76) and 5.33 (1.68-16.89) (test for trend: P = 0.03). For nonmotor features, we demonstrated positive trends with depression: 1.31 (0.47-3.61) and 5.01 (2.04-12.33) (test for trend: P < 0.0001); cognitive dysfunction: 0.69 (0.26-1.84) and 2.51 (1.00-6.29) (test for trend: P = 0.03); and an excess for those with sleep disorders: 2.00 (1.03-3.89) (P = 0.04). Psychotic symptoms were not associated with tremor or postural instability scores, but there was an association with freezing of gait: 3.83 (1.67-8.75) (P < 0.002). Psychotic symptoms were not associated with the presence of any examined polymorphisms in the apolipoprotein, alpha-synuclein, or microtubule associated protein tau genes. This is the largest study to examine correlates of psychotic symptoms in Parkinson's disease. We discovered a novel association with freezing of gait. We demonstrated an association with depression and duration of disease, both of which were inconsistently related in previous studies, and confirmed the association with age, cognitive dysfunction, and sleep disorders.

Topics: Age Factors; Aged; alpha-Synuclein; Apolipoproteins E; Cognition Disorders; Community Health Planning; Female; Humans; Logistic Models; Male; Middle Aged; Parkinson Disease; Polymorphism, Single Nucleotide; Psychotic Disorders; Risk Factors; Severity of Illness Index; tau Proteins

Topics: Aged; alpha-Synuclein; Atrophy; Brain; Cognition Disorders; Depressive Disorder; Diagnosis, Differential; Disease Progression; Electroencephalography; Fatal Outcome; Gait Disorders, Neurologic; Genetic Markers; Genetic Predisposition to Disease; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Memory Disorders; Psychotic Disorders; REM Sleep Behavior Disorder; Sleep Apnea Syndromes; Urination Disorders