Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders.

Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.

Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aß-dependent expression in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid ß-peptide (Aß) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aß cascade. Exogenous Aß42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aß production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aß-induced upregulation of SPPL2b may enhance Aß production in a vicious cycle, further aggravating Aß pathology. Therefore, SPPL2b emerges as a potential anti-Aß drug target.

Cortical thickness, white matter hyperintensities, and cognition after stroke.

BACKGROUND: A thinner cerebral cortex is associated with higher white matter hyperintensity burden and cognitive impairment in community-dwelling and dementia cohorts. It is important to assess these associations in people with ischemic stroke because their cerebrovascular disease profiles are different to these cohorts. AIMS: We aimed to determine whether cortical thickness was related to white matter hyperintensity burden and cognition after ischemic stroke. METHODS: We measured cortical thickness using advanced normalization tools' "KellyKapowski" function in 244 patients with ischemic stroke or transient ischemic attack from the Virtual International Stroke Trials Archive. We measured white matter hyperintensity burden via quantitative volumes and Fazekas score. We extracted data on vascular risk factors at baseline and Mini Mental State Examination scores at one year. We assessed associations between imaging and clinical data using correlation and multiple linear regression. RESULTS: Pairwise correlation showed that higher white matter hyperintensity Fazekas score was associated with a thinner cortex (rho = -0.284, P < 0.0001). White matter hyperintensities were generally distributed adjacent to and above the lateral ventricles. Voxel-wise analyses showed statistically significant negative associations between cortical thickness and white matter hyperintensities across fronto-temporal and inferior parietal cortical regions. Mean cortical thickness was positively related to Mini Mental State Examination in pair-wise correlation (r = 0.167, P = 0.0088) but there was no independent association after adjustment for age and white matter hyperintensities (beta = 0.016, P = 0.7874). CONCLUSIONS: Cortical thickness was not an independent predictor of cognition after ischemic stroke. Further work is required to understand how white matter hyperintensities are associated with a thinner cortex in temporal regions but less so in more superior regions where white matter hyperintensities are generally found in people with stroke.

Evidence for unaltered brain electrical topography during prefrontal response control in cycloid psychoses.

OBJECTIVE: Prefrontal structures such as the anterior cingulate cortex (ACC) play a decisive role in processes of action monitoring and response control, functions often impaired in schizophrenia. Patients with cycloid psychoses exhibit some characteristic neurophysiological features not indicative of the cerebral hypofrontality observed in schizophrenia. This study aimed at examining if cycloid psychoses-unlike schizophrenias-involve a normal brain-electrical topography during a task demanding prefrontal response control. METHODS: Thirty-seven patients with cycloid psychoses and 37 healthy controls were investigated electrophysiologically while performing a Continuous Performance Test (CPT). Topographical analyses were conducted to individually quantify the Nogo-anteriorisation (NGA) as a neurophysiological index of prefrontal response control. RESULTS: The patients exhibited an unaltered topography with a mean NGA not significantly different from the controls. They did, however, differ from the control group regarding their Global Field Power (GFP), with a significantly reduced GFP (p<0.001) and decreased latencies (p<0.01) during Nogo trials. On a behavioral level, patients exhibited prolonged reaction times and an increased rate of omission errors. CONCLUSIONS: The investigated patients showed an activation of specific (presumably frontal) brain areas during Nogo trials, resulting in a frontalisation of the brain-electrical field comparable to the control group. However, the strength of this activation was apparently reduced. The patients' unaltered topographical pattern contrasts with previous findings in schizophrenic patients and supports the hypothesis that cycloid psychoses entail less severe prefrontal deficits than schizophrenias, which might be an indication of different biological backgrounds for both groups of endogenous psychoses.

Allelic variation of serotonin transporter function modulates the brain electrical response for error processing.

A functional length variation in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) influences brain function, personality traits, and susceptibility to psychiatric disorders. Here we measured prefrontal brain function by means of event-related potentials during an error processing paradigm. Physiologically, occurrence of an error elicits two specific electrical responses in the prefrontal cortex, the early error related negativity (Ne/ERN) and the later occurring error positivity (Pe), reflecting different components of error processing. Healthy subjects with one or two copies of the low-activity 5-HTTLPR short variant showed significantly higher amplitudes of the Ne/ERN and a trend to higher amplitudes of the Pe as compared to age- and gender-matched individuals homozygous for the long allele. Performance measures and latencies of these ERP-components did not differ between groups. These results indicate that the 5-HTTLPR short variant is associated with enhanced responsiveness of the brain and further supports the notion that prefrontal brain function is influenced by allelic variation in serotonin transporter function.

The scope and precision of specific temporal expectancy: evidence from a variable foreperiod paradigm.

Recent evidence from choice response time experiments with variable foreperiods (FPs) has shown that temporal expectancy can be event specific. When a certain target appears particularly frequent after one certain FP, participants tend to expect that target after that FP. This typically results in best performance for that target when it appears after that FP. In the present study, we investigated how temporally precise event-specific temporal expectancy is, and in which range of FPs it can be found. Two target stimuli were asymmetrically distributed over two "peak-FPs" and were equally distributed over 13 additional FPs. Event-specific expectancies were found for peak-FP pairs of 500/1,100 ms and 300/500 ms. Furthermore, the event expectancies generalized to a wide range of nonpeak FPs surrounding the peak FPs.

The specificity of temporal expectancy: evidence from a variable foreperiod paradigm.

In speeded choice tasks with variable foreperiods (FPs), individuals behaviourally adapt to various frequency manipulations. Adaptations have been shown to frequencies of different stimulus-response events, to frequencies of different foreperiods, and to frequencies of different event-foreperiod combinations. We have investigated how participants adapt to a situation where all three frequency manipulations are done simultaneously. Three variable foreperiod experiments are reported. In Experiment 1, one target (the peak distributed target) appeared particularly frequently after one particular FP (the peak foreperiod), while another target was less frequent and equally distributed over all foreperiods. In Experiment 2, the equally distributed target was overall more frequent than the peak distributed one. In both experiments, performance advantages for the peak distributed target were specific to the peak foreperiod, and performance advantages at the peak foreperiod were specific to the peak distributed targets. A third experiment showed that, when two differently frequent target are both equally distributed over FPs, the performance distribution over FPs is not significantly different between both targets. Together, the results suggest that participants were able to simultaneously and specifically adapt to frequency manipulations in events, foreperiods, and event-foreperiod combinations.

Temporal cueing of target-identity and target-location.

In four experiments either a short or a long foreperiod preceded the presentation of one of two targets, presented either in the center of the screen (Experiment 1) or at one of two locations (Experiments 2-4). Participants were to identify the presented target by pressing a left or a right button as quickly as possible. In Experiment 1, each of the two targets and in Experiment 2, each of the two locations appeared frequently after one and infrequently after the other foreperiod. Experiments 3 and 4 explored the combined effects of disparate frequency distributions of targets and locations to the two foreperiods. Reaction times and error rates revealed faster processing and/or less errors for respectively those targets and locations which were frequent after the current foreperiod. The data suggest that besides location-specific target expectancies (Hoffmann & Kunde, 1999) also time-specific expectancies for those targets and target-locations are formed which are likely at the respective point in time.

Unconscious manipulation of free choice in humans.

Previous research has shown that subliminally presented stimuli accelerate or delay responses afforded by supraliminally presented stimuli. Our experiments extend these findings by showing that unconscious stimuli even affect free choices between responses. Thus, actions that are phenomenally experienced as freely chosen are influenced without the actor becoming aware of the manipulation. However, the unconscious influence is limited to a response bias, as participants chose the primed response only in up to 60% of the trials. LRP data in free choice trials indicate that the prime was not ineffective in trials in which participants chose the non-primed response as then it delayed performance of the incongruently primed response.