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Bax is a proapoptotic member of the Bcl-2 family of proteins. It is believed to exert its action primarily by facilitating the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, leading to caspase activation and cell death. Because alterations in mitochondrial respiratory function, caspase activation and cell death with morphologic features compatible with apoptosis have been observed post mortem in the brain of patients with Parkinson's disease, we tried to clarify the potential role of Bax in this process in an immunohistochemical study on normal and Parkinson's disease post-mortem brain and primary mesencephalic cell cultures treated with MPP[sup +]. We found that Bax is expressed ubiquitously by dopaminergic (DA) neurons in post-mortem brain of normal and Parkinson's disease subjects as well as in vitro. Using an antibody to Bax inserted into the outer mitochondrial membrane as an index of Bax activation, no significant differences were observed between control and Parkinson's disease subjects, regardless of the mesencephalic subregion analysed. However, in Parkinson's disease subjects, the percentage of Bax-positive melanized SNpc neurons containing Lewy bodies, suggestive of DA neuronal suffering, was significantly higher than the overall percentage of Bax-positive neurons among melanized neurons. Furthermore, all melanized SNpc neurons in Parkinson's disease subjects with activated caspase-3 were also immunoreactive for Bax, suggesting that Bax anchored in the outer mitochondrial membrane of melanized SNpc neurons showing signs of neuronal suffering or apoptosis is increased compared with DA neurons that are apparently unaltered. Surprisingly, MPP[sup +] treatment of tyrosine hydroxylase (TH)-positive neurons in primary mesencephalic cultures did not cause redistribution of Bax, although cytochrome c was released from the mitochondria and nuclear condensation/fragmentation was induced. Taken together, these findings suggest that in the human pathology, Bax may be a cofactor in caspase activation, but our in vitro data fail to indicate a central role for Bax in apoptotic death of DA neurons in an experimental Parkinson's disease paradigm. [ABSTRACT FROM AUTHOR]

Dopaminergic neurones degenerate during Parkinson's disease and cell loss is most extensive in the subpopulation of melanized neurones located in the substantia nigra pars compacta. Iron accumulation, together with a lack of up-regulation of the iron-storing protein, ferritin, has been reported and may contribute to increased oxidative stress in this region. We investigated the binding activity of iron regulatory protein-1 (IRP1) to the iron-responsive element that precludes ferritin mRNA translation, in the substantia nigra of a group of parkinsonian patients who presented a statistically significant reduction in the number of nigral melanized-neurones and an increased iron content, together with unchanged H-ferritin and L-ferritin subunit levels as compared to matched controls. The levels of ferritin mRNAs and the binding activity of IRP1 to the iron-responsive element of ferritin mRNA did not differ significantly between the two groups. Moreover, there was no detectable contribution of the iron regulatory protein-2 (IRP2) binding activity. No change in IRP1 control of ferritin mRNA translation explains the lack of up-regulation of ferritin expression in cytoplasmic extracts of SNpc that would be normally expected with cytosolic iron accumulation. The data of this study do not favor changes in transcription and post-transcriptional regulation of ferritin expression in Parkinson's disease and suggest a ‘compartmentalized’ iron accumulation. [ABSTRACT FROM AUTHOR]

Abstract Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity. [ABSTRACT FROM AUTHOR]

There have been numerous important recent advances in our understanding of the causes of Parkinson’s disease (PD), the treatments available and how these are best applied for the long-term management of patients. Novel genes causing familial PD have been discovered and mechanisms leading to cell dysfunction and death identified. The PD prodrome is now a subject of great interest and clinical markers are being defined that may in future, together with biochemical markers, support an early, pre-motor diagnosis of PD. This will become important as new therapies are developed to modify disease progression. In the interim, the optimization of existing therapies remains an important priority. The value of existing and novel continuous drug delivery systems in PD is seen as providing simplified regimens, maintenance of motor control, reduction in motor complications and improved patient adherence to drug use. [ABSTRACT FROM AUTHOR]

The most pronounced neuropathological feature of Parkinson's disease (PD) is the loss of dopamine (DA) neurons in the substantia nigra compacta (SNc), which depletes striatal DA. Hypothalamic oxytocin is found to be reduced in PD patients and closely interacts with the DA system, but the role of oxytocin in PD remains unclear. Here, the disturbances of endogenous oxytocin level and the substantia nigra (SN) oxytocin receptor expression in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model is observed, correlated with the striatal tyrosine hydroxylase (TH) expression reduction. Killing/silencing hypothalamic oxytocin neurons aggravates the vulnerability of nigrostriatal DA signal to MPTP, whereas elevating oxytocin level by intranasal delivery or microinjecting into the SN promotes the resistance. In addition, knocking out SN oxytocin receptors induces the time‐dependent reductions of SNc DA neurons, striatal TH expression, and striatal DA level by increasing neuronal excitotoxicity. These results further uncover that oxytocin dampens the excitatory synaptic inputs onto DA neurons via activating oxytocin receptor‐expressed SN GABA neurons, which target GABA(B) receptors expressed in SNc DA neuron‐projecting glutamatergic axons, to reduce excitotoxicity. Thus, besides the well‐known prosocial effect, oxytocin acts as a key endogenous factor in protecting the nigrostriatal DA system. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated. The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti‐inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment. This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Background and aims: The nonmotor symptoms (NMS) of Parkinson's disease (PD) and their potential role in early diagnosis are recent debates. Herein, we aimed to investigate the association between depression and NMS of PD including sleep disorders, hyposexuality, hyposmia, constipation, and orthostatic hypotension. Methods: A total of 93 PD patients with depression and 67 PD patients without depression were included in the study, and NMS were compared between the two groups. Furthermore, the possible associations between depression severity measured by Beck Depression Inventory (BDI) and NMS were investigated using linear regression or binary logistic regression models controlled for possible confounders. Eventually, we performed a subgroup analysis in each mild, moderate, and severe depression group. Results: Orthostatic hypotension, constipation, and hyposexuality showed a significant difference between PD patients with and without depression (p < 0.001, p = 0.029, and p < 0.001, respectively). The BDI score was significantly associated with hyposexuality, Montreal cognitive assessment (MoCA), and Pittsburgh Sleep Quality (p = 0.016, p = 0.010, and p = 0.011, respectively); however, after adjustments for possible confounders, the associations of the BDI score with the MoCA score and hyposexuality remained significant (p = 0.015 and p = 0.019, respectively). Considering subgroup analysis, a similar pattern of significant results was observed particularly in the severe group. Conclusions: This study suggests a possible association between depression in PD patients and some NMS observed in the course of PD. These findings could be beneficial for early diagnosis of the disease, which eventually could make a considerable difference in the management of PD patients. Additional interventional longitudinal studies are warranted to explore how controlling depression could impact the NMS of patients with PD. [ABSTRACT FROM AUTHOR]

Objectives. The aim of this study was to investigate the impact of nonmotor symptoms (NMS) on the quality of life (QoL) outcome after subthalamic nucleus deep brain stimulation (STN-DBS) at the 1-year follow-up. Methods. Ninety-three patients diagnosed with Parkinson's disease (PD), who underwent subthalamic nucleus deep brain stimulation (STN-DBS) between April 2020 and August 2021, were included in this study. Demographic information was gathered through a self-designed questionnaire. The severity of both motor and non-motor symptoms, along with the quality of life (QoL), was assessed using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), Nonmotor Symptoms Scale (NMSS), and 8-item Parkinson's Disease Questionnaire (PDQ-8), respectively. Results. Significant differences were observed in the UPDRS-III score, NMSS summary index (SI), and subscores of six domains (sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, urinary, and sexual function) between the baseline and the 6- and 12-month follow-ups. The correlation analysis revealed positive correlations between the preoperative NMSS SI and subscores of seven domains (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, and urinary) and ΔPDQ-8. Moreover, the preoperative PDQ-8 SI (β = 0.869, P < 0.001) and the preoperative attention/memory subscore (β = −0.154, P = 0.026) were predictive of the postsurgery improvement in quality of life (QoL). Conclusion. Deep brain stimulation (DBS) led to an improvement in the patients' nonmotor symptoms (NMS) at the 1-year follow-up, along with a correlation observed between NMS and the patients' quality of life (QoL). Notably, the severity of preoperative attention/memory problems emerged as the most significant predictor of NMS influencing the QoL outcome after STN-DBS at the 1-year follow-up. [ABSTRACT FROM AUTHOR]

Background and purpose: The specific pathophysiological mechanisms underlying postural instability/gait difficulty (PIGD) and cognitive function in Parkinson's disease (PD) remain unclear. Both postural and gait control, as well as cognitive function, are associated with the cholinergic basal forebrain (cBF) system. Methods: A total of 84 PD patients and 82 normal controls were enrolled. Each participant underwent motor and cognitive assessments. Diffusion tensor imaging was used to detect structural abnormalities in the cBF system. The cBF was segmented using FreeSurfer, and its fiber tract was traced using probabilistic tractography. To provide information on extracellular water accumulation, free‐water fraction (FWf) was quantified. FWf in the cBF and its fiber tract, as well as cortical projection density, were extracted for statistical analyses. Results: Patients had significantly higher FWf in the cBF (p < 0.001) and fiber tract (p = 0.021) than normal controls, as well as significantly lower cBF projection in the occipital (p < 0.001), parietal (p < 0.001) and prefrontal cortex (p = 0.005). In patients, a higher FWf in the cBF correlated with worse PIGD score (r = 0.306, p = 0.006) and longer Trail Making Test A time (r = 0.303, p = 0.007). Attentional function (Trail Making Test A) partially mediated the association between FWf in the cBF and PIGD score (indirect effect, a*b = 0.071; total effect, c = 0.256; p = 0.006). Conclusions: Our findings suggest that degeneration of the cBF system in PD, from the cBF to its fiber tract and cortical projection, plays an important role in cognitive−motor interaction. [ABSTRACT FROM AUTHOR]

Abnormal metal distribution in vulnerable brain regions is involved in the pathogenesis of most neurodegenerative diseases, suggesting common molecular mechanisms of metal dyshomeostasis. This study aimed to compare the intra‐ and extra‐neuronal metal content and the expression of proteins related to metal homeostasis in the substantia nigra (SN) from patients with Parkinson's disease (PD), multiple sclerosis (MS), and control subjects. Metal quantification was performed via ion‐beam micro‐analysis in neuromelanin‐positive neurons and the surrounding tissue. For proteomic analysis, SN tissue lysates were analyzed on a nanoflow chromatography system hyphenated to a hybrid triple‐quadrupole time‐of‐flight mass spectrometer. We found increased amounts of iron in neuromelanin‐positive neurons and surrounding tissue in patients with PD and MS compared to controls (4‐ to 5‐fold higher) that, however, also showed large inter‐individual variations. Copper content was systematically lower (−2.4‐fold) in neuromelanin‐positive neurons of PD patients compared with controls, whereas it remained unchanged in MS. Protein–protein interaction (PPI) network analyses revealed clusters related to Fe and Cu homeostasis among PD‐deregulated proteins. An enrichment for the term "metal homeostasis" was observed for MS‐deregulated proteins. Important deregulated hub proteins included hemopexin and transferrin in PD, and calreticulin and ferredoxin reductase in MS. Our findings show that PD and MS share commonalities in terms of iron accumulation in the SN. Concomitant proteomics experiments revealed PPI networks related to metal homeostasis, substantiating the results of metal quantification. [ABSTRACT FROM AUTHOR]

Aims: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α‐synuclein (α‐syn) in the gastrointestinal tract and midbrain dopaminergic neurons. Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS‐based rat model of gut inflammation in terms of α‐syn pathology. Results: Our data support the existence of pathogenic α‐syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS‐based rat model of gut inflammation to demonstrate (i) the appearance of P‐α‐syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α‐syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. Conclusion: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut‐brain axis in initiating α‐syn aggregation and transport to the substantia nigra, resulting in neurodegeneration. [ABSTRACT FROM AUTHOR]

Neuromelanin‐sensitive magnetic resonance imaging quantitative analysis methods have provided promising biomarkers that can noninvasively quantify degeneration of the substantia nigra in patients with Parkinson's disease. However, there is a need to systematically evaluate the performance of manual and automated quantification approaches. We evaluate whether spatial, signal‐intensity, or subject specific abnormality measures using either atlas based or manually traced identification of the substantia nigra better differentiate patients with Parkinson's disease from healthy controls using logistic regression models and receiver operating characteristics. Inference was performed using bootstrap analyses to calculate 95% confidence interval bounds. Pairwise comparisons were performed by generating 10,000 permutations, refitting the models, and calculating a paired difference between metrics. Thirty‐one patients with Parkinson's disease and 22 healthy controls were included in the analyses. Signal intensity measures significantly outperformed spatial and subject specific abnormality measures, with the top performers exhibiting excellent ability to differentiate patients with Parkinson's disease and healthy controls (balanced accuracy = 0.89; area under the curve = 0.81; sensitivity =0.86; and specificity = 0.83). Atlas identified substantia nigra metrics performed significantly better than manual tracing metrics. These results provide clear support for the use of automated signal intensity metrics and additional recommendations. Future work is necessary to evaluate whether the same metrics can best differentiate atypical parkinsonism, perform similarly in de novo and mid‐stage cohorts, and serve as longitudinal monitoring biomarkers. [ABSTRACT FROM AUTHOR]

The establishment of animal models for Parkinson's disease (PD) has been challenging. Nevertheless, once established, they will serve as valuable tools for elucidating the causes and pathogenesis of PD, as well as for developing new strategies for its treatment. Following the recent discovery of a series of PD causative genes in familial cases, teleost fishes, including zebrafish and medaka, have often been used to establish genetic PD models because of their ease of breeding and gene manipulation, as well as the high conservation of gene orthologs. Some of the fish lines can recapitulate PD phenotypes, which are often more pronounced than those in rodent genetic models. In addition, a new experimental teleost fish, turquoise killifish, can be used as a sporadic PD model, because it spontaneously manifests age‐dependent PD phenotypes. Several PD fish models have already made significant contributions to the discovery of novel PD pathological features, such as cytosolic leakage of mitochondrial DNA and pathogenic phosphorylation in α‐synuclein. Therefore, utilizing various PD fish models with distinct degenerative phenotypes will be an effective strategy for identifying emerging facets of PD pathogenesis and therapeutic modalities. [ABSTRACT FROM AUTHOR]

Decision‐making during mixed‐strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed‐strategy decision‐making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty‐six PD patients (ages 49–85, Hoehn and Yahr Stages 1–3) and 22 healthy controls (ages 54–75) competed in a mixed‐strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed‐strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within‐subject, multi‐centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val158Met), rs6277 (C957T) and rs907094 (encoding DARPP‐32). PD and control participants displayed comparable mixed‐strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow‐up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD. [ABSTRACT FROM AUTHOR]

Background: Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. Objective: The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. Methods: Drug‐naive PD patients who underwent N‐(3‐[18F]fluoropropyl)‐2‐carbomethoxy‐3‐(4‐iodophenyl) nortropane positron emission tomography scans and video‐oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society–Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. Results: One‐hundred twenty‐four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS‐UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey‐Complex‐Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin‐predominant region, but did not correlate with parkinsonism severity scores. Conclusion: Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background and purpose: Alpha‐synuclein seed amplification assays (α‐syn SAAs) are promising diagnostic methods for Parkinson's disease (PD) and other synucleinopathies. However, there is limited consensus regarding the diagnostic and differential diagnostic performance of α‐syn SAAs on biofluids and peripheral tissues. Methods: A comprehensive research was performed in PubMed, Web of Science, Embase and Cochrane Library. Meta‐analysis was performed using a random‐effects model. A network meta‐analysis based on an ANOVA model was conducted to compare the relative accuracy of α‐syn SAAs with different specimens. Results: The pooled sensitivity and specificity of α‐syn SAAs in distinguishing PD from healthy controls or non‐neurodegenerative neurological controls were 0.91 (95% confidence interval [CI] 0.89‐0.92) and 0.95 (95% CI 0.94‐0.96) for cerebrospinal fluid (CSF); 0.91 (95% CI 0.86–0.94) and 0.92 (95% CI 0.87‐0.95) for skin; 0.80 (95% CI 0.66‐0.89) and 0.87 (95% CI 0.69‐0.96) for submandibular gland; 0.44 (95% CI 0.30–0.59) and 0.92 (95% CI 0.79–0.98) for gastrointestinal tract; 0.79 (95% CI 0.70–0.86) and 0.88 (95% CI 0.77–0.95) for saliva; and 0.51 (95% CI 0.39‐0.62) and 0.91 (95% CI 0.84‐0.96) for olfactory mucosa (OM). The pooled sensitivity and specificity were 0.91 (95% CI 0.89–0.93) and 0.50 (95% CI 0.44–0.55) for CSF, 0.92 (95% CI 0.83–0.97) and 0.22 (95% CI 0.06–0.48) for skin, and 0.55 (95% CI 0.42–0.68) and 0.50 (95% CI 0.35–0.65) for OM in distinguishing PD from multiple system atrophy. The pooled sensitivity and specificity were 0.92 (95% CI 0.89–0.94) and 0.84 (95% CI 0.73–0.91) for CSF, 0.92 (95% CI 0.83–0.97) and 0.88 (95% CI 0.64–0.99) for skin and 0.63 (95% CI 0.52‐0.73) and 0.86 (95% CI 0.64‐0.97) for OM in distinguishing PD from progressive supranuclear palsy. The pooled sensitivity and specificity were 0.94 (95% CI 0.90–0.97) and 0.95 (95% CI 0.77–1.00) for CSF and 0.94 (95% CI 0.84–0.99) and 0.86 (95% CI 0.42–1.00) for skin in distinguishing PD from corticobasal degeneration. Conclusions: α‐Synuclein SAAs of CSF, skin, saliva, submandibular gland, gastrointestinal tract and OM are promising diagnostic assays for PD, with CSF and skin α‐syn SAAs demonstrating higher diagnostic performance. [ABSTRACT FROM AUTHOR]

Gene expression plays a critical role in the pathogenesis of Parkinson's disease (PD). How gene expression profiles are correlated with functional‐metabolic architecture remains obscure. We enrolled 34 PD patients and 25 age‐and‐sex‐matched healthy controls for simultaneous 18F‐FDG‐PET/functional MRI scanning during resting state. We investigated the functional gradients and the ratio of standard uptake value. Principal component analysis was used to further combine the functional gradients and glucose metabolism into functional‐metabolic architecture. Using partial least squares (PLS) regression, we introduced the transcriptomic data from the Allen Institute of Brain Sciences to identify gene expression patterns underlying the affected functional‐metabolic architecture in PD. Between‐group comparisons revealed significantly higher gradient variation in the visual, somatomotor, dorsal attention, frontoparietal, default mode, and subcortical network (pFDR <.048) in PD. Increased FDG‐uptake was found in the somatomotor and ventral attention network while decreased FDG‐uptake was found in the visual network (pFDR <.008). Spatial correlation analysis showed consistently affected patterns of functional gradients and metabolism (p = 2.47 × 10−8). PLS analysis and gene ontological analyses further revealed that genes were mainly enriched for metabolic, catabolic, cellular response to ions, and regulation of DNA transcription and RNA biosynthesis. In conclusion, our study provided genetic pathological mechanism to explain imaging‐defined brain functional‐metabolic architecture of PD. [ABSTRACT FROM AUTHOR]

Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD‐like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper‐deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP. [ABSTRACT FROM AUTHOR]

Background: The outcome of clinical trials in neurodegeneration can be highly uncertain due to the presence of a strong placebo effect. Objectives: To develop a longitudinal model that can enhance the success of future Parkinson's disease trials by quantifying trial‐to‐trial variations in placebo and active treatment response. Methods: A longitudinal model‐based meta‐analysis was conducted on the total score of Unified Parkinson's Disease Rating Scale (UPDRS) Parts 1, 2, and 3. The analysis included aggregate data from 66 arms (observational [4], placebo [28], or investigational‐drug‐treated [34]) from 4 observational studies and 17 interventional trials. Inter‐study variabilities in key parameters were estimated. Residual variability was weighted by the size of study arms. Results: The baseline total UPDRS was estimated to average at 24.5 points. Disease score was estimated to worsen by 3.90 points/year for the duration of the treatments; whilst notably, arms with a lower baseline progressed faster. The model captured the transient nature of the placebo response and sustained symptomatic drug effect. Both placebo and drug effects peaked within 2 months; although, 1 year was needed to observe the full treatment difference. Across these studies, the progression rate varied by 59.4%, the half‐life for offset of placebo response varied by 79.4%, and the amplitude for drug effect varied by 105.3%. Conclusion: The longitudinal model‐based meta‐analysis describes UPDRS progression rate, captures the dynamics of the placebo response, quantifies the effect size of the available therapies, and sets the expectation of uncertainty for future trials. The findings provide informative priors to enhance the rigor and success of future trials of promising agents, including potential disease modifiers. © 2023 GSK. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The year 2023 marks the 30th anniversary of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD). This procedure prompted a universal interest in DBS for various brain disorders and resulted in a unique expansion of clinical and scientific collaboration between many disciplines, with impact on many aspects of society. Objective: To study the anthropology of DBS, that is, its ethno‐geographic origins, its evolution, its impact on clinicians and scientists, and its influence on society at large. Material and Methods: The authors scrutinized the geo‐ethnic origins of the pioneers of modern DBS, and they evaluated, based on the literature and on a long‐term praxis, the development of DBS and its impact on clinicians, on healthcare, and on society. Results: Scientists and clinicians from various geo‐ethnic origins pioneered modern DBS, leading to worldwide spread of this procedure and to the establishment of large multidisciplinary teams in many centers. Neurologists became actively involved in surgery and took on new laborious tasks of programming ever more complicated DBS systems. Publications sky‐rocketed and the global spread of DBS impacted positively on several aspects of society, including healthcare, awareness of neurological diseases, interdisciplinary relations, conferences, patient organizations, unemployment, industry, etc. Conclusions: STN DBS has boosted the field of deep brain electrotherapy for many neurological and psychiatric illnesses, and DBS has generated a global benefit on many aspects of society, well beyond its clinical benefits on symptoms of diseases. With the ever‐increasing indications for DBS, more positive global impact is expected. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in advanced Parkinson's disease (PD) patients, but the degree of motor improvement varies across individuals. PD pathology involves the changes of iron spatial distribution in the deep gray matter nuclei. Purpose: To explore the relationship between the iron spatial distribution and motor improvement among PD patients who underwent STN‐DBS surgery in three regions: substantia nigra (SN), STN, and dentate nucleus (DN). Study Type: Prospective. Subjects: Forty PD patients (49.7 ± 8.8 years, 22 males/18 females) who underwent bilateral STN‐DBS. Field Strength/Sequence: A 3 T preoperative three‐dimensional spoiled bipolar‐readout multi‐echo gradient recalled echo and two‐dimensional fast spin echo sequences. Assessment: Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale part III (MDS‐UPDRS III) scores were assessed 2–3 days before and 6 months after STN‐DBS. The first‐ and second‐order texture features in regions of interest were measured on susceptibility maps. Statistical Tests: Intraclass correlation coefficient was used to determine the consistency of the region of interest volumes delineated by the two raters. Pearson or Spearman's correlation coefficients were used to assess the relationship between motor improvement after DBS and texture features. A P‐value <0.05 was considered statistically significant. Results: MDS‐UPDRS III scores were reduced by 59.9% after STN‐DBS in 40 PD patients. Motor improvement correlated with second‐order texture parameters in the SN including angular second moment (r = −0.449), correlation (rho = 0.326), sum of squares (r = 0.402), sum of entropy (rho = 0.421), and entropy (r = 0.410). Additionally, DBS outcome negatively correlated with mean susceptibility values in the DN (r = −0.400). Data Conclusion: PD patients with a more homogeneous iron distribution throughout the SN or a higher iron concentration in the DN responded worse to STN‐DBS. Level of Evidence: 2 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

18F‐Fluorodeoxyglucose positron emission tomography (18F‐FDG PET) is widely employed to reveal metabolic abnormalities linked to Parkinson's disease (PD) at a systemic level. However, the individual metabolic connectome details with PD based on 18F‐FDG PET remain largely unknown. To alleviate this issue, we derived a novel brain network estimation method for individual metabolic connectome, that is, Jensen‐Shannon Divergence Similarity Estimation (JSSE). Further, intergroup difference between the individual's metabolic brain network and its global/local graph metrics was analyzed to investigate the metabolic connectome's alterations. To further improve the PD diagnosis performance, multiple kernel support vector machine (MKSVM) is conducted for identifying PD from normal control (NC), which combines both topological metrics and connection. Resultantly, PD individuals showed higher nodal topological properties (including assortativity, modularity score, and characteristic path length) than NC individuals, whereas global efficiency and synchronization were lower. Moreover, 45 most significant connections were affected. Further, consensus connections in occipital, parietal, and frontal regions were decrease in PD while increase in subcortical, temporal, and prefrontal regions. The abnormal metabolic network measurements depicted an ideal classification in identifying PD of NC with an accuracy up to 91.84%. The JSSE method identified the individual‐level metabolic connectome of 18F‐FDG PET, providing more dimensional and systematic mechanism insights for PD. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation of the subthalamic nucleus (STN‐DBS) is an effective and evidence‐based treatment for idiopathic Parkinson's disease (iPD). A minority of patients does not sufficiently benefit from STN‐DBS. Objective: The predictive validity of the levodopa challenge for individual patients is analyzed. Methods: Data from patients assessed with a preoperative Levodopa‐test and a follow‐up examination (mean ± standard deviation: 9.15 months ±3.39) from Kiel (n = 253), Berlin (n = 78) and Toronto (n = 98) were studied. Insufficient DBS outcome was defined as an overall UPDRS‐III reduction <33% compared to UPDRS‐III in med‐off at baseline or alternatively if the minimal clinically important improvement of 5 points was not reached. Single UPDRS‐items and sub‐scores were dichotomized. Following exploratory analysis, we trained supervised regression‐ and classification models for outcome prediction. Results: Data analysis confirmed significant correlation between the absolute UPDRS‐III reduction during Levodopa challenge and after stimulation. But individual improvement was inaccurately predicted with a large range of up to 30 UPDRS III points. Further analysis identified preoperative UPDRS‐III/med‐off‐scores and preoperative Levodopa‐improvement as most influential factors. The models for UPDRS‐III and sub‐scores improvement achieved comparably low accuracy. Conclusions: With large prediction intervals, the Levodopa challenge use for patient counseling is limited, though remains important for excluding non‐responders to Levodopa. Despite these deficiencies, the current practice of patient selection is highly successful and builds not only on the Levodopa challenge. However, more specific motor tasks and further paraclinical tools for prediction need to be developed. [ABSTRACT FROM AUTHOR]

Although many entities have been established within the broad spectrum of Parkinson disease (PD) and atypical parkinsonisms, they are often difficult to differentiate. To clarify the current clinical diagnostic conditions and problems in PD and atypical parkinsonisms, we analyzed volumes of the Annuals of the Pathological Autopsy Cases in Japan. Among 130 105 autopsies conducted from 2007 to 2016 throughout Japan, patients were included in the study if they had been either clinically or pathologically diagnosed with PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Autopsy rates were 6.4% for clinically diagnosed PD, 34.1% for MSA, 16.3% for PSP, and 17.4% for CBD. The specificities and sensitivities of clinical diagnoses were 88.0% and 82.0% for PD, 95.2% and 86.0% for MSA, 82.7% and 73.2% for PSP, and 55.4% and 57.7% for CBD, respectively. Clinical diagnoses had relatively high accuracy, but low autopsy rates are of concern. Many patients with rarer disorders were clinically misdiagnosed with PD, a more common disorder. Autopsy rates, irrespective of specific disorders, should be increased to detect rare diseases. Increasing autopsy rates will increase the available clinical information regarding pathologically confirmed patients and contribute to more accurate clinical diagnoses. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that ferroptosis, a unique regulated cell death modality that is morphologically and mechanistically different from other forms of cell death, plays a vital role in the pathophysiological process of neurodegenerative diseases, and strokes. Accumulating evidence supports ferroptosis as a critical factor of neurodegenerative diseases and strokes, and pharmacological inhibition of ferroptosis as a therapeutic target for these diseases. In this review article, the core mechanisms of ferroptosis are overviewed and the roles of ferroptosis in neurodegenerative diseases and strokes are described. Finally, the emerging findings in treating neurodegenerative diseases and strokes through pharmacological inhibition of ferroptosis are described. This review demonstrates that pharmacological inhibition of ferroptosis by bioactive small‐molecule compounds (ferroptosis inhibitors) could be effective for treatments of these diseases, and highlights a potential promising therapeutic avenue that could be used to prevent neurodegenerative diseases and strokes. This review article will shed light on developing novel therapeutic regimens by pharmacological inhibition of ferroptosis to slow down the progression of these diseases in the future. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha‐synuclein (α‐syn). Although the formation of α‐syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll‐like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α‐syn and modulate its uptake by other cells. Lymphocyte‐activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α‐syn internalization; however, a recent study has disputed this role. Internalized α‐syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐1β, IL‐2, and IL‐6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N‐acetylcysteine (NAC), an anti‐inflammatory and anti‐carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti‐inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild‐type α‐syn were treated with TNF‐α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF‐α‐induced inflammation and apoptosis. SNCA gene transcription and α‐syn protein expression were validated by q‐PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q‐PCR. TNF‐α not only increased inflammation but also increased endogenous and overexpressed α‐syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation‐mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha‐synuclein overexpression, via a TLR2‐associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD. [ABSTRACT FROM AUTHOR]

Background: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) cohorts have provided insights into the earliest neurodegenerative processes in α‐synucleinopathies. Even though polysomnography (PSG) remains the gold standard for diagnosis, an accurate questionnaire‐based algorithm to identify eligible subjects could facilitate efficient recruitment in research. Objective: This study aimed to optimize the identification of subjects with iRBD from the general population. Methods: Between June 2020 and July 2021, we placed newspaper advertisements, including the single‐question screen for RBD (RBD1Q). Participants' evaluations included a structured telephone screening consisting of the RBD screening questionnaire (RBDSQ) and additional sleep‐related questionnaires. We examined anamnestic information predicting PSG‐proven iRBD using logistic regressions and receiver operating characteristic curves. Results: Five hundred forty‐three participants answered the advertisements, and 185 subjects fulfilling inclusion and exclusion criteria were screened. Of these, 124 received PSG after expert selection, and 78 (62.9%) were diagnosed with iRBD. Selected items of the RBDSQ, the Pittsburgh Sleep Quality Index, the STOP‐Bang questionnaire, and age predicted iRBD with high accuracy in a multiple logistic regression model (area under the curve >80%). When comparing the algorithm to the sleep expert decision, 77 instead of 124 polysomnographies (62.1%) would have been carried out, and 63 (80.8%) iRBD patients would have been identified; 32 of 46 (69.6%) unnecessary PSG examinations could have been avoided. Conclusions: Our proposed algorithm displayed high diagnostic accuracy for PSG‐proven iRBD cost‐effectively and may be a convenient tool for research and clinical settings. External validation sets are warranted to prove reliability. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Nigrosome 1 (NG1), a small cluster of dopaminergic cells in the substantia nigra and visible in the susceptibility map‐weighted magnetic resonance image (SMwI), is severely affected in Parkinson's disease (PD). However, the degree of nigrostriatal degeneration according to the visibility of NG1 has not yet been well elucidated. Methods: We consecutively recruited 138 PD and 78 non‐neurodegenerative disease (non‐ND) patients, who underwent both 18F‐FP‐CIT positron emission tomography (PET) and SMwI. Three neurologists and one radiologist evaluated the visibility of NG1 in SMwI. The participants were thereby grouped into visible, intermediate, and non‐visible groups. Nigrostriatal dopaminergic input was calculated using the specific binding ratio (SBR) of the 18F‐FP‐CIT PET. We determined the threshold of regional SBR for discriminating NG1 visibility and the probability for NG1 visibility according to regional SBR. Results: Visual rating of NG1 showed excellent interobserver agreements as well as high sensitivity and specificity to differentiate the PD group from the non‐ND group. NG1 was visible in seven patients (5.1%) in the PD group, who had relatively short disease duration or less severe loss of striatal dopamine. The threshold of putaminal SBR reduction on the more affected side for the disappearance of NG1 was 45.5%, and the probability for NG1 visibility dropped to 50% after the reduction of putaminal SBR to 41% from the normal mean. Conclusions: Almost half loss of nigrostriatal dopaminergic input is required to dissipate the hyperintensity of NG1 on SMwI, suggesting its utility in diagnosing PD only after the onset of the motor symptoms. [ABSTRACT FROM AUTHOR]

Saccade performance has been reported to be altered in Parkinson's disease (PD), however, with a large variability between studies as both motor and cognitive impairment interfere with oculomotor control. The aim of this study was to identify different patterns in saccade alterations in PD using a data‐driven approach and to explore their relationship with cognitive phenotypes. Sixty‐one participants with PD and 25 controls performed eye‐tracking (horizontal and vertical prosaccades, antisaccades) and neuropsychological testing. Hierarchical cluster analysis was applied to the eye‐tracking data to subsequently compare the clusters based on demographical, clinical and cognitive characteristics. The three identified clusters of saccade alterations differed in cognitive profiles from healthy controls, but not in PD‐related motor symptoms or demographics. The rate of directive errors in the antisaccade task was increased in clusters 1 and 2. Further, cluster 1 was defined by a general disinhibition of reflexive saccades and executive dysfunction in the neuropsychological evaluation. In cluster 2, prolonged saccade latencies and hypometria were accompanied by multidomain cognitive impairment. The cluster 3 showed increased antisaccade latency and vertical hypometria despite lack of evidence for cognitive impairment. Our results suggest that there may be at least two opposing patterns of saccade alterations associated with cognitive impairment in PD, which may explain some of the contradictory results of previous studies. [ABSTRACT FROM AUTHOR]

Parkinson's disease is among the most common forms of neurodegenerative illness, with present treatment being primarily symptomatic and frequently coming with substantial adverse effects. Neuronal degeneration may arise due to a variety of pathological events, like inflammatory responses, neurotransmitter dysregulation, oxidative damage, mitochondrial malfunction, apoptosis, and genetic factors. The health issue and financial burden brought on by Parkinson's disease can worsen as the population ages. In the search for new and secure therapeutic agents for Parkinson's disease, several natural compounds have been shown to exert considerable neuroprotective benefits. Crocin, a naturally occurring carotenoid molecule, was found to have neuroprotective potential in the therapy of this disorder. Taking into account, the outcomes of various studies and the restorative actions of crocin, the present study emphasized the protective ability of crocin in this disease. Given the strong evidence supporting the neuroprotective ability of crocin, it is inferred that crocin inhibits inflammatory, apoptotic, and antioxidant processes through multiple mechanisms. Therefore, this compound is considered a safe and effective therapeutic choice for neurodegenerative illnesses like Parkinson's disease. However, more research on its efficacy as a treatment of Parkinson's disease is needed, specifically examining its mechanisms and the results obtained in clinical trials. [ABSTRACT FROM AUTHOR]

Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H‐ferritin is critical. Endothelial cells of the blood–brain barrier are the site of iron transport regulation. The movement of iron through endothelial cells into the brain can be divided into three distinct processes: uptake, transcytosis, and release. Each process possesses external and internal influences on the regulation at each stage. This review discusses the mechanisms of iron uptake, transcytosis, and release at the blood–brain barrier, as well as the elements that contribute to regulation. Additionally, we explore the dysregulation of brain iron in Alzheimer's disease, Parkinson's disease, and restless legs syndrome. [ABSTRACT FROM AUTHOR]

Background: An absent dorsolateral nigral hyperintensity (DNH) is a common finding in patients with neurodegenerative parkinsonism at high or ultra‐high field susceptibility‐weighted magnetic resonance imaging (SWI). Objective: Despite increasing use of high field magnetic resonance imaging (MRI) in specialized centers, these scanners are still frequently unavailable in primary care or outpatient facilities and underdeveloped or emerging countries. Therefore, the aim of the present study was to evaluate the diagnostic utility of DNH assessment at 1.5 versus 3 T MRI to distinguish patients with neurodegenerative parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), from healthy controls (HC). Methods: Absence of DNH was assessed on visual inspection of anonymized 1.5 T and 3.0 T SWI scans in a case–control study including 86 patients with neurodegenerative parkinsonism and 33 healthy controls (HC). All study participants were consecutively recruited to undergo 1.5 and 3 T MRI. Results: Overall correct classification was 81.7% (95% CI, 72.6–88.4%) for 1.5 T and 95.7% (95% CI, 89.1–98.7%) for 3 T MRI in discriminating neurodegenerative parkinsonism from controls. However, while DNH was bilaterally present in all but one of the HC at 3 T MRI, it was rated as abnormal (at least unilateral absence) in 15 of 22 HC at 1.5 T MRI, resulting in a specificity of 31.8%. Conclusions: The results of the present study demonstrate an insufficient specificity of visual assessment of DNH at 1.5 T MRI for the diagnosis of neurodegenerative parkinsonism. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) can be diagnosed despite the presence of asymmetrical parkinsonism depending on the clinical diagnostic criteria. Some studies have reported that atrophy of the superior cerebellar peduncle (SCP) is more frequent in PSP than in Parkinson's disease. There have also been reports of PSP cases with an asymmetrically atrophic SCP. Therefore, we analyzed 48 specimens from consecutive autopsy cases that were neuropathologically diagnosed as PSP to investigate the laterality of brain lesions, including the SCP. We measured the width of the SCP and evaluated the laterality of atrophy. We semi‐quantitatively evaluated neuronal loss, atrophy/myelin pallor, and tau pathology in three steps. Asymmetrical atrophy of the SCP was present in seven (14.6%) of 48 cases. The atrophic side of the SCP corresponded to the dominant side of the tau pathology in the cerebellar dentate nucleus. It was opposite to the dominant side of the myelin pallor and tau pathology in the red nucleus and of the tau pathology in the central tegmental tract and inferior olivary nucleus, coinciding with the neurologically systematic anatomy of the Guillain–Mollaret triangle. Neurodegeneration of PSP can progress asymmetrically from one side to the initially intact side in PSP with an initial predominance of Richardson's syndrome, progressive gait freezing, ocular motor dysfunction, parkinsonism, or corticobasal syndrome. To our knowledge, no previous study has reported asymmetrical PSP neuropathology; this is the first study to report the presence of PSP cases with asymmetrical SCP atrophy and systematically asymmetrical degeneration of the Guillain–Mollaret triangle. [ABSTRACT FROM AUTHOR]

Background: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. Objective: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. Method: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18F]fluorodeoxyglucose ([18F]FDG) PET and [11C]UCB‐J, respectively. Volumes‐of‐interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios‐1 values were obtained for 14 pre‐selected brain regions. Between‐group comparisons were conducted at voxel‐level. Results: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non‐demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel‐wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. Conclusion: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18F]FDG PET and [11C]UCB‐J PET in Lewy body patients. The magnitude of reduced [18F]FDG uptake was greater than the corresponding decline in [11C]UCB‐J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Real‐time quaking‐induced conversion (RT‐QuIC) and protein misfolding cyclic amplification (PMCA) have been developed to detect minute amounts of amyloidogenic proteins via amplification techniques and have been used to detect misfolded α‐synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) and other source materials of patients with Parkinson's Disease and other synucleinopathies. Objectives: The aim of this systematic review and meta‐analysis was to evaluate the diagnostic accuracy of αSyn seed amplification assays (αSyn‐SAAs), including RT‐QuIC and PMCA, using CSF as source material to differentiate synucleinopathies from controls. Methods: The electronic MEDLINE database PubMed was searched for relevant articles published until June 30, 2022. Study quality assessment was performed using the QUADAS‐2 toolbox. A random effects bivariate model was exploited for data synthesis. Results: Our systematic review identified 27 eligible studies according to the predefined inclusion criteria, of which 22 were included in the final analysis. Overall, 1855 patients with synucleinopathies and 1378 non‐synucleinopathies as control subjects were included in the meta‐analysis. The pooled sensitivity and specificity to differentiate synucleinopathies from controls with αSyn‐SAA were 0.88 (95% CI, 0.82–0.93) and 0.95 (95% CI, 0.92–0.97), respectively. Evaluating the diagnostic performance of RT‐QuIC in a subgroup analysis for the detection of patients with multiple system atrophy the pooled sensitivity decreased to 0.30 (95% CI, 0.11–0.59). Conclusions: While our study clearly demonstrated a high diagnostic performance of RT‐QuIC and PMCA for differentiating synucleinopathies with Lewy bodies from controls, results for the diagnosis of multiple system atrophy were less robust. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is pathologically defined by the death of dopaminergic (DA) neurons within the pars compacta of the substantia nigra. To date, the cause of this multifaceted disease remains largely unclear, which may contribute in part to a current lack of disease‐modifying therapies. Recent advances in single‐cell and spatial genomic profiling tools have provided powerful new ways to measure cellular state changes in brain diseases. Here, we describe how these tools have offered insight into these complex disorders and highlight a recently performed comprehensive study of DA neuron susceptibility in PD. The data generated by this recent work provide evidence for the role of specific pathways and common genetic variants resulting in the loss of a critical DA subtype in PD. We conclude by outlining a set of basic and translational opportunities that arise from those data and insights gathered from this work. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Degeneration of the substantia nigra (SN) may contribute to levodopa‐induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear. Objective: To further understand the pathogenesis of patients with PD with LID (PD‐LID), we explored the structural and functional characteristics of SN in PD‐LID using multimodal magnetic resonance imaging (MRI). Methods: Twenty‐nine patients with PD‐LID, 37 patients with PD without LID (PD‐nLID), and 28 healthy control subjects underwent T1‐weighted MRI, quantitative susceptibility mapping, neuromelanin‐sensitive MRI, multishell diffusion MRI, and resting‐state functional MRI. Different measures characterizing the SN were obtained using a region of interest–based approach. Results: Compared with patients with PD‐nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast‐to‐noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD‐LID. The intracellular volume fraction of the posterior SN in PD‐LID was significantly higher compared with PD‐nLID (P = 0.037). Resting‐state fMRI indicated that PD‐LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD‐nLID (P = 0.031), and the functional connectivity changes in PD‐LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042). Conclusions: Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD‐LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD‐LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Clinical diagnostic accuracy of Parkinson's disease (PD) remains suboptimal. Changes in disease concept may have improved clinical diagnostic accuracy in the past decade. However, current clinical diagnostic criteria have not been validated against neuropathological confirmation. Objectives: This study aims to provide up‐to‐date clinical diagnostic accuracy data and validate current clinical diagnostic criteria for PD against neuropathology. Methods: A retrospective review of medical records of consecutive patients with parkinsonism from the Queen Square Brain Bank was performed between 2009 and 2019. Clinical diagnosis was documented at early (within 5 years of motor symptom onset) and final stages and categorized by movement disorder experts or regular clinicians. Movement Disorder Society Parkinson's disease (MDS‐PD) diagnostic criteria were retrospectively applied. Diagnostic accuracy parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as the gold standard. Results: A total of 267 patients (141 PD and 126 non‐PD parkinsonism) were included. Clinical diagnostic accuracy was 97.2% for experts, 92.5% for the MDS clinically probable PD criteria, and 90.3% for clinicians. Similar figures were obtained when applied at an early stage (91.5%, 89.5%, and 84.2% diagnostic accuracy, respectively). MDS clinically established early PD criteria demonstrated very high specificity (98.4%) at early stages. Conclusions: Our results showed an important improvement in PD clinical diagnostic accuracy in clinical practice over the past decade, more marked at early stages of the disease. MDS‐PD diagnostic criteria is a valid tool in clinical practice and research for the identification of PD patients showing excellent sensitivity and specificity, although movement disorder experts' diagnosis remains the gold standard PD diagnosis during life. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the incidence rate of Parkinson's disease dementia (PDD) according to age and disease duration by sex. Furthermore, we explored the effect of each cardiometabolic syndrome and depression on the incidence of PDD. Methods: Using data from the Korean National Health Insurance Service, 79,622 patients with de novo Parkinson's disease (PD) aged ≥40 years between January 2002 and December 2010 were followed to December 2019. We analyzed the incidence of PDD according to age at PD diagnosis and disease duration. To determine cardiometabolic syndromes and depression that affected PDD, we used Fine and Gray competing regression after controlling for age and sex. Results: During the 12.5‐year follow‐up period, the incidence of PDD increased with age at PD diagnosis (0.81–45.31 per 1000 person‐years among those aged 40–44 and over 80 years, respectively) and longer disease duration (22.68 per 1000 person‐years in 1–2 years to 34.16 per 1000 person‐years in 15–16 years). Hypertension (subdistribution hazard ratio [SHR] = 1.11; 95% confidence interval [CI] 1.07–1.16), diabetes (SHR = 1.09; 95% CI 1.05–1.14), dyslipidemia (SHR = 1.15; 95% CI 1.11–1.20), and depression (SHR = 1.36; 95% CI 1.30–1.41) independently increased the risk for PDD. Conclusions: Our findings provide insights into cardiometabolic syndromes as modifiable risk factors for incident PDD. Furthermore, our results will help in designing public health policies with respect to controlling cardiometabolic syndromes and depression to prevent incident PDD in patients with PD. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation of the subthalamic nucleus (STN‐DBS) is an effective treatment for Parkinson's disease (PD). The long‐term benefit in PD patients with STN‐DBS in comparison to medical treatment (MT) alone has not yet been demonstrated conclusively. Objectives: To judge the long‐term outcome of patients with STN‐DBS. Methods: To assess the evolution of PD symptoms and health‐related quality of life (HRQoL) after deep brain stimulation (DBS) surgery, we conducted a cross‐sectional analysis of 115 patients with STN‐DBS with rater‐based scales and self‐reported questionnaires. In addition, we screened records of all our STN‐DBS patients (2001–2019, n = 162 patients) for the onset of the morbidity milestones (falls, hallucinations, dementia, and nursing home placement) to assess disability‐free life expectancy. Results: In the first year of STN‐DBS, levodopa equivalent dose was reduced and motor function improved. Nonmotor symptoms and cognition remained stable. These effects were similar to previous studies. Morbidity milestones occurred 13 ± 7 years after diagnosis. Motor function, cognition, and HRQoL significantly worsened after the occurrence of any milestone, confirming the clinical relevance of these milestones. After onset of the first milestone, mean survival time was limited to 5 ± 0.8 years, which is comparable with patients with PD but without STN‐DBS. Conclusions: On average, PD patients with STN‐DBS live with their disease for a longer time, and morbidity milestones occur later in the disease course than in PD patients with MT. As judged by morbidity milestones, morbidity remains compressed into the final 5 years of life in PD patients with STN‐DBS. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. Objective: To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. Methods: We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software. Results: The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA. Conclusions: Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Motor imagery (MI), the mental simulation of movement in the absence of overt motor output, has demonstrated potential as a technique to support rehabilitation of movement in neurological conditions such as Parkinson's disease (PD). Existing evidence suggests that MI is largely preserved in PD, but previous studies have typically examined global measures of MI and have not considered the potential impact of individual differences in symptom presentation on MI. The present study investigated the influence of severity of overall motor symptoms, bradykinesia and tremor on MI vividness scores in 44 individuals with mild to moderate idiopathic PD. Linear mixed effects modelling revealed that imagery modality and the severity of left side bradykinesia significantly influenced MI vividness ratings. Consistent with previous findings, participants rated visual motor imagery (VMI) to be more vivid than kinesthetic motor imagery (KMI). Greater severity of left side bradykinesia (but not right side bradykinesia) predicted increased vividness of KMI, while tremor severity and overall motor symptom severity did not predict vividness of MI. The specificity of the effect of bradykinesia to the left side may reflect greater premorbid vividness for the dominant (right) side or increased attention to more effortful movements on the left side of the body resulting in more vivid motor imagery. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) for Parkinson's disease (PD) is generally contraindicated in persons with dementia but it is frequently performed in people with mild cognitive impairment or normal cognition, and current clinical guidelines are primarily based on these cohorts. Objectives: To determine if moderately cognitive impaired individuals including those with mild dementia could meaningfully benefit from DBS in terms of motor and non‐motor outcomes. Methods: In this retrospective case‐control study, we identified a cohort of 40 patients with PD who exhibited moderate (two or more standard deviations below normative scores) cognitive impairment (CI) during presurgical workup and compared their 1‐year clinical outcomes to a cohort of 40 matched patients with normal cognition (NC). The surgery targeted subthalamus, pallidus or motor thalamus, in a unilateral, bilateral or staged approach. Results: At preoperative baseline, the CI cohort had higher Unified Parkinson's Disease Rating Scale (UPDRS) subscores, but similar levodopa responsiveness compared to the NC cohort. The NC and CI cohorts demonstrated comparable degrees of postoperative improvement in the OFF‐medication motor scores, motor fluctuations, and medication reduction. There was no difference in adverse event rates between the two cohorts. Outcomes in the CI cohort did not depend on the target, surgical staging, or impaired cognitive domain. Conclusions: Moderately cognitively impaired patients with PD can experience meaningful motor benefit and medication reduction with DBS. [ABSTRACT FROM AUTHOR]

Disruption of the gut‐brain axis in Parkinson's disease (PD) may lead to motor symptoms and PD pathogenesis. Recently, the neuroprotective potential of different PPARδ‐agonists has been shown. We aimed to reveal the effects of erucic acid, peroxisome proliferator‐activated receptors (PPARs)‐ligand in rotenone‐induced PD model in zebrafish, focusing on the gut‐brain axis. Adult zebrafish were exposed to rotenone and erucic acid for 30 days. Liquid chromatography‐mass spectrometry and tandem mass spectrometry (LC–MS/MS) analysis was performed. Raw files were analysed by Proteome Discoverer 2.4 software; peptide lists were searched against Danio rerio proteins. STRING database was used for protein annotations or interactions. Lipid peroxidation (LPO), nitric oxide (No), alkaline phosphatase, superoxide dismutase, glutathione S‐transferase (GST), acetylcholinesterase and the expressions of PD‐related genes were determined. Immunohistochemical tyrosine hydroxylase (TH) staining was performed. LC–MS/MS analyses allowed identification of over 2000 proteins in each sample. The 2502 and 2707 proteins overlapped for intestine and brain. The 196 and 243 significantly dysregulated proteins in the brain and intestines were found in rotenone groups. Erucic acid treatment corrected the changes in the expression of proteins associated with cytoskeletal organisation, transport and localisation and improved locomotor activity, expressions of TH, PD‐related genes (lrrk2, park2, park7, pink1) and oxidant‐damage in brain and intestines in the rotenone group as evidenced by decreased LPO, No and increased GST. Our results showed beneficial effects of erucic acid as a PPARδ‐ligand in neurotoxin‐induced PD model in zebrafish. We believe that our study will shed light on the mechanism of the effects of PPARδ agonists and ω9‐fatty acids in the gut‐brain axis of PD. [ABSTRACT FROM AUTHOR]

MRI has been used to develop biomarkers for movement disorders such as Parkinson disease (PD) and other neurodegenerative disorders with parkinsonism such as progressive supranuclear palsy and multiple system atrophy. One of these imaging biomarkers is neuromelanin (NM), whose integrity can be assessed from its contrast and volume. NM is found mainly in certain brain stem structures, namely, the substantia nigra pars compacta (SNpc), the ventral tegmental area, and the locus coeruleus. Another major biomarker is brain iron, which often increases in concert with NM degeneration. These biomarkers have the potential to improve diagnostic certainty in differentiating between PD and other neurodegenerative disorders similar to PD, as well as provide a better understanding of pathophysiology. Mapping NM in vivo has clinical importance for gauging the premotor phase of PD when there is a greater than 50% loss of dopaminergic SNpc melanized neurons. As a metal ion chelator, NM can absorb iron. When NM is released from neurons, it deposits iron into the intracellular tissues of the SNpc; the result is iron that can be imaged and measured using quantitative susceptibility mapping. An increase of iron also leads to the disappearance of the nigrosome‐1 sign, another neuroimage biomarker for PD. Therefore, mapping NM and iron changes in the SNpc are a practical means for improving early diagnosis of PD and in monitoring disease progression. In this review, we discuss the functions and location of NM, how NM‐MRI is performed, the automatic mapping of NM and iron content, how NM‐related imaging biomarkers can be used to enhance PD diagnosis and differentiate it from other neurodegenerative disorders, and potential advances in NM imaging methods. With major advances currently evolving for rapid imaging and artificial intelligence, NM‐related biomarkers are likely to have increasingly important roles for enhancing diagnostic capabilities in PD. Evidence Level: 1 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 = 51, n2 = 101), corticobasal degeneration (CBD) (n1 = 11, n2 = 3), progressive supranuclear palsy (PSP) (n1 = 22, n2 = 21), multiple system atrophy (MSA) (n1 = 31, n2 = 26), and healthy control (HC) (n1 = 48, n2 = 30) participants, as well as Alzheimer's disease (AD) (n2 = 23) patients in the second cohort. Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin‐2 levels compared with HC were observed. In AD, levels of 14‐3‐3 zeta/delta, beta‐ and gamma‐synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini‐Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre‐synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β‐estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β‐estimate = 0.32, P = 0.021). Conclusions: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) and other neurodegenerative parkinsonisms are characterised by loss of striatal dopaminergic neurons. Dopamine functional deficits can be measured in vivo using positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) ligands assessing either presynaptic (e.g. dopamine synthesis and storage, transporter density) or postsynaptic terminals (i.e. D2 receptors availability). Nuclear medicine imaging thus helps the clinician to separate degenerative forms of parkinsonism with other neurological conditions, e.g. essential tremor or drug‐induced parkinsonism. With the present study, we aimed at summarizing the current evidence about dopaminergic molecular imaging in the diagnostic evaluation of PD, atypical parkinsonian syndromes and dementia with Lewy bodies (DLB), as well as its potential to distinguish these conditions and to estimate disease progression. In fact, PET/SPECT methods are clinically validated and have been increasingly integrated into diagnostic guidelines (e.g. for PD and DLB). In addition, there is novel evidence on the classification properties of extrastriatal signal. Finally, dopamine imaging has an outstanding potential to detect neurodegeneration at the premotor stage, including REM‐sleep behavior disorder and olfactory loss. Therefore, inclusion of subjects at an early stage for clinical trials can largely benefit from a validated in vivo biomarker such as presynaptic dopamine pathways PET/SPECT assessment. [ABSTRACT FROM AUTHOR]

Aims: N6‐methyladenosine modification of RNA (m6A) regulates translational control, which may influence neuronal dysfunction underlying neurodegenerative diseases. Methods: Using microscopy and a machine learning approach, we performed cellular profiling of m6A‐RNA abundance and YTHDF1/YTHDF3 m6A reader expression within four regions of the human brain from non‐affected individuals and individuals with Parkinson's disease, dementia with Lewy bodies or mild cognitive impairment (MCI). Results: In non‐diseased tissue, we found that m6A‐modified RNAs showed cell‐type and sub‐compartment‐specific variation. YTHDF1 and YTHDF3 showed opposing expression patterns in the cerebellum and the frontal and cingulate cortices. Machine learning quantitative image analysis revealed that m6A‐modified transcripts were significantly altered in localisation and abundance in disease tissue with significant decreases in m6A‐RNAs in Parkinson's disease, and significant increases in m6A‐RNA abundance in dementia with Lewy bodies. MCI tissue showed variability across regions but similar to DLB; in brain areas with an overall significant increase in m6A‐RNAs, modified RNAs within dendritic processes were reduced. Using mass spectrometry proteomic datasets to corroborate our findings, we found significant changes in YTHDF3 and m6A anti‐reader protein abundance in Alzheimer's disease (AD) and asymptomatic AD/MCI tissue and correlation with cognitive resilience. Conclusions: These results provide evidence for disrupted m6A regulation in Lewy body diseases and a plausible mechanism through which RNA processing could contribute to the formation of Lewy bodies and other dementia‐associated pathological aggregates. The findings suggest that manipulation of epitranscriptomic processes influencing translational control may lead to new therapeutic approaches for neurodegenerative diseases.Using microscopy and a machine learning approach, we performed subcellular profiling of m6A‐RNA abundance in human brain from non‐affected individuals and individuals with neurodegenerative diseases. m6A‐RNAs were found consistently more abundant in dementia with Lewy bodies tissue and significantly reduced or misplaced in brain tissue from individuals with Parkinson's disease. The findings of disrupted m6A‐RNAs in Lewy body diseases are consistent with evidence for alterations in the control of RNA translation contributing to the formation of protein aggregate neurotoxic structures. [ABSTRACT FROM AUTHOR]

Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D1–5Rs), which belong to the G protein‐coupled receptor family. Antagonists and partial agonists of D2Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D2R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4‐(2,3‐dichlorophenyl), 4‐(2‐methoxyphenyl)‐, 4‐(benzo[b]thiophen‐4‐yl)‐1‐substituted piperazine, and 4‐(6‐fluorobenzo[d]isoxazol‐3‐yl)piperidine moieties are critical for high D2R affinity. Four to six atoms chains are optimal for D2R affinity with 4‐butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D2R affinity. In this review, we provide a thorough overview of the therapeutic potential of D2R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D2R ligands, which have been developed in the last decade (2010–2021), and belong to the 1,4‐disubstituted aromatic cyclic amine group. Due to the abundance of data, allosteric D2R ligands and D2R modulators from patents are not discussed in this review. [ABSTRACT FROM AUTHOR]

Neuromelanins are compounds accumulating in neurons of human and animal brain during aging, with neurons of substantia nigra and locus coeruleus having the highest levels of neuromelanins. These compounds have melanic, lipid, peptide, and inorganic components and are contained inside special autolysosomes. Neuromelanins can participate in neuroprotective or toxic processes occurring in Parkinson's disease according to cellular environment. Their synthesis depends on the concentration of cytosolic catechols and is a protective process since it prevents the toxic accumulation of catechols‐derived reactive compounds. Neuromelanins can be neuroprotective also by binding reactive/toxic metals to produce stable and non‐toxic complexes. Extraneuronal neuromelanin released by dying dopamine neurons in Parkinson's disease activates microglia which generate reactive oxygen species, reactive nitrogen species, and proinflammatory molecules, thus producing still neuroinflammation and neuronal death. Synthetic neuromelanins have been prepared with melanic, protein structure, and metal content closely mimicking the natural brain pigment, and these models are also able to activate microglia. Neuromelanins have different structure, synthesis, cellular/subcellular distribution, and role than melanins of hair, skin, and other tissues. The main common aspect between brain neuromelanin and peripheral melanin is the presence of eumelanin and/or pheomelanin moieties in their structure. [ABSTRACT FROM AUTHOR]