Dopaminergic Deficit Research Articles

Reward insensitivity is associated with dopaminergic deficit in rapid eye movement sleep behaviour disorder.

Idiopathic rapid eye movement sleep behaviour disorder (iRBD) has now been established as an important marker of the prodromal stage of Parkinson's disease and related synucleinopathies. However, although dopamine transporter single photon emission computed tomography (SPECT) has been used to demonstrate the presence of nigro-striatal deficit in iRBD, quantifiable correlates of this are currently lacking. Sensitivity to rewarding stimuli is reduced in some people with Parkinson's disease, potentially contributing to aspects of the neuropsychiatric phenotype in these individuals. Furthermore, a role for dopaminergic degeneration is suggested by the fact that reward insensitivity can be improved by dopaminergic medications. Patients with iRBD present a unique opportunity to study the relationship between reward sensitivity and early dopaminergic deficit in the unmedicated state. Here, we investigate whether a non-invasive, objective measure of reward sensitivity might be a marker of dopaminergic status in prodromal Parkinson's disease by comparing with SPECT/CT measurement of dopaminergic loss in the basal ganglia. Striatal dopaminergic deficits in iRBD are associated with progression to Parkinsonian disorders. Therefore, identification of a clinically measurable correlate of this degenerative process might provide a basis for the development of novel risk stratification tools. Using a recently developed incentivized eye-tracking task, we quantified reward sensitivity in a cohort of 41 patients with iRBD and compared this with data from 40 patients with Parkinson's disease and 41 healthy controls. Patients with iRBD also underwent neuroimaging with dopamine transporter SPECT/CT. Overall, reward sensitivity, indexed by pupillary response to monetary incentives, was reduced in iRBD cases compared with controls and was not significantly different to that in patients with Parkinson's disease. However, in iRBD patients with normal dopamine transporter SPECT/CT imaging, reward sensitivity was not significantly different from healthy controls. Across all iRBD cases, a positive association was observed between reward sensitivity and dopaminergic SPECT/CT signal in the putamen. These findings demonstrate a direct relationship between dopaminergic deficit and reward sensitivity in patients with iRBD and suggest that measurement of pupillary responses could be of value in models of risk stratification and disease progression in these individuals.

PET imaging in animal models of Parkinson’s disease

Alpha-synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, are characterized by aberrant accumulation of alpha-synuclein and synaptic dysfunction leading to motor and cognitive deficits. Animal models of alpha-synucleinopathy have greatly facilitated the mechanistic understanding of the disease and the development of therapeutics. Various transgenic, alpha-synuclein fibril-injected, and toxin-injected animal models of Parkinson’s disease and multiple system atrophy that recapitulate the disease pathology have been developed and widely used. Recent advances in positron emission tomography have allowed the noninvasive visualization of molecular alterations, underpinning behavioral dysfunctions in the brains of animal models and the longitudinal monitoring of treatment effects. Imaging studies in these disease animal models have employed multi-tracer PET designs to reveal dopaminergic deficits together with other molecular alterations. This review focuses on the development of new positron emission tomography tracers and studies of alpha-synuclein, synaptic vesicle glycoprotein 2A neurotransmitter receptor deficits such as dopaminergic receptor, dopaminergic transporter, serotonergic receptor, vesicular monoamine transporter 2, hypometabolism, neuroinflammation, mitochondrial dysfunction and leucine rich repeat kinase 2 in animal models of Parkinson’s disease. The outstanding challenges and emerging applications are outlined, such as investigating the gut-brain-axis by using positron emission tomography in animal models, and provide a future outlook.

Advancement of biomolecular engineering in Parkinson disease

Parkinson's Condition (PD) is the second most common degenerative neurological disease, affecting 10 million people globally. Nigrostriatal degeneration is linked to decreased motor and non-motor functioning in this chronic illness. Resting tremor, stiffness, akinesia (or bradykinesia), and postural instability are the four cardinal symptoms of Parkinson's disease. Because the symptoms of Parkinson's disease are similar to those of other age-related disorders like SWEDD (scans without evidence of dopaminergic deficit), essential tremors, and Parkinson's disease, early diagnosis is difficult. A synucleinopathy is Parkinson's disease (PD) with Lewy Bodies (DLB).Although both genetic and environmental variables are assumed to play a role in Parkinson's disease (PD), there was no direct evidence to support either as a causal component until recently. Six distinct genes have been discovered as producing familial PD in the last eight years. They back up the idea that similar pathogenetic pathways exist across the spectrum of Parkinson's disease etiologies. Mutations in α-synuclein, parkin, UCHL1, DJ1, PINK1, and LRRK2 cause.Parkinson's disease, which is inherited in a Mendelian form. Overexpression of α- synuclein and parkin causes mitochondrial issues, but DJ1 and PINK1 are mitochondrial proteins. These same proteins regulate proteasomal function and play a role in the oxidative stress response.Doped carbon nanotubes, especially phosphorus-doped carbon nanotubes, can efficiently prevent the formation of α- synuclein amyloid, suggesting that they could be utilized to treat Parkinson's disease. More in vitro and clinical research is, however, necessary. As previously stated, αsynuclein could be a therapeutic target for Parkinson's disease and other synucleinopathies. The most promising option would be small chemicals that may modify the structure of protofibrillar forms of α-synuclein and render them nonpathogenic. Given the pathogenic consequences of αsynuclein's feed-forward amplification loops, a range of therapeutic options will almost certainly be required.

The VTA dopaminergic system as diagnostic and therapeutical target for Alzheimer's disease.

Neuropsychiatric symptoms (NPS) occur in nearly all patients with Alzheimer's Disease (AD). Most frequently they appear since the mild cognitive impairment (MCI) stage preceding clinical AD, and have a prognostic importance. Unfortunately, these symptoms also worsen the daily functioning of patients, increase caregiver stress and accelerate the disease progression from MCI to AD. Apathy and depression are the most common of these NPS, and much attention has been given in recent years to understand the biological mechanisms related to their appearance in AD. Although for many decades these symptoms have been known to be related to abnormalities of the dopaminergic ventral tegmental area (VTA), a direct association between deficits in the VTA and NPS in AD has never been investigated. Fortunately, this scenario is changing since recent studies using preclinical models of AD, and clinical studies in MCI and AD patients demonstrated a number of functional, structural and metabolic alterations affecting the VTA dopaminergic neurons and their mesocorticolimbic targets. These findings appear early, since the MCI stage, and seem to correlate with the appearance of NPS. Here, we provide an overview of the recent evidence directly linking the dopaminergic VTA with NPS in AD and propose a setting in which the precocious identification of dopaminergic deficits can be a helpful biomarker for early diagnosis. In this scenario, treatments of patients with dopaminergic drugs might slow down the disease progression and delay the impairment of daily living activities.

Studying cognitive function in patients with a long-standing diagnosis of SWEDD

IntroductionThe cognitive profile of patients with longstanding clinical Parkinsonism possessing scans without evidence of dopaminergic deficit (SWEDD) remains unclear from previous studies. MethodsWe studied 47 patients recruited in the Parkinson's Progression Markers Initiative with SWEDD as baseline diagnosis. They were subdivided by final clinical diagnoses after a 2-year follow-up period into 25 patients with either clinical evidence of Parkinson's Disease (PD) or unclassified parkinsonism and normal SPECT imaging (“true SWEDDs”), 6 patients with a psychogenic illness exhibiting Parkinsonism, 6 patients who had phenoconverted to PD based on reduced striatal dopaminergic activity on imaging, and 10 patients with another tremulous condition. Cognitive symptoms were compared between these subgroups, as well as with 62 PD patients and 195 healthy controls (HCs), at baseline and follow-ups. ResultsA significant difference in working memory was found between true SWEDDs and HCs (P = 0.009), but not true SWEDDs and PD patients (P = 0.432), nor PD patients and HCs (P = 0.154). The prevalence of attentional impairment was also significantly different between the three groups (P < 0.001). SWEDD subgroups possessed similar cognitive symptoms irrespective of their final clinical diagnosis. Psychogenic, phenoconverted and tremulous SWEDDs also possessed stable cognitive symptoms over the 2-year period whilst true SWEDDs, PD patients and HCs experienced significant changes in working memory. ConclusionsOur results, particularly relating to working memory and attention, add to the knowledge of other true SWEDD non-motor symptoms to facilitate earlier diagnosis and improved management strategies for these patients.

Convolutional Neural Network-Based Parkinson Disease Classification Using SPECT Imaging Data

In this paper, we used the single-photon emission computerized tomography (SPECT) imaging technique to visualize the deficiency of dopamine-generated patterns inside the brain. These patterns are used to establish a patient’s disease progression, which helps distinguish the patients into different categories. Furthermore, we used a convolutional neural network (CNN) model to classify the patients based on the dopamine level inside the brain. The dataset used throughout this paper is the Parkinson’s progressive markers initiative (PPMI) dataset. The collected dataset was pre-processed and data amplification was performed to balance the imbalanced dataset. A CNN-based neural network was defined to classify input SPECT images into four categories. The motivation behind the proposed model is to reduce the number of resources consumed while maintaining the performance of the classification model. This will help the healthcare ecosystem run the classification model on mobile devices. The proposed model contains 14 layers with input layers, convolutional layers, max-pool layers, flatten layers, and dense layers with different dimensions. The dense layer classifies the patients into four different categories, including PSD, healthy control, scans without evidence of dopaminergic deficit (SWEDD), and GenReg PSD from the entire SPECT imaging dataset, which is used to establish the disease progression of different patients using SPECT images. The proposed model is trained with a large dataset with 58,692 images for training and 11,738 images for validation, and 7826 for testing. The proposed model outperforms the classification models from the surveyed papers. The proposed model’s accuracy is 0.889, recall is 0.9012, the precision is 0.9104, and the F1-score is 0.9057.

Automated video-based assessment of facial bradykinesia in de-novo Parkinson’s disease

Even though hypomimia is a hallmark of Parkinson’s disease (PD), objective and easily interpretable tools to capture the disruption of spontaneous and deliberate facial movements are lacking. This study aimed to develop a fully automatic video-based hypomimia assessment tool and estimate the prevalence and characteristics of hypomimia in de-novo PD patients with relation to clinical and dopamine transporter imaging markers. For this cross-sectional study, video samples of spontaneous speech were collected from 91 de-novo, drug-naïve PD participants and 75 age and sex-matched healthy controls. Twelve facial markers covering areas of forehead, nose root, eyebrows, eyes, lateral canthal areas, cheeks, mouth, and jaw were used to quantitatively describe facial dynamics. All patients were evaluated using Movement Disorder Society-Unified PD Rating Scale and Dopamine Transporter Single-Photon Emission Computed Tomography. Newly developed automated facial analysis tool enabled high-accuracy discrimination between PD and controls with area under the curve of 0.87. The prevalence of hypomimia in de-novo PD cohort was 57%, mainly associated with dysfunction of mouth and jaw movements, and decreased variability in forehead and nose root wrinkles (p < 0.001). Strongest correlation was found between reduction of lower lip movements and nigro-putaminal dopaminergic loss (r = 0.32, p = 0.002) as well as limb bradykinesia/rigidity scores (r = −0.37 p < 0.001). Hypomimia represents a frequent, early marker of motor impairment in PD that can be robustly assessed via automatic video-based analysis. Our results support an association between striatal dopaminergic deficit and hypomimia in PD.

Impact of Nutrition, Microbiota Transplant and Weight Loss Surgery on Dopaminergic Alterations in Parkinson's Disease and Obesity.

Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by dopaminergic neuron degeneration and α-synuclein aggregation in the substantia nigra pars compacta of the midbrain. Emerging evidence has shown that dietary intake affects the microbial composition in the gut, which in turn contributes to, or protects against, the degeneration of dopaminergic neurons in affected regions of the brain. More specifically, the Mediterranean diet and Western diet, composed of varying amounts of proteins, carbohydrates, and fats, exert contrasting effects on PD pathophysiology via alterations in the gut microbiota and dopamine levels. Interestingly, the negative changes in the gut microbiota of patients with PD parallel changes that are seen in individuals that consume a Western diet, and are opposite to those that adhere to a Mediterranean diet. In this review, we first examine the role of prominent food groups on dopamine bioavailability, how they modulate the composition and function of the gut microbiota and the subsequent effects on PD and obesity pathophysiology. We then highlight evidence on how microbiota transplant and weight loss surgery can be used as therapeutic tools to restore dopaminergic deficits through optimizing gut microbial composition. In the process, we revisit dietary metabolites and their role in therapeutic approaches involving dopaminergic pathways. Overall, understanding the role of nutrition on dopamine bioavailability and gut microbiota in dopamine-related pathologies such as PD will help develop more precise therapeutic targets to rescue dopaminergic deficits in neurologic and metabolic disorders.

Structural connectivity alterations in the motor network of patients with scans without evidence of dopaminergic deficit (SWEDD).

Approximatively, 10% of patients initially diagnosed with Parkinson's disease (PD) show preserved presynaptic dopaminergic function in the nigrostriatal pathway on DAT-SPECT imaging. This syndrome is not compatible with PD diagnosis, and is known as scans without evidence of dopaminergic deficit (SWEDD). To investigate structural connectivity of cerebello-subcortico-cortical networks, including the nigrostriatal pathway, in an international cohort of subjects with SWEDD compared to normal controls using probabilistic tractography. Twenty-eight patients with SWEDD and 21 age- and sex-matched healthy controls (HC) were selected from the Parkinson's Progression Markers Initiative (PPMI) database. All participants underwent whole-brain 3D T1-weighted and diffusion-weighted MRI, as well as DAT-SPECT. Probabilistic tractography was performed in network-mode between regions of the cerebello-thalamo-basal ganglia-cortical circuits, to extract the connectivity strength between pairs of nodes of the circuit, as well as volumetric and diffusion measures of each reconstructed tract. Analysis of covariance with age and sex as covariates of non-interest was performed to assess group differences. Statistical significance was set at p < 0.05 after false-discovery-rate correction for multiple comparisons. Compared to HC, patients with SWEDD showed increased fractional anisotropy in bilateral thalamo-putamen-precentral, left nigro-putaminal and left thalamo-pallidal pathways. Furthermore, we found decreased mean streamline length in bilateral thalamo-nigro-cerebellar pathways and in the left nigro-caudate connection. Clinical heterogeneity of SWEDD syndrome may account for involvement of different brain circuits, such as the cerebello-thalamo-cortical and the nigrostriatal pathways, characteristic of different tremulous disorders.

245 Cognitive function in patients with a long-standing diagnosis of SWEDD

IntroductionPatients with clinical features of Parkinson’s Disease (PD), but scans without evidence of dopaminergic deficit are termed SWEDDs. Only a portion of these patients retain their SWEDDs diagnosis later in life and are here regarded as ‘true SWEDDs’. Cognitive symptoms of ‘true SWEDDs’ remain unclear yet important to optimise their management. We used data from the Parkinson’s Progression Markers Initiative to investigate these further.MethodologyBaseline cognitive data of 25 SWEDDs, who retained diagnoses after 2 years of follow up (confirmed by normal 123I-FP-CIT SPECT scans), were compared with that of 62 de novo PD and 195 healthy control (HC) subjects. Data was analysed using SPSS Statistics.ResultsNo significant difference was found when comparing ‘true SWEDDs’ to de novo PD patients and HCs in tests of global cognition, visuospatial function, executive function and attention. However, Hopkins Verbal Learning Test-Revised (HVLT-R) showed a significant difference between the three groups (P=0.004), maintained when specifically analysing ‘true SWEDDs’ versus HCs (P=0.009).ConclusionOur data suggest a significant difference in memory function between ‘true SWEDDs’ and HCs, as demonstrated by the HVLT-R test. This suggests memory-stimulating therapies are important for managing ‘true SWEDDs’, however further work is required to validate these findings.aaronjesuthasan@gmail.com

Explainable machine learning with pairwise interactions for the classification of Parkinson's disease and SWEDD from clinical and imaging features.

Scans without evidence of dopaminergic deficit (SWEDD) refers to patients who mimics motor and non-motor symptoms of Parkinson’s disease (PD) but showing integrity of dopaminergic system. For this reason, the differential diagnosis between SWEDD and PD patients is often not possible in absence of dopamine imaging. Machine Learning (ML) showed optimal performance in automatically distinguishing these two diseases from clinical and imaging data. However, the most common applied ML algorithms provide high accuracy at expense of findings intelligibility. In this work, a novel ML glass-box model, the Explainable Boosting Machine (EBM), based on Generalized Additive Models plus interactions (GA2Ms), was employed to obtain interpretability in classifying PD and SWEDD while still providing optimal performance. Dataset (168 healthy controls, HC; 396 PD; 58 SWEDD) was obtained from PPMI database and consisted of 178 among clinical and imaging features. Six binary EBM classifiers were trained on feature space with (SBR) and without (noSBR) dopaminergic striatal specific binding ratio: HC-PDSBR, HC-SWEDDSBR, PD-SWEDDSBR and HC-PDnoSBR, HC-SWEDDnoSBR, PD-SWEDDnoSBR. Excellent AUC-ROC (1) was reached in classifying HC from PD and SWEDD, both with and without SBR, and by PD-SWEDDSBR (0.986), while PD-SWEDDnoSBR showed lower AUC-ROC (0.882). Apart from optimal accuracies, EBM algorithm was able to provide global and local explanations, revealing that the presence of pairwise interactions between UPSIT Booklet #1 and Epworth Sleepiness Scale item 3 (ESS3), MDS-UPDRS-III pronation-supination movements right hand (NP3PRSPR) and MDS-UPDRS-III rigidity left upper limb (NP3RIGLU) could provide good performance in predicting PD and SWEDD also without imaging features.

Dopaminergic Positron Emission Tomography Imaging in the Alpha-Synuclein Preformed Fibril Model Reveals Similarities to Early Parkinson's Disease.

BackgroundPositron emission tomography (PET) imaging in early Parkinson's disease (PD) subjects reveals that increased dopamine (DA) turnover and reduced dopamine transporter (DAT) density precede decreases in DA synthesis and storage. The rat α‐synuclein preformed fibril (α‐syn PFF) model provides a platform to investigate DA dynamics during multiple stages of α‐syn inclusion‐triggered nigrostriatal degeneration.ObjectivesWe investigated multiple aspects of in vivo dopaminergic deficits longitudinally and similarities to human PD using translational PET imaging readouts.MethodsLongitudinal imaging was performed every 2 months in PFF and control rats for 7 months. [18F]‐Fluoro‐3,4‐dihydroxyphenyl‐L‐alanine (FDOPA) imaging was performed to investigate DA synthesis and storage (Kocc) and DA turnover, estimated by its inverse, the effective distribution volume ratio (EDVR). 11C‐Methylphenidate (MP) was used to estimate DAT density (BPND).ResultsEarly DA turnover increases and DAT binding decreases were observed in the ipsilateral striatum of PFF rats, progressing longitudinally. EDVR decreased 26%, 38%, and 47%, and BPND decreased 36%, 50%, and 65% at the 2‐, 4‐, and 6‐month time points, respectively, compared to ipsilateral control striatum. In contrast, deficits in DA synthesis and storage were not observed in the ipsilateral striatum of PFF rats compared to control injections and were relatively preserved up to 6 months (Kocc decreased 20% at 6 months).ConclusionsThe relative preservation of DA synthesis and storage compared to robust progressive deficits in DAT density and increases in DA turnover in the rat α‐syn PFF model display remarkable face validity to dopaminergic alterations in human PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Prospective F-18 FDOPA PET Imaging Study in Human PD.

We present the findings of our final prospective study submitted to the U.S. Food and Drug Administration (FDA) for New Drug Application (NDA) approval for the use of 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (F-18 FDOPA) positron emission tomography (PET) imaging for Parkinson's disease (PD). The primary aim was to determine the sensitivity, specificity, and predictive values of F-18 FDOPA PET in parkinsonian patients with respect to clinical standard-of-truth (SOT). Secondary outcomes included the inter-rater reliability, and correlation of quantitative measures for PET with dopaminergic status. In 68 parkinsonian subjects, F-18 FDOPA PET scan from 80 to 100 min was acquired following a CT scan. Scan images were presented to one expert in F-18 FDOPA image interpretation and two physicians with prior experience in I-123 FPCIT single-photon emission computed tomography image interpretation. Fifty-six subjects completed the study with a follow-up for SOT determination. Image readers were blind to the clinical/quantitative data; SOT clinician was blind to the image data. For 47 of the 56 patients, SOT was in agreement with the PET scan results. For nine patients, SOT suggested dopaminergic deficit, whereas the imaging showed normal uptake. The specificity and positive predictive values are 91% and 92%, respectively, suggesting high probability that those who test positive by the PET scan truly have dopaminergic degeneration. The sensitivity was 73%. Inter-rater agreement was 0.6-0.8 between the different readers. Our prospective study demonstrates high specificity and moderate sensitivity of F-18 FDOPA PET for PD. We received NDA approval in October 2019. The online version contains supplementary material available at 10.1007/s13139-022-00748-4.

Machine Learning for Early Parkinson's Disease Identification within SWEDD Group Using Clinical and DaTSCAN SPECT Imaging Features.

Early Parkinson’s Disease (PD) diagnosis is a critical challenge in the treatment process. Meeting this challenge allows appropriate planning for patients. However, Scan Without Evidence of Dopaminergic Deficit (SWEDD) is a heterogeneous group of PD patients and Healthy Controls (HC) in clinical and imaging features. The application of diagnostic tools based on Machine Learning (ML) comes into play here as they are capable of distinguishing between HC subjects and PD patients within an SWEDD group. In the present study, three ML algorithms were used to separate PD patients from HC within an SWEDD group. Data of 548 subjects were firstly analyzed by Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA) techniques. Using the best reduction technique result, we built the following clustering models: Density-Based Spatial (DBSCAN), K-means and Hierarchical Clustering. According to our findings, LDA performs better than PCA; therefore, LDA was used as input for the clustering models. The different models’ performances were assessed by comparing the clustering algorithms outcomes with the ground truth after a follow-up. Hierarchical Clustering surpassed DBSCAN and K-means algorithms by 64%, 78.13% and 38.89% in terms of accuracy, sensitivity and specificity. The proposed method demonstrated the suitability of ML models to distinguish PD patients from HC subjects within an SWEDD group.

Onset pattern of nigrostriatal denervation in early Parkinson's disease.

The striatal dopaminergic deficit in Parkinson's disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as the disease progresses. Clinically, upper-limb onset of cardinal motor features is the rule. Thus, according to current understanding of striatal somatotopy (i.e. the lower limb is dorsal to the upper limb) the assumed pattern of early dorsal striatal dopaminergic denervation in Parkinson's disease does not fit with an upper-limb onset. We have examined the topography of putaminal denervation in a cohort of 23 recently diagnosed de novo Parkinson's disease patients and 19 age-/gender-matched healthy subjects assessed clinically and by 18F-DOPA PET; 15 patients were re-assessed after 2 years. There was a net upper-limb predominance of motor features at onset. Caudal denervation of the putamen was confirmed in both the more- and less-affected hemispheres and corresponding hemibodies. Spatial covariance analysis of the most affected hemisphere revealed a pattern of 18F-DOPA uptake rate deficit that suggested focal dopamine loss starting in the posterolateral and intermediate putamen. Functional MRI group-activation maps during a self-paced motor task were used to represent the somatotopy of the putamen and were then used to characterize the decline in 18F-DOPA uptake rate in the upper- and lower-limb territories. This showed a predominant decrement in both hemispheres, which correlated significantly with severity of bradykinesia. A more detailed spatial analysis revealed a dorsoventral linear gradient of 18F-DOPA uptake rate in Parkinson's disease patients, with the highest putamen denervation in the caudal intermediate subregion (dorsoventral plane) compared to healthy subjects. The latter area coincides with the functional representation of the upper limb. Clinical motor assessment at 2-year follow-up showed modest worsening of parkinsonism in the primarily affected side and more noticeable increases in the upper limb in the less-affected side. Concomitantly, 18F-DOPA uptake rate in the less-affected putamen mimicked that recognized on the most-affected side. Our findings suggest that early dopaminergic denervation in Parkinson's disease follows a somatotopically related pattern, starting with the upper-limb representation in the putamen and progressing over a 2-year period in the less-affected hemisphere. These changes correlate well with the clinical presentation and evolution of motor features. Recognition of a precise somatotopic onset of nigrostriatal denervation may help to better understand the onset and progression of dopaminergic neurodegeneration in Parkinson's disease and eventually monitor the impact of putative therapies.

α-Synuclein Radiotracer Development and In Vivo Imaging: Recent Advancements and New Perspectives.

ABSTRACTα‐Synucleinopathies including idiopathic Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy share overlapping symptoms and pathological hallmarks. Selective neurodegeneration and Lewy pathology are the main hallmarks of α‐synucleinopathies. Currently, there is no imaging biomarker suitable for a definitive early diagnosis of α‐synucleinopathies. Although dopaminergic deficits detected with single‐photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers can support clinical diagnosis by confirming the presence of dopaminergic neurodegeneration, dopaminergic imaging cannot visualize the preceding disease process, nor distinguish α‐synucleinopathies from tauopathies with dopaminergic neurodegeneration, especially at early symptomatic disease stage when clinical presentation is often overlapping. Aggregated α‐synuclein (αSyn) could be a suitable imaging biomarker in α‐synucleinopathies, because αSyn aggregation and therefore, Lewy pathology is evidently an early driver of α‐synucleinopathies pathogenesis. Additionally, several antibodies and small molecule compounds targeting aggregated αSyn are in development for therapy. However, there is no way to directly measure if or how much they lower the levels of aggregated αSyn in the brain. There is clearly a paramount diagnostic and therapeutic unmet medical need. To date, aggregated αSyn and Lewy pathology inclusion bodies cannot be assessed ante‐mortem with SPECT or PET imaging because of the suboptimal binding characteristics and/or physicochemical properties of current radiotracers. The aim of this narrative review is to highlight the suitability of aggregated αSyn as an imaging biomarker in α‐synucleinopathies, the current limitations with and lessons learned from αSyn radiotracer development, and finally to propose antibody‐based ligands for imaging αSyn aggregates as a complementary tool rather than an alternative to small molecule ligands. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling.

Dopamine is a neurotransmitter that plays a critical role both peripherally and centrally in vital functions such as cognition, reward, satiety, voluntary motor movements, pleasure, and motivation. Optimal dopamine bioavailability is essential for normal brain functioning and protection against the development of neurological diseases. Emerging evidence shows that gut microbiota have significant roles in maintaining adequate concentrations of dopamine via intricate, bidirectional communication known as the microbiota-gut-brain axis. The vagus nerve, immune system, hypothalamus–pituitary–adrenal axis, and microbial metabolites serve as important mediators of the reciprocal microbiota-gut-brain signaling. Furthermore, gut microbiota contain intrinsic enzymatic activity that is highly involved in dopamine metabolism, facilitating dopamine synthesis as well as its metabolite breakdown. This review examines the relationship between key genera of gut microbiota such as Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium, Enterococcus, and Ruminococcus and their effects on dopamine. The effects of gut dysbiosis on dopamine bioavailability and the subsequent impact on dopamine-related pathological conditions such as Parkinson’s disease are also discussed. Understanding the role of gut microbiota in modulating dopamine activity and bioavailability both in the periphery and in the central nervous system can help identify new therapeutic targets as well as optimize available methods to prevent, delay, or restore dopaminergic deficits in neurologic and metabolic disorders.

Anxiety predicts impulsive-compulsive behaviours in Parkinson's disease: Clinical relevance and theoretical implications

Patients with Parkinson's disease (PD) often present symptoms of anxiety, depression and apathy. These negative affect manifestations have been recently associated with the presence of impulsive compulsive behaviours (ICBs). However, their relation with the use of dopamine replacement therapy (DRT), a renewed risk factor for ICBs, is still not fully understood. Elucidating the role of these different ICBs predictors in PD could inform both prevention/intervention recommendations as well as theoretical models. In the present study, we have analysed data collected in 417 PD patients, 50 patients with Parkinsonian symptoms but with scan without evidence of dopaminergic deficit (SWEDD), and 185 healthy controls (HC). We examined each patient's clinical profile over a two-year time window, investigating the role of both negative affect and DRT on ICBs. Results confirmed the presence of higher levels of anxiety in both the clinical groups, and of higher level of ICBs in SWEDD patients, respect to both PD and HC. Mixed model analyses revealed a statistically significant association between anxiety and ICBs in the SWEDD patients who did not take any DRT. Findings suggest the independence between anxiety and DRT in ICBs development, and provide new evidence for the motivational opponency theoretical framework.

Testing efficacy of the nicotine protection of the substantia nigra pars compacta in a rat Parkinson disease model. Ultrastructure study

ABSTRACT Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with subsequent motor manifestations. This study aimed to assess the ameliorative effects of nicotine, in rotenone-induced PD rat model. Thirty adult male Albino Wistar rats were divided into three equal groups. Group I received an injection of normal saline. Group II received subcutaneous injection of rotenone at a dose of 1.5 mg/kg every other day. Group III received rotenone in the same previous dose and nicotine at a dose of 1.5 mg/kg daily. After 11 days of treatment, body weight (BW) and rat motor behavior were estimated. Specimens from the midbrain were processed for light and electron microscopy. The expression of tyrosine hydroxylase (TH), α-synuclein, and GFAP was examined. Serum levels of total antioxidant capacity (TAC) and malondialdehyde (MDA), and striatal levels of dopamine (DA) were analyzed. Group III revealed a significant improvement in BW and motor activity. Nicotine upregulated the expression of TH, downregulated the expression of α-synuclein and GFAP. The levels of MDA and TAC were improved but were still far from those of the control. Striatal DA levels increased. Nicotine activated the neurons and glial cells. The vascular endothelium, however, did not elicit improvement. Although nicotine ameliorated the loss of the dopaminergic neurons and motor deficit, it did not show improvement of vascular endothelium. It is still necessary to examine nicotin’s ability to maintain the dopaminergic neurons in a good functioning state.

Restricting feeding to dark phase fails to entrain circadian activity and energy expenditure oscillations in Pitx3-mutant Aphakia mice.

Metabolic homeostasis is under circadian regulation to adapt energy requirements to light-dark cycles. Feeding cycles are regulated by photic stimuli reaching the suprachiasmatic nucleus via retinohypothalamic axons and by nutritional information involving dopaminergic neurotransmission. Previously, we reported that Pitx3-mutant Aphakia mice with altered development of the retinohypothalamic tract and the dopaminergic neurons projecting to the striatum, are resistant to locomotor and metabolic entrainment by time-restricted feeding. In their Matters Arising article, Scarpa etal. (2022) challenge this conclusion using mice from the same strain but following a different experimental paradigm involving calorie restriction. Here, we address their concerns by extending the analyses of our previous data, by identifying important differences in the experimental design between both studies and by presenting additional results on the dopaminergic deficit in the brain of Aphakia mice. This Matters Arising Response article addresses the Matters Arising article by Scarpa etal. (2022), published concurrently in Cell Reports.