• Parkinson’s disease
• REM sleep behavior disorder
• machine learning
• neurodegenerative disorders
• phenoconversion
• survival analysis

• 2017M3C7A1029688 National Research Foundation of Korea
• 2017R1A2B2012280 National Research Foundation of Korea
• NRF-2020R1C1C1013160 National Research Foundation of Korea

• Parkinson's disease
• cohort study
• mental health
• worrier trait
• worry

• Deep brain stimulation
• Motor symptoms
• Nonmotor symptoms
• Parkinson's disease
• Zona incerta

• Humans
• Parkinson Disease/therapy
• Parkinson Disease/physiopathology
• Zona Incerta
• Animals
• Deep Brain Stimulation/methods

• Células troncales pluripotentes inducidas
• Dopaminergic neurons
• Enfermedad de Parkinson
• Induced pluripotent stem cells
• Modelo preclínico
• Neurodegeneración
• Neurodegeneration
• Neuronas dopaminérgicas
• Parkinson’s disease
• Preclinical model
• Tratamiento
• Treatment

• Adult
• Humans
• Parkinson Disease/drug therapy
• Induced Pluripotent Stem Cells/pathology
• Neurodegenerative Diseases
• Dopaminergic Neurons
• Neuroprotective Agents/pharmacology

• Deep brain stimulation
• Olfactory bulb
• Olfactory disorders
• Parkinson's disease
• Subthalamic nucleus

• Humans
• Parkinson Disease/therapy
• Parkinson Disease/drug therapy
• Smell
• Deep Brain Stimulation
• Subthalamic Nucleus/physiology
• Treatment Outcome

• Parkinson’s disease
• biomarkers
• exercise
• neuroendocrine
• neurohormone

• K23 NS123506 NINDS NIH HHS
• UL1 TR001422 NCATS NIH HHS

• Braak's Theory
• Gut Microbiome
• Gut-brain axis
• Neurologial Disorders
• Parkinson's Disease

• Humans
• Parkinson Disease
• Gastrointestinal Microbiome
• Neurodegenerative Diseases
• Probiotics/therapeutic use
• Brain

• Parkinson’s disease
• cardiometabolic syndrome
• depression
• incidence
• modifiable risk factor
• osteoporosis

• Microbiome
• Parkinson’s disease
• alpha-synuclein
• fecal microbiota transplantation
• gastrointestinal tract
• prebiotics
• probiotics
• prodromal symptoms

• DBS
• Diencephalon
• FGATIR
• Functional neurosurgery
• Neuroanatomy
• Parkinson’s disease
• Subthalamic nucleus
• Track-density imaging

• Basal Ganglia/anatomy & histology
• Basal Ganglia/diagnostic imaging
• Brain
• Humans
• Magnetic Resonance Imaging/methods
• Neurosurgical Procedures/methods
• Thalamus/anatomy & histology
• Thalamus/diagnostic imaging

• Glutamate
• Hydromethylthionine
• Mouse model
• Parkinson's disease
• Synaptosomes
• α-Synuclein

Delusional parasitosis is characterized by a false belief of being infested with parasites, insects, or worms. This illness is observed in patients with Parkinson’s disease and is usually related to dopaminergic treatment. To our knowledge, no cases of delusional parasitosis have been reported as a premotor symptom or non-motor symptom of Parkinson’s disease.

A 75-year-old woman presented with a complaint of itching that she ascribed to the presence of insects in her skin, and she had erythematous plaques on her trunk, arms, buttocks, and face. These symptoms started two months before the visit to the hospital. She took medication, including antipsychotics, with a diagnosis of delusional parasitosis, and the delusion improved after three months. A year later, antipsychotics were discontinued, and anxiety and depression were controlled with medication. However, she complained of bradykinesia, masked face, hand tremor, and mild rigidity, and we performed fluorinated N-3-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography (PET), which showed mildly decreased DAT binding in the right anterior putamen and caudate nucleus. Parkinson’s disease was diagnosed on the basis of PET and clinical symptoms.

In conclusion, delusional parasitosis can be considered a non-motor sign of Parkinson’s disease along with depression, anxiety, and constipation.

• Delusional parasitosis
• Psychotic symptom
• Parkinson’s disease
• Nonmotor symptom
• Premotor symptom
• Case report

• Parkinson’s disease
• geriatric
• musculoskeletal
• older adult
• orthopedic
• pain
• rehabilitation

• Aged
• Humans
• Musculoskeletal Pain/epidemiology
• Musculoskeletal Pain/etiology
• Parkinson Disease/complications
• Parkinson Disease/epidemiology
• Prevalence

• K23 HD100569 NICHD NIH HHS
• National Institutes of Health

Standard treatment of Parkinson’s disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important neurosurgical intervention often used as alternative treatment to drug therapy; however, it can be associated with increase of impulsive behaviors. This descriptive review focused on studies investigating the correlation between Deep brain stimulation of the subthalamic nucleus and impulsivity in Parkinson’s disease patients, arguing, the action’s mechanism and the specific role of the subthalamic nucleus. We searched on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From initial 106 studies, only 15 met the search criteria. Parkinson’s Disease patients with and without Deep Brain Stimulation were compared with healthy controls, through 16 different tasks that assessed some aspects of impulsivity. Both Deep brain stimulation of the subthalamic nucleus and medication were associated with impulsive behavior and influenced decision-making processes. Moreover, findings demonstrated that: Impulse Control Disorders (ICDs) occurred soon after surgery, while, in pharmacological treatment, they appeared mainly after the initiation of treatment or the increase in dosage, especially with dopamine agonists. The subthalamic nucleus plays a part in the fronto-striato-thalamic-cortical loops mediating motor, cognitive, and emotional functions: this could explain the role of the Deep Brain Stimulation in behavior modulation in Parkinson’s Disease patients. Indeed, increase impulsivity has been reported also after deep brain stimulation of the subthalamic nucleus independently by dopaminergic medication status.

• Decision-making
• Deep brain stimulation
• Impulse control disorders
• Impulsivity
• Parkinson’s disease

• Deep Brain Stimulation/methods
• Deep Brain Stimulation/psychology
• Dopamine/metabolism
• Dopamine Agents/pharmacology
• Dopamine Agents/therapeutic use
• Humans
• Impulsive Behavior/drug effects
• Impulsive Behavior/physiology
• Parkinson Disease/diagnosis
• Parkinson Disease/metabolism
• Parkinson Disease/therapy
• Subthalamic Nucleus/drug effects
• Subthalamic Nucleus/metabolism

• Autonomic nervous system
• Cardiovascular reflexes
• De novo Parkinon's disease
• Parkinson's disease
• Sudomotor function

• Extracellular vesicles
• Gait
• Learning/memory
• Parkinson’s disease model

• Administration, Intranasal
• Animals
• Behavior, Animal
• Child
• Corpus Striatum/pathology
• Disease Models, Animal
• Extracellular Vesicles/metabolism
• Extracellular Vesicles/ultrastructure
• Female
• Gait
• Humans
• Male
• Memory
• Nissl Bodies/metabolism
• Oxidopamine
• Parkinson Disease/pathology
• Parkinson Disease/physiopathology
• Parkinson Disease/therapy
• Rats, Wistar
• Substantia Nigra/pathology
• Time Factors
• Tyrosine 3-Monooxygenase/metabolism
• Rats

• No. SEN-15090 Lietuvos Mokslo Taryba

• Células troncales pluripotentes inducidas
• Dopaminergic neurons
• Enfermedad de Parkinson
• Induced pluripotent stem cells
• Modelo preclínico
• Neurodegeneración
• Neurodegeneration
• Neuronas dopaminérgicas
• Parkinson's disease
• Preclinical model
• Tratamiento
• Treatment

• Comorbidity
• Databases, Factual
• Humans
• Huntington Disease/complications
• Huntington Disease/psychology
• Medicaid
• Mental Disorders/epidemiology
• Parkinson Disease/complications
• Parkinson Disease/psychology
• Prevalence
• Retrospective Studies
• United States

• MR/M008592/1 Medical Research Council
• F. Hoffmann‐La Roche Ltd

• MAO-B inhibitors
• Parkinson's disease
• genetherapy
• nanoparticles
• rasagiline
• safinamide
• selegiline

• A2A receptor
• Adenosine
• KW6002
• Parkinson’s disease
• clinical trial
• istradefylline
• safety
• therapy

•

Mild behavioral impairment in PD is linked to altered corticostriatal connectivity.

Mild behavioral impairment (MBI) is a syndrome characterized by later life onset, sustained neuropsychiatric symptoms as a marker of dementia risk. In Parkinson's disease (PD), MBI has been associated with worse cognitive abilities and increased cortical atrophy. However, the circuit level correlates of MBI have not been investigated in this population. Our objective was to investigate the relationship between MBI and corticostriatal connectivity in PD patients. This emphasis on corticostriatal connectivity was due to the significant role of these circuits in neuropsychiatric and cognitive symptoms across disease conditions.

Seventy-four non-demented patients with PD were administered the MBI-checklist, and classified as having high MBI (PD-MBI; n = 21) or low MBI scores (PD-noMBI; n = 53). Corticostriatal connectivity was assessed with both an atlas and seed-based analysis. The atlas analysis consisted of calculating the average connectivity between the striatal network and the default mode (DMN), central executive (CEN), and saliency networks (SAN). Structural measurements of cortical thickness and volume were also assessed. PD-MBI and PD-noMBI patients were compared, along with a group of age matched healthy control subjects (HC; n = 28). Subsequently, a seed analysis assessed the relationship of MBI scores with the connectivity of twelve seeds within the striatum while controlling for cognitive ability. A complementary analysis assessed the relationship between striatal connectivity and cognition, while controlling for MBI-C.

PD-MBI demonstrated decreased connectivity between the striatum and both the DMN and SAN compared to PD-noMBI and HC. The decreased connectivity between the striatum and the SAN was explained partly by increased atrophy within the SAN in PD-MBI. The seed analysis revealed a relationship between higher MBI scores and lower connectivity of the left caudate head to the dorsal anterior cingulate cortex and left middle frontal gyrus. Higher MBI-C scores were also related to decreased connectivity of the right caudate head with the anterior cingulate cortex, precuneus, and left supramarginal gyrus, as well as increased connectivity to the left hippocampus and right cerebellar hemisphere. Caudate-precuneus connectivity was independently associated with both global behavioural and cognitive scores.

These results suggest PD-MBI is associated with altered corticostriatal connectivity, particularly between the head of the caudate and cortical regions associated with the DMN and SAN. In particular, caudate-precuneus connectivity is associated with both global behavioral and cognitive symptoms in PD.

• Basal ganglia
• Cognition
• Corticostriatal connectivity
• Default mode network
• Mild behavioral impairment
• Parkinson's disease
• Resting state

Pain is highly prevalent in patients with Parkinson’s disease (PD), but underlying pathophysiological mechanisms are largely unclear. In many chronic pain syndromes deficits in endogenous pain inhibition have been detected that can be assessed using conditioned pain modulation paradigms. Previous studies employing this approach in medicated PD patients did not find abnormal pain inhibition. However, these results might have been confounded by residual dopaminergic medication.

An established conditioned pain modulation paradigm was used in 17 drug-naïve de novo PD patients and 17 healthy age and gender-matched controls. We tested i) whether conditioned pain modulation responses differed between the patient and control group and ii) whether pain inhibition differed between PD subtypes.

PD patients and healthy controls did not differ in their conditioned pain modulation responses. Furthermore, there were no significant differences in CPM responses depending on the PD subtype. However, at a descriptive level, tremor-dominant patients showed a tendency for better descending pain inhibition compared to akinetic-rigid and mixed type patients.

In this first study investigating conditioned pain modulation in de novo PD patients, we found no additional impairment in descending pain modulation besides the known age-related decline. Our findings indicate that mechanisms other than an impaired descending inhibition contribute to high pain prevalence rates in PD and suggest that mechanisms underlying pain may differ between PD subtypes.

The online version of this article (10.1186/s42466-019-0029-x) contains supplementary material, which is available to authorized users.

• CPM
• Descending inhibition
• Dopamine
• Neurodegeneration

• Alzheimer’s disease
• EHR
• EMR
• artificial intelligence
• machine learning
• transcriptomic analysis

• Animals
• Artificial Intelligence
• Drug Repositioning/methods
• Humans
• Neurodegenerative Diseases/drug therapy

• R01 AG057683 NIA NIH HHS
• R01 AG060393 NIA NIH HHS
• T32 GM008568 NIGMS NIH HHS
• F31 AG058439 NIA NIH HHS

Key pathological features of Parkinson's Disease (PD) include the progressive degeneration of midbrain dopaminergic (DA) neurons and hindbrain noradrenergic (NA) neurons. The loss of DA neurons has been extensively studied and is the main cause of motor dysfunction. Importantly, however, there are a range of ‘non‐movement’ related features of PD including cognitive dysfunction, sleep disturbances and mood disorders. The origins for these non‐motor symptoms are less clear, but a possible substrate for cognitive decline may be reduced adult‐hippocampal neurogenesis, which is reported to be impaired in PD. The mechanisms underlying reduced neurogenesis in PD are not well established. Here we tested the hypothesis that NA and DA depletion, as occurs in PD, impairs hippocampal neurogenesis. We used 6‐hydroxydopamine or the immunotoxin dopamine‐β‐hydroxylase‐saporin to selectively lesion DA or NA neurons, respectively, in adult Sprague Dawley rats and assessed hippocampal neurogenesis through phenotyping of cells birth‐dated using 5‐bromo‐2′‐deoxyuridine. The results showed no difference in proliferation or differentiation of newborn cells in the subgranular zone of the dentate gyrus after NA or DA lesions. This suggests that impairment of hippocampal neurogenesis in PD likely results from mechanisms independent of, or in addition to degeneration of DA and NA neurons.

• catecholamines
• dentate gyrus
• endogenous stem-cells
• neurodegeneration

LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD.

• LRRK2
• Parkinson's disease
• Parkinsonism
• chromosomes
• dopamine
• genes
• glutamate
• mouse
• neuroscience
• synapse

• Parkinson’s disease
• intranasal MPTP
• neuroimmune RAGE network
• nonmotor symptoms
• physical exercise

• Animals
• Brain/immunology
• Brain/metabolism
• Exercise Test/methods
• Male
• Neuroimmunomodulation/physiology
• Parkinsonian Disorders/immunology
• Parkinsonian Disorders/rehabilitation
• Physical Conditioning, Animal/methods
• Physical Conditioning, Animal/physiology
• Rats
• Rats, Wistar
• Receptor for Advanced Glycation End Products/biosynthesis
• Receptor for Advanced Glycation End Products/immunology
• Treatment Outcome

Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology.

• ">l-DOPA
• Parkinson’s disease
• deep brain stimulation
• dopamine
• olfaction
• striatum
• substantia nigra

• Intranasal MPTP
• Neurodegeneration
• Parkinson’s disease
• Succinobucol

• Alzheimer’s disease
• Biomarker
• Ghrelin
• Neurodegeneration
• Parkinson’s disease

• D2/3 dopamine receptors
• Parkinson’s disease
• anxiety
• apathy
• depression
• dopaminergic nigrostriatal system
• impulse control disorders
• impulsivity

• Case-Control Studies
• Disease Progression
• Early Diagnosis
• Humans
• Olfaction Disorders/diagnosis
• Parkinson Disease/diagnosis
• Parkinson Disease/physiopathology
• REM Sleep Behavior Disorder/diagnosis
• ROC Curve
• Support Vector Machine

Pain is highly prevalent in patients with Parkinson’s disease (PD), but little is known about the underlying pathophysiological mechanisms. The susceptibility to pain is known to depend on ascending and descending pathways. Because parts of the descending pain inhibitory system involve dopaminergic pathways, dysregulations in dopaminergic transmission might contribute to altered pain processing in PD. Deficits in endogenous pain inhibition can be assessed using conditioned pain modulation (CPM) paradigms.

Applying such a paradigm, we investigated i) whether CPM responses differ between PD patients and healthy controls, ii) whether they are influenced by dopaminergic medication and iii) whether there are effects of disease-specific factors. 25 patients with idiopathic PD and 30 healthy age- and gender-matched controls underwent an established CPM paradigm combining heat pain test stimuli at the forearm and the cold pressor task on the contralateral foot as the conditioning stimulus. PD patients were tested under dopaminergic medication and after at least 12 hours of medication withdrawal.

No significant differences between CPM responses of PD patients and healthy controls or between PD patients “on” and “off” medication were found. These findings suggest (i) that CPM is insensitive to dopaminergic modulations and (ii) that PD is not related to general deficits in descending pain inhibition beyond the known age-related decline. However, at a trend level, we found differences between PD subtypes (akinetic-rigid, tremor-dominant, mixed) with the strongest impairment of pain inhibition in the akinetic-rigid subtype.

There were no significant differences between CPM responses of patients compared to healthy controls or between patients “on” and “off” medication. Differences between PD subtypes at a trend level point towards different pathophysiological mechanisms underlying the three PD subtypes which warrant further investigation and potentially differential therapeutic strategies in the future.

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin^−/−) to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin^−/− mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination), anxiety (elevated plus-maze), depressive-like behavior (forced swimming and tail suspension) and motor function (rotarod, grasping strength and pole). However, parkin^−/− mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP). These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin^−/− mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.

• Animals
• Behavior, Animal
• Disease Models, Animal
• Dopamine/metabolism
• Gene Deletion
• Hippocampus/metabolism
• Hippocampus/physiopathology
• Homozygote
• Locomotion
• Long-Term Potentiation
• Male
• Memory
• Mice
• Mice, Knockout
• Motor Activity
• Nerve Endings/metabolism
• Parkinson Disease/diagnosis
• Parkinson Disease/genetics
• Parkinson Disease/physiopathology
• Phenotype
• Ubiquitin-Protein Ligases/deficiency
• Ubiquitin-Protein Ligases/genetics

Cardiac sympathetic neurodegeneration and dysautonomia affect patients with sporadic and familial Parkinson's disease (PD) and are currently proposed as prodromal signs of PD. We have recently developed a nonhuman primate model of cardiac dysautonomia by iv 6-hydroxydopamine (6-OHDA). Our in vivo findings included decreased cardiac uptake of a sympathetic radioligand and circulating catecholamines; here we report the postmortem characterization of the model. Ten adult rhesus monkeys (5–17 yrs old) were used in this study. Five animals received 6-OHDA (50 mg/kg iv) and five were age-matched controls. Three months post-neurotoxin the animals were euthanized; hearts and adrenal glands were processed for immunohistochemistry. Quantification of immunoreactivity (ir) of stainings was performed by an investigator blind to the treatment group using NIH ImageJ software (for cardiac bundles and adrenals, area above threshold and optical density) and MBF StereoInvestigator (for cardiac fibers, area fraction fractionator probe). Sympathetic cardiac nerve bundle analysis and fiber area density showed a significant reduction in global cardiac tyrosine hydroxylase-ir (TH; catecholaminergic marker) in 6-OHDA animals compared to controls. Quantification of protein gene protein 9.5 (pan-neuronal marker) positive cardiac fibers showed a significant deficit in 6-OHDA monkeys compared to controls and correlated with TH-ir fiber area. Semi-quantitative evaluation of human leukocyte antigen-ir (inflammatory marker) and nitrotyrosine-ir (oxidative stress marker) did not show significant changes 3 months post-neurotoxin. Cardiac nerve bundle α-synuclein-ir (presynaptic protein) was reduced (trend) in 6-OHDA treated monkeys; insoluble proteinase-K resistant α-synuclein (typical of PD pathology) was not observed. In the adrenal medulla, 6-OHDA monkeys had significantly reduced TH-ir and aminoacid decarboxylase-ir. Our results confirm that systemic 6-OHDA dosing to nonhuman primates induces cardiac sympathetic neurodegeneration and loss of catecholaminergic enzymes in the adrenal medulla, and suggests that this model can be used as a platform to evaluate disease-modifying strategies aiming to induce peripheral neuroprotection.

• animal biology
• biomarker based
• heterogenization
• reverse-translated

• Animals
• Drug Evaluation, Preclinical
• Humans
• Models, Animal
• Neurosciences
• Research Design
• Validation Studies as Topic

• R21 NS088841 NINDS NIH HHS
• R21NS088841R21NS088841 NINDS NIH HHS