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Journal of Parkinson's Disease 2024The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric... (Review)
Review
The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson's disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal -prevention.
Topics: Humans; Parkinson Disease; Environmental Exposure; Brain; Lewy Body Disease; alpha-Synuclein
PubMed: 38607765
DOI: 10.3233/JPD-240019 -
Journal of Neurology Sep 2023Among people with Parkinson's disease (PD), non-motor symptoms (NMS) are a well-recognised cause of significant morbidity and poor quality of life. Yet, it is only more...
Among people with Parkinson's disease (PD), non-motor symptoms (NMS) are a well-recognised cause of significant morbidity and poor quality of life. Yet, it is only more recently that NMS have been recognised to affect the lives of patients with atypical parkinsonian syndromes in a similar fashion. The aim of this article is to highlight and compare the relative prevalence of NMS among patients with atypical parkinsonian syndromes in the published literature, which largely remain underreported and unaddressed in routine clinical practice. All NMS that are recognised to occur in PD are also found to commonly occur in atypical parkinsonian syndromes. In particular, excessive daytime sleepiness is more prevalent among atypical parkinsonian syndromes (94.3%) compared to PD (33.9%) or normal controls (10.5%) (p < 0.001). Urinary dysfunction (not limited to urinary incontinence) is not only found to occur in MSA (79.7%) and PD (79.9%), but has also been reported in nearly half of the patients with PSP (49.3%), DLB (42%) and CBD (53.8%) (p < 0.001). Apathy is significantly more common among the atypical parkinsonian syndromes [PSP (56%), MSA (48%), DLB (44%), CBD (43%)] compared to PD (35%) (p = 0.029). Early recognition and addressing of NMS among atypical parkinsonian syndromes may help improve the holistic patient care provided and may encompass a range of conservative and pharmacotherapeutic treatments to address these symptoms.
Topics: Humans; Quality of Life; Parkinsonian Disorders; Parkinson Disease; Apathy; Prevalence; Supranuclear Palsy, Progressive; Multiple System Atrophy
PubMed: 37316556
DOI: 10.1007/s00415-023-11807-x -
Molecular Medicine (Cambridge, Mass.) Mar 2024Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of...
BACKGROUND
Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of dopamine neurons have died making dopamine-related motor phenotypes unreliable markers of the earlier stages of the disease. There are other non-motor symptoms, such as depression, that may present decades before motor symptoms.
METHODS
Because serotonin is implicated in depression, here we use niche, fast electrochemistry paired with mathematical modelling and machine learning to, for the first time, robustly evaluate serotonin neurochemistry in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
RESULTS
Mice treated with acute MPTP had lower concentrations of in vivo, evoked and ambient serotonin in the hippocampus, consistent with the clinical comorbidity of depression with PD. These mice did not chemically respond to SSRI, as strongly as control animals did, following the clinical literature showing that antidepressant success during PD is highly variable. Following L-DOPA administration, using a novel machine learning analysis tool, we observed a dynamic shift from evoked serotonin release in the hippocampus to dopamine release. We hypothesize that this finding shows, in real time, that serotonergic neurons uptake L-DOPA and produce dopamine at the expense of serotonin, supporting the significant clinical correlation between L-DOPA and depression. Finally, we found that this post L-DOPA dopamine release was less regulated, staying in the synapse for longer. This finding is perhaps due to lack of autoreceptor control and may provide a ground from which to study L-DOPA induced dyskinesia.
CONCLUSIONS
These results validate key prior hypotheses about the roles of serotonin during PD and open an avenue to study to potentially improve therapeutics for levodopa-induced dyskinesia and depression.
Topics: Mice; Animals; Levodopa; Dopamine; Serotonin; Antiparkinson Agents; Dyskinesia, Drug-Induced; Parkinson Disease; Parkinsonian Disorders; Biomarkers
PubMed: 38429661
DOI: 10.1186/s10020-023-00773-9 -
Revue Neurologique Jun 2024Synucleopathies, specifically Parkinson's disease, are still incurable and available therapeutic options are scarce and symptomatic. The autophagy-lysosomal-endosomal... (Review)
Review
Synucleopathies, specifically Parkinson's disease, are still incurable and available therapeutic options are scarce and symptomatic. The autophagy-lysosomal-endosomal system is an indigenous mechanism to manage the proteome. Excess/misfolded protein accumulation activates this system, which degrades the undesired proteins via lysosomes. Cells also eliminate these proteins by releasing them into the extracellular space via exosomes. However, the sutophagy-lysosomal-endosomal system becomes unfunctional in Parkinson's disease and there is accumulation and spread of pathogenic alpha-synuclein. Neuronal degeneration results Owing to pathogenic alpha-synuclein. Thus, the autophagy-lysosomal-endosomal system could be a promising target for neuroprotection. In the present review, we discuss the autophagy-lysosomal-endosomal system as an emerging target for the management of Parkinson's disease. Modulation of these targets associated with the autophagy-lysosomal-endosomal system can aid in clearing pathogenic alpha-synuclein and prevent the degeneration of neurons.
Topics: Humans; Parkinson Disease; Autophagy; Lysosomes; Animals; alpha-Synuclein; Endosomes; Molecular Targeted Therapy
PubMed: 37586941
DOI: 10.1016/j.neurol.2023.07.007 -
Parkinsonism & Related Disorders Apr 2024Neurofeedback (NF) techniques support individuals to self-regulate specific features of brain activity, which has been shown to impact behavior and potentially... (Review)
Review
Neurofeedback (NF) techniques support individuals to self-regulate specific features of brain activity, which has been shown to impact behavior and potentially ameliorate clinical symptoms. Electrophysiological NF (epNF) may be particularly impactful for patients with Parkinson's disease (PD), as evidence mounts to suggest a central role of pathological neural oscillations underlying symptoms in PD. Exaggerated beta oscillations (12-30 Hz) in the basal ganglia-cortical network are linked to motor symptoms (e.g., bradykinesia, rigidity), and beta is reduced by successful therapy with dopaminergic medication and Deep Brain Stimulation (DBS). PD patients also experience non-motor symptoms related to sleep, mood, motivation, and cognitive control. Although less is known about the mechanisms of non-motor symptoms in PD and how to successfully treat them, low frequency neural oscillations (1-12 Hz) in the basal ganglia-cortical network are particularly implicated in non-motor symptoms. Here, we review how cortical and subcortical epNF could be used to target motor and non-motor specific oscillations, and potentially serve as an adjunct therapy that enables PD patients to endogenously control their own pathological neural activities. Recent studies have demonstrated that epNF protocols can successfully support volitional control of cortical and subcortical beta rhythms. Importantly, this endogenous control of beta has been linked to changes in motor behavior. epNF for PD, as a casual intervention on neural signals, has the potential to increase understanding of the neurophysiology of movement, mood, and cognition and to identify new therapeutic approaches for motor and non-motor symptoms.
Topics: Humans; Parkinson Disease; Neurofeedback; Basal Ganglia; Movement; Beta Rhythm; Deep Brain Stimulation
PubMed: 38245382
DOI: 10.1016/j.parkreldis.2024.106010 -
International Review of Neurobiology 2024The heterogeneity of non-motor features observed in people with Parkinson's disease (PD) is often dominated by one or more symptoms belonging to the neuropsychiatric... (Review)
Review
The heterogeneity of non-motor features observed in people with Parkinson's disease (PD) is often dominated by one or more symptoms belonging to the neuropsychiatric spectrum, such as cognitive impairment, psychosis, depression, anxiety, and apathy. Due to their high prevalence in people with PD (PwP) and their occurrence in every stage of the disease, from the prodromal to the advanced stage, it is not surprising that PD can be conceptualised as a complex neuropsychiatric disorder. Despite progress in understanding the pathophysiological mechanisms underlying the neuropsychiatric signs and symptoms in PD, and better identification and diagnosis of these symptoms, effective treatments are still a major unmet need. The impact of these symptoms on the quality of life of PwP and caregivers, as well as their contribution to the overall non-motor symptom burden can be greater than that of motor symptoms and require a personalised, holistic approach. In this chapter, we provide a general clinical overview of the major neuropsychiatric symptoms of PD.
Topics: Humans; Anxiety; Cognitive Dysfunction; Parkinson Disease; Psychotic Disorders; Quality of Life
PubMed: 38341232
DOI: 10.1016/bs.irn.2023.11.001 -
Cell Reports Oct 2023The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the...
The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the underlying mechanisms nor the type of neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr neurons (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other SNr cells. We also report that only SNr-PV+ neurons' intrinsic excitability is reduced by downregulation of sodium leak channels in a PD mouse model. Interestingly, in anesthetized parkinsonian mice in vivo, SNr-PV+ neurons display a bursty pattern of activity dependent on glutamatergic tone. Finally, we demonstrate that chemogenetic inhibition of SNr-PV+ neurons is sufficient to alleviate motor impairments in parkinsonian mice. Overall, our findings establish cell-type-specific dysfunction in experimental parkinsonism in the SNr and provide a potential cellular therapeutic target to alleviate motor symptoms in PD.
Topics: Mice; Animals; Pars Reticulata; Substantia Nigra; Parvalbumins; Neurons; Parkinson Disease
PubMed: 37843977
DOI: 10.1016/j.celrep.2023.113287 -
Brain : a Journal of Neurology Apr 2024Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within...
Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.
Topics: Humans; Parkinson Disease; Apathy; Dopamine; Motivation; Neurotransmitter Agents
PubMed: 38305691
DOI: 10.1093/brain/awae025 -
CNS Neuroscience & Therapeutics Aug 2023In this study, we aimed to investigate the effect of neuropsychiatric symptoms (NPS) on the rate of cognitive decline for both global cognition and specific cognitive...
AIMS
In this study, we aimed to investigate the effect of neuropsychiatric symptoms (NPS) on the rate of cognitive decline for both global cognition and specific cognitive domains in a cohort of patients from the Parkinson's Progression Markers Initiative (PPMI).
METHOD
Prospectively longitudinal data were obtained from the PPMI cohort. NPS, including depression, anxiety, apathy, psychosis, impulse control disorders (ICDs), and cognition ability, were evaluated by a series of questionnaires. Linear mixed-effects models were used to investigate the relationship between NPS and the rate of cognitive decline. Generalized estimating equations (GEEs) were used to investigate the relationship between NPS and the occurrence of mild cognitive impairment (MCI).
RESULTS
In total, 423 patients with Parkinson's disease (PD) were recruited at baseline and 395, 378, 366, 346, and 315 participants were followed up at 1, 2, 3, 4, and 5 years, respectively. Depression, anxiety, apathy, and psychosis were associated with global cognitive decline. Except for those with ICDs, patients with psychosis, depression, anxiety, and apathy were more likely to meet the criteria for MCI. Patients with depression and anxiety showed a progressive decline in four major cognitive domains. Apathy and ICDs were separately associated with a progressive decline in processing speed-attention and memory, respectively.
CONCLUSIONS
Neuropsychiatric symptoms, including psychosis, depression, anxiety, and apathy, could be used to predict future cognitive decline in patients with PD.
Topics: Humans; Parkinson Disease; Cognitive Dysfunction; Apathy; Psychotic Disorders; Cognition; Neuropsychological Tests
PubMed: 36924300
DOI: 10.1111/cns.14173 -
CNS Neuroscience & Therapeutics Feb 2024Glucosylceramidase (GBA) variants and onset age significantly affect clinical phenotype and progression in Parkinson's disease (PD). The current study compared clinical...
OBJECTIVE
Glucosylceramidase (GBA) variants and onset age significantly affect clinical phenotype and progression in Parkinson's disease (PD). The current study compared clinical characteristics at baseline and cognitive and motor progression over time among patients having GBA-related PD (GBA-PD), early-onset idiopathic PD (early-iPD), and late-onset idiopathic PD (late-iPD).
METHODS
We recruited 88 GBA-PD, 167 early-iPD, and 488 late-iPD patients in this study. A subset of 50 GBA-PD, 81 early-iPD, and 223 late-iPD patients was followed up at least once, with a 3.0-year mean follow-up time. Linear mixed-effects models helped evaluate the rate of change in the Unified Parkinson's Disease Rating Scale motor and Montreal Cognitive Assessment scores.
RESULTS
At baseline, the GBA-PD group showed more severe motor deficits and non-motor symptoms (NMSs) than the early-iPD group and more NMSs than the late-iPD group. Moreover, the GBA-PD group had more significant cognitive and motor progression, particularly bradykinesia and axial impairment, than the early-iPD and late-iPD groups at follow-up. However, the early-onset GBA-PD (early-GBA-PD) group was similar to the late-onset GBA-PD (late-GBA-PD) group in baseline clinical features and cognitive and motor progression.
CONCLUSION
GBA-PD patients exhibited faster cognitive and motor deterioration than early-iPD and late-iPD patients. Thus, subtype classification based on genetic characteristics rather than age at onset could enhance the prediction of PD disease progression.
Topics: Humans; Age of Onset; Cognitive Dysfunction; Glucosylceramidase; Mutation; Parkinson Disease
PubMed: 37563866
DOI: 10.1111/cns.14387