-
Journal of Neuroscience Research Mar 2024Synaptic dysfunction and altered synaptic pruning are present in people with Parkinsonian disorders. Dopamine loss and alpha-synuclein accumulation, two hallmarks of... (Review)
Review
Synaptic dysfunction and altered synaptic pruning are present in people with Parkinsonian disorders. Dopamine loss and alpha-synuclein accumulation, two hallmarks of Parkinson's disease (PD) pathology, contribute to synaptic dysfunction and reduced synaptic density in PD. Atypical Parkinsonian disorders are likely to have unique spatiotemporal patterns of synaptic density, differentiating them from PD. Therefore, quantification of synaptic density has the potential to support diagnoses, monitor disease progression, and treatment efficacy. Novel radiotracers for positron emission tomography which target the presynaptic vesicle protein SV2A have been developed to quantify presynaptic density. The radiotracers have successfully investigated synaptic density in preclinical models of PD and people with Parkinsonian disorders. Therefore, this review will summarize the preclinical and clinical utilization of SV2A radiotracers in people with Parkinsonian disorders. We will evaluate how SV2A abundance is associated with other imaging modalities and the considerations for interpreting SV2A in Parkinsonian pathology.
Topics: Humans; Parkinsonian Disorders; Parkinson Disease; Positron-Emission Tomography; Synapses; Dopamine; Brain
PubMed: 37814917
DOI: 10.1002/jnr.25253 -
Der Nervenarzt Aug 2023Dysphagia is a clinically relevant problem in Parkinson's disease as well as in atypical Parkinsonian syndromes, such as multiple system atrophy and diseases from the... (Review)
Review
Dysphagia is a clinically relevant problem in Parkinson's disease as well as in atypical Parkinsonian syndromes, such as multiple system atrophy and diseases from the spectrum of 4‑repeat tauopathies, which affect most patients to a varying degree in the course of their disease. This results in relevant restrictions in daily life due to impaired intake of food, fluids, and medication with a subsequent reduction in quality of life. This article not only gives an overview of the pathophysiological causes of dysphagia in the various Parkinson syndromes, but also presents screening, diagnostic and treatment procedures that have been investigated for the different diseases.
Topics: Humans; Deglutition Disorders; Quality of Life; Parkinsonian Disorders; Parkinson Disease; Multiple System Atrophy
PubMed: 37115255
DOI: 10.1007/s00115-023-01475-7 -
Neurological Sciences : Official... Mar 2024The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive...
The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.
Topics: Female; Humans; Middle Aged; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; tau Proteins; Parkinson Disease; Mutation; Parkinsonian Disorders
PubMed: 37730935
DOI: 10.1007/s10072-023-07081-4 -
Movement Disorders : Official Journal... Aug 2023To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation.
OBJECTIVE
To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation.
BACKGROUND
LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers.
METHODS
Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration.
RESULTS
TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change.
CONCLUSIONS
Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Brain; DNA-Binding Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Parkinsonian Disorders; Protein Serine-Threonine Kinases
PubMed: 37218402
DOI: 10.1002/mds.29449 -
Cell Reports Nov 2023The subthalamic nucleus (STN) is critical for behavioral control; its dysregulation consequently correlated with neurological and neuropsychiatric disorders, including...
The subthalamic nucleus (STN) is critical for behavioral control; its dysregulation consequently correlated with neurological and neuropsychiatric disorders, including Parkinson's disease. Deep brain stimulation (DBS) targeting the STN successfully alleviates parkinsonian motor symptoms. However, low mood and depression are affective side effects. STN is adjoined with para-STN, associated with appetitive and aversive behavior. DBS aimed at STN might unintentionally modulate para-STN, causing aversion. Alternatively, the STN mediates aversion. To investigate causality between STN and aversion, affective behavior is addressed using optogenetics in mice. Selective promoters allow dissociation of STN (e.g., Pitx2) vs. para-STN (Tac1). Acute photostimulation results in aversion via both STN and para-STN. However, only STN stimulation-paired cues cause conditioned avoidance and only STN stimulation interrupts on-going sugar self-administration. Electrophysiological recordings identify post-synaptic responses in pallidal neurons, and selective photostimulation of STN terminals in the ventral pallidum replicates STN-induced aversion. Identifying STN as a source of aversive learning contributes neurobiological underpinnings to emotional affect.
Topics: Animals; Mice; Subthalamic Nucleus; Avoidance Learning; Deep Brain Stimulation; Parkinson Disease; Parkinsonian Disorders
PubMed: 37925641
DOI: 10.1016/j.celrep.2023.113328 -
Movement Disorders : Official Journal... Sep 2023PREDICT-PD is a United Kingdom population-based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm. (Meta-Analysis)
Meta-Analysis
BACKGROUND
PREDICT-PD is a United Kingdom population-based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm.
METHODS
A randomly selected, representative sample of participants in PREDICT-PD were examined using several motor assessments, including the motor section of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III, at baseline (2012) and after an average of 6 years of follow-up. We checked for new PD diagnoses in participants seen at baseline and examined the association between risk scores and incident sub-threshold parkinsonism, motor decline (increasing ≥5 points in MDS-UPDRS-III) and single motor domains in the MDS-UPDRS-III. We replicated analyses in two independent datasets (Bruneck and Parkinson's Progression Markers Initiative [PPMI]).
RESULTS
After 6 years of follow-up, the PREDICT-PD higher-risk group (n = 33) had a greater motor decline compared with the lower-risk group (n = 95) (30% vs. 12.5%, P = 0.031). Two participants (both considered higher risk at baseline) were given a diagnosis of PD during follow-up, with motor signs emerging between 2 and 5 years before diagnosis. A meta-analysis of data from PREDICT-PD, Bruneck, and PPMI showed an association between PD risk estimates and incident sub-threshold parkinsonism (odds ratio [OR], 2.01 [95% confidence interval (CI), 1.55-2.61]), as well as new onset bradykinesia (OR, 1.69 [95% CI, 1.33-2.16]) and action tremor (OR, 1.61 [95% CI, 1.30-1.98]).
CONCLUSIONS
Risk estimates using the PREDICT-PD algorithm were associated with the occurrence of sub-threshold parkinsonism, including bradykinesia and action tremor. The algorithm could also identify individuals whose motor examination experience a decline over time. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Tremor; Hypokinesia; Mental Status and Dementia Tests; Algorithms; Disease Progression
PubMed: 37317903
DOI: 10.1002/mds.29496 -
Parkinsonism & Related Disorders May 2024Our ability to define, understand, and classify Parkinson's disease (PD) has undergone significant changes since the disorder was first described in 1817. Clinical... (Review)
Review
Our ability to define, understand, and classify Parkinson's disease (PD) has undergone significant changes since the disorder was first described in 1817. Clinical features and neuropathologic signatures can now be supplemented by in-vivo interrogation of genetic and biological substrates of disease, offering great opportunity for further refining the diagnosis of PD. In this mini-review, we discuss the historical perspectives which shaped our thinking surrounding the definition and diagnosis of PD. We highlight the clinical, genetic, pathologic and biologic diversity which underpins the condition, and proceed to discuss how recent developments in our ability to define biologic and pathologic substrates of disease might impact PD definition, diagnosis, individualised prognostication, and personalised clinical care. We argue that Parkinson's 'disease', as currently diagnosed in the clinic, is actually a syndrome. It is the outward manifestation of any array of potential dysfunctional biologic processes, neuropathological changes, and disease aetiologies, which culminate in common outward clinical features which we term PD; each person has their own unique disease, which we can now define with increasing precision. This is an exciting time in PD research and clinical care. Our ability to refine the clinical diagnosis of PD, incorporating in-vivo assessments of disease biology, neuropathology, and neurogenetics may well herald the era of biologically-based, precision medicine approaches PD management. With this however comes a number of challenges, including how to integrate these technologies into clinical practice in a way which is acceptable to patients, promotes meaningful changes to care, and minimises health economic impact.
Topics: Humans; Parkinson Disease
PubMed: 38360507
DOI: 10.1016/j.parkreldis.2024.106041 -
Current Neuropharmacology 2024While symptomatic pharmacological therapy remains the main therapeutic strategy for Parkinson's disease (PD), over the last two decades, surgical approaches have become... (Review)
Review
While symptomatic pharmacological therapy remains the main therapeutic strategy for Parkinson's disease (PD), over the last two decades, surgical approaches have become more commonly used to control levodopa-induced motor complications and dopamine-resistant and non-motor symptoms of PD. In this paper, we discuss old and new surgical treatments for PD and the many technological innovations in this field. We have initially reviewed the relevant surgical anatomy as well as the pathological signaling considered to be the underlying cause of specific symptoms of PD. Subsequently, early attempts at surgical symptom control will be briefly reviewed. As the most well-known surgical intervention for PD is deep brain stimulation, this subject is discussed at length. As deciding on whether a patient stands to benefit from DBS can be quite difficult, the different proposed paradigms for precisely this are covered. Following this, the evidence regarding different targets, especially the subthalamic nucleus and internal globus pallidus, is reviewed as well as the evidence for newer proposed targets for specific symptoms. Due to the rapidly expanding nature of knowledge and technological capabilities, some of these new and potential future capabilities are given consideration in terms of their current and future use. Following this, we have reviewed newer treatment modalities, especially magnetic resonance-guided focused ultrasound and other potential surgical therapies, such as spinal cord stimulation for gait symptoms and others. As mentioned, the field of surgical alleviation of symptoms of PD is undergoing a rapid expansion, and this review provides a general overview of the current status and future directions in the field.
Topics: Humans; Parkinson Disease; Treatment Outcome; Subthalamic Nucleus; Levodopa; Globus Pallidus; Deep Brain Stimulation
PubMed: 36411569
DOI: 10.2174/1570159X21666221121094343 -
Tidsskrift For Den Norske Laegeforening... May 2024Parkinson's disease is characterised by the core motor symptoms: bradykinesia, rigidity and tremor. The disease also has a number of non-motor symptoms, such as visual... (Review)
Review
Parkinson's disease is characterised by the core motor symptoms: bradykinesia, rigidity and tremor. The disease also has a number of non-motor symptoms, such as visual impairment. Patients may experience blurred vision, sensitivity to light, difficulties in reading, and a subjective feeling of rapid eye fatigue. The visual impairments also affect the patients' motor skills, as vision compensates for poor postural control and difficulty initiating movement. It is important to identify common but frequently underdiagnosed visual impairment, and initiate measures that can increase quality of life and pattern of movement. In this clinical review we present the most common visual impairments in Parkinson's disease, as well as providing advice for improved visual function.
Topics: Humans; Parkinson Disease; Vision Disorders; Quality of Life
PubMed: 38747667
DOI: 10.4045/tidsskr.23.0716 -
Age and Ageing Oct 2023Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Ageing is considered to be the greatest risk factor for PD, with...
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Ageing is considered to be the greatest risk factor for PD, with a complex interplay between genetics and the environment. With population ageing, the prevalence of PD is expected to escalate worldwide; thus, it is of utmost importance to reduce the burden of PD. To date, there are no therapies to cure the disease, and current treatment strategies focus on the management of symptoms. Older adults often have multiple chronic diseases and geriatric syndromes, which further complicates the management of PD. Healthcare systems and care models necessary to address the broad needs of older PD patients are largely unavailable. In this New Horizon article, we discuss various aspects of PD from an ageing perspective, including disease management. We highlight recent advancements in PD therapies and discuss new care models with the potential to improve patient's quality of life.
Topics: Humans; Aged; Parkinson Disease; Quality of Life; Aging
PubMed: 37847793
DOI: 10.1093/ageing/afad186