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While Parkinsons disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinsons Disease Rating Scale III but were insufficient in degree to diagnose Parkinsons disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinsons disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinsons disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.

Parkinsonism is presented as a motor syndrome characterized by rigidity, tremors, and bradykinesia, with Parkinson's disease (PD) being the predominant cause. The discovery that those motor symptoms result from the death of dopaminergic cells in the substantia nigra led to focus most of parkinsonism research on the basal ganglia (BG). However, recent findings point to an active involvement of the cerebellum in this motor syndrome. Here, we have developed a multiscale computational model of the rodent brain's BG–cerebellar network. Simulations showed that a direct effect of dopamine depletion on the cerebellum must be taken into account to reproduce the alterations of neural activity in parkinsonism, particularly the increased beta oscillations widely reported in PD patients. Moreover, dopamine depletion indirectly impacted spike-time-dependent plasticity at the parallel fiber-Purkinje cell synapses, degrading associative motor learning as observed in parkinsonism. Overall, these results suggest a relevant involvement of cerebellum in parkinsonism associative motor symptoms. [ABSTRACT FROM AUTHOR]

Background: Parkinson disease (PD) is one of the disabling neurological disorders. The etiology of Parkinson disease is still unknown. Hepatitis C virus is one of the neurotropic viruses which is incriminated in the pathogenesis of Parkinson disease. Hepatitis C virus might affect the dopaminergic neurons, affecting the advancement of PD. Methods: This study is observational, cross-sectional study done on 2 phases: one phase on PD patients without history of HCV and another phase on HCV patients with no history of PD. 104 PD patient were tested for HCV antibodies and 40 HCV patients with various grades of liver fibrosis were assessed for early pre-motor symptoms of parkinsonism. Results: Among patients with parkinsonism, HCV Abs testing was negative in all the studied patients. On the other hand, chronic HCV group included 40 patients, 27.5% were cirrhotic (11/40). Child C patients showed significantly higher percentages of non-motor parkinsonian symptoms, and regarding the HCV group, the majority (85%) of the patients show cognitive impairment, (27.5%) were at stage 1 of anxious mood, while half (50%) of the patients were at stage 1 of fatigue as evaluated by UPDRS Score. Cirrhosis was a significant factor for having non-motor (early) parkinsonism. Conclusion: Here we show that advanced cirrhosis is associated with a variety of neurological symptoms including parkinsonian, which needs awareness for better preventive and therapeutic measures for early treatment of hepatitis avoiding the occurrence of cirrhosis, which can lead to parkinsonism. [ABSTRACT FROM AUTHOR]

Novel work in adult zebrafish, Danio rerio, to recapitulate human neurodegenerative disease has proven useful in both pharmaceutical development and research on genetic disease. Due to high genetic homology to humans, affordable husbandry, relatively quick life cycle breeding times, and robust embryo production, zebrafish offer a promising model to test pharmaceutical performance in a high throughput, in vivo setting. Currently, most research in zebrafish models of Parkinson's disease induces the disease in larval or embryonic stage organisms due to ease of administration, with advancement through developmental stages taking only a matter of days. The use of early-stage organisms limits the usability of zebrafish as models for adult disease and specifically age-related neurodegenerative conditions. Recently, researchers have sought to extend the usability of zebrafish into models for Parkinson's disease. Specifically, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has emerged as a prodrug that upon injection well-encompasses the biochemical mechanisms and symptomology associated with Parkinson's disease. By utilizing MPTP in an adult zebrafish model, advancements in Parkinson's disease research may be achieved. This paper highlights the recent research on this model, comparing it to the human form of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear. Objective: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. Methods: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. Results: During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (N = 3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (n = 1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values <0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. Conclusions: Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti‐inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn‐induced Parkinsonism. Experimental Approach: Naïve zebrafish were exposed to 2 mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ. Key Results: DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn‐induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection. Conclusion and Implications: DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn‐induced Parkinsonism. [ABSTRACT FROM AUTHOR]

Background: An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants. Objective: To describe which methodological adjustments were made to the study protocol because of these developments. Methods: We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan. Discussion: This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment. [ABSTRACT FROM AUTHOR]

Aim: Neurological manifestations are common in patients with chronic liver diseases. This study aimed to depict the association between liver cirrhosis and Parkinson's disease (PD) and propose a clinically relevant diagnostic scheme. Methods: We examined patients' medical records with PD and chronic liver impairment secondary to cirrhosis or liver metastases for temporal correlations between liver insult and Parkinsonian signs. Results: Thirty-five individuals with PD and chronic liver impairment were included due to either cirrhosis or liver metastases. In all 22 patients with PD and liver metastases, the diagnosis of PD preceded the diagnosis of cancer. Conversely, patients with cirrhosis were often diagnosed with liver impairment before diagnosing PD. Age at diagnosis did not account for this difference. Conclusions: This study reinforces the potential clinical association between cirrhosis and PD. We also provide a diagnostic scheme that may guide therapeutic interventions and prognostic assessments. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The primary pathological features of PD include the presence of α‐synuclein aggregates and Lewy bodies, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Recently, omega‐3 fatty acids (ω‐3 PUFAs) have been under investigation as a preventive and/or therapeutic strategy for PD, primarily owing to their antioxidant and anti‐inflammatory properties. Therefore, the objective of this study was to conduct a systematic review of the literature, focusing on studies that assessed the effects of ω‐3 PUFAs in rodent models mimicking human PD. The search was performed using the terms "Parkinson's disease," "fish oil," "omega 3," "docosahexaenoic acid," and "eicosapentaenoic acid" across databases PUBMED, Web of Science, Science Direct, Scielo, and Google Scholar. Following analysis based on predefined inclusion and exclusion criteria, 39 studies were included. Considering behavioral parameters, pathological markers of the disease, quantification of ω‐3 PUFAs in the brain, as well as anti‐inflammatory, antioxidant, and anti‐apoptotic effects, it can be observed that ω‐3 PUFAs exhibit a potential neuroprotective effect in PD. In summary, this systematic review presents significant scientific evidence regarding the effects and mechanisms underlying the neuroprotective properties of ω‐3 PUFAs, offering valuable insights for the development of future clinical investigations. [ABSTRACT FROM AUTHOR]

Background: Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy‐demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs. Methods: This review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis. Results: mtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear‐encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification. Conclusion: A comprehensive deep‐phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype‐phenotype interplay of PMDs. [ABSTRACT FROM AUTHOR]

Background: Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. Objectives: We would like to highlight a rare but important differential of corticobasal syndrome. Methods: A 78‐year‐old female had a 4‐year history of predominantly right‐hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right‐sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post‐mortem. Results: The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau‐related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. Conclusions: Pick's disease can rarely present with clinical features of corticobasal syndrome. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Creutzfeldt‐Jakob disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder. This case highlights parkinsonism as a rare initial manifestation of sporadic CJD (sCJD), emphasizing the need for heightened clinical awareness to prevent misdiagnosis. Early and accurate diagnosis of sCJD is crucial for preventing potential iatrogenic transmission and optimizing patient management. Creutzfeldt‐Jakob disease (CJD) is a fatal neurodegenerative illness. While movement disorders may be present at the onset of the disease in about half of those with sporadic CJD (sCJD), parkinsonism is a rare initial presentation. In this article, we report a case of CJD with parkinsonism as the initial presentation of the disease. We report a 69‐year‐old lady with initial symptoms of gait difficulty, tremor, and bradykinesia. Later, she developed cognitive impairment, ataxia, chin tremor, and myoclonic jerks. Her condition worsened to the point of akinetic mutism. She was diagnosed with probable sCJD after detecting protein 14‐3‐3 in her cerebrospinal fluid and observing typical imaging features.This case report illustrates important aspects of an inevitably fatal and rapidly progressing disease's early presentation and clinical features. The uncommon initial presentations of sCJD should be considered with the intent of preventing misdiagnosis in the future. Early diagnosis of sCJD can prevent possible iatrogenic disease transmission and improve patient care. [ABSTRACT FROM AUTHOR]

It is known that the presence of CAA codons in the CAG tract affects the nature and time of disease onset caused by the expansion of trinucleotide repeats. The mechanisms leading to the occurrence of these diseases should be sought not only at the level of the physiological role of the ATXN2 protein, but also at the DNA level. These mechanisms are associated with non-canonical configurations (hairpins) that can form in the CAG tract. The tendency of hairpins to slide along the corresponding threads is usually considered important to explain the expansion of the CAG tract. At the same time, hairpins occur in areas of open states. Previous studies on the role of CAA interruptions have suggested that, under certain conditions, they can stabilize the dynamics of the hairpin, preventing the expansion of the CAG tract. We calculated the probability of additional open state zones occurrence in the CAG tract using an angular mathematical model of DNA. The calculations made it possible to establish that CAA interruptions affect the stability of the CAG tract, and this influence, depending on the localization of the interruption, can both increase and decrease the stability of the CAG tract. [ABSTRACT FROM AUTHOR]

Background and Objectives: Vertical rhythmic dyskinetic movements that are primarily drug-induced and affect solely the jaw, mouth, and lips without involving the tongue have been historically described as "rabbit" syndrome (RS). Evidence on the unique features and implications of this disorder remains limited. This literature review aims to evaluate the clinical–epidemiological profile, pathological mechanisms, and management of this movement disorder. Materials and Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction published between 1972 and 2024. Results: A total of 85 articles containing 146 cases of RS were found. The mean frequency of RS among adults in psychiatric hospitals was 1.2% (range 0–4.4%). The mean age of affected patients was 49.2 (SD: 17.5), and 63.6% were females. Schizophrenia was the most frequent comorbidity found in 47.6%, followed by bipolar disorder (17.8%), major depressive disorder (10.3%), and obsessive–compulsive disorder (3.7%). Five cases were idiopathic. The most common medications associated with RS were haloperidol (17%), risperidone (14%), aripiprazole (7%), trifluoperazine (5%), and sulpiride (5%). The mean duration of pharmacotherapy before RS was 21.4 weeks (SD: 20.6). RS occurred in association with drug-induced parkinsonism (DIP) in 27.4% and with tardive dyskinesia (TD) in 8.2% of cases. Antipsychotic modification and/or anticholinergic drugs resulted in full or partial recovery in nearly all reported cases in which they were prescribed. Conclusions: RS occurs as a distinct drug-induced syndrome associated primarily but not exclusively with antipsychotics. Distinguishing RS from TD is important because the treatment options for the two disorders are quite different. By contrast, RS may be part of a spectrum of symptoms of DIP with similar course, treatment outcomes, and pathophysiology. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Until recently, about three‐quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype–phenotype relationships at a global scale.To identify the multi‐ancestry spectrum of monogenic PD.The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD‐causing genes. In contrast, the Global Parkinson's Genetics Program's Monogenic Network took a different approach by targeting PD centers underrepresented or not yet represented in the medical literature.In this article, we describe combining both efforts in a merger project resulting in a global monogenic PD cohort with the buildup of a sustainable infrastructure to identify the multi‐ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expressivity of monogenic PD.This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Dual-phase fluorine-18 labeled N-3-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET) scans could be used to support disorders like Parkinson's disease (PD). Dopamine transporter (DAT) binding and cerebral perfusion are associated with ageing and gender. We investigated the effects of age and gender on non-degenerative parkinsonism, using automated quantification in striatum: specific binding ratios (SBRs) for DAT binding in delayed phase PET (dCIT) and standardized-uptake-value ratios (SUVRs) for cerebral perfusion in early phase PET (eCIT). We also examined the correlations between SBR and SUVR. Methods: This retrospective study analyzed subjects with dual-phase 18F-FP-CIT PET scans. The eCIT images were acquired immediately post-injection, and dCIT images were taken 120 min later. With Brightonix software, automated quantification of SBRs for dCIT and SUVRs for eCIT were acquired from visually normal scans. The effects of aging and gender were assessed by regressing SBRs and SUVRs on age for both genders. The correlations between SUVRs and SBRs were evaluated. Results: We studied 79 subjects (34 males and 45 females). An age-related reduction in SBRs was observed in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for both genders. SUVRs were found to negatively correlate with age in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for males and in the dorsal striatum and caudate nucleus for females. Positive correlations between SBRs and SUVRs in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for male and in the dorsal striatum, caudate nucleus, and putamen for females. Conclusions: Using quantified values from dual-phase 18F-FP-CIT PET with a single injection, we demonstrate a negative impact of age on SBRs (DAT binding) in the striatum for both genders and SUVRs (cerebral perfusion) in the dorsal striatum and caudate nucleus for both genders and in the ventral striatum and putamen for males. Additionally, we found positive associations between SBR and SUVR values in the dorsal striatum, caudate nucleus, and putamen for both genders and in the ventral striatum for males. [ABSTRACT FROM AUTHOR]

Vertical gaze palsy, a neurological impairment affecting the upward and downward movement of the eyes, can be caused by various disorders. Understanding this phenomenon is essential for accurate diagnosis and effective management. This review aims to present a practical overview of vertical gaze palsy, its manifestation in various movement disorders, and the clinical relevance of such impairments. We did a thorough non-systematic search of the literature in PubMed with various keywords such as ‘gaze palsy’, ‘vertical gaze palsy’, ‘gaze abnormality’, and ‘eye movement disorder’. Vertical gaze palsy can manifest in various disorders such as Parkinson’s disease, atypical Parkinsonian syndromes, Niemann-Pick disease type C, Wilson’s disease, Whipple’s disease, prion disease, and several others. This comprehensive review elucidates the spectrum of movement disorders linked to vertical gaze palsy, exploring the specific ways it manifests and the complexities in diagnosing the condition. The list of movement disorders causing vertical gaze palsy is extremely wide, encompassing neurodegenerative, metabolic, infectious, autoimmune disorders, and intoxication with certain substances and specific medications. The differential diagnosis consists of various etiologies with heterogeneous presentations that may overlap and mimic each other. We hope that this paper will assist practitioners in managing the complex process of diagnosing a patient with vertical gaze palsy. [ABSTRACT FROM AUTHOR]

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a central nervous system calcium deposition disorder with symmetrical basal ganglia calcification. Most PFBC cases are caused by SLC20A2 gene variant. We report a Chinese female patient with PFBC and dopamine-responsive parkinsonism who had motor fluctuations and dyskinesia and recovered effectively after symptomatic medication adjustment. A novel heterozygous missense variant was found by whole-exome sequencing and proven harmful by family validation and genetic analysis. This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment. [ABSTRACT FROM AUTHOR]

Background: Quality of life (QOL) and treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers are important factors to consider when developing treatment strategies. Objective: To investigate factors associated with QOL in patients with DLB, and to examine factors associated with activities of daily living (ADL) if ADL was associated with QOL. Methods: We previously conducted a questionnaire survey study to investigate the treatment needs of patients with DLB and their caregivers. This pre-specified additional analysis evaluated the Physical Component Score (PCS) and Mental Component Score (MCS) of the Short Form-8 for QOL, and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II total score for ADL. Results: In total, 231 patient– caregiver pairs and 38 physicians were included. Multivariable analysis of QOL showed that the MDS-UPDRS Part II total score (standard regression coefficient [β], – 0.432) was associated with the PCS, and presence of depression (β, – 0.330) was associated with the MCS. The severity of postural instability/gait disorder (PIGD) (β, 0.337) and rigidity (β, 0.266), presence of hallucinations (β, 0.165), male sex (β, 0.157), and use of "short stay" or "small-scale, multifunctional home care" (β, 0.156) were associated with worsened ADL. Conclusions: In patients with DLB, QOL was negatively impacted by severity of ADL disability and depression, and ADL was negatively impacted by severity of PIGD and rigidity, hallucinations, male sex, and use of "short stay" or "small-scale, multifunctional home care." [ABSTRACT FROM AUTHOR]

Cysteamine hydrochloride (Cys-HCl) has been established as a potent ulcerogenic agent of the gastrointestinal (GI) system. GI dysfunction and olfactory deficits are the most common clinical symptoms of many movement disorders, including Parkinson's disease (PD). Cys-HCl has been shown to interfere with dopamine, a neurotransmitter crucial for motor, olfactory, and cognitive functions. However, the reports on the effect of Cys-HCl treatment on the behavioral aspects and functions of the dopamine system appear to be inconsistent. Therefore, we revisited the impact of Cys-HCl on the motor function in experimental mice using a battery of behavioral tests, such as the pole test (PT), beam-walking test (BWT), and rotarod test (RDT), while the olfactory ability and cognitive functions were examined through the buried-food test (BFT) and Y-maze test. Furthermore, we investigated the effect of Cys-HCl on the number of dopaminergic tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and olfactory bulb (OB) of the experimental mice using immunohistochemistry. The results revealed that Cys-HCl administration in the mice induced significant impairments in their motor balance and coordination, as their movement-related performances were markedly reduced in terms of the behavioral tasks. Mice exposed to Cys-HCl showed pronounced reductions in their odor discrimination abilities as well as cognitive impairments. Strikingly, the number of TH-positive neurons was found to be reduced in the SN and OB of the Cys-HCl-treated group, which is a bonafide neuropathogenic hallmark of PD. This study highlights the potential neurotoxic effects of Cys-HCl in experimental brains and suggests further investigation into its role in the pathogenesis of Parkinsonism. [ABSTRACT FROM AUTHOR]

AbstractLoss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. Methods: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). Results: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. Conclusions: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD. [ABSTRACT FROM AUTHOR]

Background: Subacute sclerosing panencephalitis (SSPE) is a complication of measles, occurring after a latency of 4–10 years. It continues to occur in developing countries although resurgence is being reported from developed countries. Characteristic features include progressive neuropsychiatric issues, myoclonus, seizures, movement disorders and visual impairment. Electroencephalography (EEG) typically shows periodic generalized discharges, and elevated CSF anti‐measles antibodies are diagnostic. Movement disorders are being increasingly recognized as part of the clinical spectrum, and range from hyperkinetic (chorea, dystonia, tremor, tics) to hypokinetic (parkinsonism) disorders and ataxia. Objectives: This article aims to comprehensively review the spectrum of movement disorders associated with SSPE. Methods: A literature search was conducted in PubMed and EMBASE databases in December 2023 and articles were identified for review. Results: Movement disorders reported in SSPE included hyperkinetic (chorea, dystonia, tremor and tics), hypokinetic (parkinsonism), ataxia and extraocular movement disorders. Myoclonus, a core clinical feature, was the most frequent "abnormal movement." Movement disorders were observed in all clinical stages, and could also be a presenting feature, even sans myoclonus. Hyperkinetic movement disorders were more common than hypokinetic movement disorders. An evolution of movement disorders was observed, with ataxia, chorea and dystonia occurring earlier, and parkinsonism later in the disease. Neuroradiological correlates of movement disorders remained unclear. Conclusion: A wide spectrum of movement disorders was observed throughout the clinical stages of SSPE. Most data were derived from case reports and small case series. Multicentric longitudinal studies are required to better delineate the spectrum and evolution of movement disorders in SSPE. [ABSTRACT FROM AUTHOR]

Citrus trifoliate fruit (also known as Trifoliate orange) is one of the commercially-cultivated Citrus genus of plants belonging to the Rutaceae family. It has been traditionally-utilized in treatment of neurodegenerative disorders. However, the scientific evidence verifying this utilization needs further elucidation. Characterization of the bioactive constituents of C. trifoliata L. fruits extract and evaluating its effect on Parkinson's disease (PD) model. Rats were classified into 5 groups; control, PD, PD-treated by L-dopa/Carpidopa and PD-treated by oral Citrus trifoliata L. fruits extract (50 and 100 mg/kg). Deterioration in brain functions was evaluated through an in vivo open field, grid and catalepsy tests. The study also assessed the striatal neurotransmitters, oxidative stress markers and histopathological changes. Citrus trifoliata L. fruit extract has revealed motor improvement comparable to L-dopa and carbidopa. It has also effectively-improved oxidative stress via reduction of striatal malondialdehyde & nitric oxide along with replenishment of the striatal glutathione and superoxide dismutase. The extract caused significant reduction of the striatal myeloperoxidase activity and restoration of dopamine, γ-amino butyric acid (GABA), and acetylcholinesterase. This effect was further confirmed by amelioration of neuronal apoptosis, microgliosis and peri-neuronal vacuolation. Metabolite profiling revealed 40 constituents, with flavonoids representing the main identified class. The neuro-protective effect of Citrus trifoliata extract was achieved through the antioxidant and anti-inflammatory activities of its flavonoids, particularly hesperidin and naringin. This neuro-protective effect was evident at the behavioral, histological and neurotransmitter levels. [ABSTRACT FROM AUTHOR]

Introduction: The PRIME-NL study prospectively evaluates a new integrated and personalized care model for people with parkinsonism, including Parkinson's disease, in a selected region (PRIME) in the Netherlands. We address the generalizability and sources of selection and confounding bias of the PRIME-NL study by examining baseline and 1-year compliance data. Methods: First, we assessed regional baseline differences between the PRIME and the usual care (UC) region using healthcare claims data of almost all people with Parkinson's disease in the Netherlands (the source population). Second, we compared our questionnaire sample to the source population to determine generalizability. Third, we investigated sources of bias by comparing the PRIME and UC questionnaire sample on baseline characteristics and 1-year compliance. Results: Baseline characteristics were similar in the PRIME (n = 1430) and UC (n = 26,250) source populations. The combined questionnaire sample (n = 920) was somewhat younger and had a slightly longer disease duration than the combined source population. Compared to the questionnaire sample in the PRIME region, the UC questionnaire sample was slightly younger, had better cognition, had a longer disease duration, had a higher educational attainment and consumed more alcohol. 1-year compliance of the questionnaire sample was higher in the UC region (96%) than in the PRIME region (92%). Conclusion: The generalizability of the PRIME-NL study seems to be good, yet we found evidence of some selection bias. This selection bias necessitates the use of advanced statistical methods for the final evaluation of PRIME-NL, such as inverse probability weighting or propensity score matching. The PRIME-NL study provides a unique window into the validity of a large-scale care evaluation for people with a chronic disease, in this case parkinsonism. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders are mainly concerned with the behavioural, emotional and cognition symptoms that may be due to disturbed cerebral functions or extracerebral disease. Klotho protein is an antiaging protein that is mostly associated with cognitive changes in these disorders and thus this meta-analysis is conducted in order to find Klotho proteins association with these disorders. We searched related topics in pubmed, by using the key word i.e. Klotho and related disorder from neuropsychiatry e.g. Klotho levels and schizophrenia, Klotho levels and parkinsonism etc. Total 82 studies were found till 9th February 2021 after extensive search and 10 studies were selected for further analysis. The meta-analysis of studies was performed using the Random effect model. The forest plot represented each study in the meta-analysis, so as to make the comparison of SMD value across studies. The meta-analysis outcome demonstrated that overall schizophrenia had higher klotho levels as compared with bipolar disorder, psychosocial stress, parkinsonism, multiple sclerosis, depression, Alzheimer's disease, and healthy controls, followed by MS. The meta-analysis also found that bipolar disorder and Alzheimer's disease were associated with low klotho levels as compared to schizophrenia. The results indicate a significant association of the klotho levels and schizophrenia. Further studies are needed to characterize the potential biological roles of klotho levels in psychiatric disorders. [ABSTRACT FROM AUTHOR]

Objective To identify the characteristics of nutritional problems in patients with Parkinsonism who participated in multi-disciplinary team (MDT) and to investigate the correlation between nutritional status and dysphagia in these patients. The predictive value of video fluoroscopic swallowing study (VFSS) and EAT-10 scale for malnutrition was compared. Methods Subjects were patients with Parkinsonism participated in joint MDT consultation project in Peking Union Medical College Hospital from November 2020 to January 2023. Subjective and objective dysphagia were evaluated by EAT-10 scale score and VFSS dysphagia score. Nutritional status of the patients was evaluated by geriatric nutrition risk index (GNRI), albumin, prealbumin, serum folic acid, vitamin B12 and temporal muscle thickness. Results A total of 30 participants met the criteria and were included in the study. The age was 45-82 (66.1±9.0) years old. Six (20%) were at risk of malnutrition shown b a comprehensive nutritional status assessment using GNRI. The areas under receiver operating characteristic(ROC) curves(AUC) of VFSS dysphagia score and EAT-10 score to predict malnutrition were 0.781 (0.568-0.995) and 0.927 (0.827-1.000), respectively. EAT-10 score was correlated with GNRI(r=-0.524, P＜0.01), BMI(r=-0.618, P＜0.001), prealbumin (r=-0.616, P＜0.001). The VFSS dysphagia score was only correlated with BMI (r=-0.446, P＜0.05) and prealbumin(r=-0.387, P＜0.05). Conclusions Patients with Parkinsonism requiring MDT often have multiple micronutrient imbalance. Patients′ subjective perception of dysphagia has a greater impact on their nutritional status than objective assessment of dysphagia.

Abstract Background Parkinson disease (PD) is one of the disabling neurological disorders. The etiology of Parkinson disease is still unknown. Hepatitis C virus is one of the neurotropic viruses which is incriminated in the pathogenesis of Parkinson disease. Hepatitis C virus might affect the dopaminergic neurons, affecting the advancement of PD. Methods This study is observational, cross-sectional study done on 2 phases: one phase on PD patients without history of HCV and another phase on HCV patients with no history of PD. 104 PD patient were tested for HCV antibodies and 40 HCV patients with various grades of liver fibrosis were assessed for early pre-motor symptoms of parkinsonism. Results Among patients with parkinsonism, HCV Abs testing was negative in all the studied patients. On the other hand, chronic HCV group included 40 patients, 27.5% were cirrhotic (11/40). Child C patients showed significantly higher percentages of non-motor parkinsonian symptoms, and regarding the HCV group, the majority (85%) of the patients show cognitive impairment, (27.5%) were at stage 1 of anxious mood, while half (50%) of the patients were at stage 1 of fatigue as evaluated by UPDRS Score. Cirrhosis was a significant factor for having non-motor (early) parkinsonism. Conclusion Here we show that advanced cirrhosis is associated with a variety of neurological symptoms including parkinsonian, which needs awareness for better preventive and therapeutic measures for early treatment of hepatitis avoiding the occurrence of cirrhosis, which can lead to parkinsonism.

Abstract Background An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants. Objective To describe which methodological adjustments were made to the study protocol because of these developments. Methods We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan. Discussion This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.

Aim: Neurological manifestations are common in patients with chronic liver diseases. This study aimed to depict the association between liver cirrhosis and Parkinson’s disease (PD) and propose a clinically relevant diagnostic scheme. Methods: We examined patients’ medical records with PD and chronic liver impairment secondary to cirrhosis or liver metastases for temporal correlations between liver insult and Parkinsonian signs. Results: Thirty-five individuals with PD and chronic liver impairment were included due to either cirrhosis or liver metastases. In all 22 patients with PD and liver metastases, the diagnosis of PD preceded the diagnosis of cancer. Conversely, patients with cirrhosis were often diagnosed with liver impairment before diagnosing PD. Age at diagnosis did not account for this difference. Conclusions: This study reinforces the potential clinical association between cirrhosis and PD. We also provide a diagnostic scheme that may guide therapeutic interventions and prognostic assessments.

Abstract Background Dual-phase fluorine-18 labeled N-3-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET) scans could be used to support disorders like Parkinson’s disease (PD). Dopamine transporter (DAT) binding and cerebral perfusion are associated with ageing and gender. We investigated the effects of age and gender on non-degenerative parkinsonism, using automated quantification in striatum: specific binding ratios (SBRs) for DAT binding in delayed phase PET (dCIT) and standardized-uptake-value ratios (SUVRs) for cerebral perfusion in early phase PET (eCIT). We also examined the correlations between SBR and SUVR. Methods This retrospective study analyzed subjects with dual-phase 18F-FP-CIT PET scans. The eCIT images were acquired immediately post-injection, and dCIT images were taken 120 min later. With Brightonix software, automated quantification of SBRs for dCIT and SUVRs for eCIT were acquired from visually normal scans. The effects of aging and gender were assessed by regressing SBRs and SUVRs on age for both genders. The correlations between SUVRs and SBRs were evaluated. Results We studied 79 subjects (34 males and 45 females). An age-related reduction in SBRs was observed in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for both genders. SUVRs were found to negatively correlate with age in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for males and in the dorsal striatum and caudate nucleus for females. Positive correlations between SBRs and SUVRs in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for male and in the dorsal striatum, caudate nucleus, and putamen for females. Conclusions Using quantified values from dual-phase 18F-FP-CIT PET with a single injection, we demonstrate a negative impact of age on SBRs (DAT binding) in the striatum for both genders and SUVRs (cerebral perfusion) in the dorsal striatum and caudate nucleus for both genders and in the ventral striatum and putamen for males. Additionally, we found positive associations between SBR and SUVR values in the dorsal striatum, caudate nucleus, and putamen for both genders and in the ventral striatum for males.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Death of dopaminergic cells in the SNpc leads to manifestations of motor dysfunction and non-motor symptoms of PD. The progression of PD symptoms severely affects the quality of life of patients and poses socio-economic problems to families and society at large. The clinical and neuropathological characteristics of PD are triggered by multiple factors such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation. Notwithstanding the advancements in pharmacological therapy in PD management, there is burgeoning interest in alternative and complementary approaches, essentially nutrition and plant extracts strategies. This review gives widespread analysis of the role of nutrition and plant extracts in the management of PD. Studies that investigated the effects of various dietary compounds and plant extract on PD symptoms and progression were reviewed from existing literatures. Nutraceuticals, including vitamins and phytochemicals such as Mucuna pruriens have shown potential neuroprotective functions in preclinical and clinical studies. Indeed, these strategies ameliorate mitochondrial dysfunction, oxidative stress, and neuroinflammation, all which are implicated in the pathogenesis of PD. The neuroprotective mechanisms of nutrition and plant extracts in PD, with emphasis on their capacity to target multiple pathways implicated in PD are discussed. Additionally, challenges and limitations related with translating preclinical findings into clinical practice including standardization of dosing regimens, bioavailability, and inter-individual variability are discussed. Largely, this review elucidates on the role of nutrition and plant extracts as adjunctive therapy in PD management.