Small Particles, Big Potential: Polymeric Nanoparticles for Drug Delivery in Parkinson's Disease.

Despite the availability of a number of efficacious treatments for Parkinson's disease, their limitations and drawbacks, particularly related to low brain bioavailability and associated side effects, emphasize the need for alternative and more effective therapeutic approaches. Nanomedicine, the application of nanotechnology in medicine, has received considerable interest in recent years as a method of effectively delivering potentially therapeutic molecules to the brain. In particular, polymeric nanoparticles, constructed from biodegradable polymer, have shown great promise in enhancing therapeutic efficacy, reducing toxicity, and ensuring targeted delivery. However, their clinical translation remains a considerable challenge. This article reviews recent in vitro and in vivo studies using polymeric nanoparticles as drug and gene delivery systems for Parkinson's disease with their challenges and future directions. We are also particularly interested in the technical properties, mechanism, drugs release patterns, and delivery strategies to overcome the blood-brain barrier. © 2024 International Parkinson and Movement Disorder Society.

Clinical Diagnostic Accuracy of Parkinson's Disease: Where Do We Stand?

BACKGROUND: Clinical diagnostic accuracy of Parkinson's disease (PD) remains suboptimal. Changes in disease concept may have improved clinical diagnostic accuracy in the past decade. However, current clinical diagnostic criteria have not been validated against neuropathological confirmation. OBJECTIVES: This study aims to provide up-to-date clinical diagnostic accuracy data and validate current clinical diagnostic criteria for PD against neuropathology. METHODS: A retrospective review of medical records of consecutive patients with parkinsonism from the Queen Square Brain Bank was performed between 2009 and 2019. Clinical diagnosis was documented at early (within 5 years of motor symptom onset) and final stages and categorized by movement disorder experts or regular clinicians. Movement Disorder Society Parkinson's disease (MDS-PD) diagnostic criteria were retrospectively applied. Diagnostic accuracy parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as the gold standard. RESULTS: A total of 267 patients (141 PD and 126 non-PD parkinsonism) were included. Clinical diagnostic accuracy was 97.2% for experts, 92.5% for the MDS clinically probable PD criteria, and 90.3% for clinicians. Similar figures were obtained when applied at an early stage (91.5%, 89.5%, and 84.2% diagnostic accuracy, respectively). MDS clinically established early PD criteria demonstrated very high specificity (98.4%) at early stages. CONCLUSIONS: Our results showed an important improvement in PD clinical diagnostic accuracy in clinical practice over the past decade, more marked at early stages of the disease. MDS-PD diagnostic criteria is a valid tool in clinical practice and research for the identification of PD patients showing excellent sensitivity and specificity, although movement disorder experts' diagnosis remains the gold standard PD diagnosis during life. © 2023 International Parkinson and Movement Disorder Society.

Pathological Validation of the MDS Criteria for the Diagnosis of Multiple System Atrophy.

BACKGROUND: The recent International Parkinson and Movement Disorder Society diagnostic criteria for multiple system atrophy (MDS-MSA) have been developed to improve diagnostic accuracy although their diagnostic properties have not been evaluated. OBJECTIVES: The aims were to validate the MDS-MSA diagnostic criteria against neuropathological diagnosis and compare their diagnostic performance to previous criteria and diagnosis in clinical practice. METHODS: Consecutive patients with sporadic, progressive, adult-onset parkinsonism, or cerebellar ataxia from the Queen Square Brain Bank between 2009 and 2019 were selected and divided based on neuropathological diagnosis into MSA and non-MSA. Medical records were systematically reviewed, and clinical diagnosis was documented by retrospectively applying the MDS-MSA criteria, second consensus criteria, and diagnosis according to treating clinicians at early (within 3 years of symptom onset) and final stages. Diagnostic parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as gold standard and compared between different criteria. RESULTS: Three hundred eighteen patients (103 MSA and 215 non-MSA) were included, comprising 248 patients with parkinsonism and 70 with cerebellar ataxia. Clinically probable MDS-MSA showed excellent sensitivity (95.1%), specificity (94.0%), and accuracy (94.3%), although their sensitivity at early stages was modest (62.1%). Clinically probable MDS-MSA outperformed diagnosis by clinicians and by second consensus criteria. Clinically established MDS-MSA showed perfect specificity (100%) even at early stages although to the detriment of low sensitivity. MDS-MSA diagnostic accuracy did not differ according to clinical presentation (ataxia vs. parkinsonism). CONCLUSIONS: MDS-MSA criteria demonstrated excellent diagnostic performance against neuropathological diagnosis and are useful diagnostic tools for clinical practice and research. © 2023 International Parkinson and Movement Disorder Society.

We Move or Are We Moved? Unpicking the Origins of Voluntary Movements to Better Understand Semivoluntary Movements.

The capacity for voluntary control is seen as essential to human movements; the sense that one intended to move (willing) and those actions were self-generated (self-agency) gives the sense of voluntariness and of being in control. While the mechanisms underlying voluntary movement have long been unclear, recent neuroscientific tools have identified networks of different brain areas, namely, the prefrontal cortex, supplementary motor area, and parietal cortex, that underlie voluntary action. Dysfunction in these brain areas can result in different forms of semivoluntary movement as the borderland of voluntary and involuntary movement where a person may experience a disordered sense of will or agency, and thus the movement is experienced as unexpected and involuntary, for an otherwise voluntary-appearing movement. Tics, functional movement disorders, stereotypies, perseveration, compulsions, utilization behaviors, and motor mannerism have been described elsewhere in the context of psychoses, and are often mistaken for each other. Yet, they reflect an impairment of prefrontal cortices and related circuits rather than simple motor systems, which results in the absence of subjective recognition of the movements, in contrast to other neurological movement disorders where principal abnormalities are located within the basal ganglia and its connections. Therefore, their recognition is clinically important since they are usually associated with neurodevelopmental and neurodegenerative disorders. In this review, we first defined a conceptual framework, from both a neuroanatomical and a neurophysiological point of view, for the generation of voluntary movement. We then examined the evidence linking dysfunctions in different motor pathways to each type of movement disorder. We looked at common semivoluntary movement disorders providing an overview, where possible, of their phenomenology and brain network abnormalities for each condition. We also emphasized important clinical feature similarities and differences to increase recognition of each condition in practice.

Profiling the most elderly parkinson's disease patients: Does age or disease duration matter?

BACKGROUND: Despite our ageing populations, elderly patients are underrepresented in clinical research, and ageing research is often separate from that of Parkinson's disease (PD). To our knowledge, no previous study has focused on the most elderly ('old-old', age ≥ 85 years) patients with PD to reveal how age directly influences PD clinical progression. OBJECTIVE: We compared the clinical characteristics and pharmacological profiles, including complications of levodopa treatment, disease progression, disabilities, and comorbidities of the old-old with those of comparable younger ('young-old', age 60-75 years) PD patients. In addition, within the old-old group, we compared those with a short disease duration (< 10 years at the time of diagnosis) to those with a long disease duration ≥10 years to investigate whether prognosis was related to disease progression or aging. METHODS: This single-centre, case-control study compared 60 old-old to 92 young-old PD patients, matched for disease duration. Patients in the old-old group were also divided equally (30:30) into two subgroups (short and long disease duration) with the same mean age. We compared the groups based on several clinical measures using a conditional logistic regression. RESULTS: By study design, there were no differences between age groups when comparing disease duration, however, the proportion of men decreased with age (p = 0.002). At a comparable length of PD duration of 10 years, the old-old PD patients predominantly had significantly greater postural instability and gait disturbance (p = 0.006), higher motor scope of the Unified Parkinson's Disease Rating Scale (UPDRS-III, p<0.0001), and more advanced Hoehn & Yahr (H&Y) stage (p<0.0001). The Non-Motor Symptoms Questionnaire (NMSQuest) score was also significantly higher among the old-old (p<0.0001) compared to the young-old patients. Moreover, the distribution of NMS also differed between ages, with features of gastrointestinal problems (p<0.0001), urinary problems (p = 0.004), sleep disturbances and fatigue (p = 0.032), and cognitive impairment (p<0.0001) significantly more common in the old-old group, whereas sexual problems (p = 0.012), depression, and anxiety (p = 0.032) were more common in the young-old. No differences were found in visual hallucinations, cerebrovascular disease, and miscellaneous domains. While young-old PD patients received higher levodopa equivalent daily doses (p<0.0001) and developed a significant greater rate of dyskinesia (p = 0.002), no significant difference was observed in the rate of wearing-off (p = 0.378). Old-old patients also had greater disability, as measured by the Schwab and England scale (p<0.0001) and had greater milestone frequency specifically for dementia (p<0.0001), wheelchair placement (p<0.0001), nursing home placement (p = 0.019), and hospitalisation in the past 1 year (p = 0.05). Neither recurrent falls (p = 0.443) nor visual hallucinations (p = 0.607) were documented significantly more often in the old-old patients. CONCLUSIONS: Age and disease duration were independently associated with clinical presentation, course, and progression of PD. Age was the main predictor, but disease duration also had a strong effect, suggesting that factors of the ageing process beyond the disease process itself cause PD in the most elderly to be more severe.

COVID-19: An Early Review of Its Global Impact and Considerations for Parkinson's Disease Patient Care.

While many infectious disorders are unknown to most neurologists, COVID-19 is very different. It has impacted neurologists and other health care workers, not only in our professional lives but also through the fear and panic within our own families, colleagues, patients and their families, and even in the wider public. COVID-19 affects all sorts of individuals, but the elderly with underlying chronic conditions are particularly at risk of severe disease, or even death. Parkinson's disease (PD) shares a common profile as an age-dependent degenerative disorder, frequently associated with comorbidities, particularly cardiovascular diseases, so PD patients will almost certainly fall into the high-risk group. Therefore, the aim of this review is to explore the risk of COVID-19 in PD based on the susceptibility to severe disease, its impact on PD disease severity, potential long-term sequelae, and difficulties of PD management during this outbreak, where neurologists face various challenges on how we can maintain effective care for PD patients without exposing them, or ourselves, to the risk of infection. It is less than six months since the identification of the original COVID-19 case on New Year's Eve 2019, so it is still too early to fully understand the natural history of COVID-19 and the evidence on COVID-19-related PD is scant. Though the possibilities presented are speculative, they are theory-based, and supported by prior evidence from other neurotrophic viruses closely related to SARS-CoV-2. Neurologists should be on high alert and vigilant for potential acute and chronic complications when encountering PD patients who are suspected of having COVID-19.

Concurrence of Myasthenia Gravis and Thyroid Disorders: A Retrospective Database Study.

INTRODUCTION: Both myasthenia gravis (MG) and autoimmune thyroid diseases (AITDs) are autoimmune diseases. Graves'disease (GD) is the most common AITD reported to be associated with MG. Currently, there is limited data on prevalence and clinical features/outcomes of MG in various thyroid diseases in a large database report. METHODOLOGY: A total of 872 patients with MG and 97,251 patients with thyroid disorders had been recorded by the tertiary hospital database. The study period was between 1997 and 2017. Patients with a thyroid disorder and MG were identified by the ICD-10-CM code. Clinical courses of MG accompanied by thyroid disorders were studied. RESULTS: During the 20-year study period, there were 872 patients with MG and 97,251 patients with thyroid disorders. In the group with thyroid disorders, 28,886 patients (29.70%) had GD, 1,612 patients (1.66%) had Hashimoto's thyroiditis (HT), 13,172 patients (13.54%) had toxic goiter and 53,581 patients (55.10%) had nontoxic goiter. Ninety-seven patients had been diagnosed with both MG and thyroid disorders. Among the four types of thyroid disorders, the rate of MG was highest in HT group (9.92/1,000 HT patients). There were four significant factors among four groups of thyroid disorders including age of onset of thyroid disease (p 0.004), MG classification (p<0.001), MG treatment (p<0.001), and thymic pathology (p 0.034). Among the four groups of thyroid disorders, patients with MG and HT were diagnosed with thyroid disease at the youngest age (27 years) compared with other thyroid diseases. Additionally, the MG patients with HT also had the highest proportion of MG class 4-5 a/b (7 patients, 43.75%), received prednisolone treatment (15 patients, 93.75%), received immunosuppressants (9 patients, 56.25%), received IVIG or PLEX (5 patients, 31.30%), and had thymoma (6 patients, 46.15%). CONCLUSION: MG is most prevalent in patients with HT. Patients with both MG and HT had more severe MG status and had higher rate of thymoma.