Limitations of the α-Synuclein Seed Amplification Assay in Clinical Practice: Understanding the Pathological Diversity of Parkinson Syndrome.

This Viewpoint cautions against premature adoption of the α-synuclein seed amplification assay as a biomarker test for Parkinson disease in general neurology practice.

'A divine right to photograph': E. Graeme Robertson's (1903-1975) historical motion pictures of National Hospital staff in 1933.

In the course of researching and writing the first-ever book length biography of Edward Graeme Robertson's (1903-1975) eventful life and career in Australasian neurology, a rare 1933 cinema film recording of National Hospital staff at Queen Square has recently been rediscovered. Graeme completed his residency in neurology at Queen Square in the early 1930s and maintained close connections with his colleagues in London, thoughtfully recording them at different times using early movie cameras. Two versions of Graeme's 1933 film have been preserved, and there are also other color clips of his colleagues from later in life in the UCL Neurology archives and Robertson family collection. These remarkable films contain images of several historically significant neurologists, including Gordon Morgan Holmes (1876-1965), Samuel Alexander Kinnier Wilson (1878-1937), Derek Denny-Brown (1901-1981), Macdonald Critchley (1900-1997), and several others. We provide a contextual summary of the many clips recorded alongside an in-depth inventory of all the personalities represented in the 1933 film. Selected photographs are used to indicate the contents of these remarkable films.

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.

Rapid Voluntary Blinking as a Clinical Marker of Parkinson's Disease.

Reduced spontaneous blinking is a recognized Parkinson's disease (PD) feature. In contrast, voluntary blinking has been less studied and might serve as a measurable marker of facial bradykinesia. We tested 31 PD patients and 31 controls. Participants were filmed during conversation and a rapid blinking task. Both tasks were videorecorded to count the number of blinks per second. PD patients had lower blink rates. Rapid blinking accurately discriminated between groups with 77% sensitivity and 71% specificity. To conclude, rapid blinking may be a simple and quantifiable task of facial bradykinesia.

Decreased blinking without conscious effort is a well-known characteristic of Parkinson's disease (PD). However, voluntary blinking, which is blinking on purpose, has not been studied as much and could be a sign of slower facial movements. We studied a group of people with PD and another one without the disease. We recorded videos of them talking and doing a task where they blinked quickly. Then, we counted how many times they blinked per second in each video. We found that people with PD blinked less often. The rapid blinking task accurately distinguished between those with PD and those without it, being correct about 77% of the time for spotting PD and 71% for spotting non-PD. In conclusion, the rapid blinking task could be a simple and measurable way to identify slower facial movements in PD.

Neuroimaging and plasma evidence of early white matter loss in Parkinson's disease with poor outcomes.

Parkinson's disease is a common and debilitating neurodegenerative disorder, with over half of patients progressing to postural instability, dementia or death within 10 years of diagnosis. However, the onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in underlying pathological processes. Quantitative and sensitive measures predicting poor outcomes will be critical for targeted treatment, but most studies to date have been limited to a single modality or assessed patients with established cognitive impairment. Here, we used multimodal neuroimaging and plasma measures in 98 patients with Parkinson's disease and 28 age-matched controls followed up over 3 years. We examined: grey matter (cortical thickness and subcortical volume), white matter (fibre cross-section, a measure of macrostructure; and fibre density, a measure of microstructure) at whole-brain and tract level; structural and functional connectivity; and plasma levels of neurofilament light chain and phosphorylated tau 181. We evaluated relationships with subsequent poor outcomes, defined as development of mild cognitive impairment, dementia, frailty or death at any time during follow-up, in people with Parkinson's disease. We show that extensive white matter macrostructural changes are already evident at baseline assessment in people with Parkinson's disease who progress to poor outcomes (n = 31): with up to 19% reduction in fibre cross-section in multiple tracts, and a subnetwork of reduced structural connectivity strength, particularly involving connections between right frontoparietal and left frontal, right frontoparietal and left parietal and right temporo-occipital and left parietal modules. In contrast, grey matter volumes and functional connectivity were preserved in people with Parkinson's disease with poor outcomes. Neurofilament light chain, but not phosphorylated tau 181 levels were increased in people with Parkinson's disease with poor outcomes, and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma neurofilament light chain may be useful early markers of poor outcomes in Parkinson's disease. As new targeted treatments for neurodegenerative disease are emerging, these measures show important potential to aid patient selection for treatment and improve stratification for clinical trials.

The Motor Dysfunction Seen in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD). METHODS: A motor battery was designed and compared with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) in people with iRBD and controls. This included two keyboard-based tests (BRadykinesia Akinesia INcoordination tap test and Distal Finger Tapping) and two dual tasking tests (walking and finger tapping). RESULTS: We included 33 iRBD patients and 29 controls. The iRBD group performed both keyboard-based tapping tests more slowly (P < 0.001, P = 0.020) and less rhythmically (P < 0.001, P = 0.006) than controls. Unlike controls, the iRBD group increased their walking duration (P < 0.001) and had a smaller amplitude (P = 0.001) and slower (P = 0.007) finger tapping with dual task. The combination of the most salient motor markers showed 90.3% sensitivity for 89.3% specificity (area under the ROC curve [AUC], 0.94), which was higher than the MDS-UPDRS-III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC, 0.81) for detecting motor dysfunction. CONCLUSION: Speed, rhythm, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease.

These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither pathology type nor distribution correlate with disease severity or progression in Parkinson's disease; (3) aggregated α-synuclein in the form of Lewy bodies is not a space-occupying lesion but the insoluble fraction of its precursor, soluble monomeric α-synuclein; (4) pathology spread is passive, occurring by irreversible nucleation, not active replication; and (5) low cerebrospinal fluid α-synuclein levels predict brain atrophy and clinical disease progression. The transformation of α-synuclein into Lewy pathology may occur as a response to biological, toxic, or infectious stressors whose persistence perpetuates the nucleation process, depleting normal α-synuclein and eventually leading to Parkinson's symptoms from neuronal death. We propose testing the loss-of-function synucleinopenia hypothesis by evaluating the clinical and neurodegenerative rescue effect of replenishing the levels of monomeric α-synuclein.

Medical, surgical, and physical treatments for Parkinson's disease.

Although dopamine replacement therapy remains a core component of Parkinson's disease treatment, the onset of motor fluctuations and dyskinetic movements might require a range of medical and surgical approaches from a multidisciplinary team, and important new approaches in the delivery of dopamine replacement are becoming available. The more challenging, wide range of non-motor symptoms can also have a major impact on the quality of life of a patient with Parkinson's disease, and requires careful multidisciplinary management using evidence-based knowledge, as well as appropriately tailored strategies according to the individual patient's needs. Disease-modifying therapies are urgently needed to prevent the development of the most disabling refractory symptoms, including gait and balance difficulties, cognitive impairment and dementia, and speech and swallowing impairments. In the third paper in this Series, we present the latest evidence supporting the optimal treatment of Parkinson's disease, and describe an expert approach to many aspects of treatment choice where an evidence base is insufficient.

Apomorphine in the treatment of Parkinson's disease: a review / O uso da apomorfina no tratamento da doença de Parkinson: revisão da literatura

ABSTRACT Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.

RESUMO A optimização do tratamento da doença de Parkinson idiopática se faz um desafio, pois tem impacto direto na qualidade de vida do paciente. O melhor esquema terapêutico é o que permite o melhor controle motor com os menores efeitos adversos, através de terapêutica individualizada. A apomorfina é o único medicamento antiparkinsoniano que pode ser comparável à potência da levodopa no controle dos sintomas motores. Trata-se de um agonista dopaminérgico empregado na terapia de resgate em pacientes com flutuações motoras e também contribui para a melhora de muitos sintomas não motores. A via subcutânea, com injeções intermitentes, ou com infusão contínua, parece ser a melhor opção pela eficácia e tolerabilidade. Essa revisão resume aspectos históricos, estrutura da molécula, mecanismo de ação, indicação, contra-indicação e efeitos colaterais, compara a terapia de infusão com apomorfina com outros tratamentos, como a terapia oral, estimulação cerebral profunda e infusão enteral contínua de levodopa/carbidopa gel, e fornece instruções práticas de como iniciar o tratamento.

The relationship between the First World War and neurology: 100 years of "Shell Shock" / A relação entre a Primeira Guerra Mundial e a neurologia: 100 anos do "Shell Shock"

ABSTRACT The First World War was a global war, beginning on 28 July 1914, until 11 November 1918. Soon after the beginning of the war, there was an “epidemic” of neurological conversion symptoms. Soldiers on both sides started to present in large numbers with neurological symptoms, such as dizziness, tremor, paraplegia, tinnitus, amnesia, weakness, headache and mutism of psychosomatic origin. This condition was known as shell shock, or “war neurosis”. Because medically unexplained symptoms remain a major challenge, and considering the close relationship of symptoms described in shell shock with clinical neurology, we should study their history in order to improve future care.

RESUMO A Primeira Guerra Mundial foi uma guerra global, iniciada em 28 de julho de 1914, até 11 de novembro de 1918. Logo após o início da guerra, exatamente há 100 anos, houve uma “epidemia” de sintomas neurológicos conversivos. Soldados de ambos os lados começaram a apresentar com frequência sintomas neurológicos, tais como: tontura, tremor, paraplegia, zumbido, amnésia, fraqueza, cefaleia e mutismo de origem psicossomática. Esta condição ficou conhecida como shell shock, ou “neurose de guerra”. Como muitos sintomas e doenças inexplicadas continuam sendo um grande desafio, e considerando a estreita relação dos sintomas descritos no shell shock com a neurologia clínica, torna-se importante estudar essa parte da história com o objetivo de entendermos e melhorarmos os cuidados aos pacientes.

Georges Simenon, Inspector Maigret and his relevance to the practice of Neurology / Georges Simenon, Inspector Maigret e a sua relevância para a prática da Neurologia

ABSTRACT Georges Simenon’s work, including his famous ‘romans durs’ novels and the forensic investigations carried out by his artistic creation, Inspector Maigret, bear many similarities to some of the diagnostic methods of the founders of Neurology, particularly Jean-Martin Charcot.

RESUMO A obra de Georges Simenon, incluíndo os seus famosos “romances duros”, e as investigações criminais realizadas pela sua criação artística, o comissário Maigret, tem muitas similaridades com alguns métodos diagnósticos utilizados pelos fundadores da Neurologia, particularmente Jean-Martin Charcot.

Parkinson's disease - 200 years: the outstanding contribution of "Old Hubert" / Doença de Parkinson's 200 anos: a notável contribuição do "Velho Humberto"

ABSTRACT Two hundred years after the publication, of “An Essay on the Shaking Palsy”, this indisputable landmark in our understanding of the nature of Parkinson’s disease still remains. What is frequently overlooked, however, is the originality of James Parkinson’s ideas about how clinical observations could be segregated into diagnostic entities. Parkinson was a surgeon apothecary with wide ranging interests outside medicine including geology and paleontology. He was also a strong campaigner for social change and a political pamphleteer, writing under the nom de plume of “Old Hubert”.

RESUMO A publicação de James Parkinson intitulada “An Essay on the Shaking Palsy”, 200 anos atrás, é considerada uma obra prima de fundamental importância científica. James Parkinson foi um cirurgião apotecário com uma ampla faixa de interesses, além da medicina, incluindo geologia e paleontologia. Ele foi também um grande reformador social e panfletário político, que escreveu sob o pseudônimo de “Velho Humberto”.

Wilson's disease: the 60th anniversary of Walshe's article on treatment with penicillamine / Doença de Wilson: o 60° aniversário do artigo de Walshe no tratamento com penicilamina

ABSTRACT This historical review describes Professor Walshe's seminal contribution to the treatment of Wilson's disease on the 60th anniversary of his pioneering article on penicillamine, the first effective treatment for the condition.

RESUMO Esta revisão histórica enfatiza a contribuição seminal do Professor Walshe no tratamento da doença de Wilson (DW), com o seu trabalho pioneiro sobre o uso de penicilamina, o primeiro tratamento efetivo do mundo, publicado 60 anos atrás.

Diagnosing social anxiety in Parkinson's disease: characteristics and frequencies according to two diagnostic criteria

Abstract Background: Studies found inconsistent frequencies of social anxiety disorder (SAD) in Parkinson's disease (PD) (9.7%-50%). Previous reports did not test the impact of applying DSM-IV restrictive criteria that recommends the exclusion of secondary cases when diagnosing SAD in PD. Objective: Our aim is to estimate the frequency of social anxiety according to DSM-IV criteria and according to an inclusive broader approach. Methods: One hundred and ten PD patients were assessed for the presence of SAD using SCID-I, diagnosis of social anxiety were determined according to two different criteria: following and not following DSM-IV recommendation for exclusion of cases though to be secondary to a general medical condition. Results: SAD was present in 34 (31%) of patients, but 17 (15.5%) were secondary to a general medical condition. Patients with SAD were significantly younger, had earlier disease onset, had more severe PD symptoms, and were more frequently depressed. There was no difference in demographic and clinical features between primary and secondary SAD. Discussion: We conclude that the use of different diagnostic criteria may have a massive impact in the estimation of frequency of SAD in PD.

Availability of olfactory bulb: experience from a British Brain Bank / Disponibilidade de bulbos olfatórios em um banco de cérebro britânico: a experiência do Queen Square Brain Bank

The olfactory bulb and tract (OB/OT) are among the earliest structures in the brain to undergo pathological changes in many neurodegenerative conditions. The availability of OB/OT samples from brain specimens in brain banks therefore assumes importance. We collected data from 5 years (2006-2010) regarding the presence or absence of OB/OT material in cases received by the Queen Square Brain Bank (QSBB) for Neurological Disorders, UCL Institute of Neurology, UK, to estimate availability of OB/OT material at the brain bank and also to look for possible associations. Of the 438 cases received, 320 had complete data regarding OB/OT and 29.4% of these had OB/OT in at least one half of the specimen. Unavailability of OB/OT was associated with larger post-mortem delays (p<0.001), suggesting that the delay might render the tissue more friable and hence lead to its loss. Brains from female donors also tended to have a higher availability in our samples.

O bulbo e o trato olfatórios (OB/OT) são algumas das estruturas cerebrais mais sensíveis a neurodegeneração. A disponibilidade deste material para estudos neuropatológicos em bancos de cérebro tem, portanto, grande relevância. Coletamos dados referentes a 5 anos (2006-2010) a respeito da presença ou ausência de OB/OT no Queen Square Brain Bank (QSBB) for Neurological Disorders, parte do UCL Institute of Neurology, Reino Unido, para estimar a disponibildade deste material em um banco de cérebro, e também para estudar fatores que influenciam essa disponibilidade. Dos 438 casos recebidos, encontramos dados referentes a presença ou ausência de OB/OT em 320, dos quais 29,4% possuiam OB/OT em pelo menos um lado. A indisponibilidade de OB/OT foi associada a maior intervalo entre a morte e a autópsia(p<0.001), sugerindo que o atraso pode deixar o material mais friável, levando aperda durante a coleta. Cérebros de doadoras femininas apresentaram maior disponibilidade de OB/OT em nossa amostra.

Applying a new version of the Brazilian-Portuguese UPSIT smell test in Brazil / Aplicando uma nova versão brasileira do UPSIT no Brasil

Standardized olfactory tests are now available to quantitatively assess disorders of olfaction. A Brazilian-Portuguese version of the University of Pennsylvania Smell Identification Test (UPSIT) is currently being developed specifically for the Brazilian population. The most recent Brazilian-Portuguese version of the UPSIT (UPSIT-Br2) was administered to 88 Brazilian subjects who had no history of neurological or otorhinolaryngological disease. UPSIT-Br2 scores decreased with age, were lower in men than in women, and were lower in subjects with lower income. The degree to which the poorer performance of subjects with lower socio-economic status reflects lack of familiarity with test items is not known. Although this version of the UPSIT provides a sensitive and useful test of smell function for the Brazilian population, a revision of some test items is needed to achieve comparable norms to those found using the North American UPSIT in the United States.

Testes padronizados já estão disponíveis para testagem do olfato e uma versão em Português esta sendo desenvolvida para o University of Pennsylvania Smell Identification Test (UPSIT), especificamente para a população brasileira. A versão mais recente deste teste (chamada UPSIT-Br2) foi aplicada a 88 sujeitos brasileiros que não tinham história de qualquer problema neurológico ou otorrinolaringológico. Compatível com dados prévios da literatura, a performance no UPSIT-Br2 decaiu com a idade e foi inferior no genero masculino. Os resultados foram mais baixos em participantes de menor nível sócio-econômico e a relação deste achado com a falta de familiaridade para com os itens do teste não é conhecida. Apesar desta versão do UPSIT poder ser útil para o teste da função olfativa da população brasileira, a revisão de alguns itens se faz necessária para alcançar valores comparáveis aos dados normativos norte-americanos.