The α-synuclein seed amplification assay: Interpreting a test of Parkinson's pathology.

The α-synuclein seed amplification assay (αSyn-SAA) sensitively detects Lewy pathology, the amyloid state of α-synuclein, in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD). The αSyn-SAA harnesses the physics of seeding, whereby a superconcentrated solution of recombinant α-synuclein lowers the thermodynamic threshold (nucleation barrier) for aggregated α-synuclein to act as a nucleation catalyst ("seed") to trigger the precipitation (nucleation) of monomeric α-synuclein into pathology. This laboratory setup increases the signal for identifying a catalyst if one is present in the tissue examined.

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.

Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy-Confirmed Cohort.

Background And Objectives: Nonmotor features precede motor symptoms in many patients with multiple system atrophy (MSA). However, little is known about differences between the natural history, progression, and prognostic factors for survival in patients with MSA with nonmotor vs motor presentations. We aimed to compare initial symptoms, disease progression, and clinical features at final evaluation and investigate differences in survival and natural history between patients with MSA with motor and nonmotor presentations.

Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates.

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics.

"Flâneur neurologique in paris" - A guide to pinpointing the houses of famous neurologists in the late XIX century.

Introduction: During the last quarter of the XIX century, Paris, France, particularly the Salpêtrière Hospital was the most important centre of reference of Clinical Neurology in the world. The group based on the Salpêtrière Hospital, led by Professor Charcot, who was arguably the most celebrated neurologist in Europe.

Objective: In this historical review, we present and locate the addresses of the houses of these famous Parisian neurologists from the late XIX century.

Reflection impulsivity perceptual decision-making in patients with restless legs syndrome.

Objectives: The objective of this study was to investigate perceptual decision-making and reflection impulsivity in drug naïve patients with restless legs syndrome (RLS) and patients with dopaminergic therapy.

Methods: A total of 35 RLS patients (20 who were drug naïve regarding dopaminergic medication and 15 patients treated with dopaminergic therapy without augmentation or impulse control disorders) were included in this study. We used the Beads task and the Pixel task which assess reflection impulsivity and perceptual decision-making, respectively.

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration.

Tau is the most common misfolded protein responsible for human neurodegenerative diseases. The identification of mutations in MAPT, the gene that encodes tau, causing dementia and parkinsonism established the notion that tau aggregation is responsible for the development of disease. An increased understanding of the pathway leading from conformational changes in tau protein and tau propagation to neuronal dysfunction, cell death and clinical manifestation will be the key for the development mechanism-based therapeutic strategies for tauopathies.

Evolving concepts of chronic traumatic encephalopathy as a neuropathological entity.

Chronic traumatic encephalopathy (CTE) is a long-term neurodegenerative consequence of repetitive head impacts which can only be definitively diagnosed in post-mortem. Recently, the consensus neuropathological criteria for the diagnosis of CTE was published requiring the presence of the accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci in an irregular pattern as the mandatory features. The clinical diagnosis and antemortem prediction of CTE pathology remain challenging if not impossible due to the common co-existing underlying neurodegenerative pathologies and the lack of specific clinical pointers and reliable biomarkers.

The relationship between the First World War and neurology: 100 years of "Shell Shock".

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.

Opicapone for the management of end-of-dose motor fluctuations in patients with Parkinson's disease treated with L-DOPA.

Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy.

Haste makes waste: Decision making in patients with restless legs syndrome with and without augmentation.

Objectives: To investigate decision making in patients with primary restless legs syndrome (RLS) with and without augmentation treated with dopaminergic medication.

Methods: A total of 64 non-demented RLS patients treated with dopaminergic medication with and without augmentation were included in this study. We used an information sampling task to assess how much evidence participants gather before making a decision.

Parkinson's disease - 200 years: the outstanding contribution of "Old Hubert".

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.

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players.

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected.

Wilson's disease: the 60th anniversary of Walshe's article on treatment with penicillamine.

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.

Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology.

SEE KOBYLECKI AND MANN DOI101093/AWW267 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Animal models have shown that tau seeding and propagation are strain- and neural network-specific. The study of preclinical cases is valuable to gain insights into early pathological features of corticobasal degeneration and its progression. Three preclinical corticobasal degeneration cases and six age-matched end-stage corticobasal degeneration cases were included in this study.

Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?

Objectives: To assess the frequency of impulse control disorders (ICDs) in patients with restless legs syndrome (RLS) with and without augmentation under dopaminergic therapy in a case-control study. Augmentation and ICDs are both serious complications of dopaminergic treatment of RLS but little is known about possible associations between these drug-induced disorders.

Methods: In total, 58 patients with idiopathic RLS diagnosed according to the International Restless Legs Syndrome Study Group criteria were recruited.

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.

Background: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.

Challenges of modifying disease progression in prediagnostic Parkinson's disease.

Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies-ie, those aimed at delaying or preventing the progression to overt disease and its many complications-could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials.

Jumping to conclusions in untreated patients with Parkinson's disease.

Background: Jumping to conclusions due to impulsivity has been shown to be a sensitive marker for dopamine dysregulation and addictive behaviour patterns in treated patients with Parkinson's disease (PD). It is unknown whether drug naïve PD patients, who have never received dopaminergic therapy also have deficits in information sampling.

Methods: Twenty five de novo PD patients and twenty matched healthy controls were recruited and tested on the beads task, which is a validated information sampling task to assess reflection impulsivity and a temporal discounting questionnaire.

Coenzyme Q10 Levels Are Decreased in the Cerebellum of Multiple-System Atrophy Patients.

Background: The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases.

Methods: Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups.

The prediagnostic phase of Parkinson's disease.

The field of prediagnostic Parkinson's disease (PD) is fast moving with an expanding range of clinical and laboratory biomarkers, and multiple strategies seeking to discover those in the earliest stages or those 'at risk'. It is widely believed that the highest likelihood of securing neuroprotective benefit from drugs will be in these subjects, preceding current point of diagnosis of PD. In this review, we outline current knowledge of the prediagnostic phase of PD, including an up-to-date review of risk factors (genetic and environmental), their relative influence, and clinical features that occur prior to diagnosis.

Clinical Heterogeneity in Cerebral Hemiatrophy Syndromes.

Background: Cerebral hemiatrophy syndromes can present with variable neurological symptoms. In childhood epilepsy, mental retardation and neuropsychiatric disorders are common while in adults movement disorders, such as highly asymmetric parkinsonism or hemidystonia as well as neuropsychiatric problems have been reported.

Methods: Here, we present three adult patients with features that expand the clinical spectrum and give an overview of the most common clinical signs associated with this rare condition.

Mendelian Randomization - the Key to Understanding Aspects of Parkinson's Disease Causation?

Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease.