Earworms-A Narrative Review of Infectious Music.

This Arts and Medicine feature reviews the clinical and neurophysiologic features of earworms, music fragments heard in the mind that repeat over and over as if jammed in playback mode.

Visual hallucinations.

Visual hallucinations have intrigued neurologists and physicians for generations due to patients' vivid and fascinating descriptions. They are most commonly associated with Parkinson's disease and dementia with Lewy bodies, but also occur in people with visual loss, where they are known as Charles Bonnet syndrome. More rarely, they can develop in other neurological conditions, such as thalamic or midbrain lesions, when they are known as peduncular hallucinosis. This review considers the mechanisms underlying visual hallucinations across diagnoses, including visual loss, network dysfunction across the brain and changes in neurotransmitters. We propose a framework to explain why visual hallucinations occur most commonly in Parkinson's disease and dementia with Lewy bodies, and discuss treatment approaches to visual hallucinations in these conditions.

The motor prodromes of parkinson's disease: from bedside observation to large-scale application.

There is sufficient evidence that the pathological process that causes Parkinson's disease begins years before the clinical diagnosis is made. Over the last 15 years, there has been much interest in the existence of a prodrome in some patients, with a particular focus on non-motor symptoms such as reduced sense of smell, REM-sleep disorder, depression, and constipation. Given that the diagnostic criteria for Parkinson's disease depends on the presence of bradykinesia, it is somewhat surprising that there has been much less research into the possibility of subtle motor dysfunction as a pre-diagnostic pointer. This review will focus on early motor features and provide some advice on how to detect and measure them.

Listening with intent.

Know how to listen and you will profit even from those who talk badly. Plutarch Listening in medicine is only of value when it is combined with an ability to decipher the patient's utterances and gestures and act upon them.

Noticing in neurology.

There are three classes of people: those who see, those who see when they are shown, those who do not see Leonardo da Vinci The three cardinal qualities necessary for the ideal neurologist are observation, the ability to reason backwards inferentially and specialist knowledge. Modern medical technology has greatly increased the ability to diagnose and treat disease but it has also encouraged a benign variant of abulia, which is killing off the art and science of clinical reasoning. Intent gazing at the unfamiliar with old eyes or a long look at the familiar with new eyes offers the neurologist an opportunity to discover hitherto unnoticed diagnostic signs far beyond the resolution of the brain scanner and even the light microscope. While there may be nothing new under the sun, there are plenty of old things that no one has observed, which have the potential to greatly improve clinical practice.

James Parkinson's Chimera: syndrome or disease?

It is 200 years since James Parkinson published An Essay on the Shaking Palsy. While his monograph continues to be acclaimed for its precedence and clarity of description, what is often overlooked is the originality of Parkinson's ideas. Here we show that he appreciated the weakness of the systematic 18th century nosologies, which presupposed that medical species, the building blocks of these Linnaean taxonomic schemes, were as distinct as plant and animal species; and that Parkinson made a conceptual leap about combinations of clinical phenomena in recurring patterns, now recognised to be one of the germs of neurological thinking about syndromes. The Essay's written style underpins another aspect of significance to contemporary neurological practice - an inherent intellectual humility. In this commemorative year we locate the continuing importance of the related notions of syndrome and disease in successive frameworks of knowledge about the shaking palsy. Syndrome and disease are interpreted as dual character concepts, one clinically-based and the other restricted to pathophysiological causation. They both remain fundamental to understanding Parkinson's syndrome-disease today.

Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics.

INTRODUCTION: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive. OBJECTIVES: To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls. METHODS: CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set. RESULTS: 79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism. CONCLUSION: Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism.

9.4 T MR microscopy of the substantia nigra with pathological validation in controls and disease.

BACKGROUND: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy. METHODS: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. RESULTS: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy. CONCLUSIONS: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction.

Analysis of a distinct speech disorder seen in chronic manganese toxicity following Ephedrone abuse.

INTRODUCTION: In the last fifteen years a new cause of chronic manganese toxicity has been recognized. It follows recreational intravenous injections of Ephedrone, synthesized from a cold remedies contained pseudoephedrine. Potassium permanganate is used as an oxidant. It presents with severe parkinsonism-dystonia and a characteristic dysarthria. OBJECTIVES: We performed a focus perceptual study of dysarthria in Ephedrone induced parkinsonism and compared the findings with the speech disorders seen in Parkinson's disease (PD) and Progressive Supranuclear Palsy (PSP). METHODS: A digital voice recording, perceptual speech analysis (Darley, 1975) [18], serial neurological assessment and Brain Magnetic Resonance (MR) imaging were performed at the Lviv regional Clinical Hospital. The results were analysed at the Institute of Neurology in London. RESULTS: Dysarthria developed after 8.5±3.2months of daily intravenous Ephedrone abuse and was an initial symptom in a third of cases. It was characterised by a robotic-flat prosody, whispering or continuous phonation, an inability to regulate pitch and volume, frozen lip articulation, a variable degree of dystonic tightness, difficulties in speech initiation and palladia, There was no nasality and swallowing was normal. In some patients speech deteriorated even after the discontinuation of Ephedrone. MR imaging, performed soon after drug cessation showed T1 signal hyperintesity in striatum and pallidum, especially in the Globus Pallidum interna. CONCLUSION: Ephedrone induced chronic manganese toxicity can lead to a mixed hypokinetic-dystonic dysarthria with a distinct dystonic pattern. Perceptual speech analysis can be a helpful ancillary investigation in the differential diagnosis of parkinsonism, and may permit the recognition of chronic manganese toxicity.

Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-ß hydroxysteroid dehydrogenase type 10.

Mutations of the PARK2 and PINK1 genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson's disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-ß hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas PARK2 downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with PARK2 mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing PARK2 mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fission-promiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated HSD17B10 silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD.

A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes.

BACKGROUND: Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). OBJECTIVE: To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. METHODS: A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), ß-amyloid 1-42 (Aß42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and ß (soluble amyloid precursor protein (sAPP)α, sAPPß) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. RESULTS: CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. CONCLUSIONS: A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.

Neuropathological features of multiple system atrophy with cognitive impairment.

Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific α-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted.