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Competing Interests: Competing interests: None declared.

Fifty-five years have passed from the first description of PSP, but it is in the last decade that there has been a revolutionary change in understanding both clinical and pathophysiological aspects of this disease. Ten years ago, our knowledge about the clinical spectrum and pathophysiology of the disease was quite limited, and there was no credible clinical study on any drug treatment for this devastating disease. Today, we have discovered the wide clinical spectrum of PSP, and this led to the development of new diagnostic criteria in 2017, aiming to diagnose the disease earlier and include more phenotypes into clinical studies. Moreover, just over the past 10 years, numerous large, double-blind, clinical trials with disease-modifying agents have been conducted that provided important novel insights into disease biomarkers and progression. These studies were possible because of gained novel insights into pathophysiological processes of the disease and pave the way for the near future. In the next decade, we dare to predict the discovery of biomarkers for PSP, improvements in diagnosis using the new criteria in combination with these biomarkers, and ultimately the development of a neuroprotective therapy that could be applied to patients in a prodromal stage and spare them from this devastating disorder. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Jean-Martin Charcot (1825-1893), recognized as the founder of Neurology and the first formal teacher of nervous system diseases, died on August 16, 1893, from acute pulmonary edema secondary to myocardial infarction. In his last years, there were several descriptions of his gait and posture disorders, suggesting the diagnosis of "lower-half parkinsonism" due to cerebrovascular disease.

Of the multitude of medical and psychiatric conditions ascribed to Hitler both in his lifetime and since his suicide in April 1945, few are more substantiated than parkinsonism. While the timeline of the development of this condition, as well as its etiology, are debated, there is clear evidence for classic manifestations of the disease, most prominently a resting tremor but also stooped posture, bradykinesia, micrographia, and masked facial expressions, with progression steadily seen over his final years. Though ultimately speculation, some have suggested that Hitler suffered from progressive cognitive and mood disturbances, possibly due to parkinsonism, that affected the course of events in the war. Here, the authors discuss Hitler's parkinsonism in the context of the Third Reich and its eventual destruction, maintaining that ultimately his disease had little effect on the end result.

Walther Birkmayer, an Austrian neurologist, codiscovered the efficacy of levodopa therapy for Parkinsonism in 1961. However, little has been published regarding Birkmayer's ties to National Socialism. Through documentary review, we have determined that he was an early illegal member of the SS and the Nazi party, taking part in the "de-Jewification" of the Vienna University Clinic of Psychiatry and Neurology. He also was a leader in the Nazi racial policy office and was praised for his dedication and fanaticism despite being forced to later resign from the SS. He sought support from leading Viennese Nazis, and was able to maintain his professional status for the war's remainder. Postwar, he succeeded at reintegration personally and professionally into Austrian society, all but erasing any obvious ties to his Nazi past. His story reflects ethical transgressions regarding professional and personal behavior in response to a tyrannical regime and provides lessons for today's neuroscientists.

Parkinson disease is a severe degenerative disease, which is bewildering for its array of clinical features. Writers for the past five centuries have described the associated symptoms. Before the nineteenth century, Miguel de Cervantes wrote Don Quixote de la Mancha and William Shakespeare wrote several tragedies dealing with neurological manifestations that are characteristic of Parkinson disease. From the nineteenth century onward, writers including Charles Dickens, Samuel Beckett, Galway Kinnell, and Harold Pinter among others have showcased in their works classic manifestations of Parkinson disease. This literary attention has led to a greater awareness on the part of the general public regarding this disease and, in turn, has opened the doors to a better understanding of and a better respect for the patients affected by this disease., (© 2013 Elsevier B.V. All rights reserved.)

Purpose: Given the recent paper by Jang et al. on "A Highly Pathogenic H5N1 Influenza Virus" which reported a novel animal model of parkinsonism, we aimed to perform a complete historical review of the 20th and 21st century literature on parkinsonism and neurological manifestations of influenza., Scope: There were at least twelve major flu pandemics reported in the literature in the 20th and 21st century. Neurological manifestations most prevalent during the pandemics included delirium, encephalitis, ocular abnormalities, amyotrophy, myelopathy, radiculopathy, ataxia and seizures. Very little parkinsonism was reported with the exception of the 1917 cases originally described by von Economo., Conclusions: To date there have been surprisingly few cases of neurological issues inclusive of parkinsonism associated with influenza pandemics. Given the recent animal model of H5N1 influenza associated parkinsonism, the medical establishment should be prepared to evaluate for the re-emergence of parkinsonism during future outbreaks., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Research into familial Parkinson's disease (PD) remained at a virtual standstill in Europe and the US for several decades until a re-challenge by Japanese neurologists regarding an autosomal recessive form of PD. In 1965, our research group at Nagoya University examined familial cases of early-onset parkinsonism characterized by autosomal recessive inheritance, diurnal fluctuation of symptoms (alleviation after sleep), foot dystonia, good response to medication, and benign course without dementia. An inborn error of metabolism in some dopamine-related pathway was suspected. The clinical study of four families with the disease, named as "early-onset parkinsonism with diurnal fluctuation (EPDF)", was published in Neurology in 1973. The pathological study of a case in 1993 revealed neuronal loss without Lewy bodies in the substantia nigra. Based on these clinical and pathological evidences, EPDF was defined as a distinct disease entity. Screening for the EPDF gene was started in 1994 in collaboration with Juntendo University. With the discovery of parkin gene in 1998, EPDF was designated as PARK2. Of our 16 families examined for gene analysis, 15 proved to be PARK2, and the remaining one, PARK6., (© 2010 Japanese Society of Neuropathology.)

Inflammatory responses have been proposed as important factors in dopaminergic neuro-degeneration in Parkinsonism. Increasing evidence suggests that the alteration of the glial microenvironment induced by neuronal degeneration could be deleterious to the remaining neurons. The activation of microglia/macrophages and reactive astrocytes may have a negative effect on the surrounding parenchyma, perpetuating the neurodegenerative process. However, this alteration may also go beyond the brain parenchyma and stimulate other inflammatory changes in other systems, inducing the release of proinflammatory cytokines and probably Acute Phase Proteins (APP) and Glucocorticoids (GC). In this work we review the latest advances in the field to provide a picture of the state of the art of studies of inflammatory responses and Parkinsonism, hopefully opening up new therapeutic perspectives for patients with Parkinson's disease.

We discovered the gene for young onset autosomal recessive parkinsonism in 1998. We were gifted two lucky episodes. This is a short history on how we were able to discover the gene in a short period. We were primarily interested in the pathogenesis of sporadic Parkinson's disease (PD). We decided to do a genetic association study using a polymorphism of manganese superoxide dismutase (Mn SOD), as it is located at the pivotal position of oxidative stress and mitochondria. While we were screening many patients, we encountered what appeared to be young onset autosomal recessive family, which appeared to be linked to the sod2 locus, which had been mapped to the long arm of chromosome 6. We did linkage analysis on 13 similar families and obtained lod score above 9. Another fortune was that while doing linkage analysis, we encountered a patient who showed complete absence of one of the microsatellite markers that we were using in the linkage analysis. We thought that the marker was likely to be located within the disease gene. We started molecular cloning using this marker as the initial probe. Eventually we were able to clone a novel gene, which we named as parkin.

Rigidity is commonly defined as a resistance to passive movement. In Parkinson's disease (PD), two types of rigidity are classically recognized which may coexist, "leadpipe " and "cogwheel". Charcot was the first to investigate parkinsonian rigidity during the second half of the nineteenth century, whereas Negro and Moyer described cogwheel rigidity at the beginning of the twentieth century. Jules Froment, a French neurologist from Lyon, contributed to the study of parkinsonian rigidity during the 1920s. He investigated rigidity of the wrist at rest in a sitting position as well as in stable and unstable standing postures, both clinically and with physiological recordings using a myograph. With Gardère, Froment described enhanced resistance to passive movements of a limb about a joint that can be detected specifically when there is a voluntary action of another contralateral body part. This has been designated in the literature as the "Froment's maneuver " and the activation or facilitation test. In addition, Froment showed that parkinsonian rigidity diminishes, vanishes, or enhances depending on the static posture of the body. He proposed that in PD "maintenance stabilization " of the body is impaired and that "reactive stabilization " becomes the operative mode of muscular tone control. He considered "rigidification " as compensatory against the forces of gravity. Froment also demonstrated that parkinsonian rigidity increases during the Romberg test, gaze deviation, and oriented attention. In their number, breadth, and originality, Froment's contributions to the study of parkinsonian rigidity remain currently relevant to clinical and neurophysiological issues of PD., ((c) 2007 Movement Disorder Society.)

Vascular parkinsonism (VP) is a heterogeneous clinical entity. The idea of a relationship between cerebral vascular disease and parkinsonism may be traced back to the 1920s, when the diagnostic unit called "arteriosclerotic parkinsonism", a predecessor of VP, was established. This review is concerned with historical and contemporary views regarding the possible vascular genesis of parkinsonism. Confusion persists as a result of vaguely defined diagnostic criteria. The following types of simultaneous occurrence of parkinsonism and cerebral vascular disease (CVD) may be recognised: 1. gait disorders of the lower body parkinsonism type are caused mostly by white matter lesions in the frontal lobes; such disorders may require a diagnosis of vascular origin. We suggest replacing the term "lower body parkinsonism" with a more appropriate term not including the word "parkinsonism": an alternative term could be "cerebrovascular gait disorder"; 2. if the signs and symptoms are typical for idiopathic Parkinson's disease (IPD), the coincidence of IPD and CVD should be considered; 3. if the symptoms of parkinsonism are neither typical for IPD nor for VP, and there are clinical or MR signs of CVD, VP should be regarded as possible when alternative causes are excluded; 4. if the symptoms of parkinsonism and clinical and MR signs are typical for VP, VP should be regarded as probable; 5. if a stroke affecting the contralateral basal ganglia is followed by the occurrence of hemiparkinsonism, the diagnosis of VP is unambiguous. Vascular parkinsonism (VP) is probably one of the most frequently erroneous neurological diagnoses. The reason for this misdiagnosis is that both cerebral vascular disease (CVD) and parkinsonism usually occur at the same age. Due to the high incidence of CVD, it is possible for CVD and idiopathic Parkinson's disease (IPD) to coincide in some cases. Another reason for the misdiagnosis is that the concept of VP lacks clarity. This review aims to contribute to an improved understanding of VP in clinical practice. In this context, the term "CVD" is understood in the broad sense of a brain impairment caused by cerebral vessel pathology. It covers various concepts, as some authors use the term CVD to mean a manifestation of vascular lesions in pathologico-anatomical material or in the imaging techniques; others mean the history and clinical manifestation of cerebral ischaemia, or, more rarely, haemorrhage. The term CVD may cover large vessel disease as well as small vessel disease. This means that territorial and lacunar infarcts and white matter lesions (WML) are all considered as CVD.

Studies representing the accumulated information from the first 30 years of research effort on Guam (1950-1979) have demonstrated a varying degree of decline in the incidence of amyotrophic lateral sclerosis (ALS) and the parkinsonism-dementia complex (PDC) of Guam. Analysis with more complete information for the period 1980-1989 provides more valid estimates of the later patterns in the incidence of ALS and PDC and affords a more extensive assessment of trends over a 40-year period. The annual age-adjusted incidence of ALS was 7/100,000 and the annual age-adjusted incidence of PDC was 22/100,000 in 1989. The incidence was much higher for the period 1980-1989 than suggested in previous reports. These findings provide compelling evidence that this spectrum of neurodegenerative diseases continues to have a significant impact on the health of the Chamorro people of Guam.

The concept of vascular parkinsonism (VP) has been highly controversial since the initial paper by Critchley in 1929. This review tentatively delineates the extent of the spectrum of VP. Much confusion has arisen owing to the lack of clear definitions of parkinsonism, "atypical parkinsonism" and "pseudoparkinsonism", which we here attempt to define. Confusion has also arisen because incidental vascular lesions occurring in true idiopathic Parkinson's disease (IPD) are up to 10 times more common than parkinsonism due to cerebrovascular disease. VP is clinically heterogeneous. Most often VP is atypical and can be separated from IPD, on the basis of the presence of additional focal signs, and the absence of typical resting tremor in the upper limbs, of true akinesia (i. e.: with decrement and fatiguing of alternating movements), and of definite benefit from levodopa. Exceptionally, VP may mimic IPD or other degenerative diseases such as progressive supranuclear palsy or corticobasal degeneration. The lesions responsible for VP are mostly basal ganglia lacunes and/or subcortical white matter vasculopathy of the "Binswanger" type. Rarely, a single striatal infarct, striatal cribriform cavities or ischaemic changes in the substantia nigra have been described. Vascular "pseudo-parkinsonism" refers to isolated gait disorders called "lower body parkinsonism", "frontal-type gait disorders" or "gait ignition failure" that are reminiscent of, but distinct from, that found in IPD. The pathophysiology of VP is poorly understood. Why some patients develop parkinsonism and others do not, despite the same apparent lesion load, remains a mystery.

James Ramsay Hunt (1874-1937) was a pre-eminent twentieth-century American neurologist. The name of Ramsay Hunt is known today because several neurological disorders bear his name, including the herpetic geniculate ganglion syndrome and a form of ataxia and myoclonus. Despite his importance in the field of neurology, few biographical details have been recorded about Hunt's life. One of the authors of this report recently located Hunt's daughter. This biographical sketch was based on interviews conducted with her and review of documents in her possession, including letters written by Hunt. Details are depicted about Hunt's family background and childhood, medical education and early professional development, courtship and marriage, wartime experiences, family and social life, daily routine and professional development, as well as illness and death.

It is not clear whether parkinsonism as it is now defined - a progressive neurodegenerative disorder of the basal ganglia characterized by sharply reduced striatal dopamine levels - has always affected a significant minority of aged persons, but suggestive evidence to this effect is reviewed. THe major discussion commences, however, with the administration of various plant alkaloids to parkinsonism patients in the second half of the 19th century. Antiparkinsonian therapy since this time can be divided into a number of phases: 1. Employment of alkaloids derived from solanaceous plants: initially hyoscyamine, then hyoscien/scopolamine. 2. With the outbreak of encephalitis lethargica during the First World War, parkinsonian patient numbers increased dramatically, leading to a multiplicity of new directions, including high dose atropine and harmala alkaloid therapies. 3. The "Bulgarian treatment", popularized in western Europe in the mid-1930s, was also a belladona alkaloid-based therapy, but associated with greater efficacy and few side effects. This approach, whether as actual plant extracts or as defined combinations of belladona alkaloids, remained internationally dominant until the end of the 1940s. 4. Following the Second World War, synthetic antiparkinsonism agents were developed with the aim of overcoming the deficiencies of belladonna alkaloid therapy. These agents fell into two major classes: synthetic anticholinergic agents, such as benzhexol, and antihistaminergic drugs, including diphenhydramine. 5. A complete change in direction was heralded by the discovery in 1960 of the striatal dopamine deficit in parkinsonism. This led to the introduction of L-DOPA therapy, the first approach directed against an identified physiological abnormality in the disorder. 6. Subsequent developments have thus far refined of supplemented the L-DOPA effect. Recent attempts to develop neuroprotective or -restorative approaches are also briefly discussed. The history of antiparkinsonian therapy illustrates the fact that the nature of experimental clinical pharmacology has markedly changed during the 20th century: No longer the preserve of individual physicians, it is now based firmly on fundamental laboratory research, the clinical relevance of which is not always immediately apparent, and which is only later examined in clinical trials. It is nonetheless concluded that antiparkinsonian therapy was never 'irrational', but has always been necessarily rooted in current knowledge regarding neural and muscular function. The achievements of L-DOPA therapy, the first successful pharmacological treatment for a neurodegenerative disorder, derived from the fruitful union of hte skills and contributions of different types by laboratory scientists, pharmacologists and clinicians.