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Headaches occur when cerebrospinal fluid (CSF) pressure drops following dural puncture or trauma or spontaneously. As the features of these headaches and their accompanying symptoms might not be typical, low CSF pressure headache syndromes, and spontaneous intracranial hypotension in particular, are often misdiagnosed and underdiagnosed.The aim of this narrative review is to summarize the most recent evidence regarding the clinical presentation and the diagnosis of low CSF pressure headache syndromes.The clinical spectrum low CSF pressure headache syndromes varies significantly and key signs might be missing. Low CSF pressure headache syndromes should be included in the differential diagnosis of any case of refractory headache, even when the headache is not orthostatic, or there are normal neuroimaging findings, and/or lumbar puncture opening pressure is within normal limits. Future research should focus on controlled interventional studies on the treatment of low CSF pressure headache syndromes, which are currently lacking.

BACKGROUND A decrease in glutathione (GSH) levels is considered one of the earliest biochemical changes in Parkinson's disease (PD). OBJECTIVE The authors explored the potential role of plasma GSH as a risk/susceptibility biomarker for prodromal PD (pPD) by examining its longitudinal associations with pPD probability trajectories. METHODS A total of 405 community-dwelling participants (median age [interquartile range] = 73.2 [7.41] years) without clinical features of parkinsonism were followed for a mean (standard deviation) of 3.0 (0.9) years. RESULTS A 1 μmol/L increase in plasma GSH was associated with 0.4% (95% confidence interval [CI], 0.1%-0.7%; P = 0.017) less increase in pPD probability for 1 year of follow-up. Compared with participants in the lowest GSH tertile, participants in the highest GSH tertile had a 12.9% (95% CI, 22.4%-2.2%; P = 0.020) slower rate of increase of pPD probability for 1 year of follow-up. CONCLUSION Plasma GSH was associated with pPD probability trajectories; therefore, it might assist in the identification of individuals who are likely to reach the threshold for pPD diagnosis more rapidly. © 2021 International Parkinson and Movement Disorder Society.

Background The International Parkinson and Movement Disorder Society-endorsed Progressive Supranuclear Palsy Study Group published clinical diagnostic criteria for progressive supranuclear palsy in 2017, aiming to optimize early, sensitive and specific diagnosis. Objective To assist physicians in the application of these criteria, we developed a video-based tutorial in which all core clinical features and clinical clues are depicted and explained. Methods Patients provided written informed consent to the publication of their videos. High-quality videos along with essential descriptions were collected by the study group members. Most educational videos were selected in a structured consensus process. Results We provide 68 videos of all core clinical features and clinical clues defined by the diagnostic criteria, along with instructive descriptions of the depicted patients, examination techniques and clinical findings. Conclusions This comprehensive video-based tutorial will support physicians in the application of the diagnostic criteria of progressive supranuclear palsy.

Tauopathies are classified according to whether tau deposits predominantly contain tau isoforms with three or four repeats of the microtubule-binding domain. Those in which four-repeat (4R) tau predominates are known as 4R-tauopathies, and include progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathies and conditions associated with specific MAPT mutations. In these diseases, 4R-tau deposits are found in various cell types and anatomical regions of the brain and the conditions share pathological, pathophysiological and clinical characteristics. Despite being considered 'prototype' tauopathies and, therefore, ideal for studying neuroprotective agents, 4R-tauopathies are still severe and untreatable diseases for which no validated biomarkers exist. However, advances in research have addressed the issues of phenotypic overlap, early clinical diagnosis, pathophysiology and identification of biomarkers, setting a road map towards development of treatments. New clinical criteria have been developed and large cohorts with early disease are being followed up in prospective studies. New clinical trial readouts are emerging and biomarker research is focused on molecular pathways that have been identified. Lessons learned from failed trials of neuroprotective drugs are being used to design new trials. In this Review, we present an overview of the latest research in 4R-tauopathies, with a focus on progressive supranuclear palsy, and discuss how current evidence dictates ongoing and future research goals.

Introduction Some case series have suggested that psychotic features could occur even before the onset of motor symptoms of Parkinson's Disease (PD). Our aim was to investigate a possible association between psychotic symptoms and prodromal Parkinson's disease in a population-based cohort, the Hellenic Longitudinal Investigation of Aging and Diet study. Methods This cross-sectional study included participants aged ≥65 years without dementia or PD. We defined psychotic symptoms as the presence of at least one new hallucinatory or delusional feature, assessed with the Neuropsychiatric Inventory scale and the Columbia University Scale for Psychopathology in Alzheimer's Disease, exhibited only at follow-up and not present at baseline visit. We calculated the probability of prodromal PD (pPD) for every participant, according to the 2019 International Parkinson and Movement Disorders Society research criteria for prodromal PD. Results Participants who developed psychotic manifestations over a three-year follow up (20 of 914) had 1.3 times higher probability of pPD score (β [95%CI]: 1.3 [0.9-1.5], p=0.006) compared to non-psychotic subjects. This association was driven mostly by depressive symptoms, constipation and subthreshold parkinsonism (p Conclusion Our data indicate that emerging psychotic features evolve in parallel with the probability of pPD. This is the first study that provides evidence for the presence of psychotic experiences in pPD. The association detected needs to be confirmed in longitudinal studies.

Objective The objective of this study was to validate the recently updated research criteria for prodromal Parkinson's disease (pPD) proposed by the International Parkinson's Disease and Movement Disorders Society. Methods A total of 16 of 21 markers of pPD were ascertained in the Hellenic Longitudinal Investigation of Aging and Diet cohort composed of community-dwelling individuals aged ≥65 years. The probability of pPD was calculated for 961 individuals without Parkinson's disease (PD) or dementia with Lewy bodies at baseline who were followed-up for a median of 3 years. The ability of the criteria to predict conversion to PD/dementia with Lewy bodies was assessed by estimating their sensitivity and specificity, plotting receiver operating characteristics curves, and using logistic regression. These analyses were repeated using the original criteria. Results No incident PD/dementia with Lewy bodies case had probable pPD at baseline (ie, ≥80% pPD probability). At cut-offs of 10%, 30%, and 50% probability of pPD, the sensitivity and specificity of the criteria ranged from 4.5% to 27.3%, and 85.7% to 98.3% respectively. The area under the receiver operating characteristics curve was 0.691 (95% confidence intervals, 0.605-0.777). In logistic regression models, the criteria-derived posttest odds of pPD were a significant predictor of conversion at follow-up. The updated criteria performed similarly to the original but showed a slight increase in sensitivity. Conclusions The new criteria demonstrated suboptimal sensitivity in our random sample of community-dwelling individuals. The absence of specialized assessments with high likelihood ratios in our cohort could be hindering the demonstration of higher sensitivities. Such assessments should be a part of future validation attempts. © 2020 International Parkinson and Movement Disorder Society.

Parkinson's disease is a heterogeneous disorder in its presentation and progression, a fact important in clinical practice and in research. Clinical experience as well as data driven approaches have guided the attempts to define more homogeneous populations, i.e., different syndromes or subtypes, that share prognostic and other features. The first approach led to subtypes distinguished by age of onset, motor phenotype or the presence of nonmotor features. The second yielded subtypes defined by both motor and nonmotor symptoms. Finally, monogenic Parkinson's disease is also considered a subtype, as carriers of the same mutation likely share the same pathogenic mechanism.

Introduction: Progressive supranuclear palsy (PSP) is a common cause of atypical parkinsonism and a rapidly progressive disease that greatly burdens both patients and caregivers. Drugs with disease-modifying potential, targeting mechanisms implicated in the disease's pathogenesis are currently tested in Phase 1 and 2 trials. If proven efficacious, these compounds might provide substantial benefits not only to patients with PSP but to patients with other tauopathies as well. Areas covered: Drugs in Phase 1 and 2 trials in PSP, and Phase 2 trials in other tauopathies (Alzheimer's disease) are reviewed. Expert opinion: The rationale behind the currently tested compounds as well as the tools available to document a treatment effect offer hope for a therapeutic breakthrough in PSP. The current lack of sufficiently validated biomarkers remains a hurdle that needs to be overcome, in order to facilitate both clinical trials and the accurate prescription of future treatments.

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.

With the advent in genetics, many genetic parkinsonian conditions have been described that, in some cases, share features that resemble the widely recognized Richardson's syndrome (the commonest described phenotype of progressive supranuclear palsy pathology), corticobasal syndrome and multiple system atrophy syndromes. A positive family history, an earlier age at onset, and clinical features that are unusual for or characteristic of a certain condition, may help in the differential diagnosis. The recognition of these syndromes is quite important as, in contrast to the non-genetic atypical parkinsonian syndromes, a definite diagnosis can be made, there are implications for other generations and there may be an opportunity to participate in clinical trials with genetic treatments that are well under way.

With the advent in genetics, many genetic parkinsonian conditions have been described that, in some cases, share features that resemble the widely recognized Richardson's syndrome (the commonest described phenotype of progressive supranuclear palsy pathology), corticobasal syndrome and multiple system atrophy syndromes. A positive family history, an earlier age at onset, and clinical features that are unusual for or characteristic of a certain condition, may help in the differential diagnosis. The recognition of these syndromes is quite important as, in contrast to the non-genetic atypical parkinsonian syndromes, a definite diagnosis can be made, there are implications for other generations and there may be an opportunity to participate in clinical trials with genetic treatments that are well under way.

Progressive supranuclear palsy (PSP) is an adult-onset neurodegenerative disease, clinically characterized by prominent postural instability and falls, vertical supranuclear gaze palsy, and frontal-subcortical dementia. The etiology is still unknown but recent scientific advances have led to a consensus that the main pathogenetic event is the abnormal 4R tau deposition in the brainstem, basal ganglia, and neocortical areas. The clinical spectrum has been expanded and includes several clinical syndromes that can be underpinned by the pathological hallmark features of PSP. Attempts to identify a biomarker in the cerebrospinal fluid or a specific and sensitive neuroimaging technique have so far failed to contribute significantly to the diagnostic process. Symptomatic pharmacologic treatment of PSP is still unsatisfactory, and the effect of dopaminergic medication on the parkinsonian symptoms is limited. Although the first disease-modifying trials have failed to show any clinical benefit, they have signaled the beginning of a new era towards finding an effective treatment for this devastating disorder.

Progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy account for approximately 10% of neurodegenerative parkinsonism. Considerable clinical overlap exists between these disorders that extends to features considered characteristic of each disease. Clinical diagnostic criteria have attempted to increase the accuracy of clinical diagnosis as accurate diagnosis is necessary to inform prognosis and to facilitate the recognition of disease-modifying treatments. Currently no such treatment exists. Nevertheless, many clinical trials aiming to change the natural history of these diseases are ongoing. The spread and accumulation of abnormal proteins are among the pathophysiological mechanisms targeted. For the time being, however, only symptomatic treatment is available. Levodopa is used to treat parkinsonism, but patients usually show a poor or transient response. Amantadine is also used in practice for the same indication. Botulinum toxin can alleviate focal dystonic manifestations. Addressing non-motor manifestations is limited by the potential of available drugs to impact on other aspects of the disease. Most of the new symptomatic formulations under study are focused on orthostatic hypotension in multiple system atrophy. Exercise, occupational, physical, and speech therapy and psychotherapy should always accompany pharmacological approaches.