Mediterranean diet is associated with a lower probability of prodromal Parkinson's disease and risk for Parkinson's disease/dementia with Lewy bodies: A longitudinal study.

BACKGROUND AND PURPOSE: Lifestyle factors have been implicated in the long-lasting neurodegenerative process in prodromal Parkinson's disease (pPD). The aim was to investigate the associations between adherence to a Mediterranean diet (MeDi) and longitudinal changes of pPD probability and the development of Parkinson's disease (PD) or pPD in a Mediterranean older population. METHODS: Data from the Hellenic Longitudinal Investigation of Aging and Diet cohort (community-dwelling individuals, aged ≥ 65 years) were used. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate MeDi adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. The probability of pPD was calculated according to the updated Movement Disorder Society research criteria. RESULTS: In all, 1047 non-PD/dementia with Lewy bodies (DLB) participants were followed for 3 ± 1 years. MeDi adherence was associated with lower increase in pPD probability over time (b = -0.003, 95% confidence interval -0.006 to -0.001, p = 0.010). Forty-nine participants had incident possible/probable pPD (i.e., pPD probability ≥ 30%). Compared to the participants in the lowest quartile of MeDi adherence, those in the higher quartiles had an approximately 60%-70% lower risk for possible/probable pPD (p for trend 0.003). MeDi-pPD associations were driven by both motor and non-motor pPD markers and not from risk markers. Also, 21 participants were diagnosed with PD/DLB at follow-up. For each unit increase in the MeDi score, there was a 9%-10% lower risk for PD/DLB (hazard ratio 0.906 [95% confidence interval 0.823-0.997], p = 0.044). CONCLUSIONS: Mediterranean diet adherence is associated with lower increase in pPD probability over time and lower possible/probable pPD and PD/DLB incidence in older Mediterranean people. More studies are needed to confirm our results in other populations.

Plasma Glutathione and Prodromal Parkinson's Disease Probability.

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.

A Prospective Validation of the Updated Movement Disorders Society Research Criteria for Prodromal Parkinson's Disease.

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.

One decade ago, one decade ahead in progressive supranuclear palsy.

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.

Emerging drugs for progressive supranuclear palsy.

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.

Planimetric and Volumetric Brainstem MRI Markers in Progressive Supranuclear Palsy, Multiple System Atrophy, and Corticobasal Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND: Various MRI markers-including midbrain and pons areas (Marea, Parea) and volumes (Mvol, Pvol), ratios (M/Parea, M/Pvol), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)-have been proposed as imaging markers of Richardson's syndrome (RS) and multiple system atrophy-Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking. METHODS: Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on Marea, Parea, Mvol, Pvol, M/Parea, M/Pvol, MRPI 1, and MRPI 2. Cohen's d, as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS. RESULTS: Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen's d = -3.10; p < 0.001), followed by M/Parea and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low. CONCLUSIONS: Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/Parea and MRPIs produce smaller effect sizes for differentiating RS from controls.

Current perspectives on the recognition and diagnosis of low CSF pressure headache syndromes.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies.

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.

Late life psychotic features in prodromal Parkinson's disease.

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 (ß [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<0.05). 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.

Video-tutorial for the Movement Disorder Society criteria for progressive supranuclear palsy.

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.

Progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized pathologically by 4 repeat tau deposition in various cell types and anatomical regions. Richardson's syndrome (RS) is the initially described and one of the clinical phenotypes associated with PSP pathology, characterized by vertical supranuclear gaze paly in particular downwards, postural instability with early falls and subcortical frontal dementia. PSP can manifest as several other clinical phenotypes, including PSP-parkinsonism, -pure akinesia with gait freezing, -frontotemporal dementia, - corticobasal syndrome, - speech/language impairment. RS can also have a pathologic diagnosis other than PSP, including corticobasal degeneration, FTD-TDP-43 and others. New clinical diagnostic criteria take into account this phenotypic variability in an attempt to diagnose the disease earlier, given the current lack of a validated biomarker. At present, therapeutic options for PSP are symptomatic and insufficient. Recent large neuroprotective trials have failed to provide a positive clinical outcome, however, have led to the design of better studies that are ongoing and hold promise for a neuroprotective treatment for PSP.

Genetic mimics of the non-genetic atypical parkinsonian disorders - the 'atypical' atypical.

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.

Therapeutic Management of the Overlapping Syndromes of Atypical Parkinsonism.

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.