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Background: The accuracy of current laboratory and imaging studies for diagnosis and monitoring of Parkinsons disease (PD) severity is low and diagnosis is mainly dependent on clinical examination. Proton magnetic resonance spectroscopy (MRS) is a non-invasive technique that can assess the chemical profile of the brain. In this study, we evaluated the utility of proton MRS in diagnosis of PD and determination of its severity. Methods: Patients with PD and healthy age-matched controls were studied using proton MRS. The level of N-acetylaspartate (NAA), total creatine (Cr), and total choline (Cho), and their ratios were calculated in substantia nigra (SN), putamen (Pu), and motor cortex. PD severity was assessed by the Unified Parkinsons Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale. Results: Compared to 25 healthy controls (18 men, age: 59.00 ± 8.39 years), our 30 patients with PD (24 men, age: 63.80 ± 12.00 years, 29 under treatment) showed no significant difference in the metabolite ratios in SN, Pu, and motor cortex. Nigral level of NAA/Cr was significantly correlated with total UPDRS score in patients with PD (r = -0.35, P = 0.08). Moreover, patients with PD with Hoehn and Yahr scale score ≥ 2 had a lower NAA/Cr level in SN compared to patients with a lower stage. Conclusion: This study shows that 1.5 tesla proton MRS is unable to detect metabolite abnormalities in patients with PD who are under treatment. However, the NAA/Cr ratio in the SN might be a useful imaging biomarker for evaluation of disease severity in these patients.

Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well understood that every pathologic tauopathy may present with various clinical phenotypes based on the primary site of involvement and the spread and distribution of the pathology in the nervous system making clinicopathological correlation more and more challenging. The clinical spectrum of tauopathies includes syndromes with a strong association with an underlying primary tauopathy, including Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA)/apraxia of speech, pure akinesia with gait freezing (PAGF), and behavioral variant frontotemporal dementia (bvFTD), or weak association with an underlying primary tauopathy, including Parkinsonian syndrome, late-onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), and amnestic syndrome. Here, we discuss clinical syndromes associated with various primary tauopathies and their distinguishing clinical features and new biomarkers becoming available to improve in vivo diagnosis. Although the typical phenotypic clinical presentations lead us to suspect specific underlying pathologies, it is still challenging to differentiate pathology accurately based on clinical findings due to large phenotypic overlaps. Larger pathology-confirmed studies to validate the use of different biomarkers and prospective longitudinal cohorts evaluating detailed clinical, biofluid, and imaging protocols in subjects presenting with heterogenous phenotypes reflecting a variety of suspected underlying pathologies are fundamental for a better understanding of the clinicopathological correlations.

[This corrects the article DOI: 10.3389/fneur.2022.944806.].

BACKGROUND:There is controversial evidence about the effect of cerebellar low-frequency stimulation in patients with essential tremor (ET). OBJECTIVES:In this study we assessed safety and effectiveness of 1 Hz (low-frequency) cerebellar repetitive transcranial magnetic stimulation (rTMS) on tremor severity in patients with essential tremor in a sham-controlled crossover trial. METHODS:A total of 23 patients assigned into two groups to receive either sham (n = 10) or rTMS (n = 13) treatment, with crossing over after a two-month washout period. Intervention consisted of 900 pulses of 1 Hz rTMS at 90% resting motor threshold or the same protocol of sham stimulation over each cerebellar hemisphere for 5 consecutive days. Tremor severity was assessed by Fahn-Tolosa-Marin (FTM) scale at baseline and at days 5, 12 and 30 after intervention. The FTM consists of 3 subscales including tremor severity rating, performance of motor tasks, and functional disability. Carry-over and treatment effects were analyzed using independent samples t-test. RESULTS:There was no significant improvement in the total FTM scores in rTMS compared to the sham stimulation on day 5 (p = 0.132), day 12 (p = 0.574), or day 30 (p = 0.382). Similarly, FTM subscales, including tremor severity rating, motor tasks, and functional disability did not improve significantly after rTMS treatment. Mild headache and local pain were the most frequent adverse events. CONCLUSION:Although cerebellar rTMS seems to have acceptable safety when used in ET patients, this study could not prove any efficacy for it in reduction of tremor in these patients. Larger studies are needed to evaluate efficacy of this therapeutic intervention and to provide evidence about the optimal stimulation parameters.

The International Parkinson Disease and Movement Disorder Society PSP study group (IPMDS-PSP) recently published new clinical diagnostic criteria for progressive supranuclear palsy (PSP). Currently, there is no data regarding the accuracy of these sets of criteria for differentiating various PSP phenotypes. We discuss the accuracy of the IPMDS-PSP criteria for differentiation of patients with the PSP- Richardson phenotype (PSP-RS) from those with the PSP-Parkinsonism (PSP-P) using data from a sample of 274 clinically diagnosed PSP patients participating in the Environmental Genetic PSP (ENGENE-PSP) case control study. Using National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP) criteria and the Williams criteria we categorized 259 of these patients as probable PSP-RS and 15 as PSP-P. The IPD-MDS PSP-RS and PSP-P criteria were unable to distinguish the PSP-RS from the PSP-P phenotypes in this sample. Nearly all (92.6%; 240 out of 259) the PSP-RS patients and over half (60%; 9 out of 15) of the PSP-P patients fulfilled both the IPMDS criteria for PSP-RS and PSP-P. Applying the newly proposed multiple allocation extinction rules decreased the number of overlapping diagnoses among the NINDS-SPSP PSP-RS patients, however problems remained in the PSP-P group. Diagnostic accuracy might be improved by modification of timelines for development of falls and other parkinsonian features.

Progressive supranuclear palsy (PSP) is a four-repeat tau proteinopathy. Abnormal tau deposition is not unique for PSP and is the basic pathologic finding in some other neurodegenerative disorders such as Alzheimers disease (AD), age-related tauopathy, frontotemporal degeneration, corticobasal degeneration, and chronic traumatic encephalopathy. While AD research has mostly been focused on amyloid beta pathology until recently, PSP as a prototype of a primary tauopathy with high clinical-pathologic correlation and a rapid course is a crucial candidate for tau therapeutic research. Several novel approaches to slow disease progression are being developed. It is expected that the benefits of translational research in this disease will extend beyond the PSP population. This article reviews advances in the diagnosis, epidemiology, pathology, hypothesized etiopathogenesis, and biomarkers and disease-modifying therapeutic approaches of PSP that is leading it to become a frontrunner in translation.

INTRODUCTION:Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. AREAS COVERED:In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. EXPERT OPINION:Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.

Introduction: Cognitive disorders, characterized by transient stages and potential Alzheimer's disease, are influenced by changes in iron deposits in the brain. These changes can lead to toxicity and neuron death. Quantitative susceptibility mapping is used to accurately represent these changes, allowing for a more accurate evaluation of the time window of each cognitive disorder stage and the need for targeted treatment. Material and Methods: The Alzheimer's Disease Neuroimaging Initiative research database was used to download the data and eight healthy participants and twenty-one participants with cognitive disorders based on MMSE cognitive test scores in 5 groups of cognitively normal, Subjective Memory Concern, Early Mild Cognitive Impairment, Late Mild Cognitive Impairment and Alzheimer's disease were included in this study. Quantitative Susceptibility Mapping processing was performed using the SEPIA toolbox in MATLAB, and segmentation was performed using FSL software. Finally, statistical analyzes were performed using SPSS V26 software. Results: Statistically significant changes were observed in the QSM values of the right thalamus (p-value = 0.043) in the LMCI group and the right hippocampal nucleus (p-value = 0.050) in the control group. Conclusion: After one year, the right hippocampal nucleus shows increased iron accumulation in healthy individuals, suggesting that the nucleus is susceptible to the highest rate of iron deposition in healthy individuals. Based on this result, the hypothesis that iron deposits are the cause of the unknown cause-andeffect relationship between iron deposits and Alzheimer's disease may be confirmed. [ABSTRACT FROM AUTHOR]

Introduction: Iron deposition is vital for damaging neurons and causing different cognitive disorders. Today, using the quantitative susceptibility mapping (QSM) technique, iron deposits in other brain areas can be assessed and measured. This study aimed to identify changes in iron deposition of 12 brain nuclei through different stages of dementia using the QSM technique to introduce biomarkers for the early detection of cognitive disorders. Material and Methods: The Alzheimer's Disease Neuroimaging Initiative (ADNI) database was used to download data. A 3T MRI scanner scanned thirty-five participants with normal cognition and forty-six patients with cognitive disorders who were classified into four groups based on the severity of the condition. QSM processing determined twelve regions of interest (ROIs) by automatic nuclei segmentation and statistical analysis performed in these groups' MRI images. Results: Based on previous findings, QSM values increase proportionally to iron deposition. In this study, the increase in the QSM values of different nuclei of the early mild cognitive impairment (EMCI) stage indicates iron deposition in these participants. In the EMCI group, The QSM value of the bilateral thalamus (P<0.05) and left amygdala (P=0.006) nuclei were higher than in the control group. Based on the results of the receiver operating characteristic curve (ROC) analysis, the left amygdala (P=0.005), left putamen (P=0.002), left thalamus (P=0.05), and right thalamus (P<0.05) have an appropriate sensitivity and specificity to identify the different stages of cognitive disorders. Conclusion: The left amygdala and bilateral thalamic nuclei are the first areas exposed to iron deposition during cognitive impairment. Mentioned nuclei, especially the left amygdala, have high efficiency and sensitivity for the early detection of cognitive disorders. [ABSTRACT FROM AUTHOR]