An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.

Introduction: Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework. Methods: The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed. Results: Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability. Discussion: The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). METHOD: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. RESULTS: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. CONCLUSIONS: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Late-life mood disorder as the initial presentation of progressive supranuclear palsy: A case series.

Aim: Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder characterized by Parkinsonism, supranuclear ophthalmoplegia, postural instability, and cognitive impairment. Patients: This case series describes three patients initially diagnosed with late-life mood disorders (depression and bipolar disorder) who were later diagnosed with PSP because of the development of typical neurological symptoms. Result: The diagnostic challenge of PSP is highlighted in this case report, particularly in the early stages, when characteristic symptoms may not be present. The importance of considering PSP in the differential diagnosis of late-life mood disorders, especially in the absence of response to standard antidepressant therapy, is also emphasized. The heterogeneity of PSP is described, with various subtypes and atypical variants presenting with different clinical features. The psychiatric symptoms of PSP include apathy, disinhibition, depression, and anxiety, whereas hallucinations and delusions are less frequent. Tau positron emission tomography imaging is discussed as a potential biomarker for atypical PSP. Conclusion: Early diagnosis and intervention are crucial for improved outcomes in PSP, necessitating further research to enhance the diagnostic and treatment strategies for PSP and other neurodegenerative diseases.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Quantitative susceptibility mapping from basal ganglia and related structures: correlation with disease severity in progressive supranuclear palsy.

OBJECTIVE: We examined whether mean magnetic susceptibility values from deep gray matter structures in patients with progressive supranuclear palsy (PSP) differed from those in patients with Parkinson's disease (PD) and healthy volunteers, and correlated with the PSP rating scale. METHODS: Head of caudate nucleus, putamen, globus pallidus, substantia nigra and red nucleus were the regions of interest. Mean susceptibility values from these regions in PSP patients were estimated using quantitative susceptibility mapping. Correlations with clinical severity of disease as measured by the PSP rating scale were examined. The mean susceptibility values were also compared with those from healthy volunteers and age- and disease duration-matched patients with PD. RESULTS: Data from 26 healthy volunteers, 26 patients with PD and 27 patients with PSP, were analysed. Patients with PSP had higher mean susceptibility values from all regions of interest when compared to both the other groups. The PSP rating scale scores correlated strongly with mean susceptibility values from the red nucleus and moderately with those from the putamen and substantia nigra. The scores did not correlate with mean susceptibility values from the caudate nucleus or globus pallidus. In patients with PD, the motor deficits correlated moderately with mean susceptibility values from substantia nigra. CONCLUSIONS: In patients with PSP, mean susceptibility values indicating the severity of mineralization of basal ganglia and related structures correlate with disease severity, the correlation of red nucleus being the strongest. Further studies are warranted to explore whether mean susceptibility values could serve as biomarkers for PSP.

Behind the Mask of Parkinsonism: A Case Report and Literature Review on Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative condition that typically emerges in adulthood and does not exhibit any familial inheritance pattern. PSP is characterized by gradual stiffness in the central body, an inability to move the gaze upward voluntarily, postural instability, and a decline in cognitive function linked to frontal lobe dysfunction. Clinical assessment reveals a variety of findings, and cases of PSP frequently go unnoticed or are incorrectly diagnosed as other conditions. Notably, prominent neurotransmitter-related changes in PSP involve damage to the dopaminergic nigrostriatal pathway and cholinergic impairment in multiple regions. We hereby present a case of a 71-year-old female patient whose medical journey unfolds as a perplexing riddle. Despite the collective expertise of several physicians, she found herself bearing the weight of a misdiagnosis ascribed to Parkinson's Disease (PD) erroneously. She initially presented with recurring falls due to postural instability and bradykinesia, which progressed such that she became dependent on a walking aid. A comprehensive physical examination revealed indicators consistent with PSP.

microRNA and circRNA in Parkinson's Disease and atypical parkinsonian syndromes.

Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are atypical parkinsonian syndromes (APS) with various clinical phenotypes and considerable clinical overlap with idiopathic Parkinson's disease (iPD). This disease heterogeneity makes ante-mortem diagnosis extremely challenging with up to 24% of patients misdiagnosed. Because diagnosis is predominantly clinical, there is great interest in identifying biomarkers for early diagnosis and differentiation of the different types of parkinsonism. Compared to protein biomarkers, microRNAs (miRNAs) and circularRNAs (circRNAs) are stable tissue-specific molecules that can be accurately measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This chapter critically reviews miRNAs and circRNAs as diagnostic biomarkers and therapeutics to differentiate atypical parkinsonian disorders and their role in disease pathogenesis.

TANK-Binding Kinase 1 Mutation as a Rare Cause of Frontotemporal Dementia in a Mexican Patient: The First Case Report in a Tertiary Referral Hospital in Mexico.

Frontotemporal dementia (FTD) is a heterogeneous condition characterized by changes in behavior, personality, and language resulting from degeneration of the frontal and/or temporal lobes. A wide spectrum of clinical syndromes and an overlap with different motor disorders make this entity challenging for clinicians, both in achieving a correct diagnosis and providing proper treatment. Despite the majority of cases being sporadic, FTD has a hereditary component, and more than 10 disease-causing genes have been identified. We present the case of a Mexican patient with a positive family history of neurocognitive disorders who developed early-onset behavioral symptoms, cognitive alterations, and motor disturbances. After a comprehensive study and multiple assessments by various medical services, a molecular diagnosis was achieved by documenting a loss-of-function mutation in the TANK-binding kinase 1 (TBK1) gene, an extremely rare cause of FTD. Genetic diagnosis is crucial in these situations, as this mutation has been associated with rapid disease progression and the potential development of motor syndromes during its course. Our case underscores the challenges involved in reaching an accurate diagnosis, highlighting the importance of molecular testing. A thorough family history, past medical records, and a detailed description of symptom onset and progression are imperative, as they can significantly influence both treatment approaches and prognosis. Diagnostic errors, combined with their subsequent inappropriate treatment, can further deteriorate patients' quality of life.

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy.

OBJECTIVE: To elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. METHODS: Participants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. RESULTS: LTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. CONCLUSIONS: LTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SIGNIFICANCE: The degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature.

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are uncommon multifactorial atypical Parkinsonian syndromes, expressed by various clinical features. MSA and PSP are commonly considered sporadic neurodegenerative disorders; however, our understanding is improving of their genetic framework. The purpose of this study was to critically review the genetics of MSA and PSP and their involvement in the pathogenesis. A systemized literature search of PubMed and MEDLINE was performed up to 1 January 2023. Narrative synthesis of the results was undertaken. In total, 43 studies were analyzed. Although familial MSA cases have been reported, the hereditary nature could not be demonstrated. COQ2 mutations were involved in familial and sporadic MSA, without being reproduced in various clinical populations. In terms of the genetics of the cohort, synuclein alpha (SNCA) polymorphisms were correlated with an elevated likelihood of manifesting MSA in Caucasians, but a causal effect relationship could not be demonstrated. Fifteen MAPT mutations were linked with PSP. Leucine-rich repeat kinase 2 (LRRK2) is an infrequent monogenic mutation of PSP. Dynactin subunit 1 (DCTN1) mutations may imitate the PSP phenotype. GWAS have noted many risk loci of PSP (STX6 and EIF2AK3), suggesting pathogenetic mechanisms related to PSP. Despite the limited evidence, it seems that genetics influence the susceptibility to MSA and PSP. MAPT mutations result in the MSA and PSP pathologies. Further studies are crucial to elucidate the pathogeneses of MSA and PSP, which will support efforts to develop novel drug options.

Diagnostic Performance of Putaminal Hypointensity on Susceptibility MRI in Distinguishing Parkinson Disease from Progressive Supranuclear Palsy: A Meta-Analysis.

Background: Idiopathic Parkinson's disease (IPD) and progressive supranuclear palsy (PSP) have similar clinical signs and symptoms, making accurate clinical diagnosis difficult. T2* gradient echo (T2* GRE), susceptibility-weighted imaging (SWI), and quantitative susceptibility mapping (QSM) are susceptibility MR imaging sequences that provide more information about brain iron levels than other conventional MR imaging. Objective: This study aimed to evaluate the diagnostic power of putaminal hypointensity on T2* GRE, SWI, and QSM in distinguishing PSP from IPD. Methods: Eligible studies were identified via systematic searches of PubMed and Clarivate Analytics® Web of Science® Core Collection. Studies that satisfied the inclusion and exclusion criteria were reviewed. A meta-analysis was conducted using the hierarchical summary receiver operating characteristic curve approach. Results: Our literature search of the two databases yielded 562 primary articles, 10 of which were deemed relevant and only six were eligible for further analyses. We performed a meta-analysis of putaminal hypointensity measurements: 438 patients with IPD and 109 patients with PSP were enrolled in the quantitative synthesis. The meta-analysis of six studies with 547 patients revealed a sensitivity of 69% (95% confidence interval (CI): 33%-90%) and specificity of 91% (95% CI: 80%-96%) for putaminal hypointensity on T2* GRE, SWI, or QSM distinguishing PSP from IPD. Conclusions: Putaminal hypointensity on T2* GRE, SWI, or QSM is able to distinguish patients with PSP from those with IPD with high specificity. Further multicenter prospective studies on patients are needed to verify our results.

Clinical, cognitive, and morphometric profiles of progressive supranuclear palsy phenotypes.

The International Parkinson's and Movement Disorder Society (MDS) criteria for progressive supranuclear palsy (PSP) have broadened the clinical spectrum of the disease and established phenotypic characterization according to the predominant manifestation at onset. The objective of this study is to describe clinical/cognitive and imaging features of a monocentric cohort of PSP patients, highlighting different patterns of functional disability according to the assigned phenotype. We retrospectively reviewed clinical/imaging data of 53 PSP patients diagnosed with probable PSP according to the MDS criteria and 40 age/sex-matched healthy controls (HCs). Neurological/neuropsychological assessments were performed using standardized scales, as well as comprehensive magnetic resonance imaging (MRI) morphometric measurements. In our cohort, there were 24/53 PSP-RS (Richardson's syndrome), 13/53 PSP-P (Parkinsonism), 7/53 PSP-PGF (Progressive gait freezing), and 9/53 PSP-Cog (Cognitive impairment). PSP-Cog presented the worst motor profiles, the highest percentages of dementia and impaired functional autonomy; 4/9 PSP-Cog and 2/7 PSP-PGF died. PSP-P had the lowest motor/cognitive burden. All MRI parameters had good discriminative efficacy vs. HCs, with P/M 2.0 discriminating PSP-PGF from PSP-RS and PSP-Cog. We highlighted discrete clinical and imaging patterns that best characterize different PSP phenotypes. PSP-Cog and PSP-PGF/RS manifest greater incidence of dementia and motor disability, respectively, while PSP-P has a more benign course. The identification of different phenotypes may be the expression of different progression patterns requiring tailored approaches in terms of follow-up and treatment. These findings support the concept of discrete patterns of Tau pathology within the PSP spectrum and encourage research for phenotype-specific outcome measures.

Rhythmic auditory cueing in atypical parkinsonism: A pilot study.

Rhythmic auditory cueing (RAC) can improve gait parameters in neurological disorders such as Parkinson's disease and stroke. However, there is a lack of research on the effects of RAC in patients with atypical parkinsonian disorders (APD). Using a smartphone metronome application, we aimed to investigate the immediate effects of RAC in patients with clinically diagnosed APD, namely Progressive Supranuclear Palsy (PSP-Richardson Syndrome and other variants, PSP-nonRS), Corticobasal Syndrome (CBS), Multiple System Atrophy (MSA), and Dementia with Lewy Bodies (DLB). A total of 46 APD participants (25 PSP, 9 CBS, 8 MSA and 4 DLB; age: mean = 70.17, standard deviation = 7.15) walked at their preferred pace for 2 min without any rhythmic auditory cueing (RAC). Participants then walked the same path for another 2 min with RAC set at a tempo 10% faster than the baseline cadence of each participant. After a 10-15-min break, participants walked the same path for another 2 min without RAC to observe for carryover effects. Gait parameters [cadence (steps/minute), gait velocity (meters/minute), and stride length (centimeters)] were collected at baseline, during RAC, and post-RAC. There was a significant improvement in cadence in all participants from baseline to during RAC and post-RAC (corrected p-values = 0.009 for both). Gait velocity also improved from baseline to during RAC and post-RAC in all participants, although this improvement was not significant after correcting for multiple comparisons. The changes in cadence and gait velocity were most pronounced in PSP. In addition, our exploratory analysis showed that the cadence in the suspected TAU group (PSP+CBS) showed a significant improvement from baseline to during RAC and post-RAC (corr. p-value = 0.004 for both). This pilot study using short-term RAC in APD patients demonstrated improvements in cadence and velocity. There is an urgent need for effective gait rehabilitation modalities for patients with APD, and rhythmic cueing can be a practical and useful intervention to improve their gait pattern.

Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy.

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

MicroRNA as Candidate Biomarkers in Atypical Parkinsonian Syndromes: Systematic Literature Review.

Background and Objectives: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are rare atypical parkinsonian syndromes, characterized by motor and cognitive symptoms. Their clinical diagnosis is challenging because there are no established biomarkers. Dysregulation of microRNAs (miRNAs/miRs) has been reported to serve an important role in neurodegenerative diseases. However, the miRNA profiles of MSA and PSP patients are rarely reported. The aim of this study was to critically review the role of miRNAs as diagnostic biomarkers to differentiate these atypical parkinsonian disorders and their role in disease pathogenesis. Materials and Methods: A systematic literature search of PubMed was conducted up to February 2022 according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 15 studies were analyzed. Three studies have shown that miR-9-3p, miR-19a, miR-19b, and miR-24 are potential biomarkers for MSA. In two studies, miR-132 was downregulated, whereas miR-147a and miR-518e were upregulated in the brain tissue of PSP patients. Conclusions: The potential of miRNA is still uncertain as a potential differential diagnostic marker to identify these disorders. Pre-analytical and analytical factors of included studies were important limitations to justify the introduction of miRNAs into clinical practice.

Is the Phenotype Designation by PSP-MDS Criteria Stable Throughout the Disease Course and Consistent With Tau Distribution?

INTRODUCTION: The MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones. METHODS: Thirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx). RESULTS: Applying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed. INTERPRETATION: After the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.

Peripapillary retinal nerve fiber layer thinning in patients with progressive supranuclear palsy.

OBJECTIVES: To investigate peripapillary retinal nerve fiber layer (pRNFL) changes in patients with progressive supranuclear palsy (PSP). METHODS: We included 21 PSP patients (36 eyes) who underwent peripapillary optical coherence tomography (OCT) scans at 2.5 ± 1.3 years of disease, without ophthalmologic co-morbidities. We compared pRNFL thicknesses in PSP eyes with age-matched 22 controls (22 eyes) using generalized estimating equation model adjusting for intra-subject inter-eye correlations, age and sex. We also analyzed the correlation between the pRNFL thickness and clinical severity using Spearman's correlation. In twelve PSP patients with 3 T brain MRI volumetric scan within 1 year of OCT exam, we investigated the correlation between the pRNFL thickness and brain atrophy using Pearson's correlation. RESULTS: PSP patients had global pRNFL thinning compared to controls (beta = - 6.436, p = 0.025). Global pRNFL thickness correlated with Hoehn & Yahr stages (r = - 0.487, p = 0.025), and nasal pRNFL thinning showed a trend of correlation (uncorrected p < 0.05). Exploratory correlation analysis between global pRNFL thickness and nonmotor items in the PSP rating scale showed a trend toward association with sleep disturbances (uncorrected p = 0.008) and urinary incontinence (uncorrected p = 0.031), although not significant after Bonferroni correction (all 28 items). The patients had significant atrophy in the posterior cingulate cortex, third ventricle, pallidum, and midbrain with reduced midbrain-to-pons ratio, but no correlation was found between pRNFL thickness and brain volumes. CONCLUSION: The pRNFL seems to be affected in PSP, which is more severe with advanced disease stages. Retinal investigation in a larger longitudinal cohort would help elucidate the pathophysiological role of retinal thinning in PSP.

18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies.

Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

Neuropathology of SCA34 showing widespread oligodendroglial pathology with vacuolar white matter degeneration: a case study.

Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant inherited ataxia due to mutations in ELOVL4, which encodes one of the very long-chain fatty acid elongases. SCA38, another spinocerebellar ataxia, is caused by mutations in ELOVL5, a gene encoding another elongase. However, there have been no previous studies describing the neuropathology of either SCA34 or 38. This report describes the neuropathological findings of an 83-year-old man with SCA34 carrying a pathological ELOVL4 mutation (NM_022726, c.736T>G, p.W246G). Macroscopic findings include atrophies in the pontine base, cerebellum, and cerebral cortices. Microscopically, marked neuronal and pontocerebellar fiber loss was observed in the pontine base. In addition, in the pontine base, accumulation of CD68-positive macrophages laden with periodic acid-Schiff (PAS)-positive material was observed. Many vacuolar lesions were found in the white matter of the cerebral hemispheres and, to a lesser extent, in the brainstem and spinal cord white matter. Immunohistological examination and ultrastructural observations with an electron microscope suggest that these vacuolar lesions are remnants of degenerated oligodendrocytes. Electron microscopy also revealed myelin sheath destruction. Unexpectedly, aggregation of the four-repeat tau was observed in a spatial pattern reminiscent of progressive supranuclear palsy. The tau lesions included glial fibrillary tangles resembling tuft-shaped astrocytes and neurofibrillary tangles and pretangles. This is the first report to illustrate that a heterozygous missense mutation in ELOVL4 leads to neuronal loss accompanied by macrophages laden with PAS-positive material in the pontine base and oligodendroglial degeneration leading to widespread vacuoles in the white matter in SCA34.