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BACKGROUND: Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. OBJECTIVE: Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. METHODS: Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed. RESULTS: PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. CONCLUSIONS: PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society.

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The clinical and neuropathological characteristics of progressive supranuclear palsy (PSP) with preservation of levodopa (L-dopa) response are described in this report. We present the case of a 73-year-old Japanese man with a 13-year history of dopa-responsive Parkinsonism and abnormalities observed in metaiodobenzylguanidine (MIBG) myocardial scintigraphy, suggesting Parkinson's disease. However, autopsy results revealed PSP pathology, including tuft-shaped astrocytes and globose-type neurofibrillary tangles, without Lewy body pathology. The degeneration was moderately to severely distributed in the globus pallidus, subthalamic nucleus, and substantia nigra, whereas striatal degeneration was mild. These findings suggest an intact response to L-dopa therapy throughout the patient's lifetime. Pathological examination of cardiac sympathetic nerves revealed intact nerves, suggesting functional involvement in the MIBG abnormality. This study provides further evidence of the clinical and pathological heterogeneity of PSP. Homozygosity for both the rs564309-C allele at TRIM11 and the rs2242367-G allele at SLC2A13 might have played a protective role. This case indicates a protracted course-PSP, which may hold promise for future treatments.

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INTRODUCTION: Corticobasal degeneration (CBD) is a clinically heterogeneous neurodegenerative disorder, for which pathological investigations are essential for a definitive diagnosis. This study explored the clinical characteristics of Japanese patients with pathologically confirmed CBD. METHODS: We reviewed the data of Japanese patients with pathologically confirmed CBD who were consecutively autopsied at our institute. Clinical data were obtained from medical records and clinicopathological conferences. RESULTS: Of the 34 patients initially reviewed, three were excluded because of a lack of detailed clinical data. Of the remaining 31 patients, 16 were men and 15 were women. The mean ages at onset and death were 63.3 ± 6.7 (51-79) years and 69.1 ± 6.9 (54-86), respectively. The median disease duration was 6.0 (2.5-12) years. The clinical phenotypes were as follows: progressive supranuclear palsy syndrome (PSPS; n = 20, 64.5 %), probable or possible corticobasal syndrome (n = 6, 19.4 %), frontal behavioral-spatial syndrome (n = 4, 12.9 %), nonfluent/agrammatic variant of primary progressive aphasia (n = 1, 3.2 %). Furthermore, 28 (90.3 %) patients exhibited dysphagia with a median latency of 3.5 (1.0-10.0) years, and 22 (71.0 %) patients who underwent tube feeding survived longer than those who did not (P = 0.013). CONCLUSIONS: Compared with Western populations, a high prevalence of PSPS may be a clinical characteristic of Japanese patients with CBD. Additionally, dysphagia occurs in many patients with early latency and may shorten survival. Tube feeding contributes to the prolonged survival of patients with CBD.

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White matter hyperintensities (WMH) are considered magnetic brain imaging (MRI) biomarkers of cerebral small vessel disease but their clinical role in neurodegenerative-related disorders is poorly understood. This study describes the distribution of WMH on brain MRI in Progressive Supranuclear Palsy (PSP) in comparison with Parkinson's disease (PD) and explores their possible impact on disease's features. Sixty PSP and 33 PD patients were included. Motor symptoms, cardiovascular risk factors and the age-related white matter changes (ARWMC) score was computed to rate WMH for both groups. Pearson's correlation and linear or logistic regression analysis were used to check for relationships between ARWMC and PSP clinical scores. The mean (standard deviation) ARWMC total score in the PSP cohort was 4.66 (3.25). Any degree of WMH was present in 68% of PSP (ARWMC +). Compared to ARWMC-, ARWMC + did not have greater disease severity or more cardiovascular risk factors. WMH were frequently localized in fronto-parietal lobes and were mild in severity. Linear regression analysis showed that ARWMC total score was related to the PSP-rating scale, irrespective of age, disease duration and the Charlson modified comorbidity index. Logistic regression analysis confirmed that ARWMC total score was related to the use of wheelchair, irrespective of above-mentioned covariates. Vascular risk factors as well as severity and distribution of WMH did not have an impact on the PSP phenotype. No differences were found with PD patients. Our results suggest that WMH in PSP might be markers of neurodegenerative-related pathology rather than being simple expression of atherosclerotic cerebrovascular changes.

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BACKGROUND: It has been demonstrated that progressive supranuclear palsy (PSP) correlates with structural abnormalities in several distinct regions of the brain. However, whether there are changes in the morphological similarity network (MSN) and the relationship between changes in brain structure and gene expression remain largely unknown. METHODS: We used two independent cohorts (discovery dataset: PSP: 51, healthy controls (HC): 82; replication dataset: PSP: 53, HC: 55) for MSN analysis and comparing the longitudinal changes in the MSN of PSP. Then, we applied partial least squares regression to determine the relationships between changes in MSN and spatial transcriptional features and identified specific genes associated with MSN differences in PSP. We further investigated the biological processes enriched in PSP-associated genes and the cellular characteristics of these genes, and finally, we performed an exploratory analysis of the relationship between MSN changes and neurotransmitter receptors. RESULTS: We found that the MSN in PSP patients was mainly decreased in the frontal and temporal cortex but increased in the occipital cortical region. This difference is replicable. In longitudinal studies, MSN differences are mainly manifested in the frontal and parietal regions. Furthermore, the expression pattern associated with MSN changes in PSP involves genes implicated in astrocytes and excitatory and inhibitory neurons and is functionally enriched in neuron-specific biological processes related to synaptic signaling. Finally, we found that the changes in MSN were mainly negatively correlated with the levels of serotonin, norepinephrine, and opioid receptors. CONCLUSIONS: These results have enhanced our understanding of the microscale genetic and cellular mechanisms responsible for large-scale morphological abnormalities in PSP patients, suggesting potential targets for future therapeutic trials.

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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.

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BACKGROUND: Little is known about the characteristics and occurrence frequencies of rapid eye movements (REMs) during REM sleep in movement disorders. OBJECTIVES: The aim of this study was to detect and characterize REMs during polysomnographically defined REM sleep as recorded by electro-oculography (EOG) in 12 patients with progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD) and 12 healthy controls. METHODS: Using a modified EOG montage, we developed an algorithm that automatically detects and characterizes REMs during REM sleep based on their presumptive saccadic kinematics. RESULTS: Compared to PD and healthy controls, REM densities and REM peak velocities were significantly reduced in PSP. These effects were most pronounced in vertical REMs. CONCLUSION: Ocular motor dysfunction, one of the cardinal features of PSP, seems to be equally at play during REM sleep and wakefulness. For future studies, we provide a novel tool for the unbiased analysis of REMs during REM sleep in movement disorders.

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BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian condition that results in severe disability. There are few studies of PSP in patients of non-white European ancestry. OBJECTIVES: We aim to perform deep phenotyping in a South Asian PSP cohort to uncover possible ethnic differences in disease characteristics. METHODS: Consecutive PSP patients had their clinical records reviewed for clinical features operationalized in the Movement Disorder Society (MDS)-PSP diagnostic criteria and relevant investigations, including imaging and genetic tests. Clinical variables were summarized by descriptive statistics and Kaplan-Meier curves were generated for survival analysis. RESULTS: Twenty-seven patients, comprising Indians (78%), Pakistanis (11%) and Sri Lankans (11%) were included. Mean age of symptom onset was 63.8 ± 7.0 years and 22% of patients had an early age of onset (<60 years). The most common presenting symptom was parkinsonism (56%), followed by cognitive dysfunction (37%), falls (33%) and dysarthria (26%). The predominance types at final review were distributed across PSP-RS (67%), PSP-PGF (15%), PSP-P (15%) and PSP-F (4%). Atypical clinical features like cerebellar signs (33%), REM-sleep behavior disorder (RBD) (55%), visual hallucinations (22%), and a family history of parkinsonism (20%) were evident in a proportion of patients. CONCLUSIONS: We present a South Asian cohort of PSP patients with a higher than previously reported percentages of early-onset disease, family history and atypical clinical manifestations. These patients do not fit easily into the PSP phenotypes defined by the current MDS criteria. Dedicated clinicopathological and genetic tests are needed in this population to dissect the pathogenesis of clinically-defined PSP.

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BACKGROUND: Severe dysphagia poses a significant challenge for clinicians regarding feeding tube choices, practices, and timing due to a lack of evidence-based guidance. OBJECTIVES: To assess national clinical practices and opinions on gastrostomy use in patients with atypical parkinsonian syndromes (APS) across the UK. METHODS: Online survey was administered to clinicians and allied health professionals regarding availability of services, current use, perceived advantages, and problems associated with gastrostomy insertion. RESULTS: We received responses from 47 respondents across 12 UK centers, including 44 clinicians specialized in APS. Consensus was observed regarding primary indications for gastrostomy insertion and circumstances justifying avoidance of the procedure. Limitations in recommending gastrostomy due to insufficient evidence on safety and outcomes, survival and quality of life were identified. Widespread agreement on delays in gastrostomy discussions was highlighted as a challenge in optimizing patient care, together with variability in current practices and concerns over the lack of a standardized gastrostomy pathway, emphasizing the need for further research to address existing evidence gaps. CONCLUSION: This multi-center survey highlights agreement among clinicians on key aspects of indication, challenges, and limitations such as delayed decision-making and the absence of standardized pathways regarding the timing, method, and overall approach to gastrostomy insertion in APS. This study identified next steps to facilitate a more structured approach to future research toward a consensus on best practices for gastrostomy in APS. Addressing these challenges is crucial for enhancing patient outcomes and overall care quality in APS.

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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.

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Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized initially by falls and eye movement impairment. This multimodal imaging study aimed at eliciting structural and functional disease-specific brain alterations. T1-weighted and resting-state functional MRI were applied in multi-centric cohorts of PSP and matched healthy controls. Midbrain, cerebellum, and cerebellar peduncles showed severely low gray/white matter volume, whereas thinner cortical gray matter was observed in cingulate cortex, medial and temporal gyri, and insula. Eigenvector centrality analyses revealed regionally specific alterations. Multivariate pattern recognition classified patients correctly based on gray and white matter segmentations with up to 98 % accuracy. Highest accuracies were obtained when restricting feature selection to the midbrain. Eigenvector centrality indices yielded an accuracy around 70 % in this comparison; however, this result did not reach significance. In sum, the study reveals multimodal, widespread brain changes in addition to the well-known midbrain atrophy in PSP. Alterations in brain structure seem to be superior to eigenvector centrality parameters, in particular for prediction with machine learning approaches.

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Background: Vagal atrophy is a hallmark of Parkinson's disease (PD) and has been found to be associated with autonomic dysfunction, while analyses of the vagus nerve (VN) in atypical Parkinsonian syndromes (APS) have not yet been performed. We here investigate the characteristics of the VN in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and, in a second step, its potential as a possible biomarker for orthostatic dysregulation. Objectives: The aim was to compare the VN pathology in MSA and PSP with healthy individuals and patients with PD as a differentiating factor and to further analyse the correlation of the VN with clinical parameters and cardiovascular response. Design: We conducted a monocentric, cross-sectional cohort study in 41 APS patients and compared nerve ultrasound (NUS) parameters with 90 PD patients and 39 healthy controls. Methods: In addition to a detailed neurological history and examination, several clinical severity and motor scores were obtained. Autonomic symptoms were reported in the Scales for Outcomes in Parkinson's Disease - Autonomic questionnaire. Further scores were used to detect other non-motor symptoms, quality of life and cognition. Additionally, we performed a head up tilt test (HUTT) and NUS of the VN. We conducted correlation analyses of the VN cross-sectional area (CSA) with clinical scores and the heart rate and blood pressure variability parameters of the HUTT. Results: The examination demonstrated a high prevalence of abnormal autonomic response in both MSA (90%) and PSP (80%). The VN CSA correlated with spectral parameters of the HUTT, which are associated with sympatho-vagal imbalance. In addition, the CSA of the VN in patients with PD and PSP were significantly smaller than in healthy controls. In MSA, however, there was no marked vagal atrophy in comparison. Conclusion: The occurrence of autonomic dysfunction was high in MSA and PSP, which underlines its impact on these syndromes. Our findings indicate a connection between vagal pathology and autonomic dysfunction and might contribute to a better comprehension of APS. To further evaluate the clinical relevance and the VN as a possible marker of autonomic dysfunction in APS, prospective longitudinal observations are necessary.

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Progressive supranuclear palsy (PSP) is a rare, neurodegenerative movement disorder. Together with multiple system atrophy (MSA), Dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD), PSP forms a group of atypical parkinsonisms. The latest diagnostic criteria, published in 2017 by the Movement Disorders Society, classify PSP diagnosis into defined, probable, and possible categories based on clinical examination. However, no single test is specific and sensitive for this disease. Microribonucleic acids (miRNAs) are promising molecules, particularly in the case of diseases that lack appropriate diagnostic and treatment tools, which supports exploring their role in PSP. We aimed to systematically review the current knowledge about the role of miRNAs in PSP. This study was registered in the Open Science Framework Registry, and the protocol is available online. Primary original studies, both clinical and preclinical, written in English and assessing miRNAs in PSP were included. Systematic reviews, meta-analyses, reviews, case reports, letters to editors, commentaries, conference abstracts, guidelines/statements, expert opinions, preprints, and book chapters were excluded. The following five databases were searched: Embase, Medline Ultimate, PubMed, Scopus, and Web of Science. Each database was last searched on 18 June 2024. Eventually, nine original studies relevant to the discussed area were included. The risk of bias was not assessed. The selected research suggests that miRNAs may be considered promising biomarkers in PSP. However, the exact involvement of miRNAs in the pathogenesis of PSP is still to be determined. Several microRNAs were found to be dysregulated in patients with PSP. This applies to both brain tissue and fluids like cerebrospinal fluid CSF or blood. Several miRNAs were found that could potentially be helpful in differentiating among PSP patients, PD patients, and healthy individuals. Although some correlations and alterations have already been found, this field requires much more research. MicroRNAs are exciting and promising small molecules, and their investigation into many diseases, including PSP, may lead to significant discoveries.

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The molecular pathogenesis of degenerative parkinsonisms, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and Multiple system atrophy (MSA), remains largely unknown. To gain novel insight into molecular processes associated with these diseases, we conducted a proteome-wide expression study in prefrontal cortex tissue from a cohort of 181 individuals, comprising PD (N = 73), PSP (N = 18), MSA (N = 17) and healthy control (N = 73). Using marker gene profiles, we first assess the cellular composition of the samples and, subsequently, identify distinct protein signatures for each disease, while correcting for cell composition. Our findings indicate that all three diseases are characterized by a structural and/or functional loss of deep cortical neurons, while PD exhibits an additional decrease in somatostatin-expressing interneurons, as well as in endothelial cells. Differential protein expression analysis identified multiple proteins and pathways with disease-specific expression, some of which have previously been associated with parkinsonism or neurodegeneration in general. Notably, we observed a strong mitochondrial signature which was present in both PD and PSP, albeit of a different composition and most pronounced in PSP, but not in MSA where immunological/inflammation-related pathways dominated. Additionally, we identified protein signatures associated with the severity of α-synuclein pathology in PD and showed that these are highly enriched in an upregulation of mitochondrial processes, specifically related to oxidative phosphorylation and in particular respiratory complexes I and IV. We identify multiple novel signatures of protein expression, associated with PD, PSP, and MSA, as well as with the severity of α-synuclein pathology in the PD brain.

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Introduction: Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA) are rare neurodegenerative diseases associated with rapid decline and require complex symptom management. Caregiving responsibilities significantly increase with progression of these atypical Parkinsonian syndromes, yet care burden in these syndromes has not been researched extensively to date. Methods: The Zarit Burden Interview (ZBI) was used to assess burden in care partners of patients clinically diagnosed with PSP, CBS, or MSA seen in specialty interdisciplinary clinics at two academic movement disorders centers. Univariable and multivariable regression analyses were performed to evaluate cross-sectional demographic and clinical determinants of care partner burden. Results: A total of 139 care partners completed the ZBI (59.0% PSP, 28.1% MSA, 12.9% CBS). Cohorts at both medical centers were similar across all variables. Female gender of both patients and care partners was independently associated with higher ZBI scores. Additionally, MSA-Parkinsonian type was significantly associated with lower total care partner burden compared to PSP and CBS. Conclusion: Several determinants of higher care partner burden in atypical Parkinsonian syndromes were identified, particularly female gender and diagnosis. Healthcare professionals can consider this information when assessing individualized needs of patients and care partners and referring to disease-specific resources. Additionally, this study's methods and results highlight the potential to further explore interdisciplinary care as a means of comprehensive evaluation and support for those with atypical Parkinsonism.

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BACKGROUND AND PURPOSE: Peripheral inflammation is probably involved in the pathogenesis of progressive supranuclear palsy (PSP) and it may be a common feature with Parkinson's disease (PD). The peripheral immune profile in PSP remains unclear, as well as whether the inflammatory pathways differ from those in PD. The neutrophil-to-lymphocyte ratio (NLR) has been proven to be a well-established biomarker of systemic inflammation. This study aimed to evaluate the peripheral immune profile in PSP compared with PD. METHODS: A cross-sectional study was conducted including patients with PSP and PD and healthy controls (HCs). Leukocyte subpopulations and the NLR were measured in peripheral blood. Multivariate linear regression and post hoc tests were applied. Electronic databases were searched in November 2023 to perform meta-analyses to clarify the peripheral immune profile in PSP. RESULTS: Our cohort included 121 patients with PSP, 127 patients with PD and 266 HCs. The NLR was higher in PSP and PD compared with HCs. PSP had a higher neutrophil count compared with HCs. Whilst a lower lymphocyte count was found in PD compared with HCs, the lymphocyte count did not differ between PSP and HCs. The meta-analyses supported this immune profile. CONCLUSIONS: PSP and PD show an increased peripheral inflammation and a higher NLR compared with HCs. Different pathogenic inflammatory mechanisms are probably involved in PSP and PD, since in PSP this altered peripheral immune profile is mainly driven by neutrophils. Understanding the neutrophils' role in PSP may allow for the development of targeted therapies.

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Progressive supranuclear palsy (PSP) is a neurodegenerative movement and cognitive disorder characterized by abnormal accumulation of the microtubule-associated protein tau in the brain. Biochemically, inclusions in PSP are enriched for tau proteoforms with four microtubule-binding domain repeats (4R), an isoform that arises from alternative tau pre-mRNA splicing. While preferential aggregation and reduced degradation of 4R tau protein is thought to play a role in inclusion formation and toxicity, an alternative hypothesis is that altered expression of tau mRNA isoforms plays a causal role. This stems from the observation that PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus which contains low copy number repeats flanking a large recurrent genomic inversion. The complex genomic structural changes at the locus give rise to two dominant haplotypes, termed H1 and H2, that have the potential to markedly influence gene expression. Here, we explored haplotype-dependent differences in gene expression using a bulk RNA-seq dataset derived from human post-mortem brain tissue from PSP (n = 84) and controls (n = 77) using a rigorous computational pipeline, including alternative pre-mRNA splicing. We found 3579 differentially expressed genes in the temporal cortex and 10,011 in the cerebellum. We also found 7214 differential splicing events in the temporal cortex and 18,802 in the cerebellum. In the cerebellum, total tau mRNA levels and the proportion of transcripts encoding 4R tau were significantly increased in PSP compared to controls. In the temporal cortex, the proportion of reads that expressed 4R tau was increased in cases compared to controls. 4R tau mRNA levels were significantly associated with the H1 haplotype in the temporal cortex. Further, we observed a marked haplotype-dependent difference in KANSL1 expression that was strongly associated with H1 in both brain regions. These findings support the hypothesis that sporadic PSP is associated with haplotype-dependent increases in 4R tau mRNA that might play a causal role in this disorder.

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INTRODUCTION: We present a systematic review of phenotypes of McLeod syndrome (MLS) and a case of a 73-year-old female carrier of the genetic alteration leading to MLS with the typical progressive supranuclear palsy (PSP) phenotype. METHODS: To facilitate clinical reasoning and enable targeted diagnosis, we conducted a systematic review of the papers describing symptomatic cases of confirmed McLeod syndrome. This review follows the PRISMA 2020 statement: an updated guideline for reporting systematic reviews (Page et al in Syst Rev 10(1):89, 2021). RESULTS: The average onset of MLS was at 40.2 years of age with chorea (46%), seizures and psychiatric changes (each 13%). Very common are weakened Kell antigen (100%), changes in muscle biopsy (100%), genetic alterations in XK (100%), elevated creatine kinase (97%), acanthocytes (96%), MRI changes (95%), chorea (84%) and hyporeflexia (82%). CONCLUSION: This review of 65 males and 11 females gives a concise overview of clinical phenotypes in MLS, reinforcing our view that this female patient had PSP independent of MLS carrier status. This report highlights the pitfalls of anchoring in medical decision-making, particularly the possible diagnostic bias of a known genetic carrier status of a very rare disease.

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Purpose: This case study measured how well the Lee Silverman Voice Treatment (LSVT) improved vocal features, intelligibility, and communicative effectiveness for a multilingual participant with hypokinetic-hyperkinetic dysarthria secondary to suspected progressive supranuclear palsy. LSVT treatment was chosen for the participant due to the strengths and deficits he presented with prior to treatment, and for the anticipated challenges in treatment that may arise from the presence of multilingualism and impaired cognitive functioning. Methods: A multilingual patient in their 60's (English, Spanish, and French) with hypokinetic-hyperkinetic dysarthria secondary to suspected progressive supranuclear palsy completed the standard treatment sessions for LSVT. Assessment measures were taken at baseline, immediately post-treatment, and three-months post-treatment. Results: Improvements were measured in vocal quality, vocal loudness, intelligibility, and communicative effectiveness immediately post-treatment. Three months post-treatment, improvements in vocal quality and intelligibility were maintained. Conclusion: This case study illustrates that LSVT may be a beneficial treatment for complex clients who are multilingual and present with complex comorbidities and cognitive deficits. LSVT resulted in some meaningful changes in vocal quality, intelligibility, and communicative effectiveness for this individual. Clinicians who work with complex patients may wish to consider the theoretical underpinnings of LSVT, client profile, areas of client need, and ability and desire to complete an intensive treatment program to determine if trialing LSVT is appropriate. The use of LSVT with complex clients may yield positive outcomes.

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Tauopathy is known to be a major pathognomonic finding in important neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration. However, the mechanism by which tauopathy is triggered remains to be elucidated. We previously identified the point mutation c.11596C > G, p.Pro3866Ala in the Bassoon gene (BSN) in a Japanese family with PSP-like syndrome. We showed that mutated BSN may have been involved in its own insolubilization and tau accumulation. Furthermore, BSN mutations have also been related to various neurological diseases. In order to further investigate the pathophysiology of BSN mutation in detail, it is essential to study it in mouse models. We generated a mouse model with the mouse Bassoon p.P3882A mutation, which corresponds to the human BSN p.P3866A mutation, knock-in (KI) and we performed systematic behavioral and histological analyses. Behavioral analyses revealed impaired working memory in a Y-maze test at 3 months of age and decreased locomotor activity in the home cage at 3 and 12 months of age in KI mice compared to those in wild-type mice. Although no obvious structural abnormalities were observed at 3 months of age, immunohistochemical studies showed elevation of Bsn immunoreactivity in the hippocampus and neuronal loss without tau accumulation in the substantia nigra at 12 months of age in KI mice. Although our mice model did not show progressive cognitive dysfunction and locomotor disorder like PSP-like syndrome, dopaminergic neuronal loss was observed in the substantia nigra in 12-month-old KI mice. It is possible that BSN mutation may result in dopaminergic neuronal loss without locomotor symptoms due to the early disease stage. Thus, further clinical course can induce cognitive dysfunction and locomotor symptoms.