Putaminal T1/T2-weighted ratio is increased in PSP compared to PD and healthy controls, a multi-cohort study.

INTRODUCTION: Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is a common clinical problem. We aimed to apply the T1-/T2-weighted ratio imaging technique, based on standard clinical MRI, to reveal differences in neurodegeneration in three large cohorts. METHODS: Three cohorts, with a total of 405 participants (269 PD, 44 PSP, 38 MSA, 54 controls), were combined and T1/T2-weighted ratio image analyses were carried out. A combination of automatic segmentation and atlas-based ROI were used in this study. The cohorts were combined using the ComBat batch correction procedure. RESULTS: Group differences were found in the putamen (p = 0.040), with higher T1/T2-weighted ratio in this region in PSP compared to PD and healthy controls (p-values 0.010 and 0.007 respectively). Using putaminal T1/T2-weighted ratio for diagnostic separation, a fair performance was found in separating PSP from healthy controls, with an area under the receiver operating characteristic curve of 0.701. CONCLUSION: Different patterns of T1/T2-weighted ratio, reflecting differences in underlying pathophysiology, were found between the groups. Since T1/T2-weighted ratio can be applied to standard clinical MRI sequences to allow more quantitative analyses, this seems to be a promising biomarker for diagnostics and treatment evaluation of parkinsonian disorders for clinical trials.

[Clinical features and effects of shunt surgery in patients with progressive supranuclear palsy and idiopathic normal pressure hydrocephalus].

This study aimed to retrospectively review the frequency and clinical features of 13 patients with progressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH). All patients were found to have PSP-Richardson's syndrome (PSP-RS). Shunt surgery was effective in 5 of 11 patients (45.5%). A comparison of these 5 patients who responded to shunt surgery versus the remaining 6 patients revealed a significant difference in the reduction of frontal lobe blood flow on cerebral perfusion single-photon emission computed tomography (SPECT) (P = 0.018). These results suggest that PSP-RS is common in patients with PSP and iNPH and indicate the usefulness of cerebral perfusion SPECT in estimating the effect of shunt surgery.

Colocalization of Increased Midbrain Signals in Neuroinflammation and Tau PET Imaging Suggests the Diagnosis of Progressive Supranuclear Palsy.

ABSTRACT: Clinical overlap with multiple other neurological diseases makes the diagnosis of autoimmune encephalitis challenging; consequently, a broad range of neurological diseases are misdiagnosed as autoimmune encephalitis. A 58-year-old man presented with abnormal behavior, irritability for 3 years, oculomotor disturbance, unsteady walking, and dysphagia and was suspected as having anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis as the anti-DPPX antibody was positive in the serum. However, the therapeutic effect of immunotherapy was unsatisfactory. Subsequently, colocalization of increased midbrain signals was observed in neuroinflammation PET using [ 18 F]DPA-714 and in tau PET using [ 18 F]florzolotau, suggesting the diagnosis of progressive supranuclear palsy.

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.

Differentiating progressive supranuclear palsy from other movement disorders using transcranial sonography: a systematic review and meta-analysis.

Progressive supranuclear palsy (PSP) is an atypical parkinsonism that presents with different phenotypes. There are still no validated diagnostic biomarkers for early diagnosis of PSP. Transcranial sonography (TCS) is a promising tool in the differential diagnosis of parkinsonian disorders; however, there are no systematic investigations about the application of TCS in PSP patients. Therefore, we performed a systematic review and meta-analysis to discuss the role of TCS in diagnosing PSP by systematically searching PubMed, Cochrane Library, Chinese National Knowledge Infrastructure and Wan Fang databases. Of 66 obtained records, 16 articles, including 366 patients with PSP, were included. Our results showed the estimated random-effects pooled prevalence of substantia nigra hyperechogenicity in patients with PSP was 22% (95% CI 12-32%), lenticular nucleus hyperechogenicity was 70% (95% CI 52-82%), and enlarged third ventricle was 71% (95% CI 55-85%). Additionally, a normal echogenicity substantia nigra in TCS showed 70% sensitivity (95% CI 56-81%) and 86% specificity (95% CI 75-86%) to differentiate PSP from Parkinson's disease. In conclusion, TCS is an important supplementary biomarker for diagnosing PSP. At the same time, the diagnostic value of TCS in discriminating PSP from other atypical parkinsonism and between different PSP phenotypes needs further exploration.

The MAPT p.E342K and p.R406W mutations are associated with progressive supranuclear palsy with atypical features.

INTRODUCTION: Progressive supranuclear palsy (PSP) is an atypical parkinsonism caused by the intracerebral aggregation of the microtubule-associated protein tau (MAPT) which is encoded by MAPT gene. Although PSP is a sporadic disease, MAPT mutations have been reported in rare cases. METHODS: Among 190 patients with PSP who were recruited by the Neurodegenerative Research Group at Mayo Clinic during 2009-2023, we identified two patients who fulfilled diagnostic criteria for PSP-Richardson's syndrome (PSP-RS) and harbor novel MAPT mutations. To better investigate the potential effects of these mutations, we compared the clinical, and neuroimaging characteristics of these two patients to 20 randomly selected patients with PSP-RS without a MAPT mutation. RESULTS: MAPT c.1024G > A, p. Glu342Lys, and MAPT c.1217 G > A, p. Arg406Gln mutations were found in 2 men who developed PSP-RS with atypical features at the ages of 60 and 62 years, respectively. Glu342Lys mutation was associated with features resembling alpha-synucleinopathies (autonomic dysfunction, dream enactment behavior), while both mutations were associated with features suggestive of Alzheimer's disease with poorer performance on tests of episodic memory. Comparison of 18F-flortaucipir uptake between the two MAPT mutation cases with 20 patients without a mutation revealed increased signal on flortaucipir-PET in bilateral medial temporal lobe regions (amygdala, entorhinal cortices, hippocampus, parahippocampus) but not in PSP-related regions (globus pallidum, midbrain, superior frontal cortex and dentate nucleus of the cerebellum). CONCLUSION: Glu342Lys and Arg406Gln mutations appear to modify the PSP-RS phenotype by targeting the medial temporal lobe regions resulting in more memory loss and greater flortaucipir uptake.

New Perspectives in Radiological and Radiopharmaceutical Hybrid Imaging in Progressive Supranuclear Palsy: A Systematic Review.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by four-repeat tau deposition in various cell types and anatomical regions, and can manifest as several clinical phenotypes, including the most common phenotype, Richardson's syndrome. The limited availability of biomarkers for PSP relates to the overlap of clinical features with other neurodegenerative disorders, but identification of a growing number of biomarkers from imaging is underway. One way to increase the reliability of imaging biomarkers is to combine different modalities for multimodal imaging. This review aimed to provide an overview of the current state of PSP hybrid imaging by combinations of positron emission tomography (PET) and magnetic resonance imaging (MRI). Specifically, combined PET and MRI studies in PSP highlight the potential of [18F]AV-1451 to detect tau, but also the challenge in differentiating PSP from other neurodegenerative diseases. Studies over the last years showed a reduced synaptic density in [11C]UCB-J PET, linked [11C]PK11195 and [18F]AV-1451 markers to disease progression, and suggested the potential role of [18F]RO948 PET for identifying tau pathology in subcortical regions. The integration of quantitative global and regional gray matter analysis by MRI may further guide the assessment of reduced cortical thickness or volume alterations, and diffusion MRI could provide insight into microstructural changes and structural connectivity in PSP. Challenges in radiopharmaceutical biomarkers and hybrid imaging require further research targeting markers for comprehensive PSP diagnosis.

Corneal confocal microscopy demonstrates varying degrees of neurodegeneration in atypical parkinsonian disorders.

OBJECTIVE: We have used corneal confocal microscopy (CCM) to identify corneal nerve loss as a potential marker of neurodegeneration in participants with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). METHODS: Patients with PD (n = 19), PSP (n = 11), MSA (n = 8) and healthy controls (n = 18) underwent neurological assessment and CCM. RESULTS: Corneal nerve fibre density was significantly lower in participants with PD (p = 0.005), PSP (p = 0.005) and MSA (p = 0.0003) compared to controls. Corneal nerve branch density was significantly lower in participants with PD (p = 0.01) and MSA (p = 0.019), but not in participants with PSP (p = 0.662), compared to controls. Corneal nerve fibre length was significantly lower in participants with PD (p = 0.002) and MSA (p = 0.001) but not in participants with PSP (p = 0.191) compared to controls. CONCLUSION: CCM detects corneal nerve loss in participants with PD and MSA and to a lesser extent in PSP compared to healthy controls.

Analysis of Genetic and MRI Changes, Blood Markers, and Risk Factors in a Twin Pair Discordant of Progressive Supranuclear Palsy.

Background and Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative disease, a tauopathy, which results in a wide clinical spectrum of neurological symptoms. The diagnosis is mostly based on clinical signs and neuroimaging; however, possible biomarkers for screening have been under investigation, and the role of the gut microbiome is unknown. The aim of our study was to identify potential blood biomarkers and observe variations in the gut microbiome within a PSP discordant monozygotic twin pair. Materials and Methods: Anthropometric measurements, neuropsychological tests, and the neurological state were evaluated. Blood was collected for metabolic profiling and for the detection of neurodegenerative and vascular biomarkers. Both the gut microbiome and brain MRI results were thoroughly examined. Results: We found a relevant difference between alpha-synuclein levels and moderate difference in the levels of MMP-2, MB, Apo-A1, Apo-CIII, and Apo-H. With respect to the ratios, a small difference was observed for ApoA1/SAA and ApoB/ApoA1. Using a microbiome analysis, we also discovered a relative dysbiosis, and the MRI results revealed midbrain and frontoparietal cortical atrophy along with a reduction in overall brain volumes and an increase in white matter lesions in the affected twin. Conclusions: We observed significant differences between the unaffected and affected twins in some risk factors and blood biomarkers, along with disparities in the gut microbiome. Additionally, we detected abnormalities in brain MRI results and alterations in cognitive functions.

Striatal and thalamic automatic segmentation, morphology, and clinical correlates in Parkinsonism: Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) present similarly with bradykinesia, tremor, rigidity, and cognitive impairments. Neuroimaging studies have found differential changes in the nigrostriatal pathway in these disorders, however whether the volume and shape of specific regions within this pathway can distinguish between atypical Parkinsonian disorders remains to be determined. This paper investigates striatal and thalamic volume and morphology as distinguishing biomarkers, and their relationship to neuropsychiatric symptoms. Automatic segmentation to calculate volume and shape analysis of the caudate nucleus, putamen, and thalamus were performed in 18 PD patients, 12 MSA, 15 PSP, and 20 healthy controls, then correlated with clinical measures. PSP bilateral thalami and right putamen were significantly smaller than controls, but not MSA or PD. The left caudate and putamen significantly correlated with the Neuropsychiatric Inventory total score. Bilateral thalamus, caudate, and left putamen had significantly different morphology between groups, driven by differences between PSP and healthy controls. This study demonstrated that PSP patient striatal and thalamic volume and shape are significantly different when compared with controls. Parkinsonian disorders could not be differentiated on volumetry or morphology, however there are trends for volumetric and morphological changes associated with PD, MSA, and PSP.

Midbrain atrophy in pathologically diagnosed Lewy body disease and clinically diagnosed Parkinson's disease.

OBJECTIVE: Midbrain atrophy is considered specific to progressive supranuclear palsy (PSP) compared with Parkinson's disease (PD). We aimed to determine how often midbrain atrophy is observed in pathologically diagnosed Lewy body disease (LBD) and clinically diagnosed PD and the robustness of midbrain atrophy assessed by the One-Line Method previously developed for the diagnosis of PSP. METHODS: We studied two separate cohorts with MRI: the first pathologically diagnosed cohort consisted of patients with LBD (n = 13), PSP (n = 6), multiple system atrophy (MSA, n = 7), and corticobasal degeneration (CBD, n = 2); the second cohort consisted of patients with PD (n = 122). Midbrain length was measured using the One-Line Method and FreeSurfer estimated volumes of the subcortical nuclei. RESULTS: The area under the curve of midbrain length differentiating PSP from LBD, MSA, and CBD in a pathologically diagnosed cohort was 0.91. Midbrain length with cut-off values of 10.5 mm and 9.5 mm had a sensitivity of 100% and 67% and a specificity of 68% and 96%, respectively. In the first cohort, 7.7% and 23.0% of patients with LBD showed midbrain lengths <9.5 mm and 10.5 mm, respectively, and in the second cohort, 4.9% and 19.7% showed midbrain lengths <9.5 mm and 10.5 mm, respectively. INTERPRETATION: Midbrain length measured using the One-Line Method is helpful in the diagnosis of PSP. Some cases of pathologically diagnosed LBD and clinically diagnosed PD present with midbrain atrophy.

Uncovering distinct progression patterns of tau deposition in progressive supranuclear palsy using [18F]Florzolotau PET imaging and subtype/stage inference algorithm.

BACKGROUND: Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy with diverse clinical phenotypes. Previous post-mortem studies examined tau deposition sequences in PSP, but in vivo scrutiny is lacking. METHODS: We conducted [18F]Florzolotau tau positron emission tomography (PET) scans on 148 patients who were clinically diagnosed with PSP and 20 healthy controls. We employed the Subtype and Stage Inference (SuStaIn) algorithm to identify PSP subtype/stage and related tau patterns, comparing clinical features across subtypes and assessing PSP stage-clinical severity association. We also evaluated functional connectivity differences among subtypes through resting-state functional magnetic resonance imaging. FINDINGS: We identified two distinct subtypes of PSP: Subtype1 and Subtype2. Subtype1 typically exhibits a sequential progression of the disease, starting from subcortical and gradually moving to cortical regions. Conversely, Subtype2 is characterized by an early, simultaneous onset in both regions. Interestingly, once the disease is initiated, Subtype1 tends to spread more rapidly within each region compared to Subtype2. Individuals categorized as Subtype2 are generally older and exhibit less severe dysfunctions in areas such as cognition, bulbar, limb motor, and general motor functions compared to those with Subtype1. Moreover, they have a more favorable prognosis in terms of limb motor function. We found significant correlations between several clinical variables and the identified PSP SuStaIn stages. Furthermore, Subtype2 displayed a remarkable reduction in functional connectivity compared to Subtype1. INTERPRETATION: We present the evidence of distinct in vivo spatiotemporal tau trajectories in PSP. Our findings can contribute to precision medicine advancements for PSP. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (number 82272039, 81971641, 82021002, and 92249302); Swiss National Science Foundation (number 188350); the STI2030-Major Project of China (number 2022ZD0211600); the Clinical Research Plan of Shanghai Hospital Development Center of China (number SHDC2020CR1038B); and the National Key R&D Program of China (number 2022YFC2009902, 2022YFC2009900), the China Scholarship Council (number 202006100181); the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).

Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity.SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy.

Detailed Assessment of 18F-THK5351 Distribution Pattern in the Midbrain: Comparison With Progressive Supranuclear Palsy and Corticobasal Syndrome.

BACKGROUND: 18F-THK5351 PET is used to image ongoing astrogliosis by estimating monoamine oxidase B levels. 18F-THK5351 preferentially accumulates around the substantia nigra (SN) and periaqueductal gray (PG) in the midbrain under healthy conditions and exhibits a "trimodal pattern." In progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), the midbrain 18F-THK5351 uptake can be increased by astrogliosis, collapsing the "trimodal pattern." We aimed to elucidate cases in which the "trimodal pattern" collapses in PSP and CBS. PATIENTS AND METHODS: Participants in the PSP (n = 11), CBS (n = 17), Alzheimer disease (n = 11), and healthy control (n = 8) groups underwent 18F-THK5351 PET. Volumes of interest (VOIs) were placed on the SN, PG, and their midpoints. The midbrain uptake ratio (MUR) was calculated to assess the trimodal pattern as follows: MUR = (VOI value on the midpoint)/(VOI value on the SN and PG). Approximately, the trimodal pattern can be identified at MUR <1 but not at MUR >1. RESULTS: Compared with the healthy control group, MUR significantly increased in the PSP (P < 0.01) and CBS (P < 0.01) groups, but was unchanged in the Alzheimer disease group (P = 0.10). In the PSP group, all patients, including 2 with mild symptoms and a short disease duration, showed MUR >1. In the CBS group, MUR varied widely. CONCLUSIONS: In PSP, the trimodal pattern can collapse even in the early phase when symptoms are mild. In CBS, the trimodal pattern may or may not collapse depending on the underlying pathology.

Frequency and imaging correlates of neuropsychiatric symptoms in Progressive Supranuclear Palsy.

Neuropsychiatric symptoms are intrinsic to Progressive Supranuclear Palsy (PSP) and a spoonful of studies investigated their imaging correlates. Describe (I) the frequency and severity of neuropsychiatric symptoms in PSP and (II) their structural imaging correlates. Twenty-six PSP patients underwent Neuropsychiatric Inventory (NPI) and brain 3D T1-weighted MRI. Spearman's rho with Bonferroni correction was used to investigate correlations between NPI scores and volumes of gray matter regions. More than 80% of patients presented at least one behavioral symptom of any severity. The most frequent and severe were depression/dysphoria, apathy, and irritability/lability. Significant relationships were found between the severity of irritability and right pars opercularis volume (p < 0.001) as well as between the frequency of agitation/aggression and left lateral occipital volume (p < 0.001). Depression, apathy, and irritability are the most common neuropsychiatric symptoms in PSP. Moreover, we found a relationship between specific positive symptoms as irritability and agitation/aggression and greater volume of the right pars opercularis cortex and lower volume of the left occipital cortex, respectively, which deserve further investigations.

Spinocerebellar ataxia type 8 presents as progressive supranuclear palsy.

Spinocerebellar ataxia type 8 is a progressive neurodegenerative disease induced by expansion of CTA/CTG repeats in an untranslated region of the ATXN8/ATXN8OS gene. We report an elderly female patient presenting with rigidity, bradykinesia, ataxia and oculomotor defect at the disease onset age of 65 years old without family history, and hummingbird sign in cranial MRI, initially diagnosed as progressive supranuclear palsy (PSP). But genetic test showed that one allele of ATXN8OS gene had more than 131 CTA/CTG repeats which was a full penetrance mutant. It's possible that this is a case of PSP with an ATXN8OS gene mutation that doesn't contribute to the phenotype. Whether the ATXN8OS gene CTA/CTG repeats cause PSP phenotype needs further investigation with larger samples and pathological findings.

[18F]-FDopa positron emission tomography imaging in corticobasal syndrome.

PURPOSE: First, to investigate the patterns of [18F]-FDOPA positron emission tomography imaging in corticobasal syndrome using visual and semi-quantitative analysis and to compare them with patterns found in Parkinson's disease and progressive supranuclear palsy. Then, to search for correlations with clinical features and [18F]-FDG positron emission tomography imaging. METHODS: 27 corticobasal syndrome patients who underwent [18F]-FDOPA positron emission tomography imaging were retrospectively studied. They were compared to 27 matched Parkinson's disease patients, 12 progressive supranuclear palsy patients and 53 normal controls. Scans were visually assigned to one of the following patterns: normal; unilateral homogeneous striatal uptake reduction; putamen uptake reduction with putamen-caudate gradient. A semi-quantitative analysis of striatal regional uptake and asymmetry was performed and correlated to clinical features and [18F]-FDG positron emission tomography patterns. RESULTS: [18F]-FDOPA positron emission tomography appeared visually abnormal in only 33.5% of corticobasal syndrome patients. However, semi-quantitative analysis found putaminal asymmetry in 63%. Striatal uptake was homogeneously reduced in both putamen and caudate nucleus in corticobasal syndrome patients unlike in Parkinson's disease and progressive supranuclear palsy. No correlation was found between [18F]-FDOPA positron emission tomography and clinical features. Half of corticobasal syndrome patients presented a corticobasal degeneration pattern on [18F]-FDG positron emission tomography.  CONCLUSION: [18F]-FDOPA positron emission tomography can often be normal in corticobasal syndrome patients. Semi-quantitative analysis is useful to unmask a significant asymmetry in many of them. Homogeneous striatal uptake reduction contralateral to the clinical signs is highly suggestive of corticobasal syndrome. This finding can be helpful to better characterize this syndrome with respect to Parkinson's disease and progressive supranuclear palsy.

Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome.

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.

Case report of a patient with unclassified tauopathy with molecular and neuropathological features of both progressive supranuclear palsy and corticobasal degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region - PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.