The associations between common neuroimaging parameters of Progressive Supranuclear Palsy in magnetic resonance imaging and non-specific inflammatory factors - pilot study.

Progressive Supranuclear Palsy is an atypical parkinsonism based on tauopathic pathology. Growing interest is associated with the pathomechanism of this disease. Among theories analyzing this issue can be mentioned the one highlighting the significance of inflammation. In this study authors examined 14 patients with PSP-Richardson syndrome (PSP-RS) and 13 healthy volunteers using laboratory testing based on the analysis of interleukins 1 and 6 (IL-1 and IL-6), tau in the cerebrospinal fluid (CSF) and non-specific parameters of peripheral inflammation in the serum (IL-1, IL-6, neutrophils, lymphocytes, monocytes, platelets and the ratios based on the factors). All of the patients underwent neuroimaging using magnetic resonance imaging using 3 Tesla. The serum levels of IL-1 were positively correlated with the area of the mesencephalon, suggesting that higher levels of IL-1 are not linked with atrophic changes in this region, whereas serum levels IL-6 was positively correlated with frontal horn width and negatively correlated with superior cerebellar area. Additionally IL-6 in the serum was found to be correlated with neutrophil-to-high density lipoprotein ratio. The observations were not confirmed in the analysis of the levels of interleukins in the CSF. To the best of our knowledge this work is one of the first analyzing this issue. The outcome of the work shows that the role of interleukins associated with microglial activation may possibly differ in the context of neurodegenerative changes, moreover the role of peripheral inflammation in PSP requires further analysis.

Clinicopathologic and Neuroimaging Correlations of Nonverbal Oral Apraxia in Patients With Neurodegenerative Disease.

BACKGROUND AND OBJECTIVES: Nonverbal oral apraxia (NVOA) is the inability to plan, sequence, and execute voluntary oromotor movements in the absence of weakness. In the context of neurodegenerative disease, it remains unclear whether it is linked to a specific underlying pathologic, clinical, or neuroimaging finding. Thus, we aimed to assess the clinicopathologic and neuroimaging associations of NVOA. METHODS: We conducted a retrospective study of autopsy-confirmed patients previously assessed through an NVOA evaluation tool with a previously published cutpoint to screen for NVOA. We compared demographic and clinical characteristics and postmortem pathology between those who developed NVOA and those who did not. We also compared clinicopathologic characteristics in mild vs greater than mild NVOA and early vs late-emerging NVOA. SPM12 was used to assess patterns of gray matter loss in NVOA vs non-NVOA with age and sex included as covariates. RESULTS: A total of 104 patients (median age at symptom onset 63 years, 43% female) were included in the study. 63 (60.6%) developed NVOA. NVOA appeared at a median of 4.3 years from symptom onset. 29% developed NVOA within the first 3 years. Primary progressive apraxia of speech and the nonfluent variant of primary progressive aphasia were the most common baseline diagnoses in the NVOA group while progressive supranuclear palsy (PSP) syndrome and logopenic progressive aphasia (LPA) were the most common in patients without NVOA. Atrophy of the left lateral and medial posterior frontal cortex was related to NVOA. The most common pathologies associated with NVOA were PSP (36.5%) and corticobasal degeneration (CBD) (33.3%). In patients without NVOA, PSP (26.8%) and other pathologies (26.8%) were the most frequent. 11% of patients with NVOA had persistently mild NVOA and were more likely to have baseline diagnoses of LPA, PSP syndrome, or semantic dementia. The most frequent pathologies in this group were Alzheimer disease and PSP. The pathologic associations of greater than mild NVOA were CBD and PSP. DISCUSSION: NVOA is present in several clinical syndromes. It is most associated with PSP and CBD. NVOA is a manifestation of left lateral and medial posterior frontal cortex damage rather than a particular pathology.

Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions.

 In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.

In a study of 32 patients with progressive supranuclear palsy (PSP), we used a molecular imaging tracer called [18F]PI-2620 to measure two things: the presence of a protein called tau in deep brain areas (specifically, the globus pallidus internus and dentate nucleus) and the function of the brain's cortex by assessing blood flow (perfusion). We found that higher amounts of tau in these deep brain areas were associated with reduced blood flow in the limbic cortex, which is involved in emotion regulation. Also, the frontal areas of the brain showed reduced blood flow related to tau in these deep brain regions. However, this connection was statistically significant only for the dentate nucleus. This study suggests that the buildup of tau protein in deeper brain areas can disrupt function in parts of the brain's cortex, highlighting the damaging role of tau in PSP.

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials.

BACKGROUND: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. OBJECTIVE: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. METHODS: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. RESULTS: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. CONCLUSIONS: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Usefulness of Olfactory Bulb Measurement in 3D-FIESTA in Differentiating Parkinson Disease from Atypical Parkinsonism.

BACKGROUND AND PURPOSE: Parkinson disease is a prevalent disease, with olfactory dysfunction recognized as an early nonmotor manifestation. It is sometimes difficult to differentiate Parkinson disease from atypical parkinsonism using conventional MR imaging and motor symptoms. It is also known that olfactory loss occurs to a lesser extent or is absent in atypical parkinsonism. To the best of our knowledge, no study has examined olfactory bulb changes to differentiate Parkinson disease from atypical parkinsonism, even in an early diagnosis, and its association with conventional MR imaging findings. Hence, we aimed to assess the utility of olfactory bulb measurements in differentiating Parkinson disease from atypical parkinsonism even in the early stage. MATERIALS AND METHODS: In this retrospective study, we enrolled 108 patients with Parkinson disease, 13 with corticobasal syndrome, 15 with multiple system atrophy, and 17 with progressive supranuclear palsy who developed parkinsonism. Thirty-nine age-matched healthy subjects served as controls. All subjects underwent conventional MR imaging and 3D FIESTA for olfactory bulb measurements using manual ROI quantification of the cross-sectional olfactory bulb area using the coronal plane. Bilateral olfactory bulb measurements were averaged. For group comparisons, we used the Welch t test, and we assessed diagnostic accuracy using receiver operating characteristic analysis. RESULTS: Patients with Parkinson disease had a mean olfactory bulb area of 4.2 (SD, 1.0 mm2), significantly smaller than in age-matched healthy subjects (6.6 [SD, 1.7 mm2], P < .001), and those with corticobasal syndrome (5.4 [SD, 1.2 mm2], P < .001), multiple system atrophy (6.5 [SD, 1.2 mm2], P < .001), and progressive supranuclear palsy (5.4 [SD, 1.2 mm2], P < .001). The receiver operating characteristic analysis for the olfactory bulb area measurements showed good diagnostic performance in differentiating Parkinson disease from atypical parkinsonism, with an area under the curve of 0.87, an optimal cutoff value of 5.1 mm2, and a false-positive rate of 18%. When we compared within 2 years of symptom onset, the olfactory bulb in Parkinson disease (4.2 [SD, 1.1 mm2]) remained significantly smaller than in atypical parkinsonism (versus corticobasal syndrome (6.1 [SD, 0.7 mm2]), P < .001; multiple system atrophy (6.3 [SD, 1.4 mm2]), P < .001; and progressive supranuclear palsy (5.2 [1.3 mm2], P = .003, respectively). CONCLUSIONS: 3D FIESTA-based olfactory bulb measurement holds promise for distinguishing Parkinson disease from atypical parkinsonism, especially in the early stage.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism.

BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.

In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.

PURPOSE: [18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET. METHODS: In the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios. RESULTS: AIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls. CONCLUSION: Blood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose.

Clinical Utility of Tectal Plate Measurements on Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

BACKGROUND: Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), observed in PSP-Richardson's syndrome (PSP-RS) and to a lesser extent PSP-parkinsonism (PSP-P). OBJECTIVE: Our aim was to critically evaluate the utility of manual magnetic resonance imaging measurements of the midbrain tectal plate as a diagnostic biomarker in PSP. METHODS: Length of the tectal plate and width of the superior and inferior colliculi were measured in 40 PSP (20 PSP-RS and 20 PSP-P) patients and compared with 20 Parkinson's disease and 20 healthy control subjects. RESULTS: Tectal plate length was reduced in both PSP groups compared with Parkinson's disease and control subjects and was most abnormal in PSP-RS followed by PSP-P. Reduced tectal plate length was associated with worse PSP Rating Scale scores. CONCLUSIONS: Simple manual measurements of tectal plate length show utility as a diagnostic biomarker in PSP, particularly for PSP-RS.

Alexander disease with a novel GFAP insertion-deletion mutation mimicking progressive supranuclear palsy.

This report presents a case of Alexander disease showing clinical characteristics mimicking progressive supranuclear palsy (PSP). A 67-year-old woman complaining of motor disturbance exhibited severe atrophy of medulla, spinal cord, and midbrain tegmentum, as well as periventricular hyperintensity on cerebral MRI. Genetic analysis identified a novel in-frame deletion/insertion mutation in the exon 3 of the GFAP gene. Interestingly, neurological findings and decreased striatal uptake in dopamine transporter SPECT were suggestive of PSP. A novel GFAP gene mutation found in the present case may cause the unique clinical phenotype, which should be differentiated from PSP.

Combined blood Neurofilament light chain and third ventricle width to differentiate Progressive Supranuclear Palsy from Parkinson's Disease: A machine learning study.

INTRODUCTION: Differentiating Progressive Supranuclear Palsy (PSP) from Parkinson's Disease (PD) may be clinically challenging. In this study, we explored the performance of machine learning models based on MR imaging and blood molecular biomarkers in distinguishing between these two neurodegenerative diseases. METHODS: Twenty-eight PSP patients, 46 PD patients and 60 control subjects (HC) were consecutively enrolled in the study. Serum concentration of neurofilament light chain protein (Nf-L) was assessed by single molecule array (SIMOA), while an automatic segmentation algorithm was employed for T1-weighted measurements of third ventricle width/intracranial diameter ratio (3rdV/ID). Machine learning (ML) models with Logistic Regression (LR), Random Forest (RF), and XGBoost algorithms based on 3rdV/ID and serum Nf-L levels were tested in distinguishing among PSP, PD and HC. RESULTS: PSP patients showed higher serum Nf-L levels and larger 3rdV/ID ratio in comparison with both PD and HC groups (p < 0.005). All ML algorithms (LR, RF and XGBoost) showed that the combination of MRI and blood biomarkers had excellent classification performances in differentiating PSP from PD (AUC ≥0.92), outperforming each biomarker used alone (AUC: 0.85-0.90). Among the different algorithms, XGBoost was slightly more powerful than LR and RF in distinguishing PSP from PD patients, reaching AUC of 0.94 ± 0.04. CONCLUSION: Our findings highlight the usefulness of combining blood and simple linear MRI biomarkers to accurately distinguish between PSP and PD patients. This multimodal approach may play a pivotal role in patient management and clinical decision-making, paving the way for more effective and timely interventions in these neurodegenerative diseases.

Frontal hypometabolism in the diagnosis of progressive supranuclear palsy clinical variants.

OBJECTIVE: Frontal hypometabolism on FDG-PET is observed in progressive supranuclear palsy (PSP), although it is unclear whether it is a feature of all PSP clinical variants and hence whether it is a useful diagnostic feature. We aimed to compare the frequency, severity, and pattern of frontal hypometabolism across PSP variants and determine whether frontal hypometabolism is related to clinical dysfunction. METHODS: Frontal hypometabolism in prefrontal, premotor, and sensorimotor cortices was visually graded on a 0-3 scale using CortexID Z-score images in 137 PSP patients. Frontal asymmetry was recorded. Severity scores were used to categorize patients as premotor-predominant, prefrontal-predominant, sensorimotor-predominant, mixed-predominance, or no regional predominance. Frontal ratings were compared across PSP clinical variants, and Spearman correlations were used to assess relationships with the Frontal Assessment Battery (FAB). RESULTS: 97% showed evidence of frontal hypometabolism which was most common (100%) in the speech-language (PSP-SL), corticobasal (PSP-CBS), and frontal (PSP-F) variants and least common in the progressive gait freezing (PSP-PGF) variant (73%). PSP-SL and PSP-CBS showed more severe hypometabolism than Richardson's syndrome (PSP-RS), Parkinsonism (PSP-P), and PSP-PGF. A premotor-predominant pattern was most common in PSP-SL and PSP-CBS, with more mixed patterns in the other variants. Hypometabolism was most commonly asymmetric in PSP-SL, PSP-P, PSP-F and PSP-CBS. Worse hypometabolism in nearly all frontal regions correlated with worse scores on the FAB. CONCLUSIONS: Frontal hypometabolism is a common finding in PSP, although it varies in severity and pattern across PSP variants and will likely be the most diagnostically useful in PSP-SL and PSP-CBS.

Clinical and neuroimaging characteristics of primary lateral sclerosis with overlapping features of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS-PSP) from PSP. METHODS: Six patients with PLS-PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP-Richardson syndrome (PSP-RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F-flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated. RESULTS: Five of the six PLS-PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5-63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP-RS than PLS-PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP-RS compared to PLS-PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS-PSP compared to PSP-RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP-RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP-RS compared to PLS-PSP (AUROC = 0.74). CONCLUSIONS: Regional brain volume, tractography, and magnetic susceptibility, but not tau-PET, are useful in distinguishing PLS-PSP from PSP.

Loss of Mickey Mouse Ears' Sign in Progressive Supranuclear Palsy.

ABSTRACT: Progressive supranuclear palsy (PSP) is the most prevalent form of degenerative atypical parkinsonism. Clinical manifestations of PSP commonly encompass deficits in vertical gaze, postural stability, akinesia, and cognitive impairment. The characteristic metabolic pattern observed in PSP through FDG PET displays hypometabolism in the midbrain, striatum, thalamus, and frontal lobe. However, visual interpretation of midbrain hypometabolism poses challenges. In this report, we aim to elucidate a novel observation termed the "loss of Mickey Mouse ears' sign," which signifies midbrain hypometabolism as detected through visual assessment of FDG PET images.

Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy.

OBJECTIVES: To evaluate the effect of Alzheimer's disease (AD) -related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). METHODS: Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4-R-Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD-positive (CBS/PSP-AD) and AD-negative (CBS/PSP-noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p-tau, t-tau, and amyloid-beta, and plasma ptau-217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole-brain gray matter volume and functional networks connectivity were compared across groups. RESULTS: Data were analyzed from 87 CBS/PSP-noAD and 23 CBS/PSP-AD, 18 AD, and 30 healthy controls. CBS/PSP-noAD showed worse performance in comparison to CBS/PSP-AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP-AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP-noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP-AD compared with CBS/PSP-no AD and controls. The thalamic network connectivity was most affected in CBS/PSP-noAD. INTERPRETATION: AD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co-pathology. ANN NEUROL 2024;96:99-109.

Aberrant dynamic functional network connectivity in progressive supranuclear palsy.

BACKGROUND: The clinical symptoms of progressive supranuclear palsy (PSP) may be mediated by aberrant dynamic functional network connectivity (dFNC). While earlier research has found altered functional network connections in PSP patients, the majority of those studies have concentrated on static functional connectivity. Nevertheless, in this study, we sought to evaluate the modifications in dynamic characteristics and establish the correlation between these disease-related changes and clinical variables. METHODS: In our study, we conducted a study on 53 PSP patients and 65 normal controls. Initially, we employed a group independent component analysis (ICA) to derive resting-state networks (RSNs), while employing a sliding window correlation approach to produce dFNC matrices. The K-means algorithm was used to cluster these matrices into distinct dynamic states, and then state analysis was subsequently employed to analyze the dFNC and temporal metrics between the two groups. Finally, we made a correlation analysis. RESULTS: PSP patients showed increased connectivity strength between medulla oblongata (MO) and visual network (VN) /cerebellum network (CBN) and decreased connections were found between default mode network (DMN) and VN/CBN, subcortical cortex network (SCN) and CBN. In addition, PSP patients spend less fraction time and shorter dwell time in a diffused state, especially the MO and SCN. Finally, the fraction time and mean dwell time in the distributed connectivity state (state 2) is negatively correlated with duration, bulbar and oculomotor symptoms. DISCUSSION: Our findings were that the altered connectivity was mostly concentrated in the CBN and MO. In addition, PSP patients had different temporal dynamics, which were associated with bulbar and oculomotor symptoms in PSPRS. It suggest that variations in dynamic functional network connectivity properties may represent an essential neurological mechanism in PSP.

Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

BACKGROUND: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18F-9-fluoropropyldihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). OBJECTIVE: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using 18F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. METHODS: We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using 18F-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. RESULTS: VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. CONCLUSIONS: Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. © 2024 International Parkinson and Movement Disorder Society.

Contribution of MRI for the Early Diagnosis of Parkinsonism in Patients with Diagnostic Uncertainty.

BACKGROUND: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. OBJECTIVES: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine-learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. MATERIALS: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2-year follow-up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine-learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2-year follow-up. RESULTS: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). CONCLUSION: Our study shows the use of MRI analysis, whether by visual reading or machine-learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep Learning-based Approach for Brainstem and Ventricular MR Planimetry: Application in Patients with Progressive Supranuclear Palsy.

Purpose To develop a fast and fully automated deep learning (DL)-based method for the MRI planimetric segmentation and measurement of the brainstem and ventricular structures most affected in patients with progressive supranuclear palsy (PSP). Materials and Methods In this retrospective study, T1-weighted MR images in healthy controls (n = 84) were used to train DL models for segmenting the midbrain, pons, middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), third ventricle, and frontal horns (FHs). Internal, external, and clinical test datasets (n = 305) were used to assess segmentation model reliability. DL masks from test datasets were used to automatically extract midbrain and pons areas and the width of MCP, SCP, third ventricle, and FHs. Automated measurements were compared with those manually performed by an expert radiologist. Finally, these measures were combined to calculate the midbrain to pons area ratio, MR parkinsonism index (MRPI), and MRPI 2.0, which were used to differentiate patients with PSP (n = 71) from those with Parkinson disease (PD) (n = 129). Results Dice coefficients above 0.85 were found for all brain regions when comparing manual and DL-based segmentations. A strong correlation was observed between automated and manual measurements (Spearman ρ > 0.80, P < .001). DL-based measurements showed excellent performance in differentiating patients with PSP from those with PD, with an area under the receiver operating characteristic curve above 0.92. Conclusion The automated approach successfully segmented and measured the brainstem and ventricular structures. DL-based models may represent a useful approach to support the diagnosis of PSP and potentially other conditions associated with brainstem and ventricular alterations. Keywords: MR Imaging, Brain/Brain Stem, Segmentation, Quantification, Diagnosis, Convolutional Neural Network Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Mohajer in this issue.