Satoh, Ryota

Background TAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent. Objective This study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo. Methods Penalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda. Results The model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology. Conclusions This study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

Abstract Background The cerebellar dentate is a known site of iron accumulation and tau deposition in progressive supranuclear palsy (PSP); however, detailed iron distribution and localized volume and shape changes remain unclear across PSP clinical variants. Objective The study aimed to clarify details about regional susceptibility distribution, volume, and shape deformation in the cerebellar dentate across PSP clinical variants. Methods Sixty‐seven PSP patients, including 31 PSP‐Richardson syndrome, 12 PSP‐parkinsonism, 10 PSP‐progressive gait freezing, and 14 PSP‐cortical variants (PSP‐frontal, PSP‐speech/language, and PSP‐corticobasal syndrome), and 31 healthy controls underwent 3 Tesla magnetic resonance imaging to reconstruct quantitative susceptibility maps. Manual dentate segmentation was performed to extract magnetic susceptibility and volume adjusted for total intracranial volume. Shape deformation was assessed using Deformetrica atlas construction. Group comparisons were evaluated with Kruskal–Wallis tests and receiver operating characteristic analysis. Results Patients with PSP‐Richardson syndrome, PSP‐parkinsonism, and PSP‐cortical variants showed significantly increased dentate susceptibility compared with controls ( P < 0.05). Patients with PSP‐progressive gait freezing showed no significant susceptibility differences. Volume loss was most prominent in PSP‐cortical variants, bilaterally, and PSP‐Richardson syndrome, left hemisphere only ( P < 0.05). Shape analysis revealed subregion‐specific deformation patterns, especially in the anterior and posterior deformation in PSP‐progressive gait freezing and the ventroanterior deformation in PSP‐cortical variants. Conclusions The PSP clinical variants had different patterns of susceptibility, volume, and shape metrics, reflecting distinct neurodegenerative patterns of the cerebellar dentate. These findings contribute to our understanding of the neurobiology of PSP and may help to improve phenotypic differentiation of PSP clinical variants. © 2026 International Parkinson and Movement Disorder Society.

Background: Posterior cortical atrophy (PCA) patients typically show progressive visual decline, although language impairment can be a prominent feature. Previous studies have explored language connectivity impairment in PCA; not much is known about the exact nature of language processing disruptions in PCA. Methods: Thirty-seven PCA patients were compared with 39 cognitively unimpaired (CU) individuals. Functional connectivity was evaluated for the language processing system, which consisted of language, perceptual, motor, and cognitive networks. Linear regression was performed to compare within- and between-network connectivity across networks and within the language network in PCA compared to CU individuals. Relationships between language network connectivity, clinical performance, and gray matter volumes were also evaluated. Results: PCA showed reduced connectivity within the language and perceptual networks, along with reduced between-network connectivity compared to CU individuals. Regional connectivity breakdown within the language network was also noted. Language processing system connectivity was not associated with clinical performance on language processing tests. However, a breakdown in Broca-Wernicke, Wernicke-middle frontal gyrus, and Wernicke-frontal orbital gyrus connectivity was related to worse performance on sentence repetition. Lastly, gray matter volume was not associated with language network connectivity. Discussion: Together, these results reiterate the breakdown of language network connectivity in PCA and highlight the disruption in connectivity at the regional level within the language network. Reduced connectivity within the perceptual network and associations between reduced language network connectivity and worse performance on sentence repetition imply a breakdown within the language processing systems in PCA.

Abstract Background Quantitative susceptibility mapping ( QSM ) is a promising neuroimaging biomarker for detecting abnormal iron deposition in progressive supranuclear palsy ( PSP ); however, the QSM profile and its accuracy in autopsy‐confirmed PSP remain unexplored. Objective The aim of the study was to elucidate and validate the QSM profiles in autopsy‐confirmed PSP. Methods Eight patients with a clinically diagnosed PSP syndrome ( PSPS ) underwent antemortem 3 T magnetic resonance imaging ( MRI) scanning and subsequent pathological diagnosis, confirming 6 PSP pathology and 2 multiple system atrophy ( MSA ) pathology cases. QSM analysis and Prussian blue staining were performed across subcortical regions. Results PSP cases showed higher susceptibility than age‐matched controls in the pallidum, subthalamic nucleus, substantia nigra, and cerebellar dentate (false discovery rate [ FDR] ‐corrected P < 0.05). PSP had higher susceptibility in the subthalamic nucleus and lower susceptibility in the putamen than the clinically atypical MSA ( P = 0.08). Subcortical susceptibilities correlated with Prussian blue–stained areas ( r = 0.63, P < 0.001). Conclusions QSM could be a reliable measure to evaluate abnormal iron accumulation patterns in PSP.

Background: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder most commonly arising from a 4-repeat tauopathy that affects the programming or planning of speech, although many patients develop a Parkinson-plus syndrome. The role of neuroinflammation as a disease mechanism is unknown. We investigated the spatial pattern of neuroinflammation in PAOS using PET and evaluated whether it is associated with disease severity, presence of Parkinson-plus features, and tau PET uptake. Patients and Methods: Twenty-five PAOS patients (13 with Parkinson-plus features) and 30 controls underwent inflammatory 11C-ER176 and tau 18F-flortaucipir PET scans as well as detailed clinical assessments. Multiple linear regression analyses compared the inflammatory standardized uptake value ratio (SUVR) between PAOS and controls and assessed the relationship with clinical test scores. Pearson correlation analysis examined the relationship between inflammatory and tau SUVRs. Results: PAOS had greater neuroinflammatory SUVR than controls in the precentral, supplementary motor area, frontal gyri, putamen, pallidum, subthalamic nucleus, and red nucleus (adjusted P < 0.05). Greater neuroinflammation was associated with worse parkinsonism, and patients who had developed Parkinson-plus features showed a broader pattern of neuroinflammation, extending to prefrontal, temporal and parietal cortices. Neuroinflammation correlated with tau uptake in most (96%) PAOS patients (r > 0.3, P < 0.05). The higher correlation was associated with worse parkinsonism (r = 0.61, P < 0.05) and disease severity (r = 0.54, P < 0.05). Conclusions: 11C-ER176 PET analysis demonstrates neuroinflammation in frontal and subcortical regions in PAOS which is particularly severe and widespread with the development of Parkinson-plus clinical features. The colocalization of neuroinflammation and tau may support a relationship between these disease mechanisms.

ObjectivesThe four‐repeat (4R) tauopathies are a group of neurodegenerative diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and globular glial tauopathy (GGT). This study aimed to characterize spatiotemporal atrophy progression using structural magnetic resonance imaging (MRI) and to examine its relationship with clinical course and neuropathology in a cohort of autopsy‐confirmed 4R tauopathies.MethodsThe study included 85 autopsied patients (54 with PSP, 28 with CBD, and 3 with GGT) who underwent multiple 3T MRI scans, as well as neuropsychological, neurological, and speech/language examinations, and standardized postmortem neuropathological evaluations. An unsupervised machine‐learning algorithm, Subtype and Stage Inference (SuStaIn), was applied to the cross‐sectional brain volumes to estimate spatiotemporal atrophy patterns and data‐driven subtypes and stages in each patient. The relationships among estimated subtypes, pathological diagnoses, and longitudinal changes in clinical testing were examined.ResultsThe SuStaIn algorithm identified 2 distinct subtypes: (1) the subcortical subtype, in which atrophy progresses from the midbrain to the cortex, and (2) the cortical subtype, in which atrophy progresses from the frontal cortex to the subcortical regions. The subcortical subtype was more associated with typical PSP, whereas the cortical subtype was more associated with atypical PSP with a cortical distribution of pathology and CBD (p < 0.001). The cortical subtype had a faster rate of change on the PSP Rating Scale than the subcortical subtype (p < 0.05).InterpretationSuStaIn analysis revealed 2 MRI‐driven subtypes with distinct spatiotemporal atrophy patterns, clinical courses, and neuropathology. Our findings contribute to a comprehensive and improved understanding of disease progression and its relationship to tau pathology in 4R tauopathies. ANN NEUROL 2025;98:492–507

Abstract Normal pressure hydrocephalus is typically defined by the triad of gait disturbance, cognitive impairment, and urinary incontinence, and is characterized on MRI by disproportionately enlarged subarachnoid-space. Gait disturbance is also a commonly reported symptom in Parkinsonian disorders, especially progressive supranuclear palsy, although the frequency, clinical significance and mechanisms of hydrocephalus in these disorders are unclear. We aimed to assess the prevalence of hydrocephalic MRI parameters in a large cohort of Parkinsonian disorders and evaluate associations with clinical features and abnormalities on MRI and PET. Two hundred and thirty-eight participants with a Parkinsonian disorder, including 181 progressive supranuclear palsy, 36 corticobasal syndrome and 21 Parkinson’s disease, were enrolled from Mayo Clinic by the Neurodegenerative Research Group between September 2009 to October 2023. Automated detection of disproportionately enlarged subarachnoid-space hydrocephalus (D) was applied and using Evans’ index (E) cut-off point &gt;0.3, participants were classified based on both measures as imaging-suggestive of hydrocephalus (D+E+), enlarged subarachnoid-space only (D+E−), large Evans’ index only (D−E+) and no imaging evidence of hydrocephalus (D−E−). Demographic, clinical and imaging features, including magnetic resonance parkinsonism index, cortical and subcortical volumes, white matter hyperintensities, diffusion tractography metrics, and metabolism on PET, were compared across groups. Among the 238 participants, 24 had borderline subarachnoid space scores and were excluded. The remaining 214 participants were classified as: D+E+ (n = 20, 9%); D+E− (n = 8, 4%); D−E+ (n = 71, 33%) and D−E− (n = 115, 54%). Among the progressive supranuclear palsy participants, 11% were D+E+, 4% D+E−, 34% D−E+ and 51% D−E−. Most cases (n = 18) in the imaging-suggestive of hydrocephalus D+E+ group had progressive supranuclear palsy. The D+E+ participants were older, had more disorientation, more downgaze palsy, greater midbrain and cortical atrophy, lower striatal metabolism, greater degeneration of long-range white matter tracts, larger cistern areas and more periventricular and deep white matter hyperintensities compared to the D−E− participants without imaging evidence of hydrocephalus. The D+E− participants had the highest metabolism in the paracentral lobule and superior parietal gyrus. The D−E+ participants showed worse disease severity and greater midbrain and cortical atrophy compared to the D−E− participants. These findings demonstrate that disproportionately enlarged subarachnoid-space hydrocephalus occurs in ∼15% of progressive supranuclear palsy participants, and is associated with worse clinical and imaging outcomes, as well as white matter hyperintensities. We hypothesize that disproportionately enlarged subarachnoid-space may be a mechanistic byproduct of degeneration and subsequent cerebrospinal fluid flow re-distribution in progressive supranuclear palsy.

ObjectiveTo determine whether a machine learning model of voxel level [18f]fluorodeoxyglucose positron emission tomography (PET) data could predict progressive supranuclear palsy (PSP) pathology, as well as outperform currently available biomarkers.MethodsOne hundred and thirty‐seven autopsied patients with PSP (n = 42) and other neurodegenerative diseases (n = 95) who underwent antemortem [18f]fluorodeoxyglucose PET and 3.0 Tesla magnetic resonance imaging (MRI) scans were analyzed. A linear support vector machine was applied to differentiate pathological groups with sensitivity analyses performed to assess the influence of voxel size and region removal. A radial basis function was also prepared to create a secondary model using the most important voxels. The models were optimized on the main dataset (n = 104), and their performance was compared with the magnetic resonance parkinsonism index measured on MRI in the independent test dataset (n = 33).ResultsThe model had the highest accuracy (0.91) and F‐score (0.86) when voxel size was 6mm. In this optimized model, important voxels for differentiating the groups were observed in the thalamus, midbrain, and cerebellar dentate. The secondary models found the combination of thalamus and dentate to have the highest accuracy (0.89) and F‐score (0.81). The optimized secondary model showed the highest accuracy (0.91) and F‐scores (0.86) in the test dataset and outperformed the magnetic resonance parkinsonism index (0.81 and 0.70, respectively).InterpretationThe results suggest that glucose hypometabolism in the thalamus and cerebellar dentate have the highest potential for predicting PSP pathology. Our optimized machine learning model outperformed the best currently available biomarker to predict PSP pathology. ANN NEUROL 2025;98:410–420

We report a patient who presented clinically with progressive supranuclear palsy (PSP) but was pathologically diagnosed as having primary lateral sclerosis (PLS) with magnetic resonance imaging (MRI) with a quantitative susceptibility mapping (QSM) protocol. A 70‐year‐old man was clinically diagnosed with PSP due to early falls and unresponsiveness to levodopa therapy. Postmortem pathological examination revealed mild loss of Betz cells, gliosis, and transactive response DNA binding protein of 43 kDa (TDP‐43)‐positive inclusions in the motor cortex, leading to the pathological diagnosis of PLS. To explore methods for differentiating PLS from PSP, ante‐mortem QSM images were visually and quantitatively assessed for abnormal increases in magnetic susceptibility in the motor cortex. Prussian blue and Luxol fast blue combined with periodic acid‐Schiff staining were also performed to understand the source of the susceptibility increases. QSM showed clear hyperintense signals in the motor cortex. Magnetic susceptibility in the motor cortex was higher in the PLS patient (Z = 4.7, p < 0.001) compared to normal controls and pathologically diagnosed PSP patients. Pathological examination of the region showed intracortical myelin loss, as well as iron deposition. Underlying pathological processes for the increased magnetic susceptibility include not only iron deposition but also intracortical myelin. Our case suggests that QSM is a potential tool to differentiate PLS from PSP, providing insights for accurate diagnosis and enhancing clinical decision‐making.

AbstractINTRODUCTIONPrimary age‐related tauopathy (PART) is characterized by neurofibrillary tangles and minimal β‐amyloid deposition, diagnosed postmortem. This study investigates 18F‐flortaucipir (FTP) PET imaging for antemortem PART diagnosis.METHODSWe analyzed FTP PET scans from 50 autopsy‐confirmed PART and 13 control subjects. Temporal lobe uptake was assessed both qualitatively and quantitatively. Demographic and clinicopathological characteristics and voxel‐level uptake using SPM12 were compared between FTP‐positive and FTP‐negative cases. Intra‐reader reproducibility was evaluated with Krippendorff's alpha.RESULTSMinimal/mild and moderate FTP uptake was seen in 32% of PART cases and 62% of controls, primarily in the left inferior temporal lobe. No demographic or clinicopathological differences were found between FTP‐positive and FTP‐negative cases. High intra‐reader reproducibility (α = 0.83) was noted.DISCUSSIONFTP PET imaging did not show a specific uptake pattern for PART diagnosis, indicating that in vivo PART identification using FTP PET is challenging. Similar uptake in controls suggests non‐specific uptake in PART.Highlights 18F‐flortaucipir (FTP) PET scans were analyzed for diagnosing PART antemortem. 32% of PART cases had minimal/mild FTP uptake in the left inferior temporal lobe. Similar to PART FTP uptake was found in 62% of control subjects. No specific uptake pattern was found, challenging in vivo PART diagnosis.