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Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [ 18 F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [ 18 F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [ 18 F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [ 18 F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2-63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [ 18 F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal., Competing Interests: Declarations. Conflict of interest: MB is a member of the Neuroimaging Committee of the EANM. MB has received speaker honoraria from Roche, GE Healthcare, and Life Molecular Imaging; has advised Life Molecular Imaging; and is currently on the advisory board of MIAC. NF received speaker honoraria from Eisai and Life Molecular Imaging and consulting honoraria from MSD. CP and JL are inventors in the patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. JL reports speaker fees from Bayer Vital, Biogen and Roche; consulting fees from Axon Neuroscience and Biogen; author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers; nonfinancial support from AbbVie; and compensation for duty as part-time CMO from MODAG, all outside the submitted work. TvE reports speaker/consultant fees from Eli Lilly, Shire, H. Lundbeck A/S, and Orion Corporation, and author fees from Thieme Medical Publishers, all without conflicts of interest with regard to the submitted work. Gesine Respondek has been a full-time employee at Roche Pharmaceuticals since July 2021 and has consulted for UCB, all outside of the submitted work. AZ reports speaker fees and research support from Dr. Willmar Schwabe GmbH and author fees from Thieme Medical Publishers, Springer Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition to the submitted work, TG received consulting fees from AbbVie, Alector, Anavex, Biogen, BMS, Cogthera, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Janssen, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon; lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, Schwabe, and Synlab; and grants to his institution from Biogen, Eisai, and Roche Diagnostics. LB is a Novartis Pharma GmbH employee, unrelated to this work. All the other authors declare that no conflicts of interest exist., (© 2024. The Author(s).)

Introduction: Recent advances in biomarker research have improved the diagnosis and monitoring of Alzheimer's disease (AD), but in vivo biomarker-based workflows to assess 4R-tauopathy (4RT) patients are currently missing. We suggest a novel biomarker-based algorithm to characterize AD and 4RTs., Methods: We cross-sectionally assessed combinations of cerebrospinal fluid measures (CSF p-tau 181 and t-tau) and 18 F-PI-2620 tau-positron emission tomography (PET) in patients with AD (n = 64), clinically suspected 4RTs (progressive supranuclear palsy or corticobasal syndrome, n = 82) and healthy controls (n = 19)., Results: Elevated CSF p-tau 181 and cortical 18 F-PI-2620 binding was characteristic for AD while normal CSF p-tau 181 with elevated subcortical 18 F-PI-2620 binding was characteristic for 4RTs. 18 F-PI-2620-assessed posterior cortical hypoperfusion could be used as an additional neuronal injury biomarker in AD., Discussion: The specific combination of CSF markers and 18 F-PI-2620 tau-PET in disease-specific regions facilitates the biomarker-guided stratification of AD and 4RTs. This has implications for biomarker-aided diagnostic workflows and the advancement in clinical trials., Highlights: Novel biomarker-based algorithm for differentiating AD and 4R-tauopathies. A combination of CSF p-tau 181 and 18 F-PI-2620 discriminates AD versus 4R tauopathies. Hypoperfusion serves as an additional neuronal injury biomarker in AD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA., Methods: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores)., Results: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00)., Discussion: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD., (© 2024. The Author(s).)

Background: Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression., Objective: We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading., Methods: We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls., Results: In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (β = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (β = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET., Conclusions: Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson's Disease (PD) are in early phases of clinical testing. Involving patients' preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001-25%] of sudden death for a 99% [interquartile range: 99.999-75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001-5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients' risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients' risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option., (© 2024. The Author(s).)

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 Aβ-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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([ 18 F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [ 18 F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [ 18 F]PI-2620 tau-positron-emission-tomography (PET) imaging with [ 123 I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability., Methods: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [ 18 F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies., Results: In patients with 4R-tauopathies, [ 18 F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (β =  - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [ 18 F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (β = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [ 18 F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (β =  - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies., Conclusion: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function., (© 2024. The Author(s).)

Purpose: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA)., Methods: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level., Results: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R 2  = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912)., Conclusion: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset., (© 2023. The Author(s).)

Background and Objectives: 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD., Methods: 49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([ 18 F]GE-180) and β-amyloid-PET ([ 18 F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([ 18 F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque-dependent microglial response (slope) and the Aβ-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI)., Results: In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aβ-PET z-scores were similar. The Aβ-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aβ-plaque-dependent microglial response was not different between sexes. The Aβ-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aβ-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F (3,52)  = 3.077, p = 0.005)., Conclusion: While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque-independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD., (© 2024. The Author(s).)

Background and Objectives: Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS., Methods: We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [ 18 F]PI-2620-PET for assessing tau pathology, [ 18 F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction)., Results: Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [ 18 F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model., Discussion: [ 18 F]PI-2620 tau-PET, [ 18 F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: β T  = 0.412 ± 0.196 vs. β A  = 0.142 ± 0.123, p < 0.001; AD-CBS: β T  = 0.385 ± 0.176 vs. β A  = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (β T  = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases., (© 2023. The Author(s).)

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases., Competing Interests: Declaration of interests M. Brendel received speaker honoraria from GE healthcare, Roche, and Life Molecular Imaging and is an advisor of Life Molecular Imaging. J.H. reports personal fees, research grants, and non-financial support from Merck, Bayer, Novartis, Roche, Biogen, and Celgene and non-financial support of the Guthy-Jackson Charitable Foundation—none in relation to this study. C.P. is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. T.K. has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Teva Pharma, Merck, Novartis, Sanofi/Genzyme, Roche, and Biogen as well as grant support from Novartis and Chugai Pharma—none in relation to this study. M.K. has been on advisory boards for Biogen, medDay Pharmaceuticals, Novartis, and Sanofi; has received grant support from Sanofi and Biogen; and has received speaker fees from Abbvie, Almirall, Biogen, medDay Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi, and Teva—none in relation to this study. R.P. has received speaker honoraria, research support, and consultancy fees from Janssen, Eli Lilly, Biogen, Wilmar Schwabe, Takeda, Novo Nordisk, and Bayer Healthcare. N.K. has received speaker honoraria from Novartis and Regeneron and research grants from Regeneron—none in relationship to this study. M.I.T., H.S.B., M.N., and A.E. received speaker honoraria from Miltenyi Biotec—none in relation to this study. A.E. is co-founder of Deep Piction and 1X1 Biotech., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [ 18 F]flutemetamol-amyloid-PET and [ 18 F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease., Methods: We obtained early-phase PET recordings with [ 18 F]PI-2620 (0.5-2.5 min p.i.) and [ 18 F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores <  - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests., Results: The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90)., Conclusion: The early perfusion phases of [ 18 F]PI-2620 tau- and [ 18 F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity., (© 2022. The Author(s).)

A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi)genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology., Competing Interests: Declaration of interests Johannes Levin reports part-time employment by MODAG GmbH and a grant of the Michael J Fox Foundation for Parkinson's Research. In addition, he reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, all outside the submitted work. He is a member of the advisory board of Biogen and a member of the Data Safety Monitoring Board of Axon Neuroscience. He is beneficiary of the phantom share program of MODAG GmbH. In addition, he is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH. Bernhard Hemmer received funding by the European Union's Horizon 2020 Research and Innovation Program and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology and Roche. He holds part of two patents: one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. Wilko Weichert reports research funding from Roche, MSD, BMS and AstraZeneca. He has attended and given talks at Advisory Boards, gave advice to and served as speaker on national and international conferences for Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Amgen, Astellas, Eisai, Johnson and Johnson, Janssen, Illumina, Siemens, Agilent, ADC, GSK and Molecular Health. Stefan F. Lichtenthaler reports research funding from Shionogi and Novartis. Steffen Tiedt reports consulting fees from Alpha Apollo Inc. Christiane Gasperi reports funding from the Hertie Foundation, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and the Hans and Klementia Langmatz Stiftung. Carla Palleis reports funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology. No other disclosures were reported., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [ 18 F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer's disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [ 18 F]PI-2620 uptake and symptomatology in 4-repeat tauopathies. 72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson's syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [ 18 F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20-40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored. Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected. Our data reveal [ 18 F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [ 18 F]PI-2620 in 4-repeat tauopathies and whether [ 18 F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [ 18 F]PI-2620 PET results., Competing Interests: Declaration of Competing Interest Johannes Levin reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, non-financial support from Abbvie and compensation for duty as part-time CMO from MODAG and being beneficiary of the phantom share program of MODAG GmbH, outside the submitted work. Matthias Brendel received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and is an advisor of Life Molecular Imaging. Sabrina Katzdobler has received travel support from Life Molecular Imaging. Osama Sabri receives research support from Life Molecular Imaging. Henryk Barthel received speaker honoraria from Novartis/AAA and reader honoraria from Life Molecular Imaging. Nicolai Franzmeier received research funding from Avid Radiopharmaceuticals and consulting fees from Merck., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Early after [ 18 F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [ 18 F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [ 18 F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs., Methods: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [ 18 F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living)., Results: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R =  - 0.431; p = 0.0005)., Conclusion: [ 18 F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression., (© 2022. The Author(s).)

Objective: Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns., Methods: We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [ 18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity., Results: We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner., Interpretation: Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022;92:768-781., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the 18 F-labeled tau PET tracer 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9 H -pyrrolo[2,3- b :4,5- c ']dipyridine ( 18 F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether 18 F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) 18 F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and 18 F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual 18 F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and 18 F-PI-2620 PET. The gain of sensitivity by adding 18 F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding 18 F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 nd generation 18 F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies., (© 2022. The Author(s).)

Corticobasal syndrome (CBS) is a rare neurodegenerative condition characterized by four-repeat tau aggregation in the cortical and subcortical brain regions and accompanied by severe atrophy. The aim of this study was to evaluate partial volume effect correction (PVEC) in patients with CBS compared to a control cohort imaged with the 18-kDa translocator protein (TSPO) positron emission tomography (PET) tracer [ 18 F]GE-180. Eighteen patients with CBS and 12 age- and sex-matched healthy controls underwent [ 18 F]GE-180 PET. The cortical and subcortical regions were delineated by deep nuclei parcellation (DNP) of a 3D-T1 MRI. Region-specific subcortical volumes and standardized uptake values and ratios (SUV and SUVr) were extracted before and after region-based voxel-wise PVEC. Regional volumes were compared between patients with CBS and controls. The % group differences and effect sizes (CBS vs. controls) of uncorrected and PVE-corrected SUVr data were compared. Single-region positivity in patients with CBS was assessed by a >2 SD threshold vs. controls and compared between uncorrected and PVE-corrected data. Smaller regional volumes were detected in patients with CBS compared to controls in the right ventral striatum ( p = 0.041), the left putamen ( p = 0.005), the right putamen ( p = 0.038) and the left pallidum ( p = 0.015). After applying PVEC, the % group differences were distinctly higher, but the effect sizes of TSPO uptake were only slightly stronger due to the higher variance after PVEC. The single-region positivity of TSPO PET increased in patients with CBS after PVEC (100 vs. 83 regions). PVEC in the cortical and subcortical regions is valuable for TSPO imaging of patients with CBS, leading to the improved detection of elevated [ 18 F]GE-180 uptake, although the effect sizes in the comparison against the controls did not improve strongly.

Purpose: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [ 18 F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [ 18 F]PI-2620 tau-PET imaging of PSP., Methods: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [ 18 F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0-60, 0-50, 0-40, 0-30, and 0-20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20-40, 30-50, and 40-60 min p.i.. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier)., Results: 0-50 and 0-40 DVR showed equivalent effect sizes as 0-60 DVR (averaged Cohen's d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0-30 or 0-20 DVR. The 20-40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen's d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0-60 DVR (AUC: 0.96), 0-40 DVR (AUC: 0.96), and 20-40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%., Conclusion: Truncated and static imaging windows can be used for [ 18 F]PI-2620 PET imaging of PSP. 0-40 min dynamic scanning offers the best balance between accuracy and economic scanning., (© 2021. The Author(s).)