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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 2nd generation 18F-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.

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‐tau181 and t‐tau) and 18F‐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‐tau181 and cortical 18F‐PI‐2620 binding was characteristic for AD while normal CSF p‐tau181 with elevated subcortical 18F‐PI‐2620 binding was characteristic for 4RTs. 18F‐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 18F‐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‐tau181 and 18F‐PI‐2620 discriminates AD versus 4R tauopathies.Hypoperfusion serves as an additional neuronal injury biomarker in AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy is a neurodegenerative disease with α‐synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. Objective: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. Methods: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy‐confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. Results: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%–100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%–9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%–100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%–100% throughout). Conclusions: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: To date, studies on positron emission tomography (PET) with 18F‐fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP‐RS). Objectives: To evaluate FDG‐PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. Methods: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non‐RS variants of PSP (vPSP), and 46 age‐matched healthy controls. Two state‐of‐the art methods for the interpretation of FDG‐PET were compared: visual analysis supported by voxel‐based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP‐related pattern. Results: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false‐negative cases was 10% in the PSP‐RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false‐negative cases was 0% in the PSP‐RS subsample and 15% in the vPSP subsample. Conclusions: Visual interpretation of FDG‐PET supported by voxel‐based testing provides good accuracy for the detection of PSP‐RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP‐RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false‐positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel‐based testing of FDG‐PET in suspected PSP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Brain magnetic resonance imaging (MRI) is used to support the diagnosis of progressive supranuclear palsy (PSP). However, the value of visual descriptive, manual planimetric, automatic volumetric MRI markers and fully automatic categorization is unclear, particularly regarding PSP predominance types other than Richardson's syndrome (RS). Objectives: To compare different visual reading strategies and automatic classification of T1‐weighted MRI for detection of PSP in a typical clinical cohort including PSP‐RS and (non‐RS) variant PSP (vPSP) patients. Methods: Forty‐one patients (21 RS, 20 vPSP) and 46 healthy controls were included. Three readers using three strategies performed MRI analysis: exclusively visual reading using descriptive signs (hummingbird, morning‐glory, Mickey‐Mouse), visual reading supported by manual planimetry measures, and visual reading supported by automatic volumetry. Fully automatic classification was performed using a pre‐trained support vector machine (SVM) on the results of atlas‐based volumetry. Results: All tested methods achieved higher specificity than sensitivity. Limited sensitivity was driven to large extent by false negative vPSP cases. Support by automatic volumetry resulted in the highest accuracy (75.1% ± 3.5%) among the visual strategies, but performed not better than the midbrain area (75.9%), the best single planimetric measure. Automatic classification by SVM clearly outperformed all other methods (accuracy, 87.4%), representing the only method to provide clinically useful sensitivity also in vPSP (70.0%). Conclusions: Fully automatic classification of volumetric MRI measures using machine learning methods outperforms visual MRI analysis without and with planimetry or volumetry support, particularly regarding diagnosis of vPSP, suggesting the use in settings with a broad phenotypic PSP spectrum. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Reliable biomarkers for detecting different abnormal tau protein isoforms between neurodegenerative diseases are currently missing. Phosphorylated tau (p‐tau) in the cerebrospinal fluid (CSF) is acknowledged as a 3/4R tau biomarker in AD but not in other tauopathies. The positron emission tomography (PET) radiotracer 18F‐PI‐2620 has the potential to detect abnormal 3/4R‐tau in patients with Alzheimer's disease (AD) and 4R‐tau in Progressive Supranuclear Palsy (PSP) or Corticobasal Syndrome (CBS). This study investigates the interplay between tau‐PET and CSF p‐tau in AD and 4R‐tauopathies. Method: In this cross‐sectional analysis, 52 patients with AD, 54 patients with PSP/CBS, and 11 controls underwent lumbar puncture and 0‐60 min dynamic 18F‐PI‐2620 PET scanning. Independent t‐tests assessed group differences in standardized uptake value ratios for the 20‐40min time window (SUVr20‐40) and p‐Tau. Quantitative and voxel‐wise multiple regression analyses tested the association between SUVr20‐40 and p‐tau and group interactions, using R and SPM and controlling for age and sex. ROC analyses were performed to evaluate biomarker performance in differentiating patient groups. Result: Patients with AD showed elevated CSF p‐tau levels (p<0.05; >61 pg/ml) and SUVr20‐40 in temporal, parietal, occipital, frontal, cingulate‐insula, striatum, and amygdala (p<0.05). In patients with AD the two biomarkers correlated positively (p<0.05). Patients with clinically suspected 4R‐tauopathies did not show elevated p‐tau levels but demonstrated high tau‐PET uptake in the lentiform nucleus (p<0.05), compared to controls and AD. ROC analyses showed that temporal SUVr20‐40 (87.3%) and p‐tau levels (80.8%) were able to differentiate AD from 4R‐tauopathies, while the lentiform nucleus tau‐PET showed moderate performance at discriminated patients with 4R‐tau from those with AD (56.7%) and healthy controls (66.3%). Interestingly, the AUC increased to 70%, when excluding patients with CBS. Conclusion: The specific combination of CSF p‐tau levels and 18F‐PI‐2620 PET SUVR in disease‐specific regions facilitates biomarker‐guided stratification of AD and clinically suspected 4R‐tauopathies. [ABSTRACT FROM AUTHOR]

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 [18F]flutemetamol-amyloid-PET and [18F]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 [18F]PI-2620 (0.5–2.5 min p.i.) and [18F]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 [18F]PI-2620 tau- and [18F]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. [ABSTRACT FROM AUTHOR]

Objectives: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer's disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and β-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. Conclusions: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases. [ABSTRACT FROM AUTHOR]