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Aim: Standardized evaluation of [ 18 F]PI-2620 tau-PET scans in 4R-tauopathies represents an unmet need in clinical practice. This study aims to investigate the effectiveness of visual evaluation of [ 18 F]PI-2620 images for diagnosing 4R-tauopathies and to develop a straight-forward reading algorithm to improve objectivity and data reproducibility., Methods: A total of 83 individuals with [ 18 F]PI-2620 PET scans were included. Participants were classified as probable 4R-tauopathies (n = 29), Alzheimer's disease (AD) (n = 20), α-synucleinopathies (n = 15), and healthy controls (n = 19) based on clinical criteria. Visual assessment of tau-PET scans (choice: 4R-tauopathy, AD-tauopathy, no-tauopathy) was conducted using either 20-40-minute or 40-60-minute intervals, with raw (common) and cerebellar grey matter scaled standardized reading settings (intensity-scaled). Two readers evaluated scans independently and blinded, with a third reader providing consensus in case of discrepant primary evaluation. A regional analysis was performed using the cortex, basal ganglia, midbrain, and dentate nucleus. Sensitivity, specificity, and interrater agreement were calculated for all settings and compared against the visual reads of parametric images (0-60-minutes, distribution volume ratios, DVR)., Results: Patients with 4R-tauopathies in contrast to non-4R-tauopathies were detected at higher sensitivity in the 20-40-minute frame (common: 79%, scaled: 76%) compared to the 40-60-minute frame (common: 55%, scaled: 62%), albeit with reduced specificity in the common setting (20-40-min: 78%, 40-60-min: 95%), which was ameliorated in the intensity-scaled setting (20-40-min: 91%, 40-60-min: 96%). Combined assessment of multiple brain regions did not significantly improve diagnostic sensitivity, compared to assessing the basal ganglia alone (76% each). Evaluation of intensity-scaled parametric images resulted in higher sensitivity compared to intensity-scaled static scans (86% vs. 76%) at similar specificity (89% vs. 91%)., Conclusion: Visual reading of [ 18 F]PI-2620 tau-PET scans demonstrated reliable detection of 4R-tauopathies, particularly when standardized processing methods and early imaging windows were employed. Parametric images should be preferred for visual assessment of 4R-tauopathies., Competing Interests: Declaration of competing interest RP received honoraria for advisory boards and speaker engagements from Roche, EISAI, Eli Lilly, Biogen, Janssen-Cilag, Astra Zeneca, Schwabe, Grifols, Novo Nordisk, GSK and Tabuk. AD reports Research Support by: Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA, Ariceum Therapeutics and Speaker Honorary/Advisory Boards by: Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital, Lilly, Stock by: Siemens Healthineers, Lantheus Holding, Structured therapeutics, Lilly and a patent for 18F-JK-PSMA- 7 (Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021)., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

In Alzheimer's disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which Aβ facilitates the spreading of tau pathology. By combining Aβ positron emission tomography (PET), resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the AD spectrum, we confirmed that Aβ induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading . Last, using longitudinal tau-PET and mediation analysis, we confirmed that these Aβ-related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in AD mediated the effect of Aβ on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two AD hallmark pathologies. Together, these findings suggest that Aβ promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting Aβ-related neuronal hyperconnectivity may attenuate tau spreading in AD.

Background: The recent Movement Disorders Society (MDS)-progressive supranuclear palsy (PSP) diagnostic criteria conceptualized three clinical diagnostic certainty levels: "suggestive of PSP" for sensitive early diagnosis based on subtle clinical signs, "possible PSP" balancing sensitivity and specificity, and "probable PSP" highly specific for PSP pathology., Objective: The aim of this study was to prospectively validate the criteria against long-term clinical follow-up and characterize the diagnostic certainty increase over time., Methods: Patients with "possible PSP" or "suggestive of PSP" diagnosis and clinical follow-up were recruited in two German multicenter longitudinal observational studies (ProPSP and DescribePSP). The cumulative percentage of patients longitudinally increasing diagnostic certainty was assessed over up to 2.5 years of follow-up. The sample size per arm required to detect 30% attenuated rate in diagnostic certainty increase in trials was estimated over multiple time intervals., Results: Of 254 patients with available longitudinal data, 61 patients had low diagnostic certainty at baseline (48 suggestive of PSP, 13 possible PSP) and multiple clinical visits (median: 3, range: 2-4). The cumulative percentage of patients increasing diagnostic certainty progressed with follow-up duration (30.4% at 6 months, 51.7% at 1 year, 80.4% at 2.5 years). The sample size required to detect 30% reduction in diagnostic certainty increase rate within 1 year was 163, slightly smaller than that required using the PSP rating scale., Conclusions: Most "suggestive of PSP" patients increased diagnostic certainty upon longitudinal follow-up, providing the first prospective multicenter validation of MDS-PSP diagnostic criteria. Our data support the design of trials tailored for these early-stage patients, suggesting the PSP rating scale and the diagnostic certainty increase rate as potential endpoint measures. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau 181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau 181 . To determine effects of microglial activation on p-tau 181 , we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau 181 levels. Higher sTREM2 was associated with elevated p-tau 181 , with stronger associations in women. Similarly, ApoE4 was related to higher p-tau 181 levels and faster p-tau 181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2025. The Author(s).)

Traumatic brain injury is widely viewed as a risk factor for dementia, but the biological mechanisms underlying this association are still unclear. In previous studies, traumatic brain injury has been associated with the hallmark pathologies of Alzheimer's disease, i.e. amyloid-β plaques and neurofibrillary tangles comprised of hyperphosphorylated tau. Depending on the type and location of trauma, traumatic brain injury can induce spatially heterogeneous brain lesions that may pre-dispose for the development of Alzheimer's disease pathology in aging. Therefore, we hypothesized that a history of traumatic brain injury may be related to spatially heterogeneous amyloid-β and tau pathology patterns that deviate from the stereotypical temporo-parietal patterns in Alzheimer's disease. To test this, we included 103 Vietnam War veterans of whom 65 had experienced traumatic brain injury ( n = 40, 38.8% mild; n = 25, 24.3% moderate/severe). Most individuals had a history of 1 ( n = 35, 53.8%) or 2 ( n = 15, 23.1%) traumatic brain injury events. We included the group without a history of traumatic brain injury ( n = 38, 36.9%) as controls. The majority was cognitively normal ( n = 80, 77.7%), while a subset had mild cognitive impairment ( n = 23, 22.3%). All participants underwent [ 18 F]florbetapir/Amyvid amyloid-β PET and [ 18 F]flortaucipir/Tauvid tau-PET 39.63 ± 18.39 years after their last traumatic brain injury event. We found no differences in global amyloid-β and tau-PET levels between groups, suggesting that a history of traumatic brain injury does not pre-dispose to accumulate amyloid-β or tau pathology in general. However, we found that traumatic brain injury was associated with altered spatial patterns of amyloid-β and tau, with relatively greater deposition in fronto-parietal brain regions. These regions are prone to damage in traumatic brain injury, while they are typically only affected in later stages of Alzheimer's disease. Moreover, in our traumatic brain injury groups, the association between amyloid-β and tau was reduced in Alzheimer-typical temporal regions but increased in frontal regions that are commonly associated with traumatic brain injury. Altogether, while acknowledging the relatively small sample size and generally low levels of Alzheimer's disease pathology in this sample, our findings suggest that traumatic brain injury induces spatial patterns of amyloid-β and tau that differ from patterns observed in typical Alzheimer's disease. Furthermore, traumatic brain injury may be associated with a de-coupling of amyloid-β and tau in regions vulnerable in Alzheimer's disease. These findings indicate that focal brain damage in early/mid-life may change neurodegenerative trajectories in late-life., Competing Interests: C.G. is supported by a Dementia Fellowship grant from ZonMW (10510022110010). E.G.B.V. is PI for DIAN trials, WashU, ACI, Alnylam, CogRX therapeutics, New Amsterdam Pharma, Janssen, Roche, Vivoryon, ImmunoBrain, Alector, Biogen, BMS, Prothena, GSK, Aviadobio, Treeway. E.G.B.V. is consulent for New Amsterdam Pharma, Treeway, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, Roche, Eli Lilly en Esai. Y.A.L.P. has received funding from the Dutch Brain Foundation, ZonMW, NWO and the Mooiste Contact Fonds (both paid to her institution). Projects of R.O. received support of the European Research Council, ZonMw, NWO, National Institute of Health, Alzheimer Association, Alzheimer Nederland, Stichting Dioraphte, Cure Alzheimer’s fund, Health Holland, ERA PerMed, Alzheimerfonden, Hjarnfonden, Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. R.O. was speaker at symposia organized by GE healthcare. R.O. is an advisory board member for Asceneuron, Bristol Myers Squibb and Biogen. All the aforementioned has been paid to the institutions. R.O. is part of the editorial board of Alzheimer’s Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. N.F. received research support from the Alzheimer Forschung Initiative, the Hertie Network of Excellence in Neuroscience, the German Parkinson Foundation (DPG), the Legerlotz Foundation, the Gerhard and Ilse Schick Foundation, the Alzheimer’s Association, the Bright Focus Foundation, LMU excellence and the DFG excellence initiative, as well as speaker honoraria from Eisai, GE Healthcare, Life Molecular Imaging and Consulting Honoraria from MSD., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose of the Report: Adults with Down Syndrome (DS) have a substantially increased risk for Alzheimer's disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [ 18 F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [ 18 F]PI-2620 for the diagnosis of DS-AD., Materials and Methods: Five adults with DS (40% female, aged 43-62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [ 18 F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia., Results: Visual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages., Conclusion: Tau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD., Competing Interests: MB is a member of the Neuroimaging Committee of the EANM, received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and served as an advisor of MIAC and Life Molecular Imaging. NF received speaker and travel honoraria from Life Molecular Imaging, speaker honoraria from GE Healthcare and Eli Lilly and consulting honoraria from MSD. JL reported personal/ speaker/consulting fees from Bayer Vital, Biogen, Eisai, Teva, Zambon, Merck, Roche, Axon Neuroscience, Thieme medical publishers, W. Kohlhammer GmbH, and Modag GmbH, and having a patent for Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies pending. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Wagemann, Brendel, Franzmeier, Nübling, Gnörich, Zaganjori, Prix, Stockbauer, Wlasich, Loosli, Sandkühler, Frontzkowski, Höglinger and Levin.)

In early-stage Alzheimer's disease (AD) amyloid-β (Aβ) deposition can induce neuronal hyperactivity, thereby potentially triggering activity-dependent neuronal secretion of phosphorylated tau (p-tau), ensuing tau aggregation and spread. Therefore, cortical excitability is a candidate biomarker for early AD detection. Moreover, lowering neuronal excitability could potentially complement strategies to reduce Aβ and tau buildup. There is, however, a lack of understanding of the relationship between cortical excitability and p-tau increase in vivo . Therefore, in a sample of 658 healthy middle-aged (between the ages of 40 and 65) participants of the Barcelona Brain Health Initiative cohort study, we examined the relation of blood-based tau, phosphorylated at amino acid 181 (p-tau181), reflecting neuronal p-tau secretion; neurofilament light chain (NfL), as a passively released control for p-tau181; and electroencephalography (EEG) markers of cortical excitability. A subsample of 47 participants also completed a controlled brain perturbation approach via transcranial magnetic stimulation (TMS) with concurrent EEG. Results show that both spontaneous (i.e., resting-state) and perturbation-based TMS-EEG markers, are associated with blood p-tau181, particularly in older individuals. The perturbation-based marker was a significantly more sensitive predictor of p-tau181 concentration than the spontaneous resting state EEG-based marker. The relationships observed are not present for the NfL control. These results show that relationships between p-tau181 and cortical excitability are present in healthy middle-aged subjects and that p-tau181 increases may reflect activity-dependent secretion., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alvaro Pascual-Leone reports a relationship with Neuroelectrics that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with Magstim Inc. that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with TetraNeuron that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with Skin2Neuron that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with MedRhythms that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with Hearts-Radiant that includes: consulting or advisory. Henrik Zetterberg reports a relationship with AbbVie that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Acumen that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Alector that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Alzinova that includes: consulting or advisory. Henrik Zetterberg reports a relationship with ALZPath that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Annexon that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Apellis that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Artery Therapeutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with AZTherapies that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Cognito Therapeutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with CogRx that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Denali that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Eisai that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Merry Life that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Nervgen that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Novo Nordisk that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Optoceutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Passage Bio, Inc. that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Pinteon Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Prothena that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Red Abbey Labs that includes: consulting or advisory. Henrik Zetterberg reports a relationship with reMYND that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Roche that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Samumed that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Siemens Healthineers that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Triplet Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Wave that includes: consulting or advisory. David Bartres-Faz reports a relationship with Linus Health that includes: consulting or advisory. A.P-L is co-founder of TI solutions and co-founder and chief medical officer of Linus Health where he has shares and share-options. A.P-L is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and applications of noninvasive brain stimulation in various neurological disorders; as well as digital biomarkers of cognition and digital assessments for early diagnosis of dementia. H.Z. has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N -acetyl-l-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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: With the advent of disease-modifying therapies, accurate assessment of biomarkers indicating the presence of disease-associated amyloid beta (Aβ) pathology becomes crucial in patients with clinically suspected Alzheimer's disease (AD). We evaluated Aβ levels in cerebrospinal fluid (Aβ CSF) and Aβ levels in positron emission tomography (Aβ PET) biomarkers in a real-world memory-clinic setting to develop an efficient algorithm for clinical use., Methods: Patients were evaluated for AD-related Aβ pathology from two independent cohorts (Ludwig Maximilian University [LMU], n  = 402, and Medical University of Vienna [MUV], n  = 144). Optimal thresholds of CSF biomarkers were deduced from receiver operating characteristic curves and validated against Aβ PET positivity., Results: In both cohorts, a CSF Aβ42/40 ratio ≥ 7.1% was associated with a low risk of a positive Aβ PET scan (negative predictive value: 94.3%). Implementing two cutoffs revealed 14% to 16% of patients with intermediate results (CSF Aβ42/40 ratio: 5.5%-7.1%), which had a strong benefit from Aβ PET imaging (44%-52% Aβ PET positivity)., Discussion: A two-cutoff approach for CSF Aβ42/40 including Aβ PET imaging at intermediate results provides an effective assessment of Aβ pathology in real-world settings., Highlights: We evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid beta (Aβ) biomarkers for Alzheimer's disease in real-world cohorts.A CSF Aβ 42/40 ratio between 5.5% and 7.1% defines patients at borderline levels.Patients at borderline levels strongly benefit from additional Aβ PET imaging.Two-cutoff CSF Aβ 42/40 and PET will allow effective treatment stratification., Competing Interests: A.D. reports research support by Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA, Ariceum Therapeutics as well as speaker honorary/advisory boards by Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital, Lilly; stock by Siemens Healthineers, Lantheus Holding, Structured therapeutics, Lilly; and a patent for 18F‐JK‐PSMA‐ 7 (Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021). E.S. has received grants from Roche, Eisai, FFG/AAL, Horizon2020, and the Austrian Alzheimer Association (all to the institution); consulting fees from Biogen, Eisai, and Lilly; support for attending meetings and/or travel from Roche; and has received payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events by Biogen, Roche, Eisai, and Novartis. E.S. has participated on advisory boards (Biogen, Roche, Eisai, Sanofi) and held leadership or a fiduciary role in scientific societies (Austrian Alzheimer Association, the EAN scientific panel dementia). J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Esteve, Zambon, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is an inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4‐Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH, and is an inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. M.B. is a member of the Neuroimaging Committee of the EANM. M.B. received speaker honoraria from Roche, GE Healthcare, and Life Molecular Imaging and served as an advisor of MIAC and Life Molecular Imaging. N.F. has received speaker honoraria from Eisai, GE Healthcare, Life Molecular Imaging, and Consulting Honoraria from MSD. R.P. has received honoraria for advisory boards and speaker engagements from Roche, EISAI, Eli Lilly, Biogen, Janssen‐Cilag, Astra Zeneca, Schwabe, Grifols, Novo Nordisk, and Tabuk. W.G.K. reports consulting fees from BMS, Boehringer Ingelheim, Need Inc., mintMedical, and FalkFoundation (unrelated to the paper). All other authors declare no competing interests. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy., Methods: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 ( c9orf72 ), progranulin ( GRN ), or microtubule-associated protein tau ( MAPT ) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms., Results: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum ( p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms ( p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness., Discussion: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Purpose: Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in the brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated., Experimental Design: We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n = 41), astrocytoma WHO grade 2 (n = 7), and healthy controls (n = 20) and compared TSPO-PET signals of the non-lesion (i.e., contralateral) hemisphere. Back-translation into syngeneic SB28 glioblastoma mice was used to characterize Pet alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain., Results: Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions., Conclusions: Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression., (©2024 The Authors; Published by the American Association for Cancer Research.)

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.)

A pervasive dilemma in neuroimaging is whether to prioritize sample size or scan time given fixed resources. Here, we systematically investigate this trade-off in the context of brain-wide association studies (BWAS) using functional magnetic resonance imaging (fMRI). We find that total scan duration (sample size × scan time per participant) robustly explains individual-level phenotypic prediction accuracy via a logarithmic model, suggesting that sample size and scan time are broadly interchangeable up to 20-30 min of data. However, the returns of scan time diminish relative to sample size, which we explain with principled theoretical derivations. When accounting for fixed overhead costs associated with each participant (e.g., recruitment, non-imaging measures), prediction accuracy in many small-scale and some large-scale BWAS might benefit from longer scan time than typically assumed. These results generalize across phenotypic domains, scanners, acquisition protocols, racial groups, mental disorders, age groups, as well as resting-state and task-state functional connectivity. Overall, our study emphasizes the importance of scan time, which is ignored in standard power calculations. Standard power calculations maximize sample size, at the expense of scan time, which can result in sub-optimal prediction accuracies and inefficient use of resources. Our empirically informed reference is available for future study design: WEB&#95;APPLICATION&#95;LINK., Competing Interests: Conflict of interest DB is shareholder and advisory board member of MindState Design Labs, USA.

Background: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker., Methods: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization., Results: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia., Conclusion: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression., (© 2024. The Author(s).)

Purpose: [ 18 F]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 [ 18 F]PI-2620 PET quantification for assessing tau by regional distribution volumes (V T ). 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 [ 18 F] 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 V T and V T 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 V T 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 V T values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting V T 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). V T ratios and DV ratios outperformed SUV ratios and V T 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 [ 18 F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [ 18 F]PI-2620 V T show large variance, in contrast to regional [ 18 F]PI-2620 V T 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., (© 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.)

Aim: β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies., Methods: Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13-16 months) were examined three times by Aβ-PET ([ 18 F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30-60 min p.i. standardized uptake value ratios (SUVR CTX/WM ) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining., Results: All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆ PET =20.4 % ± 2.9 %, ∆ PET/MR =18.4 % ± 4.5 %, ∆ PET/CT =18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC) PETvs.PET/MR =83.0 %, DC PETvs.PET/CT =69.3 %, DC PET/MRvs.PET/CT =81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (z PET =11.5 ± 1.6; z PET/MR =5.3 ± 1.3; z PET/CT =3.4 ± 0.6) and effect sizes (d PET =8.5, d PET/MR =4.5, d PET/CT =4.1). However, correlations at the individual mouse level were still strong between scanners (r PETvs.PET/MR =0.96, r PETvs.PET/CT =0.91, r PET/MRvs.PET/CT =0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028)., Conclusions: Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization., Competing Interests: Declaration of competing interest L.B. is an Novartis Radiopharmaceuticals employee, unrelated to this work. M.B. received speaker honoraria from GE healthcare, Roche and Life Molecular Imaging and is an advisor of Life Molecular Imaging. All other authors do not report a conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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

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.)

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).)

Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks., Methods & Results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance., Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders., Competing Interests: F.B. is supported by the NIHR biomedical research center at UCLH. M.D. received honoraria for lectures from Bayer Vital and Sanofi Genzyme, Consultant for Hovid Berhad and Roche Pharma. G.T. has received fees as consultant or lecturer from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, BristolMyersSquibb/Pfizer, Daichi Sankyo, Portola, and Stryker outside the submitted work.

Introduction: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β 1-42 (Aβ42)-positive status., Methods: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume., Results: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001)., Discussion: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter., Highlights: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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).)

Previous studies have demonstrated resilience to AD-related neuropathology in a form of cognitive reserve (CR). In this study we investigated a relationship between CR and hypometabolic subtypes of AD, specifically the typical and the limbic-predominant subtypes. We analyzed data from 59 Aβ-positive cognitively normal (CN), 221 prodromal Alzheimer's disease (AD) and 174 AD dementia participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) from ADNI and ADNIGO/2 phases. For replication, we analyzed data from 5 Aβ-positive CN, 89 prodromal AD and 43 AD dementia participants from ADNI3. CR was estimated as standardized residuals in a model predicting cognition from temporoparietal grey matter volumes and covariates. Higher CR estimates predicted slower cognitive decline. Typical and limbic-predominant hypometabolic subtypes demonstrated similar baseline CR, but the results suggested a faster decline of CR in the typical subtype. These findings support the relationship between subtypes and CR, specifically longitudinal trajectories of CR. Results also underline the importance of longitudinal analyses in research on CR., Competing Interests: Declaration of Competing Interest SJT participated in scientific advisory boards of Roche Pharma AG, Biogen, Grifols, and MSD, and received lecture fees from Roche and MSD. FL, MJG, MD and NF have no disclosures to report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)