Progressive supranuclear palsy (PSP) is a primary 4R tauopathy. Postmortem studies identified six tau pathological stages with tau aggregation with involvement of the subthalamic nucleus and the globus pallidus, with further affliction of the striatum, cerebellum with dentate nucleus, frontal and/or occipital cortices. We aimed to test whether this staging system is also observed when an unsupervised machine learning model is used to analyze in vivo [18F]PI-2620 tau PET imaging data. Furthermore, regional differences in tau tracer binding in different PSP subtypes and corresponding clinical profiles were investigated. Methods We analyzed imaging and clinical data of 120 patients with the clinical diagnosis of PSP and of 16 healthy controls. Dynamic [18F]PI-2620 PET imaging in a multicenter setting (sites in Germany and Australia) was performed over 60min. After kinetic modeling, parametric distribution volume ratio images were analyzed and classified into different pattern subtypes and stages by use of the SuStaIn algorithm. Regional differences in tau tracer binding were assessed using statistical parametric mapping. Results The SuStaIn model distinguished three patterns of [18F]PI-2620 binding: i) a subcortical pattern, ii) a rhombencephalic pattern, and iii) a cortical pattern. The subcortical pattern showed a spatiotemporal distribution similar to the previously published PSP postmortem staging system. Subjects in different SuStaIn-derived patterns showed different clinical characteristics, including a significant association with sex (P < 0.001). Conclusion These results provide motivation to further develop [18F]PI-2620 as an imaging biomarker of PSP. They also demonstrate the potential of the SuStaIn model to reveal so-far-unknown tau tracer binding patterns in PSP, with possible implications for improved phenotyping and future anti-tau treatment decisions.

Spatial navigation deficits emerge early in Alzheimer's disease and related dementias (ADRD), yet their potential as a training target and source of digital biomarkers remains underexplored. We evaluated a smartphone-based, unsupervised wayfinding training in 58 cognitively unimpaired older adults and characterized multi-day learning trajectories derived from digital behavioral readouts in relation to neurobiological risk and reserve markers. Participants completed six training sessions navigating to points-of-interest on a university campus, with continuous GPS and app interaction recording. Compared with walking-only controls, participants improved in a pointing task and map drawing, but not in a visuospatial memory task. Higher MTL tau was associated with reduced improvements in navigation efficiency in individuals with greater hippocampal vessel distance. Higher cerebrovascular dysfunction was linked to attenuated learning on readouts reflecting information-processing demands. These findings demonstrate that real-world digital navigation training improves spatial cognition and multi-day learning trajectories show domain-specific associations with ADRD-related biomarkers.

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non-amnestic-predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. We included tau-PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n  = 139 posterior cortical atrophy/PCA-AD; n  = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n  = 35 behavioural variant AD/bvAD; n  = 43 corticobasal syndrome/CBS-AD) from 14 sites, with a subset of patients ( n  = 78) having longitudinal tau-PET data. As an independent sample, we further included regional post-mortem tau stainings from 93 atypical AD patients from two sites ( n  = 19 PCA-AD, n  = 32 lvPPA-AD, n  = 23 bvAD, n  = 19 CBS-AD). Gaussian mixture modeling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology, and 2) functional connectivity of tau-PET epicenters and tau-PET accumulation epicenters was associated with cross-sectional and longitudinal tau patterns. Tau-PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA-AD (“visual AD”) and left-hemispheric temporal predominance in lvPPA-AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau-PET levels, which was confirmed with post-mortem data (Figure 2). Moreover, the connectivity profile of tau-PET epicenters and accumulation epicenters corresponded to tau-PET progression patterns (Figure 3). Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific endpoints in clinical trials.

[18F]PI-2620 is a second-generation tau PET tracer that may detect early tau accumulation in aging. We investigated whether temporal lobe [18F]PI-2620 binding is associated with age, sex, genetic Alzheimer disease (AD) risk, plasma biomarkers of AD (plasma phosphorylated tau 217 [p-tau217], Aβ1-42/Aβ1-40), astrogliosis (glial fibrillary acidic protein), and domain-specific cognition in cognitively unimpaired (CU) older adults. Methods: In this study, 166 CU older adults (mean age, 72 ± 7 y; females, 46%; apolipoprotein ϵ4 [APOE4] carriers, 23%) and 13 young adults underwent extensive cognitive testing, blood sampling, MRI, and dynamic [18F]PI-2620 PET (0-60 min postinjection). Associations of regional [18F]PI-2620 distribution volume ratio (DVR) with age, sex, APOE4 genotype, and plasma biomarkers were examined using region-of-interest and voxelwise analyses. Additional imaging markers of age-related pathology included hippocampal volume, medial temporal lobe thickness, white matter (WM) hyperintensities, perivascular spaces, and hippocampal perfusion (R1-derived maps). Associations among temporal lobe DVR, other imaging markers, and domain-specific cognitive performance (from factor analysis) were tested. Results: In older adults, temporal [18F]PI-2620 binding was higher in women (β = 0.543, P < 0.001) and APOE4 carriers (β = 0.395, P = 0.030) and was positively associated with plasma p-tau217 (β = 0.22, P = 0.008). Voxelwise analyses showed age-related increases in basal ganglia signal, whereas WM signal was higher in younger adults. In a multiple regression model, higher temporal DVR (β = -0.36, P = 0.003) and lower hippocampal volume (β = 0.22, P = 0.007) predicted worse episodic memory and, together with demographic factors, explained approximately 30% of the variance. Conclusion: Temporal [18F]PI-2620 binding is associated with genetic AD risk, plasma p-tau217, female sex, and episodic memory deficits in CU older adults, supporting its sensitivity to early tau pathology, while highlighting the need to consider potential WM binding.

Background:It remains unclear whether dynamic amino-acid (AA) positron-emission tomography (PET) has additional diagnostic value over static AA-PET to distinguish tumor progression (TP) from treatment-related abnormalities (TRA) in patients with post-treatment glioma. Methods:This was a retrospective study of patients with glioma with suspected TP who underwent dynamic AA-PET imaging. The final diagnoses were based on histopathology and/or clinical-radiological follow-up. The static PET parameters included the mean and maximum tumor-to-brain ratio (TBRmax and TBRmean, respectively) and the dynamic PET parameters included time to peak (TTP) and area under the time activity curve (AUTAC). Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUROC). Results:In total, 33 patients with adult diffuse glioma (17 females: mean age: 55.7 ± 12.2 years) were included [13 [S-methyl-11C]methionine ([11C]MET) and 20 O-(2-[18F]fluoroethyl)-L-tyrosine (1⁸F]FET) PET examinations]. The static parameters (TBRmean and TBRmax) were significantly different between the TP and TRA groups when using [11C]MET (p = 0.019 and p = 0.013, respectively), resulting in very-good-to-excellent diagnostic accuracy (AUROC values of 0.85 and 0.93, respectively). The TBRmean values derived from [18F]FET PET data were not significantly different between the TP and TRA groups (p = 0.066). However, the [18F]FET PET data-derived TBRmax values were significantly higher in the individuals with TP (p = 0.005), indicating very good diagnostic accuracy (AUROC = 0.84). The dynamic PET parameters (time to peak and area under the time activity curve) were not significantly different between the TP and TRA groups. Conclusion:This study suggests that dynamic and static AA-PET parameters have similar diagnostic capacities to distinguish TP from TRA. While static AA-PET parameters may suffice for clinical decision-making, this study did not formally assess the incremental value of using dynamic metrics in addition to static measures.

Cognitive reserve (CR) and brain maintenance enable the brain to maintain performance despite injury and disease while also reducing neural decline by safeguarding brain structure and function. Physical activity is a potential pathway to BM and CR, as fitness relates to better cognition in older adults, though the underlying mechanisms remain unclear. To explore the role of physical fitness in BM and CR, we tested its association with brain pathology and its potential moderation of pathology's impact on cognitive performance. We collected data from 167 cognitively unimpaired participants (mean age 71.57±7.50 years; 70 females) of the ongoing SFB1436 study ( www.sfb1435.de ; Figure 1). We collected many markers, including global and verbal cognitive performance; aerobic (VO 2max ) and muscular capacity; blood-based biomarkers of Alzheimer's disease (plasma Aβ1-42/1-40, ptau217) and plasticity (serum BDNF, VEGF and Cathepsin-B); PET-derived medial temporal lobe tau burden (MTL DVR, 18 F-PI-2620 PET); and MRI-derived volumes of hippocampi, white matter hyperintensities, and perivascular spaces (PVS) in the basal ganglia (BG) and centrum semiovale regions. The tests were two-fold. We first tested whether fitness was associated with lower MTL DVR values, reduced MRI-derived volumes of brain pathology, and better cognition. Using moderation analysis, we then tested whether physical fitness moderated the relationship between pathology and cognition. We relied on ANOVA for model comparison. We adjusted models for age and sex and FDR-corrected multiple comparisons. Participants with better aerobic capacity (VO 2max ) had lower BG-PVS volumes (Figure 2a) and better global cognitive performance. Those with higher MTL tau burden had worse verbal memory (Figure 2b). We found no evidence of a relationship between physical fitness and Alzheimer's markers, plasticity-related markers, or hippocampal volume. Moderation analysis revealed that physical fitness did not moderate the relationship between MTL tau burden and verbal memory, but model comparison revealed weak evidence for CR against MTL tau. We demonstrated that aerobic fitness is related to lower BG-PVS volumes in old age and showed that aerobic fitness tends to act as CR proxy against MTL tau pathology. Aerobic fitness may help maintain cerebrovascular and glymphatic dysfunction in old age, thereby mitigating cognitive decline.

While some memory decline in old age is “normal”, there are some older individuals with maintained high cognitive performance. Using a multimodal approach including neuroimaging, fitness, genetic and questionnaire data (Figure 1A), we aimed to identify factors that are related to successful cognitive aging and whether these differ between sexes. We analyzed 165 cognitively normal older adults age ≥ 60 years from an ongoing study (SFB1436) (age=71±8years, 43% female). For all participants, we determined plasma Abeta 1-42 /Abeta 1-40 . Temporal lobe tau burden was estimated by [ 18 F]PI-2620 in a subsample (see Figure 1A for sample sizes). We assessed global white matter hyperintensity (WMH) volumes and gray matter thickness for medial temporal lobe (MTL), anterior cingulate cortex (ACC) and whole brain. We measured aerobic and muscular capacity (and blood pressure) by fitness assessment and trait/state anxiety by self-reports. Genetic profiling included KLOTHO and KIBRA polymorphisms and APOE genotype. To phenotype successful cognitive aging, we i) grouped individuals age ≥ 79.5 years into SuperAgers (N=18) based on delayed verbal recall performance ≥ normative values at age of 50-60 years versus typical agers (N=19). For the whole sample we ii) calculated cognitive age gap (CAG) as the difference between cognition-predicted age and chronological age (Figure 3A). We assessed how markers of pathology, brain structure, fitness, mental health and genetics were related to CAG, covarying for chronological age, sex and education. SuperAgers and typical agers did not differ in age, sex, education, fitness, anxiety or Abeta42/40 (all p-values>0.1). However, SuperAgers had less WMH volume, higher ACC thickness, lower blood pressure and less temporal lobe tau-tracer binding (small subgroup; ). In the whole sample, younger cognitive age related to higher MTL and global cortical thickness, less temporal tau-tracer binding, less anxiety (all p<0.05; Figure 3B) and marginally to higher muscular capacity (p=.06). Only the association between anxiety measures and CAG was moderated by sex (Figure 3B). CAG was not related to genotype. Our results suggest that successful cognitive aging is related to resistance against age-related pathology and higher brain integrity. Younger cognitive age is linked to better mental health, especially in females.

Single-session, multiparametric [¹⁸F]FET PET/MRI is used to detect tumor recurrence in high-grade glioma, but its prognostic value for overall survival remains uncertain. This study evaluated whether biological tumor volume, tumor-to-background ratio (TBRmax), cerebral blood volume (rCBVmax), and choline/NAA ratio (Cho/NAA) could predict survival in recurrent high-grade glioma. Twenty-six patients with histopathologically confirmed tumor progression underwent simultaneous [¹⁸F]FET PET/MRI. PET-derived biological tumor volume and TBRmax, MRI-derived rCBVmax, and Cho/NAA ratio were analyzed. A Cox proportional hazards model assessed associations with overall survival, adjusting for the number of lesions and treatment strategy. Biological tumor volume (hazard ratio = 2.22, 95

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

There is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial. We included 269 amyloid-β-positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA-AD; 83 logopenic variant primary progressive aphasia, lvPPA-AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS-AD) and 68 with typical AD from 12 international cohorts, who underwent tau-PET (54% [ 18 F]AV1451/[ 18 F]flortaucipir/Tauvid, 27% [ 18 F]MK6240, 19% [ 18 F]PI2620). Using Gaussian mixture modeling including amyloid-β-negative controls, cross-sectional tau-PET standardized uptake value ratios within Schaefer-200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity-based distance (using the 30% strongest positive region-to-region connections of a group-average connectivity matrix from ADNI elderly controls) and tau-PET covariance (group-average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1-4) and tau positivity probabilities were assessed accordingly. Tau positivity probabilities matched clinical variants, with a posterior pattern in PCA-AD, left-hemispheric dominant pattern in lvPPA-AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS-AD, and temporo-parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau-PET covariance was associated with shorter functional connectivity-based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3). This multi-center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant-specific endpoints in clinical trials.

While the implication of a dysfunctional dopaminergic system in Tourette syndrome (TS) is well established, the underlying pathophysiological mechanisms remain unclear. Apart from neurotransmitters, disturbed iron homeostasis and iron regulatory mechanisms are also suspected. Iron is a trace element of fundamental biological importance and is involved in the synthesis and metabolism of dopamine and its receptors and transporters. The goal of the current pre-registered, multi-modal, cross-sectional study was to investigate the relationship between potential iron homeostasis imbalances and dopaminergic system disturbances in patients with TS. Susceptibility-sensitive MRI at 7 Tesla was used to obtain surrogate measures for local brain iron in 25 patients with TS (age 30 ± 9 years, 6 female) and 40 matched control subjects. Additionally, dopamine D1 receptor availability was investigated with [11C]SCH23390 PET in a subgroup of 20 patients and 20 controls. Significantly reduced sub-cortical magnetic susceptibility, indicating reduced iron levels, was observed in TS patients in the caudate, pallidum, sub-thalamic nucleus, thalamus, red nucleus and substantia nigra. These reductions were accompanied by significant reductions of the [11C]SCH23390 binding potential indicating reduced availability of D1 receptors in the dorsal striatum. The D1 receptor abnormality correlated with tic severity. These results point to alterations of intra-synaptic dopamine release and reduced striatal D1 receptor binding, supporting the notion of disruption in multiple functional elements of the dopaminergic system. Such dopaminergic abnormalities appear to be associated with disturbances in iron homeostasis.

The atypical Parkinsonian disorder progressive supranuclear palsy (PSP) forms a diagnostic challenge, resulting in frequent misdiagnosis and delay in treatment. Although structural MRI can detect PSP signs at more advanced stages, emerging diagnostic tools such as tau-PET and quantitative susceptibility mapping (QSM) may allow for earlier detection. This exploratory study aimed to investigate differences in QSM data of patients with PSP and healthy controls (HCs) and for the first time assess possible correlations between QSM and tau-PET data in patients with PSP to explore the relationship between tau aggregation and iron susceptibility. We retrospectively investigated differences in susceptibility values of brain structures, as assessed by QSM, between 11 HCs and 31 patients with PSP [Richardson’s syndrome (PSP-RS): n = 14; other subtypes (PSP-nonRS): n = 17]. Additionally, we examined co-registered [18F]PI-2620 PET and QSM data in the 31 patients with PSP to explore the relationship between tau accumulation and susceptibility changes. Compared to HCs, patients with PSP showed higher QSM values in left nucleus caudate (p = 0.04) and bilateral dentate nucleus (p = 0.04, p = 0.01). Patients with the subtype PSP-RS showed higher QSM values than HCs in left dentate nucleus (p = 0.02). The association between the patients’ QSM and tau-PET data showed a significant positive correlation. These results suggest distinct patterns of regional iron accumulation in patients with PSP and its subtypes and support an association between iron and tau pathology. The data encourage further investigation in longitudinal studies and validation in larger cohorts to examine the value of QSM as a possible diagnostic biomarker.

PURPOSE:Heterogeneity in clinical phenotypes has led to the description of different phenotypes of Alzheimer's disease (AD). Besides the most frequent amnestic variant of AD (aAD), patients presenting with language deficits are diagnosed with logopenic variant primary progressive aphasia (lvPPA), whereas patients presenting with visual deficits are classified as posterior cortical atrophy (PCA). METHODS:This study set out to investigate the value of a multi-parametric [18F]PI-2620 tau PET/MRI protocol to distinguish aAD, lvPPA and PCA to support clinical diagnosis in 32 patients. Phenotype-specific information about tau accumulation, relative perfusion, grey matter density, functional network alterations and white matter microstructural alterations was collected. RESULTS:The aAD patients showed significantly higher tau accumulation, relative hypoperfusion and grey matter density loss in the temporal lobes compared to PCA and lvPPA patients. PCA patients, on the other hand, showed significantly higher tau accumulation in the occipital lobe as compared to aAD patients. Relative hypoperfusion in the occipital lobe and loss of functional connectivity of the posterior cingulate cortex to supplementary visual cortical regions helped to distinguish PCA from lvPPA. Tau accumulation in the cerebellum and microstructural changes in the cingulum were found to help differentiate lvPPA from aAD. CONCLUSION:This study highlights structural and functional differences between patients with different AD phenotypes. Differences in regional tau PET signals suggest that refinements in the Braak staging system are needed for the non-aAD cases. These patterns of tau accumulation align with the cascading network failure hypothesis, though more research is needed to warrant the here presented results in larger patient cohorts.

While the implication of a dysfunctional dopaminergic system in Tourette syndrome (TS) is well established, the underlying pathophysiological mechanisms remain unclear. Apart from neurotransmitters, disturbed iron homeostasis and iron regulatory mechanisms are also suspected. Iron is a trace element of fundamental biological importance and is involved in the synthesis and metabolism of dopamine and its receptors and transporters. The goal of the current pre-registered, multi-modal, cross-sectional study was to investigate the relationship between potential iron homeostasis imbalances and dopaminergic system disturbances in patients with TS. Susceptibility-sensitive MRI at 7 Tesla was used to obtain surrogate measures for local brain iron in 25 patients with TS (age 30 ± 9 years, 6 female) and 40 matched control subjects. Additionally, dopamine D1 receptor availability was investigated with [11C]SCH23390 PET in a subgroup of 20 patients and 20 controls. Significantly reduced sub-cortical magnetic susceptibility, indicating reduced iron levels, was observed in TS patients in the caudate, pallidum, sub-thalamic nucleus, thalamus, red nucleus and substantia nigra. These reductions were accompanied by significant reductions of the [11C]SCH23390 binding potential indicating reduced availability of D1 receptors in the dorsal striatum. The D1 receptor abnormality correlated with tic severity. These results point to alterations of intra-synaptic dopamine release and reduced striatal D1 receptor binding, supporting the notion of disruption in multiple functional elements of the dopaminergic system. Such dopaminergic abnormalities appear to be associated with disturbances in iron homeostasis.

Alzheimer's Disease (AD) pathology accumulates early in the medial temporal lobe (MTL), crucial for spatial navigation. As spatial navigation is among the first cognitive functions affected by AD, it may benefit from targeted behavioral interventions. We investigated the potential of a novel smartphone‐assisted real‐world wayfinding training, tailored for healthy older adults, to improve their spatial abilities and explored associations with hippocampal vascularization and AD biomarkers. 38 cognitively healthy older adults (62–84 years; 18 females) participated in a 3‐week navigation training, using our smartphone application “Explore” (Figure 1). Training involved finding several locations displayed on a map in the medical campus area of Magdeburg, Germany, while GPS data were recorded. Pre‐ and post‐training, participants underwent fMRI, performed a pointing task in a virtual campus version, and completed the VWLT. At pre‐assessment, AD pathology was characterized by plasma sampling (Abeta1‐42/1‐40, Ptau217) and [18F]PI‐2620 PET in a subsample. Hippocampal vascularization was assessed by 7T angiography. Performance in the virtual pointing task and a map drawing test was compared to a control group ( n = 20) who performed a walking task of equal length without a navigational component. Additionally, changes in different mobile wayfinding performance indicators and their associations with AD biomarkers and hippocampal vascularization (i.e., mean distance of hippocampus to surrounding vessels) were examined. Performance in the pointing task and map drawing, but not in the VWLT ( p = .321), significantly improved due to the training (all p <.001; Figure 2A C). The control group showed no improvements in navigation. Training benefits were also evident in the mobile data (all p ≤.017; Figure 3A‐E). Better wayfinding efficiency was associated with less vessel distance to hippocampus, r=.44, p = .012, and the number of orientation stops was negatively related to pTau217, r=‐.38, p = .019 (Figure 3F). We provide evidence that a remotely administered real‐world wayfinding training enhances wayfinding abilities and improves spatial memory in older adults. Importantly, hippocampal vascularization may benefit wayfinding efficiency. Higher pTau217 was related to fewer orientation stops during navigation. As a next step, potential mediating effects between vascularization and AD pathology on wayfinding performance will be investigated.

White matter hyperintensities (WMHs) are commonly observed in aging and neurodegenerative diseases, but their impact on the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) system remains unclear. This study investigates the relationship between WMHs and gray matter nicotinic signaling, aiming to elucidate potential pathways contributing to neurodegeneration. Multimodal imaging data using PET and MR imaging from 39 participants, including 19 healthy controls and 20 patients with Alzheimer’s disease dementia (AD), were analyzed. WMHs were identified on T1-weighted MPRAGE and T2-weighted TSE MR images using advanced segmentation algorithms. Probabilistic fiber tracking was applied to determine WMH-connected gray matter. PET-based total distribution volume (VT) values of the α4β2-nAChR tracer (-)-[18F]Flubatine were compared between WMH-affected and unaffected gray matter regions. WMH volumes were significantly correlated with age, Fazekas and MMSE scores, but no differences in absolute or relative WMH volumes were observed between healthy controls and patients with AD. PET-based VT values in WMH-connected gray matter showed no significant difference from contralateral unaffected regions, regardless of disease status or WMH burden. However, intra-individual differences in VT values correlated with Fazekas scores, presumably driven by patients with AD. Pathway-based analyses revealed decreased VT values in the medial cholinergic pathway of patients with AD but no significant differences in lateral pathways. This study shows that WMHs do not significantly alter gray matter nicotinic signaling in directly connected regions. However, the results suggest subtle associations between WMH severity and specific cholinergic pathways, particularly in AD.

Cognitive ageing is marked by progressive decline in episodic memory and dopaminergic function, yet the extent to which individual differences in dopaminergic system integrity influence memory under motivational contexts remains unclear. In this study, we investigated how baseline D2/D3 receptor availability (BPND) in key dopaminergic pathways relates to reward-modulated memory performance in healthy older adults. Thirty-three healthy seniors (aged 64-85) underwent two session concurrent MR-PET imaging with [1F]fallypride involving scene categorisation task with high- and low-motivational contexts. We quantified BPND across nine dopaminergic regions of interest and examined their relationships with recognition memory performance at short (∼15m) and long (∼24h) delays. Baseline D2/D3 receptor availability showed high test-retest reliability and regionally distinct profiles, suggesting it reflects a stable neurochemical characteristic in healthy ageing, and principal axis factor analysis revealed two partially independent dopaminergic subsystems (dorsal striatal vs mesolimbic) based on interindividual patterns in receptor densities. Region-specific associations further linked D2/D3 receptor availability to distinct memory outcomes. Higher caudate D2/D3 receptor availability was associated with a liberal response bias (increased hits and false alarms both), whereas higher putamen D2/D3 predicted more durable long-term memory retention. Greater thalamic D2/D3 receptor availability correlated with fewer short-term false memories, while greater D2/D3 receptor availability in the amygdala was associated with better recognition at longer delays. In contrast, higher midbrain (substantia nigra and ventral tegmental area) D2/D3 availability which was linked to poorer reward-related memory performance. These findings suggest several complementary dopaminergic circuits supporting episodic memory. Our results highlight dopaminergic neuromodulation as a key factor in cognitive ageing and a potential target for interventions to bolster memory in late life. Patient consent and ethics approval All subjects who were included in this study have provided their consent prior to their participation, following the guidelines of the ethics committee at University Hospital Magdeburg in Magdeburg, Germany. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, SFB1315 B06 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, SFB1436 A08 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, SFB779 A07 AlzheimerM-BM-^Rs Research UK, https://ror.org/02ymzm013, SRF2018B-004

Background/Objectives: Positron emission tomography (PET) imaging with radiolabeled amino acids is increasingly used in glioma patients for biopsy planning, tumor delineation, prognostication, and therapy response assessment. This study investigated whether baseline amino acid PET imaging could identify regions at risk of future tumor recurrence. Methods: Retrospective case series of 14 patients with high-grade glioma. Contrast-enhanced magnetic resonance imaging (MRI) data of tumor recurrence and baseline imaging (PET-MRI) were co-registered. Volumes of interest (VOIs) of the high-grade glioma were derived from contrast-enhanced MRI at baseline and follow-up and from amino acid PET at baseline. The Dice similarity coefficient (DSC) was used to assess the overlap between VOIs. Furthermore, dynamic and static PET parameters were compared between the VOIs derived from contrast-enhanced MRI at follow-up and from the region of increased amino acid transport at baseline. Results: Regions of tumor recurrence in high-grade glioma patients overlap significantly more with baseline regions of increased amino acid transport on PET compared to regions of contrast enhancement on baseline MRI (p < 0.001). However, the static and dynamic PET statistics did not differentiate between regions that would later develop tumor recurrence and other areas of increased amino acid transport at baseline. Conclusions: These findings reaffirm the ability of amino acid PET to visualize the infiltrative components of gliomas not detected by contrast-enhanced MRI. Also, this study supports the role of amino acid PET in visualizing glioma infiltration beyond the MRI-visible tumor, but also indicates that accurately predicting the specific regions of recurrence based on baseline PET remains limited.