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INTRODUCTION: Subjective cognitive decline (SCD) in amyloid-positive (Aß+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer's disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies. METHODS: Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models. RESULTS: In the combined and stratified cohorts, Aß+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aß- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings. DISCUSSION: Aß+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials. HIGHLIGHTS: SCD in amyloid-positive (Aß+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aß+ older adults with SCD could be a target population for interventional trials.
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Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.
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Cuerpo Estriado , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , Imagen por Resonancia Magnética , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Estudios de Cohortes , Dihidroxifenilalanina/análogos & derivados , Conectoma , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatologíaRESUMEN
In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.
In a study of 32 patients with progressive supranuclear palsy (PSP), we used a molecular imaging tracer called [18F]PI-2620 to measure two things: the presence of a protein called tau in deep brain areas (specifically, the globus pallidus internus and dentate nucleus) and the function of the brain's cortex by assessing blood flow (perfusion). We found that higher amounts of tau in these deep brain areas were associated with reduced blood flow in the limbic cortex, which is involved in emotion regulation. Also, the frontal areas of the brain showed reduced blood flow related to tau in these deep brain regions. However, this connection was statistically significant only for the dentate nucleus. This study suggests that the buildup of tau protein in deeper brain areas can disrupt function in parts of the brain's cortex, highlighting the damaging role of tau in PSP.
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Motor performance (MP) is essential for functional independence and well-being, particularly in later life. However, the relationship between behavioural aspects such as sleep quality and depressive symptoms, which contribute to MP, and the underlying structural brain substrates of their interplay remains unclear. This study used three population-based cohorts of younger and older adults (n=1,950) from the Human Connectome Project-Young Adult (HCP-YA), HCP-Aging (HCP-A), and enhanced Nathan Kline Institute-Rockland sample (eNKI-RS). Several canonical correlation analyses were computed within a machine learning framework to assess the associations between each of the three domains (sleep quality, depressive symptoms, grey matter volume (GMV)) and MP. The HCP-YA analyses showed progressively stronger associations between MP and each domain: depressive symptoms (unexpectedly positive, r=0.13, SD=0.06), sleep quality (r=0.17, SD=0.05), and GMV (r=0.19, SD=0.06). Combining sleep and depressive symptoms significantly improved the canonical correlations (r=0.25, SD=0.05), while the addition of GMV exhibited no further increase (r=0.23, SD=0.06). In young adults, better sleep quality, mild depressive symptoms, and GMV of several brain regions were associated with better MP. This was conceptually replicated in young adults from the eNKI-RS cohort. In HCP-Aging, better sleep quality, fewer depressive symptoms, and increased GMV were associated with MP. Robust multivariate associations were observed between sleep quality, depressive symptoms and GMV with MP, as well as age-related variations in these factors. Future studies should further explore these associations and consider interventions targeting sleep and mental health to test the potential effects on MP across the lifespan.
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Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer's disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson's disease is limited. Our study involved 151 Parkinson's patients from the Parkinson's Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson's patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.
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INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Compuestos de Anilina , Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Anciano , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Pronóstico , Persona de Mediana Edad , Estudios Longitudinales , Estilbenos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , BenzotiazolesRESUMEN
We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.
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Fenotipo , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Tomografía de Emisión de Positrones/métodos , Proteínas tau/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Piridinas , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Radiofármacos/farmacocinéticaRESUMEN
Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has established the precision oncology paradigm in lung cancer. Most patients with EGFR-mutated lung cancer respond but eventually acquire resistance. Methods: Patients exhibiting the EGFR p.T790M resistance biomarker benefit from sequenced targeted therapy with osimertinib. We hypothesized that metabolic response as detected by 18F-FDG PET after short-course osimertinib identifies additional patients susceptible to sequenced therapy. Results: Fourteen patients with EGFR-mutated lung cancer and resistance to first- or second-generation EGFR TKI testing negatively for EGFR p.T790M were enrolled in a phase II study. Five patients (36%) achieved a metabolic 18F-FDG PET response and continued osimertinib. In those, the median duration of treatment was not reached (95% CI, 24 mo to not estimable), median progression-free survival was 18.7 mo (95% CI, 14.6 mo to not estimable), and median overall survival was 41.5 mo. Conclusion: Connecting theranostic osimertinib treatment with early metabolic response assessment by PET enables early identification of patients with unknown mechanisms of TKI resistance who derive dramatic clinical benefit from sequenced osimertinib. This defines a novel paradigm for personalization of targeted therapies in patients with lung cancer dependent on a tractable driver oncogene.
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Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Terapia Molecular Dirigida , Mutación , Tomografía de Emisión de Positrones , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Compuestos de Anilina/uso terapéutico , Fluorodesoxiglucosa F18 , Acrilamidas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano de 80 o más Años , Indoles , PirimidinasRESUMEN
BACKGROUND: Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC). METHODS: 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as "minor" (adaption of radiation field) or "major" (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue. RESULTS: Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields ("minor change") in 5/32 patients (16%) and changed treatment regimen ("major change") in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p < 0.001)) with similar results for nuclear medical FTVs. IHC revealed heterogenous FAP-expression in all specimens (mean H-score: 36.3 (SD 24.6)) without correlation between FAP expression in IHC and FAPI tracer uptake in PET/CT. CONCLUSION: We report first data on the use of PET with FAPI-46 for patients with EC, who are scheduled to receive RT. Tumor uptake was high and not depending on FAP expression in TME. Further, FAPI-46/dual-tracer PET had relevant impact on management in this setting. Our data calls for prospective evaluation of FAPI-46/dual-tracer PET to improve clinical outcomes of EC.
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Neoplasias Esofágicas , Quinolinas , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/radioterapia , Tomografía de Emisión de Positrones , Microambiente TumoralRESUMEN
To prevent motion artifacts in small animal positron emission tomography (PET), animals are routinely scanned under anesthesia or physical restraint. Both may potentially alter metabolism and neurochemistry. This study investigates the feasibility of fully awake acquisition and subsequent absolute quantification of dynamic brain PET data via pharmacokinetic modelling in moving rats using the glutamate 5 receptor radioligand [11C]ABP688 and point source based motion correction. Five male rats underwent three dynamic [11C]ABP688 PET scans: two test-retest awake PET scans and one scan under anesthesia for comparison. Specific radioligand binding was determined via the simplified reference tissue model (reference: cerebellum) and outcome parameters BPND and R1 were evaluated in terms of stability and reproducibility. Test-retest measurements in awake animals gave reliable results with high correlations of BPND (y = 1.08 × -0.2, r = 0.99, p < 0.01) and an acceptable variability (mean over all investigated regions 15.7 ± 2.4%). Regional [11C]ABP688 BPNDs under awake and anesthetized conditions were comparable although in awake scans, absolute radioactive peak uptakes were lower and relative blood flow in terms of R1 was higher. Awake small animal PET with absolute quantification of neuroreceptor availability is technically feasible and reproducible thereby providing a suitable alternative whenever effects of anesthesia are undesirable, e.g. in sleep research.
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Objectives: Apraxia is a core feature of Alzheimer's disease, but the pathomechanism of this characteristic symptom is not well understood. Here, we systematically investigated apraxia profiles in a well-defined group of patients with Alzheimer's disease (AD; N=32) who additionally underwent PET imaging with the second-generation tau PET tracer [18F]PI-2620. We hypothesized that specific patterns of tau pathology might be related to apraxic deficits. Methods: Patients (N=32) with a biomarker-confirmed diagnosis of Alzheimer's disease were recruited in addition to a sample cognitively unimpaired controls (CU 1 ; N=41). Both groups underwent in-depth neuropsychological assessment of apraxia (Dementia Apraxia Screening Test; DATE and the Cologne Apraxia Screening; KAS). In addition, static PET imaging with [18F]PI-2620 was performed to assess tau pathology in the AD patients. To specifically investigate the association of apraxia with regional tau-pathology, we compared the PET-data from this group with an independent sample of amyloid-negative cognitively intact participants (CU 2; N=54) by generation of z-score-deviation maps as well as voxel- based multiple regression analyses. Results: We identified significant clusters of tau-aggregation in praxis-related regions (e.g., supramarginal gyrus, angular gyrus, temporal, parietal and occipital regions) that were associated with apraxia. These regions were similar between the two apraxia assessments. No correlations between tau-tracer uptake in primary motor cortical or subcortical brain regions and apraxia were observed. Conclusions: These results suggest that tau deposition in specific cortical brain regions may induce local neuronal dysfunction leading to a dose-dependent functional decline in praxis performance.
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The inverse effects of creatine supplementation and sleep deprivation on high energy phosphates, neural creatine, and cognitive performances suggest that creatine is a suitable candidate for reducing the negative effects of sleep deprivation. With this, the main obstacle is the limited exogenous uptake by the central nervous system (CNS), making creatine only effective over a long-term diet of weeks. Thus far, only repeated dosing of creatine over weeks has been studied, yielding detectable changes in CNS levels. Based on the hypothesis that a high extracellular creatine availability and increased intracellular energy consumption will temporarily increase the central creatine uptake, subjects were orally administered a high single dose of creatinemonohydrate (0.35 g/kg) while performing cognitive tests during sleep deprivation. Two consecutive 31P-MRS scans, 1H-MRS, and cognitive tests were performed each at evening baseline, 3, 5.5, and 7.5 h after single dose creatine (0.35 g/kg) or placebo during sub-total 21 h sleep deprivation (SD). Our results show that creatine induces changes in PCr/Pi, ATP, tCr/tNAA, prevents a drop in pH level, and improves cognitive performance and processing speed. These outcomes suggest that a high single dose of creatine can partially reverse metabolic alterations and fatigue-related cognitive deterioration.
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Creatina , Privación de Sueño , Humanos , Creatina/farmacología , Creatina/metabolismo , Privación de Sueño/metabolismo , Sistema Nervioso Central/metabolismo , Cognición/fisiología , Fosfatos/farmacologíaRESUMEN
Parkinson's disease (PD) is currently diagnosed largely on the basis of expert judgement with neuroimaging serving only as a supportive tool. In a recent study, we identified a hypometabolic midbrain cluster, which includes parts of the substantia nigra, as the best differentiating metabolic feature for PD-patients based on group comparison of [18F]-fluorodeoxyglucose ([18F]-FDG) PET scans. Longitudinal analyses confirmed progressive metabolic changes in this region and, an independent study showed great potential of nigral metabolism for diagnostic workup of parkinsonian syndromes. In this study, we applied a machine learning approach to evaluate midbrain metabolism measured by [18F]-FDG PET as a diagnostic marker for PD. In total, 51 mid-stage PD-patients and 16 healthy control subjects underwent high-resolution [18F]-FDG PET. Normalized tracer update values of the midbrain cluster identified by between-group comparison were extracted voxel-wise from individuals' scans. Extracted uptake values were subjected to a random forest feature classification algorithm. An adapted leave-one-out cross validation approach was applied for testing robustness of the model for differentiating between patients and controls. Performance of the model across all runs was evaluated by calculating sensitivity, specificity and model accuracy for the validation data set and the percentage of correctly categorized subjects for test data sets. The random forest feature classification of voxel-based uptake values from the midbrain cluster identified patients in the validation data set with an average sensitivity of 0.91 (Min: 0.82, Max: 0.94). For all 67 runs, in which each of the individuals was treated once as test data set, the test data set was correctly categorized by our model. The applied feature importance extraction consistently identified a subset of voxels within the midbrain cluster with highest importance across all runs which spatially converged with the left substantia nigra. Our data suggest midbrain metabolism measured by [18F]-FDG PET as a promising diagnostic imaging tool for PD. Given its close relationship to PD pathophysiology and very high discriminatory accuracy, this approach could help to objectify PD diagnosis and enable more accurate classification in relation to clinical trials, which could also be applicable to patients with prodromal disease.
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OBJECTIVES: Higher-educated patients with Alzheimer disease (AD) can harbor greater neuropathologic burden than those with less education despite similar symptom severity. In this study, we assessed whether this observation is also present in potential preclinical AD stages, namely in individuals with subjective cognitive decline and clinical features increasing AD likelihood (SCD+). METHODS: Amyloid-PET information ([18F]Flutemetamol or [18F]Florbetaben) of individuals with SCD+, mild cognitive impairment (MCI), and AD were retrieved from the AMYPAD-DPMS cohort, a multicenter randomized controlled study. Group classification was based on the recommendations by the SCD-I and NIA-AA working groups. Amyloid PET images were acquired within 8 months after initial screening and processed with AMYPYPE. Amyloid load was based on global Centiloid (CL) values. Educational level was indexed by formal schooling and subsequent higher education in years. Using linear regression analysis, the main effect of education on CL values was tested across the entire cohort, followed by the assessment of an education-by-diagnostic-group interaction (covariates: age, sex, and recruiting memory clinic). To account for influences of non-AD pathology and comorbidities concerning the tested amyloid-education association, we compared white matter hyperintensity (WMH) severity, cardiovascular events, depression, and anxiety history between lower-educated and higher-educated groups within each diagnostic category using the Fisher exact test or χ2 test. Education groups were defined using a median split on education (Md = 13 years) in a subsample of the initial cohort, for whom this information was available. RESULTS: Across the cohort of 212 individuals with SCD+ (M(Age) = 69.17 years, F 42.45%), 258 individuals with MCI (M(Age) = 72.93, F 43.80%), and 195 individuals with dementia (M(Age) = 74.07, F 48.72%), no main effect of education (ß = 0.52, 95% CI -0.30 to 1.58), but a significant education-by-group interaction on CL values, was found (p = 0.024) using linear regression modeling. This interaction was driven by a negative association of education and CL values in the SCD+ group (ß = -0.11, 95% CI -4.85 to -0.21) and a positive association in the MCI group (ß = 0.15, 95% CI 0.79-5.22). No education-dependent differences in terms of WMH severity and comorbidities were found in the subsample (100 cases with SCD+, 97 cases with MCI, 72 cases with dementia). DISCUSSION: Education may represent a factor oppositely modulating subjective awareness in preclinical stages and objective severity of ongoing neuropathologic processes in clinical stages.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/epidemiología , Amiloide , Péptidos beta-Amiloides , Proteínas Amiloidogénicas , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/epidemiología , Escolaridad , Estudios Longitudinales , Tomografía de Emisión de Positrones , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Stereotypical isocortical tau protein pathology along the Braak stages has been described as an instigator of neurodegeneration in Alzheimer's disease (AD). Less is known about tau pathology in motor regions, although higher-order motor deficits such as praxis dysfunction are part of the clinical description. Here, we examined how tau pathology in cytoarchitectonically mapped regions of the primary and higher-order motor network in comparison to primary visual and sensory regions varies across the clinical spectrum of AD. We analyzed tau PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort in patients with mild cognitive impairment (MCI; N = 84) and dementia of the Alzheimer's disease type (DAD; N = 25). Additionally, an amyloid-negative sample of healthy older individuals (HC; N = 26) were included. Standard uptake ratio values (SUVRs) were extracted in native space from the left and the right hemispheres. A repeated measurement analysis of variance was conducted to assess the effect of diagnostic disease category on tau pathology in the individual motor regions, controlling for age. We observed that tau pathology varies as a function of diagnostic category in predominantly higher motor regions (i.e., supplementary motor area, superior parietal lobe, angular gyrus, and dorsal premotor cortex) compared to primary visual, sensory and motor regions. Indeed, tau in higher-order motor regions was significantly associated with decline in cognitive function. Together, these results expand our knowledge on the in vivo pattern of tau pathology in AD and suggest that higher motor regions are not spared from tau aggregation in the course of disease, potentially contributing to the symptomatic appearance of the disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Neuroimagen , Tomografía de Emisión de Positrones/métodos , Disfunción Cognitiva/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
PURPOSE: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. METHODS: A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9⯱ 12.3â¯min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. RESULTS: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. CONCLUSION: Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging.
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Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Quinolinas , Humanos , Fluorodesoxiglucosa F18 , Radioisótopos de Galio , Carga Tumoral , Neoplasias/diagnóstico por imagenRESUMEN
In a previous study, regional reductions in cerebral glucose metabolism have been demonstrated in the tauopathy mouse model rTg4510 (Endepols et al., 2022). Notably, glucose hypometabolism was present in some brain regions without co-localized synaptic degeneration measured with [18F]UCB-H. We hypothesized that in those regions hypometabolism may reflect reduced functional connectivity rather than synaptic damage. To test this hypothesis, we performed seed-based metabolic connectivity analyses using [18F]FDG-PET data in this mouse model. Eight rTg4510 mice at the age of seven months and 8 non-transgenic littermates were injected intraperitoneally with 11.1 ± 0.8 MBq [18F]FDG and spent a 35-min uptake period awake in single cages. Subsequently, they were anesthetized and measured in a small animal PET scanner for 30 min. Three seed-based connectivity analyses were performed per group. Seeds were selected for apparent mismatch between [18F]FDG and [18F]UCB-H. A seed was placed either in the medial orbitofrontal cortex, dorsal hippocampus or dorsal thalamus, and correlated with all other voxels of the brain across animals. In the control group, the emerging correlative pattern was strongly overlapping for all three seed locations, indicating a uniform fronto-thalamo-hippocampal resting state network. In contrast, rTg4510 mice showed three distinct networks with minimal overlap. Frontal and thalamic networks were greatly diminished. The hippocampus, however, formed a new network with the whole parietal cortex. We conclude that resting-state functional networks are fragmented in the brain of rTg4510 mice. Thus, hypometabolism can be explained by reduced functional connectivity of brain areas devoid of tau-related pathology, such as the thalamus.
Asunto(s)
Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Animales , Ratones , Fluorodesoxiglucosa F18/metabolismo , Ratones Transgénicos , Encéfalo/metabolismo , Mapeo Encefálico , Modelos Animales de Enfermedad , Imagen por Resonancia MagnéticaRESUMEN
Deviations of brain age from chronologic age, known as the brain age gap (BAG), have been linked to neurodegenerative diseases such as Alzheimer disease (AD). Here, we compare the associations of MRI-derived (atrophy) or 18F-FDG PET-derived (brain metabolism) BAG with cognitive performance, neuropathologic burden, and disease progression in cognitively normal individuals (CNs) and individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Methods: Machine learning pipelines were trained to estimate brain age from 185 matched T1-weighted MRI or 18F-FDG PET scans of CN from the Alzheimer's Disease Neuroimaging Initiative and validated in external test sets from the Open Access of Imaging and German Center for Neurodegenerative Diseases-Longitudinal Cognitive Impairment and Dementia studies. BAG was correlated with measures of cognitive performance and AD neuropathology in CNs, SCD subjects, and MCI subjects. Finally, BAG was compared between cognitively stable and declining individuals and subsequently used to predict disease progression. Results: MRI (mean absolute error, 2.49 y) and 18F-FDG PET (mean absolute error, 2.60 y) both estimated chronologic age well. At the SCD stage, MRI-based BAG correlated significantly with beta-amyloid1-42 (Aß1-42) in cerebrospinal fluid, whereas 18F-FDG PET BAG correlated with memory performance. At the MCI stage, both BAGs were associated with memory and executive function performance and cerebrospinal fluid Aß1-42, but only MRI-derived BAG correlated with phosphorylated-tau181/Aß1-42 Lastly, MRI-estimated BAG predicted MCI-to-AD progression better than 18F-FDG PET-estimated BAG (areas under the curve, 0.73 and 0.60, respectively). Conclusion: Age was reliably estimated from MRI or 18F-FDG PET. MRI BAG reflected cognitive and pathologic markers of AD in SCD and MCI, whereas 18F-FDG PET BAG was sensitive mainly to early cognitive impairment, possibly constituting an independent biomarker of brain age-related changes.