Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.

Continuous innovation in precision radio-guided surgery.

Since its origins, nuclear medicine has faced technological changes that led to modifying operating modes and adapting protocols. In the field of radioguided surgery, the incorporation of preoperative scintigraphic imaging and intraoperative detection with the gamma probe provided a definitive boost to sentinel lymph node biopsy to become a standard procedure for melanoma and breast cancer. The various technological innovations and consequent adaptation of protocols come together in the coexistence of the disruptive and the gradual. As obvious examples we have the introduction of SPECT/CT in the preoperative field and Drop-in probes in the intraoperative field. Other innovative aspects with possible application in radio-guided surgery are based on the application of artificial intelligence, navigation and telecare.

Impact of simulated reduced injected dose on the assessment of amyloid PET scans.

PURPOSE: To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [18F]flutemetamol and [18F]florbetaben. METHODS: Cognitively impaired and unimpaired individuals (N = 250, 36% Aß-positive) were included and injected with [18F]flutemetamol (N = 175) or [18F]florbetaben (N = 75). PET scans were acquired in list-mode (90-110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aß-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aß- and Aß + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated. RESULTS: At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [18F]flutemetamol and [18F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were < 1.5%. AUCs for discriminating Aß- from Aß + scans were high (AUC ≥ 0.94) across dose levels, and visual assessment showed intra-reader agreement of > 80% for both tracers. CONCLUSION: This proof-of-concept study showed that for both [18F]flutemetamol and [18F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances.

Differential effects of sleep on brain structure and metabolism at the preclinical stages of AD.

INTRODUCTION: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self-reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals. METHODS: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel-wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status. RESULTS: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self-reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages. DISCUSSION: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD-related neurodegeneration in areas involved in sleep-wake regulation may induce or worsen sleep disturbances. Highlights Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology. Poor sleep exacerbates brain changes observed in preclinical AD. Sleep is an appealing therapeutic strategy for preventing AD.

APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals.

PURPOSE: To determine whether the APOE-ε4 allele modulates the relationship between regional ß-amyloid (Aß) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants. METHODS: The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [18F]flutemetamol Aß positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aß PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aß PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer's Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume. RESULTS: In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aß PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum. CONCLUSION: CU APOE-ε4 carriers with a positive Aß PET VR in regions known to accumulate amyloid at later stages of the Alzheimer's disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aß PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD. CLINICALTRIALS: gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969 .

Evaluating the performance of Bayesian and frequentist approaches for longitudinal modeling: application to Alzheimer's disease.

Linear mixed effects (LME) modelling under both frequentist and Bayesian frameworks can be used to study longitudinal trajectories. We studied the performance of both frameworks on different dataset configurations using hippocampal volumes from longitudinal MRI data across groups-healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients, including subjects that converted from MCI to AD. We started from a big database of 1250 subjects from the Alzheimer's disease neuroimaging initiative (ADNI), and we created different reduced datasets simulating real-life situations using a random-removal permutation-based approach. The number of subjects needed to differentiate groups and to detect conversion to AD was 147 and 115 respectively. The Bayesian approach allowed estimating the LME model even with very sparse databases, with high number of missing points, which was not possible with the frequentist approach. Our results indicate that the frequentist approach is computationally simpler, but it fails in modelling data with high number of missing values.

Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer's continuum.

PURPOSE: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. METHODS: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-ß (Aß) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aß and tau status (AT stages). RESULTS: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aß pathology but became negative in Aß-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. CONCLUSIONS: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.

Brain alterations in the early Alzheimer's continuum with amyloid-ß, tau, glial and neurodegeneration CSF markers.

Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-ß and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-ß/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-ß-positive tau-negative participants with respect to the reference amyloid-ß-negative tau-negative group. Both amyloid-ß and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-ß in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-ß/tau stages. Taken together, our results show that CSF amyloid-ß and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes.

Presurgical evaluation of drug-resistant paediatric focal epilepsy with PISCOM compared to SISCOM and FDG-PET.

PURPOSE: Children with drug-resistant focal epilepsy have a compromised quality of life. Epilepsy surgery can control or significantly reduce the seizures. We assessed and compared the usefulness of PISCOM, a new nuclear imaging processing technique, with SISCOM and 18F-FDG PET (FDG-PET) in pre-surgical evaluation of paediatric drug-resistant focal epilepsy. METHODS: Twenty-two children with pharmcorefractory epilepsy, mainly extratemporal, who had undergone pre-surgical assessment including SISCOM and FDG-PET and with postsurgical favorable outcome (Engel class I or II) for at least two years, were included in this proof-of-concept study. All abnormalities observed in SISCOM, FDG-PET and PISCOM were compared with each other and with the known epileptogenic zone (EZ) based on surgical treatment, histopathologic and surgical outcome results. Global interobserver agreement, Cohen's Kappa coeficient and PABAK statistic were calculated for each technique. RESULTS: PISCOM concordance with the known EZ was significantly higher than SISCOM (p<0.05), and no statistically differences were found with FDG-PET. PISCOM showed successful identification in 19 of 22 cases (86%), successful concordant with FDG-PET in 17 (77%), and SISCOM in 11 (50%). If we consider PISCOM and FDG-PET results together, both techniques successfully localized the known EZ in all cases. The measures of agreement between two experts in nuclear medicine were higher in PISCOM than in SISCOM and FDG-PET. CONCLUSION: PISCOM could provide complementary presurgical information in drug-resistant paediatric focal epilepsy, particularly in cases in which FDG-PET is doubtful or negative, replacing SISCOM and sparing the use of interictal SPECT.

Evaluation of patients with advanced epithelial ovarian cancer before primary treatment: correlation between tumour burden assessed by [18F]FDG PET/CT volumetric parameters and tumour markers HE4 and CA125.

OBJECTIVES: Accurate assessment of disease extent is required to select the best primary treatment for advanced epithelial ovarian cancer patients. Estimation of tumour burden is challenging and it is usually performed by means of a surgical procedure. Imaging techniques and tumour markers can help to estimate tumour burden non-invasively. 2-[18F]FDG PET/CT allows the evaluation of the whole-body disease. This study aimed to correlate HE4 and CA125 serum concentrations with tumour burden evaluated by volumetric 2-[18F]FDG PET/CT parameters in advanced high-grade epithelial ovarian cancer. METHODS: We included 66 patients who underwent 2-[18F]FDG PET/CT and serum tumour markers determination before primary treatment. Volumes of interest were delimited in every pathological uptake. Whole-body metabolic tumour volume (wb_MTV) and total lesion glycolysis (wb_TLG) were calculated summing up every VOI's MTV value. SUVmax thresholds were set at 40% (MTV40 and TLG40) and 50% (MTV50 and TLG50). In addition, four VOI subgroups were defined: peritoneal carcinomatosis, retroperitoneal nodes, supradiaphragmatic nodes, and distant metastases. MTV and TLG were calculated for each group by adding up the corresponding MTV values. TLG was calculated likewise. RESULTS: wb_MTV and wb_TLG were found to be significantly correlated with serum CA125 and HE4 concentrations. The strongest correlation was observed between HE4 and wb_MTV40 (r = 0.62, p < 0.001). Pearson's correlation coefficients between peritoneal carcinomatosis MTV40 and tumour markers were 0.61 (p < 0.0001) and 0.29 (p = 0.02) for HE4 and CA125 respectively. None of these tumour markers showed a positive correlation with tumour load outside the abdominal cavity assessed by volumetric parameters. CONCLUSION: HE4 performs better than CA125 to predict metabolic tumour burden in high-grade epithelial ovarian cancer before primary treatment. 2-[18F]FDG PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution. These results support the usefulness of HE4 and PET/CT to improve the stratification of these patients in clinical practice. KEY POINTS: • In patients with high-grade advanced ovarian epithelial carcinoma, both CA125 and HE4 correlate to whole-body tumour burden assessed by PET/CT before primary treatment. • HE4 estimates peritoneal disease much better than CA125. • PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution.

CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.

BACKGROUND AND OBJECTIVES: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. METHODS: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers ß-amyloid (Aß)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aß PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aß pathology, tau pathology, and neurodegeneration markers. RESULTS: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aß load (as measured by CSF Aß42/40 and Aß PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aß deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions. DISCUSSION: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aß pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT02485730.

How to inject ictal SPECT? From manual to automated injection.

BACKGROUND: Successful surgery depends on the accurate localization of epileptogenic zone before surgery. Ictal SPECT is the only imaging modality that allows identification of the ictal onset zone by measuring the regional cerebral blood flow at the time of injection. The main limitation of ictal SPECT in epilepsy is the complex methodology of the tracer injection during a seizure. To overcome this limitation, we present the main features of the first automated injector for ictal SPECT (epijet, LemerPax; La Chapelle -sur-Erdre; France). In this study we compared traditional manual injection with automated injection for ictal SPECT in 122 patients with drug-resistant epilepsy. METHODS: The study included 55 consecutive prospective patients with drug-resistant epilepsy undergoing injection with the automated injector. The control group was our retrospective database of a historic pool of 67 patients, injected manually from 2014 to 2016. Calculated annual exposure/radioactive dose for operators was measured. Injection time, seizure focus localization with ictal SPECT, as well as repeated hospitalizations related to inconclusive findings of the SPECT were compared in these two groups of patients. RESULTS: There were no differences in the average injection time with epijet (13 s) compared with the traditional manual injection (14 s). The seizure focus was successfully localized with ictal SPECT with epijet in 44/55 (80 %) patients and with manual injection in 46/67 (68 %) patients (p = 0.097). Repeated studies were required in 9/67 (23 %) patients in the manual injection group compared to 3 patients (7%) in the epijet group (p = 0.141). Calculated annual exposure/dose for operators of 0.39 mSv/year and administered dose error inferior to 5% are other advantages of epijet. CONCLUSION: The first results using epijet are promising in adjustment of the injection dose, reducing the rate of radiation exposure for patients and nurses, maintaining the same injection time and allowing high SPECT accuracy. These preliminary results support the use of an automated injection system to inject radioactive ictal SPECT doses in epilepsy units.

Cognitively unimpaired individuals with a low burden of Aß pathology have a distinct CSF biomarker profile.

BACKGROUND: Understanding the changes that occur in the transitional stage between absent and overt amyloid-ß (Aß) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aß pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. METHODS: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aß42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aß pathology: (1) positive CSF Aß42/40 and < 30 Centiloids in Aß PET, (2) positive CSF Aß42/40 and negative Aß PET visual read, and (3) 20-40 Centiloid range in Aß PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aß-negative group, adjusted by age and sex. RESULTS: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aß-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. CONCLUSIONS: There are biologically meaningful Aß-downstream effects in individuals with a low burden of Aß pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aß pathology for clinical trials. TRIAL REGISTRATION: NCT02485730.

SimPET-An open online platform for the Monte Carlo simulation of realistic brain PET data. Validation for 18 F-FDG scans.

PURPOSE: SimPET (www.sim-pet.org) is a free cloud-based platform for the generation of realistic brain positron emission tomography (PET) data. In this work, we introduce the key features of the platform. In addition, we validate the platform by performing a comparison between simulated healthy brain FDG-PET images and real healthy subject data for three commercial scanners (GE Advance NXi, GE Discovery ST, and Siemens Biograph mCT). METHODS: The platform provides a graphical user interface to a set of automatic scripts taking care of the code execution for the phantom generation, simulation (SimSET), and tomographic image reconstruction (STIR). We characterize the performance using activity and attenuation maps derived from PET/CT and MRI data of 25 healthy subjects acquired with a GE Discovery ST. We then use the created maps to generate synthetic data for the GE Discovery ST, the GE Advance NXi, and the Siemens Biograph mCT. The validation was carried out by evaluating Bland-Altman differences between real and simulated images for each scanner. In addition, SPM voxel-wise comparison was performed to highlight regional differences. Examples for amyloid PET and for the generation of ground-truth pathological patients are included. RESULTS: The platform can be efficiently used for generating realistic simulated FDG-PET images in a reasonable amount of time. The validation showed small differences between SimPET and acquired FDG-PET images, with errors below 10% for 98.09% (GE Discovery ST), 95.09% (GE Advance NXi), and 91.35% (Siemens Biograph mCT) of the voxels. Nevertheless, our SPM analysis showed significant regional differences between the simulated images and real healthy patients, and thus, the use of the platform for converting control subject databases between different scanners requires further investigation. CONCLUSIONS: The presented platform can potentially allow scientists in clinical and research settings to perform MC simulation experiments without the need for high-end hardware or advanced computing knowledge and in a reasonable amount of time.

Cerebral amyloid-ß load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum.

INTRODUCTION: The association between cerebral amyloid-ß accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages. METHODS: In 318 cognitively unimpaired participants, we assessed the association between amyloid-ß PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated. RESULTS: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-ß on sTREM2 and NfL was also tau-independent. DISCUSSION: Early amyloid-ß accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.

Visual assessment of [18F]flutemetamol PET images can detect early amyloid pathology and grade its extent.

PURPOSE: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR. METHODS: [18F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [18F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density. RESULTS: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERADSOT-based classification (i.e., any region mCERADSOT > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aß plaque was observed in all FP cases. Regional VR was also associated with regional plaque density. CONCLUSION: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease.

BACKGROUND: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. METHODS: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. RESULTS: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aß42/40 ratio (ß = 0.099, p = 0.032) and negatively associated with CSF p-tau (ß = - 0.141, p = 0.005), t-tau (ß = - 0.147 p = 0.004) and neurogranin levels (ß = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. CONCLUSIONS: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-ß accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. TRIAL REGISTRATION: NCT01835717 , NCT02485730 , NCT02685969 .

Quantitative informant- and self-reports of subjective cognitive decline predict amyloid beta PET outcomes in cognitively unimpaired individuals independently of age and APOE ε4.

INTRODUCTION: Amyloid beta (Aß) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict Aß positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals. METHODS: A total of 261 participants from the ALFA+ study underwent [18F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict Aß PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to Aß status. RESULTS: Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted Aß PET outcome. Longitudinal increase of self-reported executive decline was predictive of Aß in women (P = .003). DISCUSSION: Subjective reports of cognitive decline are useful to predict Aß and may improve recruitment strategies.

Intensity normalization methods in brain FDG-PET quantification.

BACKGROUND: The lack of standardization of intensity normalization methods and its unknown effect on the quantification output is recognized as a major drawback for the harmonization of brain FDG-PET quantification protocols. The aim of this work is the ground truth-based evaluation of different intensity normalization methods on brain FDG-PET quantification output. METHODS: Realistic FDG-PET images were generated using Monte Carlo simulation from activity and attenuation maps directly derived from 25 healthy subjects (adding theoretical relative hypometabolisms on 6 regions of interest and for 5 hypometabolism levels). Single-subject statistical parametric mapping (SPM) was applied to compare each simulated FDG-PET image with a healthy database after intensity normalization based on reference regions methods such as the brain stem (RRBS), cerebellum (RRC) and the temporal lobe contralateral to the lesion (RRTL), and data-driven methods, such as proportional scaling (PS), histogram-based method (HN) and iterative versions of both methods (iPS and iHN). The performance of these methods was evaluated in terms of the recovery of the introduced theoretical hypometabolic pattern and the appearance of unspecific hypometabolic and hypermetabolic findings. RESULTS: Detected hypometabolic patterns had significantly lower volumes than the introduced hypometabolisms for all intensity normalization methods particularly for slighter reductions in metabolism . Among the intensity normalization methods, RRC and HN provided the largest recovered hypometabolic volumes, while the RRBS showed the smallest recovery. In general, data-driven methods overcame reference regions and among them, the iterative methods overcame the non-iterative ones. Unspecific hypermetabolic volumes were similar for all methods, with the exception of PS, where it became a major limitation (up to 250 cm3) for extended and intense hypometabolism. On the other hand, unspecific hypometabolism was similar far all methods, and usually solved with appropriate clustering. CONCLUSIONS: Our findings showed that the inappropriate use of intensity normalization methods can provide remarkable bias in the detected hypometabolism and it represents a serious concern in terms of false positives. Based on our findings, we recommend the use of histogram-based intensity normalization methods. Reference region methods performance was equivalent to data-driven methods only when the selected reference region is large and stable.

Prodromal Parkinson disease in patients with idiopathic hyposmia.

BACKGROUND: Idiopathic hyposmia (IH) is a prodromal marker of Parkinson disease (PD). However, IH is common in the general population and only a minority will develop PD. Identification of individuals with IH at prodromal stage of PD would serve to select them to implement neuroprotective agents, when available. OBJECTIVE: To identify prodromal PD in IH patients using the Movement Disorders Society (MDS) research criteria for prodromal PD. METHODS: We applied the MDS research criteria for prodromal PD to 25 consecutive patients older than 50 years who were self-referred for smell loss and had IH, and to 18 controls. A number of risk and prodromal PD markers were assessed in all participants including REM sleep behavior disorder (RBD) by video-polysomnography and nigrostriatal dopaminergic dysfunction by DAT-SPECT. After follow-up of 4.7 ± 2.2 years, participants were re-assessed to look for incident PD. RESULTS: Prodromal PD probability was higher in patients than in controls (19.45 ± 34.9% versus 1.74 ± 4.48%; p = 0.019). Four (16%) patients met the criteria of prodromal PD surpassing 80% probability (99.8%, 99.5%, 88.3%, 86.4%). Three (12%) patients had RBD and four (16%) abnormal DAT-SPECT. At the end of follow-up, one (4%) IH patient who had RBD and baseline prodromal PD probability of 86.4% developed PD, while all controls remained disease free. CONCLUSIONS: Prodromal PD is infrequent among IH patients. MDS research criteria for prodromal PD are useful to identify a subgroup of IH patients at high risk of PD when RBD is assessed by video-polysomnography and nigrostriatal dopamine deficiency with DAT-SPECT.