Introduction: With the shift of research focus to personalized medicine in Alzheimer's Dementia (AD), there is an urgent need for tools that are capable of quantifying a patient's risk using diagnostic biomarkers. The Medical Informatics Platform (MIP) is a distributed e-infrastructure federating large amounts of data coupled with machine-learning (ML) algorithms and statistical models to define the biological signature of the disease. The present study assessed (i) the accuracy of two ML algorithms, i.e., supervised Gradient Boosting (GB) and semi-unsupervised 3C strategy (Categorize, Cluster, Classify-CCC) implemented in the MIP and (ii) their contribution over the standard diagnostic workup. Methods: We examined individuals coming from the MIP installed across 3 Italian memory clinics, including subjects with Normal Cognition (CN, n = 432), Mild Cognitive Impairment (MCI, n = 456), and AD (n = 451). The GB classifier was applied to best discriminate the three diagnostic classes in 1,339 subjects, and the CCC strategy was used to refine the classical disease categories. Four dementia experts provided their diagnostic confidence (DC) of MCI conversion on an independent cohort of 38 patients. DC was based on clinical, neuropsychological, CSF, and structural MRI information and again with addition of the outcome from the MIP tools. Results: The GB algorithm provided a classification accuracy of 85% in a nested 10-fold cross-validation for CN vs. MCI vs. AD discrimination. Accuracy increased to 95% in the holdout validation, with the omission of each Italian clinical cohort out in turn. CCC Redolfi et al. MIP Pilot Study identified five homogeneous clusters of subjects and 36 biomarkers that represented the disease fingerprint. In the DC assessment, CCC defined six clusters in the MCI population used to train the algorithm and 29 biomarkers to improve patients staging. GB and CCC showed a significant impact, evaluated as +5.99% of increment on physicians' DC. The influence of MIP on DC was rated from "slight" to "significant" in 80% of the cases. Discussion: GB provided fair results in classification of CN, MCI, and AD. CCC identified homogeneous and promising classes of subjects via its semi-unsupervised approach. We measured the effect of the MIP on the physician's DC. Our results pave the way for the establishment of a new paradigm for ML discrimination of patients who will or will not convert to AD, a clinical priority for neurology.

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures.

INTRODUCTIONAmnestic mild cognitive impairment (aMCI) is emerging as a heterogeneous condition.METHODSWe looked at a cohort of N = 207 aMCI subjects, with baseline fluorodeoxyglucose positron emission tomography (FDG‐PET), T1 magnetic resonance imaging, cerebrospinal fluid (CSF), apolipoprotein E (APOE), and neuropsychological assessment. An algorithm based on FDG‐PET hypometabolism classified each subject into subtypes, then compared biomarker measures and clinical progression.RESULTSThree subtypes emerged: hippocampal sparing–cortical hypometabolism, associated with younger age and the highest level of Alzheimer's disease (AD)‐CSF pathology; hippocampal/cortical hypometabolism, associated with a high percentage of APOE ε3/ε4 or ε4/ε4 carriers; medial–temporal hypometabolism, characterized by older age, the lowest AD‐CSF pathology, the most severe hippocampal atrophy, and a benign course. Within the whole cohort, the severity of temporo‐parietal hypometabolism, correlated with AD‐CSF pathology and marked the rate of progression of cognitive decline.DISCUSSIONFDG‐PET can distinguish clinically comparable aMCI at single‐subject level with different risk of progression to AD dementia or stability. The obtained results can be useful for the optimization of pharmacological trials and automated‐classification models.Highlights Algorithm based on FDG‐PET hypometabolism demonstrates distinct subtypes across aMCI; Three different subtypes show heterogeneous biological profiles and risk of progression; The cortical hypometabolism is associated with AD pathology and cognitive decline; MTL hypometabolism is associated with the lowest conversion rate and CSF‐AD pathology.

IntroductionHippocampal volume is one of the main biomarkers of Alzheimer’s Dementia (AD). Over the years, advanced tools that performed automatic segmentation of Magnetic Resonance Imaging (MRI) T13D scans have been developed, such as FreeSurfer (FS) and ACM-Adaboost (AA). Hippocampal volume is considered abnormal when it is below the 5th percentile of the normative population. The aim of this study was to set norms, established from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, for hippocampal volume measured with FS v.6.0 and AA tools in the neuGRID platform (www.neugrid2.eu) and demonstrate their applicability for the Italian population.MethodsNorms were set from a large group of 545 healthy controls belonging to ADNI. For each pipeline, subjects with segmentation errors were discarded, resulting in 532 valid segmentations for FS and 421 for AA (age range 56–90 years). The comparability of ADNI and the Italian Brain Normative Archive (IBNA), representative of the Italian general population, was assessed testing clinical variables, neuropsychological scores and normalized hippocampal volumes. Finally, percentiles were validated using the Italian Alzheimer’s disease Repository Without Borders (ARWiBo) as external independent data set to evaluate FS and AA generalizability.ResultsHippocampal percentiles were checked with the chi-square goodness of fit test. P-values were not significant, showing that FS and AA algorithm distributions fitted the data well. Clinical, neuropsychological and volumetric features were similar in ADNI and IBNA (p > 0.01). Hippocampal volumes measured with both FS and AA were associated with age (p < 0.001). The 5th percentile thresholds, indicating left/right hippocampal atrophy were respectively: (i) below 3,223/3,456 mm3 at 56 years and 2,506/2,415 mm3 at 90 years for FS; (ii) below 4,583/4,873 mm3 at 56 years and 3,831/3,870 mm3 at 90 years for AA. The average volumes computed on 100 cognitively intact healthy controls (CN) selected from ARWiBo were close to the 50th percentiles, while those for 100 AD patients were close to the abnormal percentiles.DiscussionNorms generated from ADNI through the automatic FS and AA segmentation tools may be used as normative references for Italian patients with suspected AD.