Publications by authors named "Giovanni B Frisoni"

417 Publications

Societal and equity challenges for Brain Health Services. A user manual for Brain Health Services-part 6 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):173. Epub 2021 Oct 11.

Cambridge Public Health, University of Cambridge, Cambridge, UK.

Brain Health Services are a novel approach to the personalized prevention of dementia. In this paper, we consider how such services can best reflect their social, cultural, and economic context and, in doing so, deliver fair and equitable access to risk reduction. We present specific areas of challenge associated with the social context for dementia prevention. The first concentrates on how Brain Health Services engage with the "at-risk" individual, recognizing the range of factors that shape an individual's risk of dementia and the efficacy of risk reduction measures. The second emphasizes the social context of Brain Health Services themselves and their ability to provide equitable access to risk reduction. We then elaborate proposals for meeting or mitigating these challenges. We suggest that considering these challenges will enable Brain Health Services to address two fundamental questions: the balance between an individualized "high-risk" and population focus for public health prevention and the ability of services to meet ethical standards of justice and health equity.
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http://dx.doi.org/10.1186/s13195-021-00885-6DOI Listing
October 2021

Dementia risk communication. A user manual for Brain Health Services-part 3 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):170. Epub 2021 Oct 11.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Growing evidence suggests dementia incidence can be reduced through prevention programs targeting risk factors. To accelerate the implementation of such prevention programs, a new generation of brain health services (BHS) is envisioned, involving risk profiling, risk communication, risk reduction, and cognitive enhancement. The purpose of risk communication is to enable individuals at risk to make informed decisions and take action to protect themselves and is thus a crucial step in tailored prevention strategies of the dementia incidence. However, communicating about dementia risk is complex and challenging.In this paper, we provide an overview of (i) perspectives on communicating dementia risk from an ethical, clinical, and societal viewpoint; (ii) insights gained from memory clinical practice; (iii) available evidence on the impact of disclosing APOE and Alzheimer's disease biomarker test results gathered from clinical trials and observational studies; (iv) the value of established registries in light of BHS; and (v) practical recommendations regarding effective strategies for communicating about dementia risk.In addition, we identify challenges, i.e., the current lack of evidence on what to tell on an individual level-the actual risk-and on how to optimally communicate about dementia risk, especially concerning worried yet cognitively unimpaired individuals. Ideally, dementia risk communication strategies should maximize the desired impact of risk information on individuals' understanding of their health/disease status and risk perception and minimize potential harms. More research is thus warranted on the impact of dementia risk communication, to (1) evaluate the merits of different approaches to risk communication on outcomes in the cognitive, affective and behavioral domains, (2) develop an evidence-based, harmonized dementia risk communication protocol, and (3) develop e-tools to support and promote adherence to this protocol in BHSs.Based on the research reviewed, we recommend that dementia risk communication should be precise; include the use of absolute risks, visual displays, and time frames; based on a process of shared decision-making; and address the inherent uncertainty that comes with any probability.
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http://dx.doi.org/10.1186/s13195-021-00840-5DOI Listing
October 2021

Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services-part 4 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):171. Epub 2021 Oct 11.

Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.

Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. Based on the findings, we formulate recommendations for implementing precision risk reduction strategies into new services called Brain Health Services. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: non-pharmacological multidomain interventions (i.e., combining two or more intervention domains), target population including individuals without dementia, and primary outcomes including cognitive/functional performance changes and/or incident cognitive impairment or dementia. Further literature searches covered the following topics: sub-group analyses assessing potential modifiers for the intervention effect on cognition in the multidomain prevention trials, dementia risk scores used as surrogate outcomes in multidomain prevention trials, dementia risk scores in relation to brain pathology markers, and cardiovascular risk scores in relation to dementia. Multidomain intervention studies conducted so far appear to have mixed results and substantial variability in target populations, format and intensity of interventions, choice of control conditions, and outcome measures. Most trials were conducted in high-income countries. The differences in design between the larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. One such successful trial has already developed an operational model for implementing the intervention into practice. Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, especially concerning low- and middle-income countries and integration of dementia prevention with existing cerebrovascular prevention programs. A precision risk reduction approach may be most effective for dementia prevention. Such an approach could be implemented in Brain Health Services.
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http://dx.doi.org/10.1186/s13195-021-00875-8DOI Listing
October 2021

Brain Health Services: organization, structure, and challenges for implementation. A user manual for Brain Health Services-part 1 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):168. Epub 2021 Oct 11.

Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.

Dementia has a devastating impact on the quality of life of patients and families and comes with a huge cost to society. Dementia prevention is considered a public health priority by the World Health Organization. Delaying the onset of dementia by treating associated risk factors will bring huge individual and societal benefit. Empirical evidence suggests that, in higher-income countries, dementia incidence is decreasing as a result of healthier lifestyles. This observation supports the notion that preventing dementia is possible and that a certain degree of prevention is already in action. Further reduction of dementia incidence through deliberate prevention plans is needed to counteract its growing prevalence due to increasing life expectancy.An increasing number of individuals with normal cognitive performance seek help in the current memory clinics asking an evaluation of their dementia risk, preventive interventions, or interventions to ameliorate their cognitive performance. Consistent evidence suggests that some of these individuals are indeed at increased risk of dementia. This new health demand asks for a shift of target population, from patients with cognitive impairment to worried but cognitively unimpaired individuals. However, current memory clinics do not have the programs and protocols in place to deal with this new population.We envision the development of new services, henceforth called Brain Health Services, devoted to respond to demands from cognitively unimpaired individuals concerned about their risk of dementia. The missions of Brain Health Services will be (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction, and (iv) cognitive enhancement. In this paper, we present the organizational and structural challenges associated with the set-up of Brain Health Services.
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http://dx.doi.org/10.1186/s13195-021-00827-2DOI Listing
October 2021

Protocols for cognitive enhancement. A user manual for Brain Health Services-part 5 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):172. Epub 2021 Oct 11.

Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000, Caen, France.

Cognitive complaints in the absence of objective cognitive impairment, observed in patients with subjective cognitive decline (SCD), are common in old age. The first step to postpone cognitive decline is to use techniques known to improve cognition, i.e., cognitive enhancement techniques.We aimed to provide clinical recommendations to improve cognitive performance in cognitively unimpaired individuals, by using cognitive, mental, or physical training (CMPT), non-invasive brain stimulations (NIBS), drugs, or nutrients. We made a systematic review of CMPT studies based on the GRADE method rating the strength of evidence.CMPT have clinically relevant effects on cognitive and non-cognitive outcomes. The quality of evidence supporting the improvement of outcomes following a CMPT was high for metamemory; moderate for executive functions, attention, global cognition, and generalization in daily life; and low for objective memory, subjective memory, motivation, mood, and quality of life, as well as a transfer to other cognitive functions. Regarding specific interventions, CMPT based on repeated practice (e.g., video games or mindfulness, but not physical training) improved attention and executive functions significantly, while CMPT based on strategic learning significantly improved objective memory.We found encouraging evidence supporting the potential effect of NIBS in improving memory performance, and reducing the perception of self-perceived memory decline in SCD. Yet, the high heterogeneity of stimulation protocols in the different studies prevent the issuing of clear-cut recommendations for implementation in a clinical setting. No conclusive argument was found to recommend any of the main pharmacological cognitive enhancement drugs ("smart drugs", acetylcholinesterase inhibitors, memantine, antidepressant) or herbal extracts (Panax ginseng, Gingko biloba, and Bacopa monnieri) in people without cognitive impairment.Altogether, this systematic review provides evidence for CMPT to improve cognition, encouraging results for NIBS although more studies are needed, while it does not support the use of drugs or nutrients.
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http://dx.doi.org/10.1186/s13195-021-00844-1DOI Listing
October 2021

Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services-part 2 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):169. Epub 2021 Oct 11.

College of Medicine and Health, University of Exeter, Exeter, UK.

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disease. In this article, we review key potentially modifiable risk factors and genetic risk factors and discuss assessment of risk factors as well as additional fluid and imaging biomarkers that may enhance risk profiling. We then outline multidomain measures and risk profiling and provide practical guidelines for Brain Health Services, with consideration of outstanding uncertainties and challenges. Users of Brain Health Services should undergo risk profiling tailored to their age, level of risk, and availability of local resources. Initial risk assessment should incorporate a multidomain risk profiling measure. For users aged 39-64, we recommend the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score, whereas for users aged 65 and older, we recommend the Brief Dementia Screening Indicator (BDSI) and the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI). The initial assessment should also include potentially modifiable risk factors including sociodemographic, lifestyle, and health factors. If resources allow, apolipoprotein E ɛ4 status testing and structural magnetic resonance imaging should be conducted. If this initial assessment indicates a low dementia risk, then low intensity interventions can be implemented. If the user has a high dementia risk, additional investigations should be considered if local resources allow. Common variant polygenic risk of late-onset AD can be tested in middle-aged or older adults. Rare variants should only be investigated in users with a family history of early-onset dementia in a first degree relative. Advanced imaging with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) or amyloid PET may be informative in high risk users to clarify the nature and burden of their underlying pathologies. Cerebrospinal fluid biomarkers are not recommended for this setting, and blood-based biomarkers need further validation before clinical use. As new technologies become available, advances in artificial intelligence are likely to improve our ability to combine diverse data to further enhance risk profiling. Ultimately, Brain Health Services have the potential to reduce the future burden of dementia through risk profiling, risk communication, personalized risk reduction, and cognitive enhancement interventions.
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http://dx.doi.org/10.1186/s13195-021-00895-4DOI Listing
October 2021

Resting State Alpha Electroencephalographic Rhythms Are Affected by Sex in Cognitively Unimpaired Seniors and Patients with Alzheimer's Disease and Amnesic Mild Cognitive Impairment: A Retrospective and Exploratory Study.

Cereb Cortex 2021 Oct 6. Epub 2021 Oct 6.

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.

In the present retrospective and exploratory study, we tested the hypothesis that sex may affect cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms recorded in normal elderly (Nold) seniors and patients with Alzheimer's disease and mild cognitive impairment (ADMCI). Datasets in 69 ADMCI and 57 Nold individuals were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands and fixed beta (14-30 Hz) and gamma (30-40 Hz) bands. Each group was stratified into matched females and males. The sex factor affected the magnitude of rsEEG source activities in the Nold seniors. Compared with the males, the females were characterized by greater alpha source activities in all cortical regions. Similarly, the parietal, temporal, and occipital alpha source activities were greater in the ADMCI-females than the males. Notably, the present sex effects did not depend on core genetic (APOE4), neuropathological (Aβ42/phospho-tau ratio in the cerebrospinal fluid), structural neurodegenerative and cerebrovascular (MRI) variables characterizing sporadic AD-related processes in ADMCI seniors. These results suggest the sex factor may significantly affect neurophysiological brain neural oscillatory synchronization mechanisms underpinning the generation of dominant rsEEG alpha rhythms to regulate cortical arousal during quiet vigilance.
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http://dx.doi.org/10.1093/cercor/bhab348DOI Listing
October 2021

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.

JAMA Netw Open 2021 Sep 1;4(9):e2125584. Epub 2021 Sep 1.

FORUM Pharmaceuticals Incorporated, Waltham, Massachusetts.

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations.

Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency.

Design, Setting, And Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021.

Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days.

Main Outcomes And Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]).

Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03).

Conclusions And Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible.

Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463943PMC
September 2021

Alzheimer's Disease Biomarkers in Idiopathic Normal Pressure Hydrocephalus: Linking Functional Connectivity and Clinical Outcome.

J Alzheimers Dis 2021 ;83(4):1717-1728

Department of Clinical Neurosciences, Division of Neurology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Background: Alzheimer's disease (AD) pathology impacts the response to treatment in patients with idiopathic normal pressure hydrocephalus (iNPH), possibly through changes in resting-state functional connectivity (rs-FC).

Objective: To explore the relationship between cerebrospinal fluid biomarkers of AD and the default mode network (DMN)/hippocampal rs-FC in iNPH patients, based on their outcome after cerebrospinal fluid tap test (CSFTT), and in patients with AD.

Methods: Twenty-six iNPH patients (mean age: 79.9±5.9 years; 12 females) underwent MRI and clinical assessment before and after CSFTT and were classified as responders (Resp) or not (NResp), based on the improvement at the timed up and go test and walking speed. Eleven AD patients (mean age: 70.91±5.2 years; 5 females), matched to iNPH for cognitive status, were also included. DMN and hippocampal rs-FC was related to amyloid-β42 and phosphorylated tau (pTau) levels.

Results: Lower amyloid-β42 levels were associated with reduced inter- and intra-network rs-FC in NResp, and the interaction between amyloid-β42 and rs-FC was a predictor of outcome after CSFTT. The rs-FC between DMN and salience networks positively correlated to amyloid-β42 levels in both NResp and AD patients. The increase in the inter-network rs-FC after CSFTT was associated with higher pTau and lower amyloid-β42 levels in NResp, and to lower pTau levels in Resp.

Conclusion: Amyloid-β42 and pTau impact on rs-FC and its changes after CSFTT in iNPH patients. The interaction between AD biomarkers and rs-FC might explain the responder status in iNPH.
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http://dx.doi.org/10.3233/JAD-210534DOI Listing
January 2021

Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies.

Front Aging Neurosci 2021 21;13:712545. Epub 2021 Jul 21.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. : To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. : An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. : The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.
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http://dx.doi.org/10.3389/fnagi.2021.712545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335587PMC
July 2021

Using normative modelling to detect disease progression in mild cognitive impairment and Alzheimer's disease in a cross-sectional multi-cohort study.

Sci Rep 2021 08 3;11(1):15746. Epub 2021 Aug 3.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Normative modelling is an emerging method for quantifying how individuals deviate from the healthy populational pattern. Several machine learning models have been implemented to develop normative models to investigate brain disorders, including regression, support vector machines and Gaussian process models. With the advance of deep learning technology, the use of deep neural networks has also been proposed. In this study, we assessed normative models based on deep autoencoders using structural neuroimaging data from patients with Alzheimer's disease (n = 206) and mild cognitive impairment (n = 354). We first trained the autoencoder on an independent dataset (UK Biobank dataset) with 11,034 healthy controls. Then, we estimated how each patient deviated from this norm and established which brain regions were associated to this deviation. Finally, we compared the performance of our normative model against traditional classifiers. As expected, we found that patients exhibited deviations according to the severity of their clinical condition. The model identified medial temporal regions, including the hippocampus, and the ventricular system as critical regions for the calculation of the deviation score. Overall, the normative model had comparable cross-cohort generalizability to traditional classifiers. To promote open science, we are making all scripts and the trained models available to the wider research community.
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http://dx.doi.org/10.1038/s41598-021-95098-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333350PMC
August 2021

A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

Eur J Nucl Med Mol Imaging 2021 Jul 30. Epub 2021 Jul 30.

Department of Clinical Physiology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.

Purpose: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers.

Materials And Methods: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention.

Results: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders.

Conclusion: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.
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http://dx.doi.org/10.1007/s00259-021-05483-0DOI Listing
July 2021

Management of Alzheimer's disease takes a leap forward.

Lancet Neurol 2021 08;20(8):586-587

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden; Memory Clinic, Skåne University Hospital, Skåne, Sweden.

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http://dx.doi.org/10.1016/S1474-4422(21)00198-8DOI Listing
August 2021

Norms for Automatic Estimation of Hippocampal Atrophy and a Step Forward for Applicability to the Italian Population.

Front Neurosci 2021 28;15:656808. Epub 2021 Jun 28.

Laboratory of Neuroinformatics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Introduction: Hippocampal 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.

Methods: Norms 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.

Results: Hippocampal percentiles were checked with the chi-square goodness of fit test. -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 ( > 0.01). Hippocampal volumes measured with both FS and AA were associated with age ( < 0.001). The 5th percentile thresholds, indicating left/right hippocampal atrophy were respectively: (i) below 3,223/3,456 mm at 56 years and 2,506/2,415 mm at 90 years for FS; (ii) below 4,583/4,873 mm at 56 years and 3,831/3,870 mm 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.

Discussion: Norms generated from ADNI through the automatic FS and AA segmentation tools may be used as normative references for Italian patients with suspected AD.
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http://dx.doi.org/10.3389/fnins.2021.656808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273578PMC
June 2021

Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients.

J Alzheimers Dis 2021 ;82(4):1797-1808

Laboratory of Alzheimer's Neuroimaging and Epidemiology (LANE), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Background: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer's disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL).

Objective: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI.

Methods: We collected core AD markers (amyloid-β 42 [Aβ42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks' perfusion, cerebellar volume, and processing speed.

Results: Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aβ42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = -0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features.

Conclusion: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.
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http://dx.doi.org/10.3233/JAD-210531DOI Listing
January 2021

Resting State Alpha Electroencephalographic Rhythms Are Differently Related to Aging in Cognitively Unimpaired Seniors and Patients with Alzheimer's Disease and Amnesic Mild Cognitive Impairment.

J Alzheimers Dis 2021 ;82(3):1085-1114

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.

Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8-13 Hz).

Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8-12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer's disease (ADMCI).

Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands, as well as fixed beta (14-30 Hz) and gamma (30-40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles).

Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores.

Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD.
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http://dx.doi.org/10.3233/JAD-201271DOI Listing
September 2021

Inter-Cohort Validation of SuStaIn Model for Alzheimer's Disease.

Front Big Data 2021 20;4:661110. Epub 2021 May 20.

Laboratory of Neuroinformatics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Alzheimer's disease (AD) is a neurodegenerative disorder which spans several years from preclinical manifestations to dementia. In recent years, interest in the application of machine learning (ML) algorithms to personalized medicine has grown considerably, and a major challenge that such models face is the transferability from the research settings to clinical practice. The objective of this work was to demonstrate the transferability of the Subtype and Stage Inference (SuStaIn) model from well-characterized research data set, employed as training set, to independent less-structured and heterogeneous test sets representative of the clinical setting. The training set was composed of MRI data of 1043 subjects from the Alzheimer's disease Neuroimaging Initiative (ADNI), and the test set was composed of data from 767 subjects from OASIS, Pharma-Cog, and ViTA clinical datasets. Both sets included subjects covering the entire spectrum of AD, and for both sets volumes of relevant brain regions were derived from T1-3D MRI scans processed with Freesurfer v5.3 cross-sectional stream. In order to assess the predictive value of the model, subpopulations of subjects with stable mild cognitive impairment (MCI) and MCIs that progressed to AD dementia (pMCI) were identified in both sets. SuStaIn identified three disease subtypes, of which the most prevalent corresponded to the typical atrophy pattern of AD. The other SuStaIn subtypes exhibited similarities with the previously defined hippocampal sparing and limbic predominant atrophy patterns of AD. Subject subtyping proved to be consistent in time for all cohorts and the staging provided by the model was correlated with cognitive performance. Classification of subjects on the basis of a combination of SuStaIn subtype and stage, mini mental state examination and amyloid-β cerebrospinal fluid concentration was proven to predict conversion from MCI to AD dementia on par with other novel statistical algorithms, with ROC curves that were not statistically different for the training and test sets and with area under curve respectively equal to 0.77 and 0.76. This study proves the transferability of a SuStaIn model for AD from research data to less-structured clinical cohorts, and indicates transferability to the clinical setting.
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http://dx.doi.org/10.3389/fdata.2021.661110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173213PMC
May 2021

Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET).

Alzheimers Dement (N Y) 2021 31;7(1):e12136. Epub 2021 May 31.

Chambers-Grundy Center for Transformative Neuroscience Department of Brain Health, School of Integrated Health Sciences University of Nevada Las Vegas (UNLV) Las Vegas Nevada USA.

Introduction: A previous phase 2b study supported the use of the 5-HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis.

Methods: MINDSET was a global, double-blind, randomized, placebo-controlled trial in 1315 mild-to-moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co-primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL).

Results: There were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co-primary endpoints ADAS-Cog (-0.36 [-0.95, 0.22],  = 0.2249) and ADCS-ADL (-0.09 [-0.90, 0.72],  = 0.8260). Intepirdine demonstrated a favorable safety profile similar to placebo.

Discussion: Intepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild-to-moderate AD dementia patients.
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http://dx.doi.org/10.1002/trc2.12136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165732PMC
May 2021

Simulating the outcome of amyloid treatments in Alzheimer's disease from imaging and clinical data.

Brain Commun 2021 28;3(2):fcab091. Epub 2021 Apr 28.

Université Côte d'Azur, INRIA Sophia Antipolis, EPIONE Research Project, 06902, Sophia-Antipolis, France.

In this study, we investigate SimulAD, a novel quantitative instrument for the development of intervention strategies for disease-modifying drugs in Alzheimer's disease. SimulAD is based on the modeling of the spatio-temporal dynamics governing the joint evolution of imaging and clinical biomarkers along the history of the disease, and allows the simulation of the effect of intervention time and drug dosage on the biomarkers' progression. When applied to multi-modal imaging and clinical data from the Alzheimer's Disease Neuroimaging Initiative the method enables to generate hypothetical scenarios of amyloid lowering interventions. The results quantify the crucial role of intervention time, and provide a theoretical justification for testing amyloid modifying drugs in the pre-clinical stage. Our experimental simulations are compatible with the outcomes observed in past clinical trials, and suggest that anti-amyloid treatments should be administered at least 7 years earlier than what is currently being done in order to obtain statistically powered improvement of clinical endpoints.
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http://dx.doi.org/10.1093/braincomms/fcab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168944PMC
April 2021

Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): rationale and study design.

Alzheimers Res Ther 2021 05 25;13(1):105. Epub 2021 May 25.

Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.

Background: Subjective cognitive decline (SCD) is the subjective perception of a decline in memory and/or other cognitive functions in the absence of objective evidence. Some SCD individuals however may suffer from very early stages of neurodegenerative diseases (such as Alzheimer's disease, AD), minor psychiatric conditions, neurological, and/or somatic comorbidities. Even if a theoretical framework has been established, the etiology of SCD remains far from elucidated. Clinical observations recently lead to the hypothesis that individuals with incipient AD may have overestimated metacognitive judgements of their own cognitive performance, while those with psychiatric disorders typically present underestimated metacognitive judgements. Moreover, brain connectivity changes are known correlates of AD and psychiatric conditions and might be used as biomarkers to discriminate SCD individuals of different etiologies. The aim of the COSCODE study is to identify metacognition, connectivity, behavioral, and biomarker profiles associated with different etiologies of SCD. Here we present its rationale and study design.

Methods: COSCODE is an observational, longitudinal (4 years), prospective clinical cohort study involving 120 SCD, and 80 control study participants (40 individuals with no cognitive impairment, and 40 living with mild cognitive impairment - MCI, or dementia due to AD), all of which will undergo diffusion magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) as well as behavioral and biomarker assessments at baseline and after 1 and 2 years. Both hypothesis-driven and data-driven cluster analysis approaches will be used to identify SCD sub-types based on metacognition, connectivity, behavioral, and biomarker features.

Conclusion: COSCODE will allow defining and interpreting the constellation of signs and symptoms associated with different etiologies of SCD, paving the way to the development of cost-effective risk assessment and prevention protocols.
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http://dx.doi.org/10.1186/s13195-021-00846-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152092PMC
May 2021

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

Department of Medicine and Surgery, Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.

Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.

Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.

Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.
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http://dx.doi.org/10.1002/alz.12365DOI Listing
May 2021

Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.

Lancet Neurol 2021 06 29;20(6):484-496. Epub 2021 Apr 29.

Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, La Jolla, CA, USA; Alzheimer Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA.

In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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http://dx.doi.org/10.1016/S1474-4422(21)00066-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339877PMC
June 2021

Treatment by low-dose brain radiation therapy improves memory performances without changes of the amyloid load in the TgF344-AD rat model.

Neurobiol Aging 2021 07 23;103:117-127. Epub 2021 Mar 23.

Division of Nuclear Medicine and Molecular Imaging, Diagnostic Department, Geneva University Hospitals, and NimtLab, Faculty of Medicine, Geneva University, Geneva, Switzerland. Electronic address:

Alzheimer's disease (AD) is a neurodegenerative condition affecting memory performance. This pathology is characterized by intracerebral amyloid plaques and tau tangles coupled with neuroinflammation. During the last century, numerous therapeutic trials unfortunately failed highlighting the need to find new therapeutic approaches. Low-dose brain radiotherapy (LD-RT) showed efficacy to reduce amyloid load and inflammation in patients with peripheral diseases. In this study, the therapeutic potential of 2 LD-RT schedules was tested on the TgF344-AD rat model of AD. Fifteen-month-old rats were irradiated with 5 fractions of 2 Gy delivered either daily or weekly. The daily treatment induced an improvement of memory performance in the Y-maze. In contrast, the weekly treatment increased the microglial reactivity in the hippocampus. A lack of effect of both regimens on amyloid pathology was unexpectedly observed. The positive effect on cognition encourages to further evaluate the LD-RT therapeutic potential and highlights the impact of the design choice of the LD-RT regimen.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.008DOI Listing
July 2021

EEG measures for clinical research in major vascular cognitive impairment: recommendations by an expert panel.

Neurobiol Aging 2021 07 10;103:78-97. Epub 2021 Mar 10.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales; Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, Australia.

Vascular contribution to cognitive impairment (VCI) and dementia is related to etiologies that may affect the neurophysiological mechanisms regulating brain arousal and generating electroencephalographic (EEG) activity. A multidisciplinary expert panel reviewed the clinical literature and reached consensus about the EEG measures consistently found as abnormal in VCI patients with dementia. As compared to cognitively unimpaired individuals, those VCI patients showed (1) smaller amplitude of resting state alpha (8-12 Hz) rhythms dominant in posterior regions; (2) widespread increases in amplitude of delta (< 4 Hz) and theta (4-8 Hz) rhythms; and (3) delayed N200/P300 peak latencies in averaged event-related potentials, especially during the detection of auditory rare target stimuli requiring participants' responses in "oddball" paradigms. The expert panel formulated the following recommendations: (1) the above EEG measures are not specific for VCI and should not be used for its diagnosis; (2) they may be considered as "neural synchronization" biomarkers to enlighten the relationships between features of the VCI-related cerebrovascular lesions and abnormalities in neurophysiological brain mechanisms; and (3) they may be tested in future clinical trials as prognostic biomarkers and endpoints of interventions aimed at normalizing background brain excitability and vigilance in wakefulness.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.003DOI Listing
July 2021

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 09 31;17(9):1452-1464. Epub 2021 Mar 31.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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http://dx.doi.org/10.1002/alz.12322DOI Listing
September 2021

Rationale, Design, and Methodology of a Prospective Cohort Study for Coping with Behavioral and Psychological Symptoms of Dementia: The RECage Project.

J Alzheimers Dis 2021 ;80(4):1613-1627

FERB Alzheimer Centre, Gazzaniga, Italy.

Background: Behavioral and psychological symptoms of dementia (BPSD) are quite challenging problems during the dementia course. Special Care Units for people with dementia (PwD) and BPSD (SCU-B) are residential medical structures, where BPSD patients are temporarily admitted, in case of unmanageable behavioral disturbances at home.

Objective: RECage (REspectful Caring for AGitated Elderly) aspires to assess the short and long-term effectiveness of SCU-Bs toward alleviating BPSD and improving the quality of life (QoL) of PwD and their caregivers.

Methods: RECage is a three-year, prospective study enrolling 500 PwD. Particularly, 250 community-dwelling PwDs presenting with severe BPSD will be recruited by five clinical centers across Europe, endowed with a SCU-B, for a short period of time; a second similar group of 250 PwD will be followed by six other no-SCU-B centers solely via outpatient visits. RECage's endpoints include short and long-term SCU-B clinical efficacy, QoL of patients and caregivers, cost-effectiveness of the SCU-B, psychotropic drug consumption, caregivers' attitude toward dementia, and time to nursing home placement.

Results: PwD admitted in SCU-Bs are expected to have diminished rates of BPSD and better QoL and their caregivers are also expected to have better QoL and improved attitude towards dementia, compared to those followed in no-SCU-Bs. Also, the cost of care and the psychotropic drug consumption are expected to be lower. Finally, PwD followed in no-SCU-Bs are expected to have earlier admission to nursing homes.

Conclusion: The cohort study results will refine the SCU-B model, issuing recommendations for implementation of SCU-Bs in the countries where they are scarce or non-existent.
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http://dx.doi.org/10.3233/JAD-201215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203243PMC
September 2021

The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update.

Eur J Nucl Med Mol Imaging 2021 07 10;48(7):2070-2085. Epub 2021 Mar 10.

NIMTlab - Neuroimaging and Innovative Molecular Tracers Laboratory, University of Geneva, Geneva, Switzerland.

Background: The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research.

Methods: We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers.

Results: The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures.

Discussion: This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.
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http://dx.doi.org/10.1007/s00259-020-05120-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175304PMC
July 2021

Diagnostic value of amyloid-PET and tau-PET: a head-to-head comparison.

Eur J Nucl Med Mol Imaging 2021 07 27;48(7):2200-2211. Epub 2021 Feb 27.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Purpose: Assess the individual and combined diagnostic value of amyloid-PET and tau-PET in a memory clinic population.

Methods: Clinical reports of 136 patients were randomly assigned to two diagnostic pathways: AMY-TAU, amyloid-PET is presented before tau-PET; and TAU-AMY, tau-PET is presented before amyloid-PET. Two neurologists independently assessed all reports with a balanced randomized design, and expressed etiological diagnosis and diagnostic confidence (50-100%) three times: (i) at baseline based on the routine diagnostic workup, (ii) after the first exam (amyloid-PET for the AMY-TAU pathway, and tau-PET for the TAU-AMY pathway), and (iii) after the remaining exam. The main outcomes were changes in diagnosis (from AD to non-AD or vice versa) and in diagnostic confidence.

Results: Amyloid-PET and tau-PET, when presented as the first exam, resulted in a change of etiological diagnosis in 28% (p = 0.006) and 28% (p < 0.001) of cases, and diagnostic confidence increased by 18% (p < 0.001) and 19% (p < 0.001) respectively, with no differences between exams (p > 0.05). We observed a stronger impact of a negative amyloid-PET versus a negative tau-PET (p = 0.014). When added as the second exam, amyloid-PET and tau-PET resulted in a further change in etiological diagnosis in 6% (p = 0.077) and 9% (p = 0.149) of cases, and diagnostic confidence increased by 4% (p < 0.001) and 5% (p < 0.001) respectively, with no differences between exams (p > 0.05).

Conclusion: Amyloid-PET and tau-PET significantly impacted diagnosis and diagnostic confidence in a similar way, although a negative amyloid-PET has a stronger impact on diagnosis than a negative tau-PET. Adding either of the two as second exam further improved diagnostic confidence.

Trial Number: PB 2016-01346.
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http://dx.doi.org/10.1007/s00259-021-05246-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175315PMC
July 2021
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