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PurposeIn 2017, the Geneva Alzheimer’s disease (AD) strategic biomarker roadmap initiative proposed a framework of the systematic validation AD biomarkers to harmonize and accelerate their development and implementation in clinical practice. Here, we use this framework to examine the translatability of the second-generation tau PET tracers into the clinical context.MethodsAll available literature was systematically searched based on a set of search terms that related independently to analytic validity (phases 1–2), clinical validity (phase 3–4), and clinical utility (phase 5). The progress on each of the phases was determined based on scientific criteria applied for each phase and coded as fully, partially, preliminary achieved or not achieved at all.ResultsThe validation of the second-generation tau PET tracers has successfully passed the analytical phase 1 of the strategic biomarker roadmap. Assay definition studies showed evidence on the superiority over first-generation tau PET tracers in terms of off-target binding. Studies have partially achieved the primary aim of the analytical validity stage (phase 2), and preliminary evidence has been provided for the assessment of covariates on PET signal retention. Studies investigating of the clinical validity in phases 3, 4, and 5 are still underway.ConclusionThe current literature provides overall preliminary evidence on the establishment of the second-generation tau PET tracers into the clinical context, thereby successfully addressing some methodological issues from the tau PET tracer of the first generation. Nevertheless, bigger cohort studies, longitudinal follow-up, and examination of diverse disease population are still needed to gauge their clinical validity.

The use of social tasks in the neuropsychological assessment of the behavioral variant of frontotemporal dementia (bvFTD) is at present not required by diagnostic guidelines, despite extensive literature shows relevant social cognitive dysfunctions in such patients. In this systematic review, we explored the clinical maturity of social cognition measures in the diagnosis of bvFTD. Papers were selected according to the PRISMA guidelines by searching the PubMed and Medline databases. Only papers reporting indices of diagnostic accuracy and/or sensitivity/specificity in classifying bvFTD from controls or from other relevant diseases were considered. Quality of evidence was assessed through QUADAS-2. Among the 663 articles entered in the paper selection only 14 papers were eligible for the scope of the present review and showed an overall moderate-to-low quality. The major risk of bias was the lack of pathological confirmation. The evaluation of the accuracy of social cognition tasks in bvFTD detection compared to normal controls, as well as in the discrimination with Alzheimer’s disease and psychiatric patients, is mainly focused on emotion recognition and theory of mind. However, the use of different cognitive measures, variable task formats and the limited normative data hamper study comparability. Although literature seems to suggest that emotion recognition and ToM tasks could be the best choice to ensure a high diagnostic accuracy in clinical settings, further comparative studies are required and no recommendation concerning the use of a specific social task in bvFTD diagnosis can be currently provided.

PurposeThe research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology.MethodsA panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of clinical validity of tau PET ligands of the THK family and PBB3 was assessed based on the 5-phase development framework before the meeting and discussed during the workshop.ResultsPET radioligands of the THK family discriminate well between healthy controls and patients with AD dementia (phase 2; partly achieved) and recent evidence suggests an accurate diagnostic accuracy at the mild cognitive impairment (MCI) stage of the disease (phase 3; partly achieved). The phases 2 and 3 were considered not achieved for PBB3 since no evidence exists about the ligand’s diagnostic accuracy. Preliminary evidence exists about the secondary aims of each phase for all ligands.ConclusionMuch work remains for completing the aims of phases 2 and 3 and replicating the available evidence. However, it is unlikely that the validation process for these tracers will be completed, given the presence of off-target binding and the development of second-generation tracers with improved binding and pharmacokinetic properties.

Covid-19 pandemic is exerting a tragic impact all around the world. First-person experience of life-threatening and stressful events can modify individuals’ risk perception, and, consequently, risk-taking behaviours. Here we investigated risk-taking profiles in 130 Italian residents, and compared healthcare to non-healthcare workers, during the lockdown phase. We ad hoc developed the “Covid-19 Risk Task”, including the classic monetary Holt-Laury Paired Lottery Task (Monetary Condition, MC) and two new ecological conditions exploring Covid-19 related risk-taking aptitudes in relation to different health (Health Status Condition, HsC) and employment (Employment Status Condition, EsC) outcomes. Results showed that, in the whole sample, individuals were more risk-averse in MC than in HsC and EsC. Moreover, a payoff increase produced a shift toward more risk-averse behaviours in MC, but not in HsC and EsC, where we found an opposite trend suggesting a more risk-loving behaviour. Finally, we found that healthcare workers were significantly less risk-averse compared to non-healthcare workers in EsC, but not in MC and HsC. These findings provided evidence of the possible effects of Covid-19 outbreak on risk-taking aptitudes. The negative impact on human choices and, consequently, on the whole world economy of this catastrophic life event must not be underestimated.

PurposeAssess the individual and combined diagnostic value of amyloid-PET and tau-PET in a memory clinic population.MethodsClinical 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.ResultsAmyloid-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).ConclusionAmyloid-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 numberPB 2016-01346.

ABSTRACT Background Sex‐based differences in cognitive and behavioral symptoms have been previously reported in Parkinson's disease (PD), as well as the effects of motor lateralization and phenotypes at onset. However, no studies investigated the interaction between these variables. Objective We aimed to evaluate whether sex differences interact with motor phenotype and lateralization at the onset of cognitive and neurobehavioral symptoms. Methods: Data from 304 PD patients (119 women and 185 men) were retrospectively examined, including comprehensive neurologic, neuropsychological, and neurobehavioral assessments. MANCOVAs on tests divided based on the results of a principal component analysis were performed to compare cognitive and behavioral performance, considering sex, motor phenotype at onset, and onset lateralization as grouping variables. Analyses were also performed on a subsample of patients (n = 200) in which subgroups were balanced in terms of motor and demographic features. Results: Significant sex effects were found, with females showing higher performance compared to males in verbal long‐term memory (p = 0.00003), social cognition (p = 0.0001), and naming tasks (p = 0.03009). Significant interactions between motor phenotype and sex were found: rigid‐akinetic (RA) females showed higher performance than other groups in a verbal memory task (p = 0.0183), and tremor‐dominant (TD) females made more errors than the other groups in an inhibitory control task (p = 0.03853). Interestingly, RA females performed better on verbal learning than tremor‐dominant (TD) males (p = 0.00911), suggesting that sex effects overcome motor phenotype in this cognitive function. No significant interactions were found between sex and lateralization at onset concerning cognitive variables. However, patients with right‐sided onset, in particular females, self‐reported higher levels of behavioral symptoms. Conclusions: These results emphasize the complex relationship between demographic and PD motor features in delineating the clinical phenotype, which should be considered in designing patient‐tailored strategies for disease monitoring and intervention. Patients with Parkinson's disease (PD) show variability in clinical manifestations, with symptoms depending on sex, type, and their lateralization at onset (motor phenotype and lateralization). While these factors have been investigated individually, their interaction has not. Therefore, the aim of our study was to verify how sex differences interact with motor features to affect non‐motor symptoms. To do this, we collected data from 304 patients (119 women and 185 men), who underwent assessment of motor symptoms, cognitive abilities, and mood disturbances. Statistical analyses were performed on cognitive and behavioral performance, considering sex, motor phenotype, and lateralization at onset as grouping variables. We found significant sex differences across multiple cognitive domains: women outperformed men in verbal memory and naming and emotion recognition, while men performed better in visuospatial tasks. In addition, women reported higher levels of depression and anxiety than men. We also found a significant interaction between sex and motor phenotype: females with rigidity at onset (RA onset) showed better performance than other groups in a verbal memory task. Interestingly, this group outperformed males with tremor at onset (TD onset) in verbal memory, suggesting that sex may have a stronger influence than motor phenotype in this cognitive area. Sex and motor phenotype also interact in an inhibitory control task, where TD females made more errors. Right‐side onset—in particular in women—was associated with more depression symptoms compared to the other groups. Overall, these findings show that sex interacts in a complex way with onset motor features. This aspect should be considered for patient‐tailored treatment strategies.

Neural responses in striatal, limbic and somatosensory brain regions track individual differences in loss aversion, i.e. the higher sensitivity to potential losses compared with equivalent gains in decision-making under risk. The engagement of structures involved in the processing of aversive stimuli and experiences raises a further question, i.e. whether the tendency to avoid losses rather than acquire gains represents a transient fearful overreaction elicited by choice-related information, or rather a stable component of one's own preference function, reflecting a specific pattern of neural activity. We tested the latter hypothesis by assessing in 57 healthy human subjects whether the relationship between behavioral and neural loss aversion holds at rest, i.e. when the BOLD signal is collected during 5minutes of cross-fixation in the absence of an explicit task. Within the resting-state networks highlighted by a spatial group Independent Component Analysis (gICA), we found a significant correlation between strength of activity and behavioral loss aversion in the left ventral striatum and right posterior insula/supramarginal gyrus, i.e. the very same regions displaying a pattern of neural loss aversion during explicit choices. Cross-study analyses confirmed that this correlation holds when voxels identified by gICA are used as regions of interest in task-related activity and vice versa. These results suggest that the individual degree of (neural) loss aversion represents a stable dimension of decision-making, which reflects in specific metrics of intrinsic brain activity at rest possibly modulating cortical excitability at choice. •Loss aversion correlates with striatal and insular intrinsic brain activity.•Striatal and insular intrinsic brain activity predicts the degree of loss aversion.•Neural loss aversion occurs in the voxels correlating with loss aversion at rest.•Neural loss aversion is a stable feature of brain reward and interoceptive systems.•Behavioral loss aversion likely represents a stable dimension of decision-making.

Pharmacological treatments in Parkinson’s disease (PD), albeit effective in alleviating many motor symptoms, have limited effects in non-motor signatures as cognitive impairment, as well as in other aspects included postural instability. Consequently, complementary interventions are nowadays a prerogative of clinical practice managing PD symptomatology. In this pilot longitudinal study, we recruited twenty-four PD patients participating in one of two interventions: adapted Argentine Tango or group-based physiotherapy. Participants underwent a motor and neuropsychological evaluation before and after four months of activities, carried out twice a week. We found a general stabilization of motor and cognitive abilities, with significant improvements in several motor skills, mainly pertaining to static and dynamic balance, similarly in both groups. At cognitive level, we measured a significant improvement in both groups in the Action Naming task. Interestingly, only PD patients in the Tango group improved their performance in the test measuring facial emotion recognition. These findings highlight the crucial role that physical activities have in the stabilization and slowdown of disease’s progression in PD. They further highlight the beneficial effects of a group-based physical intervention, which, especially in the case of Tango, could lead to behavioral ameliorations in domains other than the motor, such as emotion recognition.

PurposeThe A/T/N model is a research framework proposed to investigate Alzheimer’s disease (AD) pathological bases (i.e., amyloidosis A, neurofibrillary tangles T, and neurodegeneration N). The application of this system on clinical populations is still limited. The aim of the study is to evaluate the topography of T distribution by 18F-flortaucipir PET in relation to A and N and to describe the A/T/N status through imaging biomarkers in memory clinic patients.MethodsEighty-one patients with subjective and objective cognitive impairment were classified as A+/A− and N+/N− through amyloid PET and structural MRI. Tau deposition was compared across A/N subgroups at voxel level. T status was defined through a global cut point based on A/N subgroups and subjects were categorized following the A/T/N model.ResultsA+N+ and A+N− subgroups showed higher tau burden compared to A−N− group, with A+N− showing significant deposition limited to the medial and lateral temporal regions. Global cut point discriminated A+N+ and A+N− from A−N− subjects. On A/T/N classification, 23% of patients showed a negative biomarker profile, 58% fell within the Alzheimer’s continuum, and 19% of the sample was characterized by non-AD pathologic change.ConclusionMedial and lateral temporal regions represent a site of significant tau accumulation in A+ subjects and possibly a useful marker of early clinical changes. This is the first study in which the A/T/N model is applied using 18F-flortaucipir PET in a memory clinic population. The majority of patients showed a profile consistent with the Alzheimer’s continuum, while a minor percentage showed a profile suggestive of possible other neurodegenerative diseases. These results support the applicability of the A/T/N model in clinical practice.

PurposeTo compare the incremental diagnostic value of amyloid-PET and CSF (Aβ42, tau, and phospho-tau) in AD diagnosis in patients with mild cognitive impairment (MCI) or mild dementia, in order to improve the definition of diagnostic algorithm.MethodsTwo independent dementia experts provided etiological diagnosis and relative diagnostic confidence in 71 patients on 3 rounds, based on (1) clinical, neuropsychological, and structural MRI information alone; (2) adding one biomarker (CSF amyloid and tau levels or amyloid-PET with a balanced randomized design); and (3) adding the other biomarker.ResultsAmong patients with a pre-biomarker diagnosis of AD, negative PET induced significantly more diagnostic changes than amyloid-negative CSF at both rounds 2 (CSF 67%, PET 100%, P = 0.028) and 3 (CSF 0%; PET 78%, P < 0.001); PET induced a diagnostic confidence increase significantly higher than CSF on both rounds 2 and 3.ConclusionsAmyloid-PET should be prioritized over CSF biomarkers in the diagnostic workup of patients investigated for suspected AD, as it provides greater changes in diagnosis and diagnostic confidence.Trial registrationEudraCT no.: 2014-005389-31