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Background: Alzheimer's disease (AD) includes progressive symptoms spread along a continuum of preclinical and clinical stages. Although numerous studies uncovered the neuro-cognitive changes of AD, very little is known on the natural history of brain lesions and modifications of brain networks in elderly cognitively-healthy memory complainers at risk of AD for carrying pathophysiological biomarkers (amyloidopathy and tauopathy).Objective: We analyzed resting-state electroencephalography (EEG) of 318 cognitively-healthy subjective memory complainers from the INSIGHT-preAD cohort at the time of their first visit (M0) and two-years later (M24).Methods: Using 18F-florbetapir PET-scanner, subjects were stratified between amyloid negative (A-; n = 230) and positive (A+; n = 88) groups. Differences between A+ and A- were estimated at source-level in each band-power of the EEG spectrum.Results: At M0, we found an increase of theta power in the mid-frontal cortex in A+ compared to A-. No significant association was found between mid-frontal theta and the individuals' cognitive performance. At M24, theta power increased in A+ relative to A- individuals in the posterior cingulate cortex and the pre-cuneus. Alpha band revealed a peculiar decremental trend in posterior brain regions in the A+ relative to the A- group only at M24. Theta power increase over the mid-frontal and mid-posterior cortices suggests an hypoactivation of the default-mode network in the A+ individuals and a non-linear longitudinal progression at M24.Conclusion: We provide the first source-level longitudinal evidence on the impact of brain amyloidosis on the EEG dynamics of a large-scale, monocentric cohort of elderly individuals at-risk for AD. [ABSTRACT FROM AUTHOR]

Objective: 18F‑fluoro-L‑3,4‑dihydroxyphenylalanine positron emission tomography (F‑DOPA PET) is used in glioma follow-up after radiotherapy to discriminate treatment-related changes (TRC) from tumor progression (TP). We compared the performances of a combined PET and MRI analysis with F‑DOPA current standard of interpretation. Methods: We included 76 consecutive patients showing at least one gadolinium-enhanced lesion on the T1‑w MRI sequence (T1G). Two nuclear medicine physicians blindly analyzed PET/MRI images. In addition to the conventional PET analysis, they looked for F‑DOPA uptake(s) outside T1G-enhanced areas (T1G/PET), in the white matter (WM/PET), for T1G-enhanced lesion(s) without sufficiently concordant F‑DOPA uptake (T1G+/PET), and F‑DOPA uptake(s) away from hemorrhagic changes as shown with a susceptibility weighted imaging sequence (SWI/PET). We measured lesions' F‑DOPA uptake ratio using healthy brain background (TBR) and striatum (T/S) as references, and lesions' perfusion with arterial spin labelling cerebral blood flow maps (rCBF). Scores were determined by logistic regression. Results: 53 and 23 patients were diagnosed with TP and TRC, respectively. The accuracies were 74% for T/S, 76% for TBR, and 84% for rCBF, with best cut-off values of 1.3, 3.7 and 1.25, respectively. For hybrid variables, best accuracies were obtained with conventional analysis (82%), T1G+/PET (82%) and SWI/PET (81%). T1G+/PET, SWI/PET and rCBF ≥ 1.25 were selected to construct a 3-point score. It outperformed conventional analysis and rCBF with an AUC of 0.94 and an accuracy of 87%. Conclusions: Our scoring approach combining F‑DOPA PET and MRI provided better accuracy than conventional PET analyses for distinguishing TP from TRC in our patients after radiation therapy. [ABSTRACT FROM AUTHOR]

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content. [ABSTRACT FROM AUTHOR]

Background: The cognitive reserve (CR) moderate the effect of brain pathophysiology on cognitive deficits in Alzheimer's Disease (AD) continuum. In a previous study on individuals with subjective memory complaint (SMCs), a condition at risk for AD, from the INSIGHT‐preAD cohort, we found that CR altered the association of amyloid load with neurophysiological mechanisms generating posterior electroencephalographic (EEG) alpha rhythms in quiet wakefulness. We used educational attainment (Edu) as an indicator of CR. Method: In the present work we tested the hypothesis of the interaction of Edu and cerebral amyloid‐b load with the association between posterior alpha rhythms, as revealed by resting‐state EEG (rsEEG) activity, and functional connectivity, as revealed by functional magnetic resonance imaging (fMRI, 3‐Tesla Verio system), among cholinergic basal forebrain (BF), thalamus, and posterior cortical areas. Resting‐state EEG and fMRI data were acquired in 318 cognitively intact individuals (age between 70 and 85 years) with SMC. Participants were stratified into two groups of amyloid‐positive (SMCpos) and ‐negative (SMCneg), using the standard diagnostic markers of Alzheimer's neuropathology based on cortical‐to‐cerebellum standardized uptake value ratio in the PET imaging. Then, the education attainment level was used to stratify the SMC participants in those with a low‐to‐moderate education level (SMC Edu‐) and those with a high education level (SMC Edu+). Result: Results showed a significant positive association between temporal alpha rhythms and above‐mentioned functional connectivity in the SMC cases with low brain amyloid accumulation and education attainment (SMCneg Edu‐). In contrast, the SMCneg Edu+ seniors showed the amplest posterior alpha rhythms, but not a positive association between temporal alpha rhythms and fMRI connectivity among cholinergic BF, thalamus, and posterior cerebral cortex, possibly due to a (annulation) of high CR. Of note, the SMCpos Edu+ seniors showed this positive association, possibly due to the (neutralization) of CR and brain amyloidosis (Figure 1). Conclusion: The present results suggest that, in SMC seniors, high CR affects cortical neural synchronization mechanisms generating posterior rsEEG alpha rhythms, but not through the ascending cholinergic system to the posterior cortex. Unfortunately, these CR effects may be annulled at earlier stages of Alzheimer's amyloid pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease and related dementia (ADRD) are characterized by a progressive alteration of clinical (Cognitive and Physical functions) and subclinical (Neuroimaging, blood and CSF markers) features. Understanding the sequence and timing of these alterations is of primary importance to understand the natural history of ADRD and ultimately change its course. Pathological processes underlying ADRD evolve over years prior to dementia diagnostic on a time scale that is still hypothetical before any diagnosis is made. The objective of this work was to describe the sequence of markers changes in the Memento cohort by realigning the individual marker trajectories according to a latent disease time to overcome this issue. Method: Memento cohort is a French nationwide clinic‐based study which aims at better understanding the natural history of ADRD. Participants with mild cognitive impairment or subjective cognitive complaint were enrolled and followed‐up intensively for a maximum of 5 years. In an analytical sample of 2186 participants, we considered repeated measures of 12 ADRD markers including cognitive performances (memory, verbal fluency, executive function), neuroimaging measures (hippocampal volume, cortical thicknesses, white matter hyperintensities, glucose metabolism of region of interest of FDG‐PET), and CSF (Aβ42, p‐tau, t‐tau). We defined the latent disease time by an individual shift of the observed time, and simultaneously analyzed the ADRD marker trajectories according to this latent disease time using a multivariate mixed model adjusted on potential confounders. Result: After individual realignment of the trajectories according to the latent disease time, the temporal sequence of alterations suggested that neurodegeneration preceded cognitive decline. However, such sequence largely depended on education and ApoE4 status as illustrated in the figure. Cognitive decline appeared to be delayed among participants with high level of education, whereas changes in Aβ42 and tau proteins levels in CSF seemed to appear prior to neurodegeneration and cognitive decline mainly among ApoE ε4 carriers. Conclusion: Using longitudinal multidimensional data from a large cohort, we were able to stage participants along the pathological progression of ADRD. Our results show a large heterogeneity in temporal order markers changes which could suggest the existence of several subtypes of ADRD. [ABSTRACT FROM AUTHOR]

Background and Objectives: GRN variants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG)-PET in identifying metabolic changes in presymptomatic GRN carriers (PS- GRN +) and to trace their longitudinal progression., Methods: Participants were longitudinally evaluated over 5 years in a prospective cohort study focused on GRN disease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed., Results: Among the 80 individuals enrolled in the study, 58 (27 PS- GRN + and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS- GRN + and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers ( p < 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (-1.37%) was higher than that in controls (-0.21%, p = 0.004). Lower glucose uptake was associated with higher neurofilament increase ( p = 0.003) and lower frontal cognitive scores ( p = 0.014) in PS- GRN +., Discussion: This study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinical GRN disease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials., (© 2022 American Academy of Neurology.)

The clinical and fundamental exploration of patients suffering from disorders of consciousness (DoC) is commonly used by researchers both to test some of their key theoretical predictions and to serve as a unique source of empirical knowledge about possible dissociations between consciousness and cognitive and/or neural processes. For instance, the existence of states of vigilance free of any self-reportable subjective experience [e.g. "vegetative state (VS)" and "complex partial epileptic seizure"] originated from DoC and acted as a cornerstone for all theories by dissociating two concepts that were commonly equated and confused: vigilance and conscious state. In the present article, we first expose briefly the major achievements in the exploration and understanding of DoC. We then propose a synthetic taxonomy of DoC, and we finally highlight some current limits, caveats and questions that have to be addressed when using DoC to theorize consciousness. In particular, we show (i) that a purely behavioral approach of DoC is insufficient to characterize the conscious state of patients; (ii) that the comparison between patients in a minimally conscious state (MCS) and patients in a VS [also coined as unresponsive wakefulness syndrome (UWS)] does not correspond to a pure and minimal contrast between unconscious and conscious states and (iii) we emphasize, in the light of original resting-state positron emission tomography data, that behavioral MCS captures an important but misnamed clinical condition that rather corresponds to a cortically mediated state and that MCS does not necessarily imply the preservation of a conscious state., (© The Author(s) 2021. Published by Oxford University Press.)

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)