Beyond the amyloid cascade: An update of Alzheimer's disease pathophysiology.

Alzheimer's disease (AD) is a multi-etiology disease. The biological system of AD is associated with multidomain genetic, molecular, cellular, and network brain dysfunctions, interacting with central and peripheral immunity. These dysfunctions have been primarily conceptualized according to the assumption that amyloid deposition in the brain, whether from a stochastic or a genetic accident, is the upstream pathological change. However, the arborescence of AD pathological changes suggests that a single amyloid pathway might be too restrictive or inconsistent with a cascading effect. In this review, we discuss the recent human studies of late-onset AD pathophysiology in an attempt to establish a general updated view focusing on the early stages. Several factors highlight heterogenous multi-cellular pathological changes in AD, which seem to work in a self-amplifying manner with amyloid and tau pathologies. Neuroinflammation has an increasing importance as a major pathological driver, and perhaps as a convergent biological basis of aging, genetic, lifestyle and environmental risk factors.

Interhemispheric distribution of amyloid and small vessel disease burden in cerebral amyloid angiopathy-related intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating presentation of cerebral amyloid angiopathy (CAA), but the mechanisms leading from vascular amyloid deposition to ICH are not well known. Whether amyloid burden and magnetic resonance imaging (MRI) markers of small vessel disease (SVD) are increased in the ICH-affected hemisphere compared to the ICH-free hemisphere in patients with a symptomatic CAA-related ICH was investigated. METHODS: Eighteen patients with CAA-related ICH and 18 controls with deep ICH who underwent brain MRI and amyloid positron emission tomography using 18 F-florbetapir were prospectively enrolled. In each hemisphere amyloid uptake using the standardized uptake value ratio and the burden of MRI markers of SVD including cerebral microbleeds, chronic ICH, cortical superficial siderosis, white matter hyperintensities and lacunes were evaluated. Interhemispheric comparisons were assessed by non-parametric matched-pair tests within each patient group. RESULTS: Amyloid burden was similarly distributed across the brain hemispheres in patients with CAA-related ICH (standardized uptake value ratio 1.11 vs. 1.12; P = 0.74). Cortical superficial siderosis tended to be more common in the ICH-affected hemisphere compared to the ICH-free hemisphere (61% vs. 33%; P = 0.063). Other MRI markers of SVD did not differ across brain hemispheres. In controls with deep ICH, no interhemispheric difference was observed either for amyloid burden or for MRI markers of SVD. CONCLUSIONS: Brain hemorrhage does not appear to be directly linked to amyloid burden in patients with CAA-related ICH. These findings provide new insights into the mechanisms leading to hemorrhage in CAA.

Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update.

Intracerebral hemorrhage (ICH) accounts for 15% of all strokes and approximately 50% of stroke-related mortality and disability worldwide. Patients who have experienced ICH are at high risk of negative outcome, including stroke and cognitive disorders. Vascular cognitive impairment are frequently seen after brain hemorrhage, yet little is known about them, as most studies have focused on neuropsychological outcome in ischemic stroke survivors, using well-documented acute and chronic cognitive scores. However, recent evidence supports the notion that ICH and dementia are closely related and each increases the risk of the other. The location of the lesion also plays a significant role as regards the neuropsychological profile, while the pathophysiology of ICH can indicate a specific pattern of dysfunction. Several cognitive domains may be affected, such as language, memory, executive function, processing speed and gnosis.

Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation.

OBJECTIVE: To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after chemoradiation. METHODS: Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was tend; MR acquisitions performed at tend-2M, tend-4M and tend-6M (respectively 2, 4 and 6 months before tend) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between ∆B from tend-4M to tend-2M and ∆B from tend-6M to tend-4M. The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis. RESULTS: The fraction of hypoperfused tumor volume (F_hPg) was a relevant biomarker. A ratio R(F_hPg) ≥ 0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (≥0.61) was associated with more relapse at tend compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008). CONCLUSION: Iterative analysis of F_hPg from consecutive examinations could provide surrogate markers to predict progression at the next follow-up. KEY POINTS: • Related rCBV biomarkers from DSC were assessed to anticipate GBM progression. • Biomarkers were assessed through their patterns of variation during the follow-up. • The fraction of hypoperfused tumour volume (F_hP g ) seemed to be a relevant biomarker. • An innovative ratio R(F_hP g ) could be an early surrogate marker of relapse. • A significant time gain could be achieved in the management of GBM patients.

Comparison between PET template-based method and MRI-based method for cortical quantification of florbetapir (AV-45) uptake in vivo.

PURPOSE: Florbetapir (AV-45) has been shown to be a reliable tool for assessing in vivo amyloid load in patients with Alzheimer's disease from the early stages. However, nonspecific white matter binding has been reported in healthy subjects as well as in patients with Alzheimer's disease. To avoid this issue, cortical quantification might increase the reliability of AV-45 PET analyses. In this study, we compared two quantification methods for AV-45 binding, a classical method relying on PET template registration (route 1), and a MRI-based method (route 2) for cortical quantification. METHODS: We recruited 22 patients at the prodromal stage of Alzheimer's disease and 17 matched controls. AV-45 binding was assessed using both methods, and target-to-cerebellum mean global standard uptake values (SUVr) were obtained for each of them, together with SUVr in specific regions of interest. Quantification using the two routes was compared between the clinical groups (intragroup comparison), and between groups for each route (intergroup comparison). Discriminant analysis was performed. RESULTS: In the intragroup comparison, differences in uptake values were observed between route 1 and route 2 in both groups. In the intergroup comparison, AV-45 uptake was higher in patients than controls in all regions of interest using both methods, but the effect size of this difference was larger using route 2. In the discriminant analysis, route 2 showed a higher specificity (94.1 % versus 70.6 %), despite a lower sensitivity (77.3 % versus 86.4 %), and D-prime values were higher for route 2. CONCLUSION: These findings suggest that, although both quantification methods enabled patients at early stages of Alzheimer's disease to be well discriminated from controls, PET template-based quantification seems adequate for clinical use, while the MRI-based cortical quantification method led to greater intergroup differences and may be more suitable for use in current clinical research.

A Prospective Study of Arterial Spin Labelling in Paediatric Posterior Fossa Tumour Survivors: A Correlation with Neurocognitive Impairment.

AIMS: Posterior fossa tumours (PFTs), which account for two-thirds of paediatric brain tumours, are successfully treated in about 70% of patients, but most survivors experience long-term cognitive impairment. We evaluated arterial spin labelling (ASL), a common, non-invasive magnetic resonance imaging (MRI) technique, as a biomarker of cognitive impairment in a paediatric PFT survivor population. MATERIALS AND METHODS: Sixty participants were prospectively analysed. PFT survivors were at least 5 years post-treatment and had been treated as appropriate for their age and type of tumour. Group 1 had received radiotherapy and Group 2 had not. Group 3 were healthy controls matched to Group 1 for age, sex and handedness. All participants underwent cognitive assessment and multimodal MRI, including an ASL perfusion sequence. We used semi-quantitative ASL methods to assess differences in mean perfusion in the thalamus, caudate, putamen and hippocampus. RESULTS: Statistically, no significant associations between cognitive data and radiation doses were identified. Compared with healthy controls, Group 1 patients had significantly lower overall mean perfusion values (20-30% lower, depending on the cerebral structure) and Group 2 had slightly lower mean perfusion values (5-10% lower). Perfusion values did not correlate with total prescribed irradiation doses nor with doses received by different cerebral structures. Episodic and semantic memory test scores were significantly lower in Group 1 and correlated with lower mean absolute perfusion values in the hippocampus (P < 0.04). CONCLUSIONS: These preliminary results indicate that radiotherapy affects the perfusion of specific cerebral structures and identify perfusion as a potential biomarker of hippocampus-dependent memory deficit.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Functional connectivity and cognitive changes after donepezil treatment in healthy participants.

RATIONALE: Donepezil is a potent, noncompetitive, reversible, clinically effective acetylcholinesterase inhibitor. The effects of this drug on healthy brains have seldom been investigated. OBJECTIVES: The primary objective of the present study was to identify possible functional connectivity markers of the effect of donepezil in healthy young adult volunteers. METHODS: The study had a double-blind, randomized, crossover design. 30 healthy adult volunteers underwent resting-state MRI scans during 15 days of donepezil or placebo treatment, in accordance with the design. RESULTS: Results showed significant differences in intrinsic functional connectivity between donepezil and placebo, mainly in the right executive control network (RECN). More specifically, we found a decrease in the connectivity of the right inferior parietal node with other RECN nodes. Analysis using the cingulate cortex and parahippocampal regions as seeds also revealed complex modulation of functional connectivity in the donepezil condition. CONCLUSIONS: In conclusion, donepezil treatment for 15 days may result in reorganization of resting-state networks, compared with placebo.

A totally data-driven whole-brain multimodal pipeline for the discrimination of Parkinson's disease, multiple system atrophy and healthy control.

Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are two parkinsonian syndromes that share many symptoms, albeit having very different prognosis. Although previous studies have proposed multimodal MRI protocols combined with multivariate analysis to discriminate between these two populations and healthy controls, studies combining all MRI indexes relevant for these disorders (i.e. grey matter volume, fractional anisotropy, mean diffusivity, iron deposition, brain activity at rest and brain connectivity) with a completely data-driven voxelwise analysis for discrimination are still lacking. In this study, we used such a complete MRI protocol and adapted a fully-data driven analysis pipeline to discriminate between these populations and a healthy controls (HC) group. The pipeline combined several feature selection and reduction steps to obtain interpretable models with a low number of discriminant features that can shed light onto the brain pathology of PD and MSA. Using this pipeline, we could discriminate between PD and HC (best accuracy = 0.78), MSA and HC (best accuracy = 0.94) and PD and MSA (best accuracy = 0.88). Moreover, we showed that indexes derived from resting-state fMRI alone could discriminate between PD and HC, while mean diffusivity in the cerebellum and the putamen alone could discriminate between MSA and HC. On the other hand, a more diverse set of indexes derived by multiple modalities was needed to discriminate between the two disorders. We showed that our pipeline was able to discriminate between distinct pathological populations while delivering sparse model that could be used to better understand the neural underpinning of the pathologies.

Effect of levodopa on both verbal and motor representations of action in Parkinson's disease: a fMRI study.

Previous studies have demonstrated that non-demented Parkinson's disease (PD) patients have a specific impairment of verb production compared with noun generation. One interpretation of this deficit suggested the influence of striato-frontal dysfunction on action-related verb processing. The aim of our study was to investigate cerebral changes after motor improvement due to dopaminergic medication on the neural circuitry supporting action representation in the brain as mediated by verb generation and motor imagery in PD patients. Functional magnetic resonance imaging on 8 PD patients in "ON" dopaminergic treatment state (DTS) and in "OFF" DTS was used to explore the brain activity during three different tasks: Object Naming (ObjN), Generation of Action Verbs (GenA) in which patients were asked to overtly say an action associated with a picture and mental simulation of action (MSoA) was investigated by asking subjects to mentally simulate an action related to a depicted object. The distribution of brain activities associated with these tasks whatever DTS was very similar to results of previous studies. The results showed that brain activity related to semantics of action is modified by dopaminergic treatment in PD patients. This cerebral reorganisation concerns mainly motor and premotor cortex suggesting an involvement of the putaminal motor loop according to the "motor" theory of verb processing.

Imaging nervous pathways with MR tractography.

This paper describes the state of the art of tractography, a technique which enables the virtual reconstruction of axon bundles of the central nervous system using diffusion-weighted magnetic resonance images. This technique has raised enthusiasm and expectations among specialists because it is the only non-invasive method for studying the three-dimensional architecture of axonal fibres in vivo. Tractography is a new technique used to assess the anatomy of the central nervous system, and it will be available for routine clinical use in the future. Understanding its potential applications and limitations is therefore important.