White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

Background To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity. Methods This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers. Results The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance. Conclusions The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms

Material Cycles, Industry and Service Provisioning: A Review of Low Energy and Material Demand Modelling and Scenarios

Developing transformative pathways for industry’s compliance with international climate targets requires model-based insights on how supply- and demand-side measures affect industry, material cycles, global supply chains, socio-economic activities and service provisioning supporting societal wellbeing. Herein, we review the recent literature modelling the industrial system for Low Energy and Materials Demand (LEMD) futures, resulting in lowered environmental pressures without relying on negative emissions. We identify 77 innovative studies drawing on nine distinct industry modelling traditions and critically assess system definitions and scopes, biophysical and thermodynamic consistency, granularity and heterogeneity, and operationalization of demand and service provision. We find large potentials of combined supply- and demand-side measures to reduce current economy-wide material use by -56%, energy use by -40 to -60%, and GHG emissions by -70% to net-zero. We call for strengthening interdisciplinary collaborations between industry modelling traditions and demand-side research, to produce more insightful scenarios and discuss research challenges and recommendations

Influence of Support Acidity of NiMo Sulfide Catalysts for Hydrogenation and Hydrocracking of Tetralin and Its Reaction Intermediates

Aromatic saturation is an important reaction for improving the cetane number of diesel streams. NiMo sulfide catalysts supported on alumina (Alu), silica–alumina (Si–Al), and alumina-Y zeolite (AluZ) were prepared with similar dispersions and variable acidities. These catalysts were tested in the hydroconversion of tetralin, indan, decalins, and alkylbenzenes to evaluate the effect of the support acidity in the overall activity and the distribution of products. NiMo/Alu generated essentially hydrogenated products while the presence of an acid component on the support increased not only isomerization and cracking reactions but also hydrogenated compounds formation, especially on tetralin, indan, and butylbenzene hydroconversions over NiMo/AluZ catalyst. The better hydrogenation activity of NiMo/AluZ for these reactions was associated with the presence of strong acid sites that contribute to creating protonated species which would migrate to the sulfide phase. Such species would be easier to hydrogenate due to the lower stability of the aromatic ring

Apathy in patients with cerebral amyloid angiopathy: a multimodal neuroimaging study

ObjectiveTo analyze the prevalence and associated clinical characteristics of apathy in sporadic cerebral amyloid angiopathy and investigate whether apathy was associated with disease burden and disconnections of key structures in the reward circuit through a structural and functional multi-modal neuroimaging approach.MethodsThirty-seven probable sporadic cerebral amyloid angiopathy participants without symptomatic intracranial hemorrhage or dementia (mean age, 73.3 ± 7.2, % male = 59.5%) underwent a detailed neuropsychological evaluation, including measures of apathy and depression, and a multimodal MR neuroimaging study. A multiple linear regression analysis was used to assess the association of apathy with conventional small vessel disease neuroimaging markers. A voxel-based morphometry with a small volume correction within regions previously associated with apathy and a whole-brain tract-based spatial statistics were done to identify differences in the gray matter and white matter between the apathetic and the non-apathetic groups. Gray matter regions significantly associated with apathy were further evaluated for their functional alterations as seeds in the seed-based resting-state functional connectivity analysis. Potential confounders, namely, age, gender, and measures of depression were entered as covariates in all analyses.ResultsA higher composite small vessel disease marker score (CAA-SVD) was associated with a higher degree of apathy (standardized coefficient = 1.35 (0.07 - 2.62), adjusted R2= 27.90, p = 0.04). Lower gray matter volume of the bilateral orbitofrontal cortices was observed in the apathetic group than the non-apathetic group (F = 13.20, family-wise error corrected p = 0.028). The apathetic group demonstrated a widespread decrease in white matter microstructural integrity compared to the non-apathetic group. These tracts connect key regions within and between related reward circuits. Finally, there was no significant functional alterations between the apathetic and the non-apathetic groups.ConclusionsOur findings revealed the orbitofrontal cortex as a key region in the reward circuit associated with apathy in sporadic cerebral amyloid angiopathy, independent from depression. Apathy was shown to be associated with a higher CAA-SVD score and an extensive disruption of white matter tracts, which suggested that a higher burden of CAA pathology and the disruption in large-scale white matter networks may underlie manifestations of apathy

Peak Width of Skeletonized Mean Diffusivity as Neuroimaging Biomarker in Cerebral Amyloid Angiopathy.

International audienceBackground and purpose: Whole-brain network connectivity has been shown to be a useful biomarker of cerebral amyloid angiopathy and related cognitive impairment. We evaluated an automated DTI-based method, peak width of skeletonized mean diffusivity, in cerebral amyloid angiopathy, together with its association with conventional MRI markers and cognitive functions.Materials and methods: We included 24 subjects (mean age, 74.7 [SD, 6.0] years) with probable cerebral amyloid angiopathy and mild cognitive impairment and 62 patients with MCI not attributable to cerebral amyloid angiopathy (non-cerebral amyloid angiopathy-mild cognitive impairment). We compared peak width of skeletonized mean diffusivity between subjects with cerebral amyloid angiopathy-mild cognitive impairment and non-cerebral amyloid angiopathy-mild cognitive impairment and explored its associations with cognitive functions and conventional markers of cerebral small-vessel disease, using linear regression models.Results: Subjects with Cerebral amyloid angiopathy-mild cognitive impairment showed increased peak width of skeletonized mean diffusivity in comparison to those with non-cerebral amyloid angiopathy-mild cognitive impairment (P < .001). Peak width of skeletonized mean diffusivity values were correlated with the volume of white matter hyperintensities in both groups. Higher peak width of skeletonized mean diffusivity was associated with worse performance in processing speed among patients with cerebral amyloid angiopathy, after adjusting for other MRI markers of cerebral small vessel disease. The peak width of skeletonized mean diffusivity did not correlate with cognitive functions among those with non-cerebral amyloid angiopathy-mild cognitive impairment.Conclusions: Peak width of skeletonized mean diffusivity is altered in cerebral amyloid angiopathy and is associated with performance in processing speed. This DTI-based method may reflect the degree of white matter structural disruption in cerebral amyloid angiopathy and could be a useful biomarker for cognition in this population

Peak Width of Skeletonized Mean Diffusivity: A Neuroimaging Marker for White Matter Injury

A leading cause of white matter (WM) injury in older individuals is cerebral small vessel disease (SVD). Cerebral SVD is the most prevalent vascular contributor to cognitive impairment and dementia. Therapeutic progress for cerebral SVD and other WM disorders depends on the development and validation of neuroimaging markers suitable as outcome measures in future interventional trials. Diffusion-tensor imaging (DTI) is one of the best-suited MRI techniques for assessing the extent of WM damage in the brain. But the optimal method to analyze individual DTI data remains hindered by labor-intensive and time-consuming processes. Peak width of skeletonized mean diffusivity (PSMD), a recently developed fast, fully automated DTI marker, was designed to quantify the WM damage secondary to cerebral SVD and reflect related cognitive impairment. Despite its promising results, knowledge about PSMD is still limited in the radiologic community. This focused review provides an overview of the technical details of PSMD while synthesizing the available data on its clinical and neuroimaging associations. From a critical expert viewpoint, the authors discuss the limitations of PSMD and its current validation status as a neuroimaging marker for vascular cognitive impairment. Finally, they point out the gaps to be addressed to further advance the field

A Causal Classification System for Intracerebral Hemorrhage subtypes (CLAS-ICH).

OBJECTIVE Determining the underlying causes of intracerebral hemorrhage (ICH) is of major importance because risk factors, prognosis and management differ by ICH subtype. We developed a new causal classification system for ICH Subtypes - termed CLAS-ICH - based on recent advances in neuroimaging. METHODS CLAS-ICH defines 5 ICH subtypes: Arteriolosclerosis, Cerebral Amyloid Angiopathy (CAA), Mixed small vessel disease (SVD), Other rare forms of SVD (genetic SVD and others), Secondary Causes (macrovascular causes, tumour and other rare causes). Every patient is scored in each category according to the level of diagnostic evidence: (1) well-defined ICH subtype; (2) possible underlying disease; (0) no evidence of the disease. We evaluated CLAS-ICH in a derivation cohort of 113 patients with ICH from Massachusetts General Hospital, Boston (USA) and in a derivation cohort of 203 patients from Inselspital, Bern (Switzerland). RESULTS In the derivation cohort, a well-defined ICH subtype could be identified in 74 (65.5%) patients, including 24 (21.2%) with Arteriolosclerosis, 23 (20.4%) with CAA, 18 (15.9%) with mixed SVD, and 9 (8.0%) with a secondary cause. One or more possible causes were identified in 42 (37.2%) patients. Inter-observer agreement was excellent for each category (kappa value ranging from 0.86 to 1.00). Despite substantial differences in imaging modalities, we obtained similar results in the validation cohort. INTERPRETATION CLAS-ICH is a simple and reliable classification system for ICH subtyping, that captures overlap between causes and the level of diagnostic evidence. CLAS-ICH may guide clinicians to identify ICH causes, and improve ICH classification in multicenter studies. This article is protected by copyright. All rights reserved

Peak width of skeletonized mean diffusivity in cerebral amyloid angiopathy: Spatial signature, cognitive, and neuroimaging associations

Background: Peak width of skeletonized mean diffusivity (PSMD) is a promising diffusion tensor imaging (DTI) marker that shows consistent and strong cognitive associations in the context of different cerebral small vessel diseases (cSVD). Purpose: Investigate whether PSMD (1) is higher in patients with Cerebral Amyloid Angiopathy (CAA) than those with arteriolosclerosis; (2) can capture the anteroposterior distribution of CAA-related abnormalities; (3) shows similar neuroimaging and cognitive associations in comparison to other classical DTI markers, such as average mean diffusivity (MD) and fractional anisotropy (FA). Materials and methods: We analyzed cross-sectional neuroimaging and neuropsychological data from 90 non-demented memory-clinic subjects from a single center. Based on MRI findings, we classified them into probable-CAA (those that fulfilled the modified Boston criteria), subjects with MRI markers of cSVD not attributable to CAA (presumed arteriolosclerosis; cSVD), and subjects without evidence of cSVD on MRI (non-cSVD). We compared total and lobe-specific (frontal and occipital) DTI metrics values across the groups. We used linear regression models to investigate how PSMD, MD, and FA correlate with conventional neuroimaging markers of cSVD and cognitive scores in CAA. Results: PSMD was comparable in probable-CAA (median 4.06 × 10-4mm2/s) and cSVD (4.07 × 10-4mm2/s) patients, but higher than in non-cSVD (3.30 × 10-4mm2/s;p&lt; 0.001) subjects. Occipital-frontal PSMD gradients were higher in probable-CAA patients, and we observed a significant interaction between diagnosis and region on PSMD values [F(2, 87) = 3.887,p= 0.024]. PSMD was mainly associated with white matter hyperintensity volume, whereas MD and FA were also associated with other markers, especially with the burden of perivascular spaces. PSMD correlated with worse executive function (β = -0.581,p&lt; 0.001) and processing speed (β = -0.463,p= 0.003), explaining more variance than other MRI markers. MD and FA were not associated with performance in any cognitive domain. Conclusion: PSMD is a promising biomarker of cognitive impairment in CAA that outperforms other conventional and DTI-based neuroimaging markers. Although global PSMD is similarly increased in different forms of cSVD, PSMD's spatial variations could potentially provide insights into the predominant type of underlying microvascular pathology.</p

Corpus callosum lesions are associated with worse cognitive performance in cerebral amyloid angiopathy

The impact of vascular lesions on cognition is location dependent. Here, we assessed the contribution of small vessel disease lesions in the corpus callosum to vascular cognitive impairment in cerebral amyloid angiopathy, as a model for cerebral small vessel disease. Sixty-five patients with probable cerebral amyloid angiopathy underwent 3T magnetic resonance imaging, including a diffusion tensor imaging scan, and neuropsychological testing. Microstructural white-matter integrity was quantified by fractional anisotropy and mean diffusivity. Z-scores on individual neuropsychological tests were averaged into five cognitive domains: information processing speed, executive functioning, memory, language and visuospatial ability. Corpus callosum lesions were defined as haemorrhagic (microbleeds or larger bleeds) or ischaemic (microinfarcts, larger infarcts and diffuse fluid-attenuated inversion recovery hyperintensities). Associations between corpus callosum lesion presence, microstructural white-matter integrity and cognitive performance were examined with multiple regression models. The prevalence of corpus callosum lesions was confirmed in an independent cohort of memory clinic patients with and without cerebral amyloid angiopathy (n = 82). In parallel, we assessed corpus callosum lesions on ex vivo magnetic resonance imaging in cerebral amyloid angiopathy patients (n = 19) and controls (n = 5) and determined associated tissue abnormalities with histopathology. A total number of 21 corpus callosum lesions was found in 19/65 (29%) cerebral amyloid angiopathy patients. Corpus callosum lesion presence was associated with reduced microstructural white-matter integrity within the corpus callosum and in the whole-brain white matter. Patients with corpus callosum lesions performed significantly worse on all cognitive domains except language, compared with those without corpus callosum lesions after correcting for age, sex, education and time between magnetic resonance imaging and neuropsychological assessment. This association was independent of the presence of intracerebral haemorrhage, whole-brain fractional anisotropy and mean diffusivity, and white-matter hyperintensity volume and brain volume for the domains of information processing speed and executive functioning. In the memory clinic patient cohort, corpus callosum lesions were present in 14/54 (26%) patients with probable and 2/8 (25%) patients with possible cerebral amyloid angiopathy, and in 3/20 (15%) patients without cerebral amyloid angiopathy. In the ex vivo cohort, corpus callosum lesions were present in 10/19 (53%) patients and 2/5 (40%) controls. On histopathology, ischaemic corpus callosum lesions were associated with tissue loss and demyelination, which extended beyond the lesion core. Together, these data suggest that corpus callosum lesions are a frequent finding in cerebral amyloid angiopathy, and that they independently contribute to cognitive impairment through strategic microstructural disruption of white-matter tracts