Sporadic cerebral amyloid angiopathy is a common, well-defined small vessel disease and a largely untreatable cause of intracerebral haemorrhage and contributor to age-related cognitive decline. The ...term 'cerebral amyloid angiopathy' now encompasses not only a specific cerebrovascular pathological finding, but also different clinical syndromes (both acute and progressive), brain parenchymal lesions seen on neuroimaging and a set of diagnostic criteria-the Boston criteria, which have resulted in increasingly detected disease during life. Over the past few years, it has become clear that, at the pathophysiological level, cerebral amyloid angiopathy appears to be in part a protein elimination failure angiopathy and that this dysfunction is a feed-forward process, which potentially leads to worsening vascular amyloid-β accumulation, activation of vascular injury pathways and impaired vascular physiology. From a clinical standpoint, cerebral amyloid angiopathy is characterized by individual focal lesions (microbleeds, cortical superficial siderosis, microinfarcts) and large-scale alterations (white matter hyperintensities, structural connectivity, cortical thickness), both cortical and subcortical. This review provides an interdisciplinary critical outlook on various emerging and changing concepts in the field, illustrating mechanisms associated with amyloid cerebrovascular pathology and neurological dysfunction.
Paravascular drainage of solutes, including β-amyloid (Aβ), appears to be an important process in brain health and diseases such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). ...However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aβ accumulation in the brain.
•Spontaneous low-frequency oscillations can be observed in arterioles in awake mice•Vasomotion drives paravascular clearance of solutes from the brain•Paravascular clearance is impaired in the context of cerebral amyloid angiopathy
van Veluw et al. demonstrate that vasomotion is a major driving force for paravascular clearance of solutes from the brain. Loss of vascular smooth muscle cells and reduced vasomotion in the context of amyloid deposition is associated with impaired clearance.
Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. ...Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra-high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.13mm isotropic resolution (on average) using customized hardware. The images were manually segmented into 13 different hippocampal substructures using a protocol specifically designed for this study; precise delineations were made possible by the extraordinary resolution of the scans. In addition to the subregions, manual annotations for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo, T1-weighted MRI scans of the whole brain (1mm resolution). The manual labels from the in vivo and ex vivo data were combined into a single computational atlas of the hippocampal formation with a novel atlas building algorithm based on Bayesian inference. The resulting atlas can be used to automatically segment the hippocampal subregions in structural MRI images, using an algorithm that can analyze multimodal data and adapt to variations in MRI contrast due to differences in acquisition hardware or pulse sequences. The applicability of the atlas, which we are releasing as part of FreeSurfer (version 6.0), is demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results show that the atlas and companion segmentation method: 1) can segment T1 and T2 images, as well as their combination, 2) replicate findings on mild cognitive impairment based on high-resolution T2 data, and 3) can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1mm) T1 data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and classification based on whole hippocampal volume (82% accuracy).
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•A highly detailed computational atlas of the human hippocampus built upon ex vivo MRI.•Volumes of hippocampal subregions agree well with prior histological studies.•Application to Bayesian segmentation of hippocampal subregions from in vivo MRI•The segmentation method is adaptive to MRI contrast and resolution.•The atlas and segmentation code will be released as part of FreeSurfer 6.0.
The neuropathological hallmarks of Alzheimer disease (AD) include "positive" lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and ..."negative" lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between "normal" aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.
Combined measurement of diverse molecular and anatomical traits that span multiple levels remains a major challenge in biology. Here, we introduce a simple method that enables proteomic imaging for ...scalable, integrated, high-dimensional phenotyping of both animal tissues and human clinical samples. This method, termed SWITCH, uniformly secures tissue architecture, native biomolecules, and antigenicity across an entire system by synchronizing the tissue preservation reaction. The heat- and chemical-resistant nature of the resulting framework permits multiple rounds (>20) of relabeling. We have performed 22 rounds of labeling of a single tissue with precise co-registration of multiple datasets. Furthermore, SWITCH synchronizes labeling reactions to improve probe penetration depth and uniformity of staining. With SWITCH, we performed combinatorial protein expression profiling of the human cortex and also interrogated the geometric structure of the fiber pathways in mouse brains. Such integrated high-dimensional information may accelerate our understanding of biological systems at multiple levels.
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•SWITCH controls chemical reaction kinetics for uniform, scalable tissue processing•SWITCH enables multiple rounds (> 20) of relabeling for multiplexed imaging•SWITCH is a fast, cost-effective, and easy-to-implement tissue-processing framework•Combinatorial protein expression profiling of the human visual cortex is demonstrated
A simple technique, termed SWITCH, for synchronizing key chemical reactions in tissue processing enables scalable tissue preservation and repeated labeling and imaging of biomolecules.
Since the original description of amyloid-β plaques and tau tangles more than 100 years ago, these lesions have been considered the neuropathological hallmarks of Alzheimer disease (AD). The ...prevalence of plaques, tangles and dementia increases with age, and the lesions are considered to be causally related to the cognitive symptoms of AD. Current schemes for assessing AD lesion burden examine the distribution, abundance and characteristics of plaques and tangles at post mortem, yielding an estimate of the likelihood of cognitive impairment. Although this approach is highly predictive for most individuals, in some instances, a striking mismatch between lesions and symptoms can be observed. A small subset of individuals harbour a high burden of plaques and tangles at autopsy, which would be expected to have had devastating clinical consequences, but remain at their cognitive baseline, indicating 'resilience'. The study of these brains might provide the key to understanding the 'black box' between the accumulation of plaques and tangles and cognitive impairment, and show the way towards disease-modifying treatments for AD. In this Review, we begin by considering the heterogeneity of clinical manifestations associated with the presence of plaques and tangles, and then focus on insights derived from the rare yet informative individuals who display high amounts of amyloid and tau deposition in their brains (observed directly at autopsy) without manifesting dementia during life. The resilient response of these individuals to the gradual accumulation of plaques and tangles has potential implications for assessing an individual's risk of AD and for the development of interventions aimed at preserving cognition.
The biophysical features of neurons shape information processing in the brain. Cortical neurons are larger in humans than in other species, but it is unclear how their size affects synaptic ...integration. Here, we perform direct electrical recordings from human dendrites and report enhanced electrical compartmentalization in layer 5 pyramidal neurons. Compared to rat dendrites, distal human dendrites provide limited excitation to the soma, even in the presence of dendritic spikes. Human somas also exhibit less bursting due to reduced recruitment of dendritic electrogenesis. Finally, we find that decreased ion channel densities result in higher input resistance and underlie the lower coupling of human dendrites. We conclude that the increased length of human neurons alters their input-output properties, which will impact cortical computation.
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•Direct electrical recordings to compare human and rat cortical dendrites•Longer human dendrites exhibit increased electrical compartmentalization•Reduced ion channel densities in human dendrites•Compartmentalization alters the input-output properties of human neurons
Human cortical neurons exhibit a higher degree of voltage compartmentalization compared to rodent counterparts due to lower ion channel densities across larger dendritic surfaces.
Objective
To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer F‐18‐AV‐1451 (previously known as T807), tailored to allow in ...vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.
Methods
We applied F‐18‐AV‐1451 phosphor screen autoradiography, F‐18‐AV‐1451 nuclear emulsion autoradiography, and H‐3‐AV‐1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration–tau, frontotemporal lobar degeneration–transactive response DNA binding protein 43 (TDP‐43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.
Results
Our data suggest that F‐18‐AV‐1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non‐Alzheimer tauopathy brains or to lesions containing β‐amyloid, α‐synuclein, or TDP‐43. F‐18‐AV‐1451 off‐target binding to neuromelanin‐ and melanin‐containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.
Interpretation
Our data suggest that F‐18‐AV‐1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament‐tau–containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non‐Alzheimer tauopathy cases and to the existence of some F‐18‐AV‐1451 off‐target binding. These findings provide important insights for interpreting in vivo patterns of F‐18‐AV‐1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
Reversible cerebral vasoconstriction syndromes (RCVS) and primary angiitis of the central nervous system (PACNS) are invariably considered in the differential diagnosis of new cerebral ...arteriopathies. However, prompt and accurate diagnosis remains challenging. Here we compared the features of 159 RCVS to 47 PACNS patients and developed criteria for prompt bedside diagnosis. Recurrent thunderclap headache (TCH), and single TCH combined with either normal neuroimaging, border zone infarcts, or vasogenic edema, have 100% positive predictive value for diagnosing RCVS or RCVS‐spectrum disorders. In patients without TCH and positive angiography, neuroimaging can discriminate RCVS (no lesion) from PACNS (deep/brainstem infarcts). Ann Neurol 2016;79:882–894
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